van der Boog PJ, van Kooten C, de Fijter JW, Daha MR.
Role of macromolecular IgA in IgA nephropathy.
Kidney Int. 2005 Mar;67(3):813-21. doi: 10.1111/j.1523-1755.2005.00146.x.
Abstract/Text
Primary IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, leading to progressive renal failure in almost one third of the patients. The disease is characterized by mesangial deposits of IgA. The pathogenesis of IgAN remains incompletely understood. The basic abnormality of this disorder lies within the IgA immune system rather than in the kidney. Elevated levels of IgA and IgA-containing complexes are found in sera of most patients with IgAN, but increased levels alone are not sufficient to develop IgAN. Therefore abnormal physicochemical properties of circulating IgA, such as size, charge, and glycosylation may play a role. This is supported by the presence of altered glycosylation of serum and mesangial IgA in patients with IgAN. Although the precise origin and nature of the mesangial IgA deposits are still uncertain, they contain at least in part macromolecular IgA, which may be derived from circulating IgA-containing complexes. Recently, novel insights have been obtained in the molecular composition of circulating high-molecular-weight IgA, which might include complexes with underglycosylated IgA1 and IgA-CD89 complexes. In this review various aspects of macromolecular IgA in relation to IgAN will be discussed.
Floege J.
The pathogenesis of IgA nephropathy: what is new and how does it change therapeutic approaches?
Am J Kidney Dis. 2011 Dec;58(6):992-1004. doi: 10.1053/j.ajkd.2011.05.033. Epub 2011 Aug 26.
Abstract/Text
Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis worldwide. For example, in Japan, full-blown IgA nephropathy has been detected in ~1.5% of all allograft kidneys at the time of transplant. Genetic and environmental modifiers, as well as generic progression factors (eg, hypertension), must have a major role in determining who will become clinically overt and who will experience progression. In patients with clinically overt IgA nephropathy and/or progressive disease, it now is relatively well established that the pathogenesis involves 6 major steps: (1) Increased occurrence of IgA1 with poor galactosylation in the circulation. This might relate to the migration of mucosal B cells to bone marrow, where they produce "correct" poorly galactosylated IgA. Modulation of mucosal immunity may offer new therapeutic options. (2) Generation of IgG antibodies against poorly galactosylated IgA1. This could lay the foundation for immunosuppression, whereas detection of such IgG autoantibodies may accommodate the noninvasive monitoring of IgA nephropathy. (3) Mesangial deposition and/or formation of IgG-IgA1 or IgA1-IgA1 complexes. (4) Activation of mesangial IgA receptors and/or complement; both lend themselves to therapeutic interference. (5) Mesangial cell damage and activation of secondary pathways, such as overproduction of platelet-derived growth factor, which can be targeted specifically. (6) Activation of pathomechanisms that are not specific for IgA nephropathy and that drive glomerulosclerosis and tubulointerstitial fibrosis. Although at present our therapeutic armamentarium is still limited largely to supportive care and immunosuppression in some instances, these new insights can be expected to yield novel, perhaps individualized, therapeutic options in primary and recurrent IgA nephropathy.
Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Zickerman AM, Allen AC, Talwar V, Olczak SA, Brownlee A, Holland M, Furness PN, Brunskill NJ, Feehally J.
IgA myeloma presenting as Henoch-Schönlein purpura with nephritis.
Am J Kidney Dis. 2000 Sep;36(3):E19. doi: 10.1053/ajkd.2000.16221.
Abstract/Text
IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are both characterized by IgA-mediated tissue injury, including mesangial proliferative glomerulonephritis. Abnormalities of IgA1 glycosylation are described in IgA nephropathy and HSP nephritis. IgA-antineutrophil cytoplasmic antibodies (ANCA) have been inconsistently described in the serum of patients with HSP. In IgA myeloma, the paraprotein-mediated renal lesion is typically cast nephropathy; IgAN or HSP have only rarely been reported in myeloma even when an IgA paraprotein is circulating in large concentrations. We report the case of a 50-year-old man with IgA myeloma who presented with HSP including nephritis and rapidly progressive renal failure. His IgA1 had altered O-glycosylation in the pattern seen in IgAN and also contained an IgA-ANCA. This case adds further weight to the evidence that IgA1 O-glycosylation abnormalities predispose to mesangial IgA deposition and also that IgA-ANCA may have a pathogenic role in the development of HSP.
Van Der Helm-Van Mil AH, Smith AC, Pouria S, Tarelli E, Brunskill NJ, Eikenboom HC.
Immunoglobulin A multiple myeloma presenting with Henoch-Schönlein purpura associated with reduced sialylation of IgA1.
Br J Haematol. 2003 Sep;122(6):915-7. doi: 10.1046/j.1365-2141.2003.04539.x.
Abstract/Text
Henoch-Schönlein purpura is characterized by immunoglobulin A1 (IgA1) depositions in blood vessels of the skin or in glomeruli, resulting from altered hinge region O-glycosylation. Henoch-Schönlein purpura is seldom reported as a complication of IgA1 myeloma, even when the circulating IgA concentration is very high. We report two patients with IgA1 myeloma presenting with Henoch-Schönlein purpura. The O-glycosylation of these patients' IgA1 was studied. Both patients showed increased binding to peanut agglutinin lectin, suggesting a low degree of sialylation of the hinge region of IgA1 that was confirmed by mass spectrometry. IgA multiple myeloma, secreting IgA1 molecules with decreased sialylation, presenting with a Henoch-Schönlein purpura-like syndrome was diagnosed.
Berger J, Hinglais N.
[Intercapillary deposits of IgA-IgG].
J Urol Nephrol (Paris). 1968 Sep;74(9):694-5.
Abstract/Text
千田雅代: IgA腎症の全国疫学調査成績. 厚生省特定疾患難病の疫学調査研究班 平成7年度研究事業集 1995.
Johnston PA, Brown JS, Braumholtz DA, Davison AM.
Clinico-pathological correlations and long-term follow-up of 253 United Kingdom patients with IgA nephropathy. A report from the MRC Glomerulonephritis Registry.
Q J Med. 1992 Aug;84(304):619-27.
Abstract/Text
The Medical Research Council's Glomerulonephritis Registry was used to study clinicopathological correlations and renal survival in patients with IgA nephropathy reported between 1978 and 1985. IgA nephropathy was the histological diagnosis in 9.3 per cent of all renal biopsies reported to the registry during this period, and in 18.1 per cent of those with a primary glomerulonephritis. The 10-year cumulative renal survival rate accounting for censored data (Kaplan-Meier) was 83.3 per cent. Univariate analysis of survival curves (log-rank test) found the following parameters to be significantly correlated with poor renal survival: serum creatinine > 120 mumol/l (p < 0.001), hypertension (p < 0.001), serum albumin < 40 g/l (p < 0.005), proteinuria > 1 g (p < 0.025), age > 30 years (p < 0.025), and focal mesangial proliferation (p < 0.05). There was no significant difference in renal survival between males and females. Multivariate analysis (Cox's proportional hazards model) revealed that only a serum creatinine of > 120 mumol/l and a serum albumin of < 40 g/l were independently predictive of outcome. These findings indicate marked similarities between the UK experience of IgA nephropathy and the published European experience. IgA nephropathy is not a benign condition in the UK and patients with impaired renal function and/or those with a reduced serum albumin are significantly more likely to progress to end-stage renal failure within 10 years.
Rambausek M, Hartz G, Waldherr R, Andrassy K, Ritz E.
Familial glomerulonephritis.
Pediatr Nephrol. 1987 Jul;1(3):416-8. doi: 10.1007/BF00849246.
Abstract/Text
Between 1970 and 1984, the diagnosis of glomerulonephritis was made in 860 patients on the basis of a nephritic sediment and/or renal biopsy; of these patients, 86 (10%) had at least one first-degree relative with glomerulonephritis. These patients originated from 45 families and 1674 family members were screened; 172 had glomerulonephritis, of whom 101 could be classified. The diagnostic breakdown of the 101 patients showed that 50.5% had classical Alport's syndrome; 21.8% had atypical forms; 17.8% had familial IgA glomerulonephritis; 1.9% had focal segmental glomerulosclerosis with Wolff-Parkinson-White syndrome; and 7.9% had benign familial haematuria. The proportion of patients with glomerulonephritis who had familial disease was higher than expected. The family history is an important point to consider in the examination of patients with glomerulonephritis.
Nakayama K, Ohsawa I, Maeda-Ohtani A, Murakoshi M, Horikoshi S, Tomino Y.
Prediction of diagnosis of immunoglobulin A nephropathy prior to renal biopsy and correlation with urinary sediment findings and prognostic grading.
J Clin Lab Anal. 2008;22(2):114-8. doi: 10.1002/jcla.20227.
Abstract/Text
Several clinical markers correlate well with the diagnosis and prognosis of IgA nephropathy (IgAN). In the present study, we re-evaluated the usefulness of these four clinical markers for prediction of the diagnosis of patients with IgAN through a comparison between many more patients with IgAN and those with other types of renal diseases. 364 patients with IgAN and 289 with other types of renal disease were examined. An analysis was performed prior to renal biopsy, using clinical markers including, serum IgA, serum IgA/C3 ratio, number of red blood cells in urinary sediments, and urinary protein. Patients with IgAN were divided into four groups according to histopathological findings. Presence of microscopic hematuria, persistent proteinuria, high serum IgA levels, and the serum IgA/C3 ratios are useful for prediction of diagnosis of IgAN and distinguishing it from other renal diseases. Blood pressure, urinary protein, serum uric acid, renal function, and urinary sediment findings may be useful for prediction of prognostic grading in patients with IgAN.
(Copyright ) 2008 Wiley-Liss, Inc.
no author.
[Clinical guides for immunoglobulin A (IgA) nephropathy in Japan, third version].
Nihon Jinzo Gakkai Shi. 2011;53(2):123-35.
Abstract/Text
厚生労働科学研究費補助金難治性疾患克服研究事業 進行性腎障害に関する調査研究班報告 IgA 腎症分科会 IgA 診療指針―第3 版．2011．.
Philibert D, Cattran D, Cook T.
Clinicopathologic correlation in IgA nephropathy.
Semin Nephrol. 2008 Jan;28(1):10-7. doi: 10.1016/j.semnephrol.2007.10.011.
Abstract/Text
IgA nephropathy is the most common biopsy-proven pattern of glomerulonephritis in the world. Many factors, both clinical and histologic, have been suggested to impact on prognosis. We review the wide variations in how patients with immunoglobulin A nephropathy can present and the important differences derived from the clinical pathologic setting through the description of 4 cases. These include the clinical scenarios of modest proteinuria, acute kidney injury, and the nephrotic syndrome.
Donadio JV, Grande JP.
IgA nephropathy.
N Engl J Med. 2002 Sep 5;347(10):738-48. doi: 10.1056/NEJMra020109.
Abstract/Text
Packham DK.
Thin basement membrane nephropathy and IgA glomerulonephritis: can they be distinguished without renal biopsy?
Nephrology (Carlton). 2007 Oct;12(5):481-6. doi: 10.1111/j.1440-1797.2007.00813.x.
Abstract/Text
BACKGROUND: Thin basement membrane nephropathy (TBMN) and IgA glomerulonephritis (IgA gn) are the most common primary glomerular conditions diagnosed on renal biopsy, performed for microscopic haematuria or microscopic haematuria with proteinuria. While up to 50% of patients with IgA gn will develop chronic renal failure, most patients with TBMN enjoy an excellent prognosis. Because TBMN is estimated to occur in up to 1% of the general population, differentiation between the two conditions without resort to renal biopsy is desirable.
METHODS: This retrospective analysis of 248 patients diagnosed on renal biopsy as having either TBMN or IgA gn, sought to identify clinical or biochemical factors which would have enabled confident differentiation between the two conditions to be made without resort to renal biopsy.
RESULTS: No single clinical or pathological variable adequately discriminated between the two conditions. Impaired renal function and heavy proteinuria were highly specific for IgA gn but lacked sensitivity in differentiating from TBMN. Isolated microscopic haematuria (IMH) was a more common finding in patients diagnosed with TBMN but, as a discriminator between TBMN and IgA gn, lacked sufficient specificity. However, if assumptions were made based on the differing incidence of a positive family history between IgA gn and TBMN, then specificity of >99% could be achieved.
CONCLUSION: TBMN and IgA gn cannot be distinguished on the basis of clinical or pathological variables alone. However, in patients with IMH and a positive family history of either IMH or biopsy-proven TBMN, there is usually no need for renal biopsy.
Herzenberg AM, Fogo AB, Reich HN, Troyanov S, Bavbek N, Massat AE, Hunley TE, Hladunewich MA, Julian BA, Fervenza FC, Cattran DC.
Validation of the Oxford classification of IgA nephropathy.
Kidney Int. 2011 Aug;80(3):310-7. doi: 10.1038/ki.2011.126. Epub 2011 May 4.
Abstract/Text
The Oxford classification of IgA nephropathy (IgAN) identified four pathological elements that were of prognostic value and additive to known clinical and laboratory variables in predicting patient outcome. These features are segmental glomerulosclerosis/adhesion, mesangial hypercellularity, endocapillary proliferation, and tubular atrophy/interstitial fibrosis. Here, we tested the Oxford results using an independent cohort of 187 adults and children with IgAN from 4 centers in North America by comparing the performance of the logistic regression model and the predictive value of each of the four lesions in both data sets. The cohorts had similar clinical and histological findings, presentations, and clinicopathological correlations. During follow-up, however, the North American cohort received more immunosuppressive and antihypertensive therapies. Identifying patients with a rapid decline in the rate of renal function using the logistic model from the original study in the validation data set was good (c-statistic 0.75), although less precise than in the original study (0.82). Individually, each pathological variable offered the same predictive value in both cohorts except mesangial hypercellularity, which was a weaker predictor. Thus, this North American cohort validated the Oxford IgAN classification and supports its utilization. Further studies are needed to determine the relationship to the impact of treatment and to define the value of the mesangial hypercellularity score.
Shi SF, Wang SX, Jiang L, Lv JC, Liu LJ, Chen YQ, Zhu SN, Liu G, Zou WZ, Zhang H, Wang HY.
Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the oxford classification.
Clin J Am Soc Nephrol. 2011 Sep;6(9):2175-84. doi: 10.2215/CJN.11521210. Epub 2011 Aug 18.
Abstract/Text
BACKGROUND AND OBJECTIVES: The Oxford classification of IgA nephropathy (IgAN) may aid in predicting prognosis and providing therapeutic strategy but must be validated in different ancestry.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 410 patients with IgAN, enrolled from one of the largest renal centers in China, were evaluated for the predictive value of the Oxford classification to prognosis defined as end stage renal disease. A total of 294 of these patients were prospectively treated with renin-angiotensin system blockade and immunosuppressants sequentially and were evaluated separately to assess the predictive value to therapeutic efficacy (defined as time-averaged proteinuria <1 g/d). Three pathologists reviewed specimens independently according to the Oxford classification and were blinded to clinical data.
RESULTS: Segmental glomerulosclerosis and tubular atrophy and interstitial fibrosis were independent predictive factors of end stage renal disease. Patients who had >25% of glomeruli with endocapillary hypercellularity showed higher proteinuria, lower estimated GFR, and higher mean BP than patients with less endocapillary hypercellularity. Immunosuppressive therapy showed a protective effect to prognosis of endocapillary hypercellularity in patients with endoncapillary hypercellularity could benefit from immunosuppressive therapy. Mesangial hypercellularity and tubular atrophy and interstitial fibrosis were independent factors of inefficiency of renin-angiotensin system blockade alone. Crescents were not significant in predicting prognosis or in therapeutic efficacy.
CONCLUSIONS: The Oxford classification may aid in predicting prognosis and providing a therapeutic strategy in Chinese patients with IgAN.
Yau T, Korbet SM, Schwartz MM, Cimbaluk DJ.
The Oxford classification of IgA nephropathy: a retrospective analysis.
Am J Nephrol. 2011;34(5):435-44. doi: 10.1159/000332223. Epub 2011 Sep 28.
Abstract/Text
BACKGROUND/AIMS: The Oxford classification of IgA nephropathy (IgAN) assesses the presence of mesangial hypercellularity ≥50% (M1 vs. 0), endocapillary proliferation (E1 vs. 0), segmental glomerulosclerosis (S1 vs. 0), tubular atrophy/interstitial fibrosis >25 or 50% (T1 or 2 vs. 0), and has been reported as having prognostic value. We studied the clinical significance of the classification in our adult patients with IgAN.
METHODS: Retrospective study of 54 patients with biopsy-proven IgAN seen from 1983 to 2009. The correlation between the Oxford classification and baseline renal function was assessed. The primary endpoint was a 50% reduction in eGFR or end-stage renal disease. Predictors for progression to the endpoint were determined by multivariate analyses.
RESULTS: Patients were 41 ± 15 years of age with a serum creatinine of 1.5 ± 0.8 mg/dl, eGFR of 61 ± 24 ml/min/1.73 m(2), and proteinuria of 2.0 ± 1.6 g/day. Oxford classifications were as follows: M1 = 72%, E1 = 20%, S1 = 81%, and T1 = 13%/T2 = 22%. During the follow-up of 5.8 ± 4.8 years, 19% of patients reached the primary endpoint. While the Oxford classification was associated with progressive renal disease, only the T score (T0, T1, T2) was predictive of outcome with 6, 29, and 50% of patients (p = 0.002) reaching the primary endpoint. The 10-year renal survival for T0, T1, and T2 was 100, 50, and 17%, respectively (p < 0.001). By multivariate analysis, the hazard ratio for reaching the primary endpoint was 32 for patients with T ≥1 versus T0 (p = 0.01).
CONCLUSIONS: In our experience, the Oxford classification predicts progressive renal disease, but the degree of tubulointerstitial fibrosis was the only feature independently predictive of outcome.
Copyright © 2011 S. Karger AG, Basel.
Kang SH, Choi SR, Park HS, Lee JY, Sun IO, Hwang HS, Chung BH, Park CW, Yang CW, Kim YS, Choi YJ, Choi BS.
The Oxford classification as a predictor of prognosis in patients with IgA nephropathy.
Nephrol Dial Transplant. 2012 Jan;27(1):252-8. doi: 10.1093/ndt/gfr295. Epub 2011 May 23.
Abstract/Text
BACKGROUND: In 2009, the Oxford classification was developed as a pathological classification system for immunoglobulin A nephropathy (IgAN) to predict the risk of disease progression. The aim of this retrospective study was to evaluate the clinical and pathologic relevance of the Oxford classification in Korean patients with a pathologic diagnosis of IgAN.
PATIENTS AND METHODS: We reviewed the renal pathology archives from January 2000 to December 2006 at Seoul St Mary's Hospital in Korea and identified 273 patients, who were diagnosed as having IgAN. We enrolled 197 patients who were available for further clinicopathologic analysis. All cases of IgAN were categorized according to the WHO classification, the semiquantitative classification and the Oxford classification. These pathologic classifications were compared. The clinical and laboratory findings at the time of biopsy were compared with those at the end of the follow-up according to the Oxford classification.
RESULTS: When three pathologic classifications were compared, M1, S1, E1, T1 or T2 were associated with a higher score in the activity index. S1, T1 or T2 were associated with a higher score in the chronicity index and a higher grade in the WHO classification. The clinical and laboratory findings were compared according to the Oxford classification. At the time of biopsy, the proteinuria in patients with M1 was more than that of M0 (P = 0.035). At the end of follow-up, the number of antihypertensive drugs taken among patients with M1 was greater than that of patients with M0 (P = 0.001). At the time of biopsy, the proteinuria of patients with S1 was greater than that of S0 patients (P = 0.009). At the end of follow-up, the number of patients who received immunosuppressants was increased as the grade of T increased (P = 0.000). At the end point of the follow-up, the estimated glomerular filtration rate (eGFR) decreased as the grade of T increased (P = 0.008). The time-average proteinuria after adjusting the initial proteinuria increased significantly with increasing degree of T (P = 0.000). Levels of tubular atrophy/interstitial fibrosis were predictive for survival from end-stage renal disease or of having a 50% reduction of eGFR.
CONCLUSION: The pathologic variables of the Oxford classification correlated significantly with other classifications (the WHO classification and the semiquantitative classification). The Oxford classification is a simple method for predicting renal outcome and differentiating between active and chronic lesions. We suggest that the Oxford classification offers an advantage for determining treatment policy for patients with IgAN.
Alamartine E, Sauron C, Laurent B, Sury A, Seffert A, Mariat C.
The use of the Oxford classification of IgA nephropathy to predict renal survival.
Clin J Am Soc Nephrol. 2011 Oct;6(10):2384-8. doi: 10.2215/CJN.01170211. Epub 2011 Sep 1.
Abstract/Text
BACKGROUND AND OBJECTIVES: A new classification for IgA nephropathy was recently proposed, namely the Oxford classification. It established specific pathologic features that predict the risk of progression of renal disease. This classification needs validation in different patient populations. We propose a retrospective study to evaluate the predictive value of the Oxford classification on renal survival defined by doubling creatinine or end-stage renal disease in patients with IgA nephropathy.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 183 patients with primary IgA nephropathy diagnosed between 1994 and 2005. Mean follow-up time was 77 months. Doubling creatinine occurred in 20% of the patients, and end-stage renal disease occurred in 16%. The biopsies were revisited to apply the Oxford classification. The influence of pathologic features on renal survival was analyzed in univariate and multivariate models.
RESULTS: In univariate time-dependent analyses, tubular atrophy/interstitial fibrosis, segmental glomerulosclerosis, and endocapillary hypercellularity strongly impacted doubling creatinine or end-stage renal disease. On the contrary, mesangial hypercellularity was not associated with renal outcome. In the multivariate model, only estimated GFR at baseline was a risk factor, pathologic lesions having no independent influence.
CONCLUSIONS: We confirm the usefulness of the Oxford classification to establish the renal prognosis of patients with IgA nephropathy, although renal function at baseline seems to be of a greater importance than pathologic lesions.
Koyama A, Igarashi M, Kobayashi M.
Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases.
Am J Kidney Dis. 1997 Apr;29(4):526-32. doi: 10.1016/s0272-6386(97)90333-4.
Abstract/Text
The Research Group on Progressive Renal Diseases conducted a national survey, in Japan, of cases of primary glomerulonephritis (GN) in 1985 and 1993. The results of the survey, reported here, revealed a high prevalence and relatively poor prognosis for immunoglobulin A nephropathy (IgAN). Using immunofluorescent microscopy, 47.2% of 1,063 patients were diagnosed as having IgAN; 62.8% of patients had diffuse mesangial proliferative GN, and focal mesangial proliferative GN was observed in 23.0%. Nearly 70% of the patients had no clinical symptoms, and the IgAN was detected by routine physical examination. The mean period of observation was 11.8 +/- 6.3 years. Renal survival rates for the 502 cases of IgAN, in which the start of dialysis and renal-related death were end points, were 96%, 85%, 75%, and 61% at 5, 10, 15, and 20 years, respectively, from the time of the detection of the earliest known renal abnormalities. Renal survival rates of patients with diffuse mesangial proliferative GN were 96%, 83%, 75%, and 59% at 5, 10, 15, and 20 years, respectively. At the end of the observation period, 20% of patients had improved, 45.8% showed no change, 13.5% had deteriorated, and 20.4% had renal-related death. The risk factors for renal failure by logistic multivariate analysis were serum creatinine concentration > or =1.4 mg/dL (relative risk, 3.5) and levels of urinary protein > or = +(dipstick) (relative risk, 6.4), determined at the time of biopsy. These parameters can be useful for assessing prognosis during the relatively advanced stages of this disease. It is important to note that a relatively high percentage of patients with IgAN progressed to end-stage renal failure even when their histologic findings comprised only minor glomerular abnormalities or focal proliferative changes.
Kusumoto Y, Takebayashi S, Taguchi T, Harada T, Naito S.
Long-term prognosis and prognostic indices of IgA nephropathy in juvenile and in adult Japanese.
Clin Nephrol. 1987 Sep;28(3):118-24.
Abstract/Text
For a comparative study of IgA nephropathy occurring in Japanese adolescents and adults, the clinical and histological findings and prognosis (follow-up period; 12 +/- 6 years for children and 10 +/- 5 years for adults) were compared. The subjects studied included 98 children and 86 adults. Development into renal failure occurred in 9 children (9.2%) and in 20 adults (23.3%), (p less than 0.01). The actuarial renal survival rate at year 10 after the onset of glomerulonephritis in children and adults was 95% and 80%, respectively, and at year 20, 82% and 50%, respectively. The prognosis was definitely better in the children and this was attributable to the observation that (1) the glomerular injury at the initial biopsy in children was less extensive than in adults; (2) the frequency of complication with hypertension was lower in children (27.6%) than in adults (41.9%), (p less than 0.05); (3) hypertension was one prognostic indice, even in children, after age 30; (4) after age 40, aging and arteriosclerosis were more contributory than hypertension to the progress of IgA nephropathy; and (5) the quantity of intraglomerular immune deposits and the period of deposition were not related of prognostic indices. Thus, in the long-term prognosis of IgA nephropathy in both children and adults, immunological disorders seem to have little influence while factors such as hypertension, arteriosclerosis and aging play important roles.
Chauveau D, Droz D.
Follow-up evaluation of the first patients with IgA nephropathy described at Necker Hospital.
Contrib Nephrol. 1993;104:1-5. doi: 10.1159/000422388.
Abstract/Text
Kang S, et al. Nephrol Dial Transplant 2012；27：252—8.
D'Amico G.
Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome.
Semin Nephrol. 2004 May;24(3):179-96. doi: 10.1016/j.semnephrol.2004.01.001.
Abstract/Text
Among the numerous studies published in the last 20 years that have calculated the actuarial renal survival and tried to individuate the prognostic role of the clinical and histologic features present at the onset of the disease or the time of biopsy, we chose to critically analyze the results of the most valid (23 studies). Actuarial renal survival at 10 years in adults was between 80% and 85% in most of the European, Asian, and Australian studies, but was lower than this in studies from the United States and exceeded 90% in the few studies on children. Concordance existed in this selected literature on the fact that impairment of renal function, severe proteinuria, and arterial hypertension are the strongest and more reliable clinical predictors of an unfavorable outcome. Extent of proteinuria during follow up was an even stronger predictor. In adult patients, a high score of the glomerular and tubulointerstitial lesions predicted a more rapid progression. When the single lesions were analyzed separately, glomerular sclerosis and interstitial fibrosis appeared to be the strongest, most reliable predictors of unfavorable prognosis. More controversial was the role of crescents and capsular adhesions.
Manno C, Strippoli GF, D'Altri C, Torres D, Rossini M, Schena FP.
A novel simpler histological classification for renal survival in IgA nephropathy: a retrospective study.
Am J Kidney Dis. 2007 Jun;49(6):763-75. doi: 10.1053/j.ajkd.2007.03.013.
Abstract/Text
BACKGROUND: Patients with immunoglobulin A (IgA) nephropathy may progress to end-stage renal disease (ESRD) within 10 to 20 years after renal biopsy. We evaluated factors associated with long-term renal survival by using a novel simplified histological classification.
STUDY DESIGN: Retrospective study.
SETTING & PARTICIPANTS: 437 patients (296 men, 141 women) with IgA nephropathy seen at our single center from January 1971 to December 2006. Most patients received treatment with renin-angiotensin system inhibitors.
PREDICTORS: Baseline age, sex, presence of hematuria, presence of hypertension, serum creatinine level, urine protein at baseline, and 2 histological classifications.
OUTCOMES & MEASUREMENTS: Relationship of baseline factors to time to ESRD was evaluated by means of univariate and multivariate analysis with log-rank test and the Cox proportional hazard method.
RESULTS: In a mean follow-up of 107.6 months, 72 ESRD events occurred. The 5-, 10-, 15-, and 20-year renal survival rates after renal biopsy were 94.1%, 82.1%, 73.1%, and 60.3%, respectively. Independent baseline predictors of increased ESRD risk were microhematuria with absence of recurrent macrohematuria (adjusted hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.30 to 3.65; P = 0.003), 1.0 mg/dL (88.4 mumol/L) higher serum creatinine level (HR, 1.50; 95% CI, 1.10 to 2.07; P = 0.013), proteinuria with 1.0 g/dL (10.0 g/L) greater protein (HR, 1.28; 95% CI, 1.07 to 1.52; P = 0.006), and grading of histological lesions. A 1-grade increase according to our 3-grade classification was associated with a nearly 6-fold ESRD risk increase (adjusted HR, 5.95; 95% CI, 3.54 to 10.01; P < 0.0001).
LIMITATIONS: Lack of adjustment for changes in treatment that may have occurred during the study period.
CONCLUSIONS: Renal damage progression in patients with IgA nephropathy was associated with microscopic hematuria at clinical onset, increased serum creatinine level, increased proteinuria, and grading of histological lesions. Our classification system appears simpler than other classifications and is associated with ESRD risk, which could help identify individual high-risk patients and stratify patients enrolled in randomized clinical trials into homogeneous groups.
Barbour SJ, Coppo R, Zhang H, Liu ZH, Suzuki Y, Matsuzaki K, Katafuchi R, Er L, Espino-Hernandez G, Kim SJ, Reich HN, Feehally J, Cattran DC; International IgA Nephropathy Network.
Evaluating a New International Risk-Prediction Tool in IgA Nephropathy.
JAMA Intern Med. 2019 Jul 1;179(7):942-952. doi: 10.1001/jamainternmed.2019.0600.
Abstract/Text
IMPORTANCE: Although IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation.
OBJECTIVE: To derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide.
DESIGN, SETTING, AND PARTICIPANTS: We derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan.
MAIN OUTCOMES AND MEASURES: Cox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R2D measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots.
RESULTS: The study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R2D (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (ΔC, 0.04; 95% CI, 0.03-0.04 and ΔC, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R2D (both 35.3%) were similar or better than in the validation cohort, with excellent calibration.
CONCLUSIONS AND RELEVANCE: In this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.
Wakai K, Kawamura T, Endoh M, Kojima M, Tomino Y, Tamakoshi A, Ohno Y, Inaba Y, Sakai H.
A scoring system to predict renal outcome in IgA nephropathy: from a nationwide prospective study.
Nephrol Dial Transplant. 2006 Oct;21(10):2800-8. doi: 10.1093/ndt/gfl342. Epub 2006 Jul 5.
Abstract/Text
BACKGROUND: Immunoglobulin A (IgA) nephropathy is the most common form of glomerulonephritis in the world, and a substantial number of patients develop end-stage renal disease (ESRD). Although there are several prognostic indicators, it remains difficult to predict the renal outcome in individual patients.
METHODS: A prospective cohort study was conducted in 97 clinical units in Japan from 1995 to 2002. We analysed the data from 2269 patients using proportional hazards models in order to determine the predictors of ESRD in IgA nephropathy and to develop a scoring system to estimate ESRD risk.
RESULTS: During the follow-up (median, 77 months), 207 patients developed ESRD. Systolic hypertension, proteinuria, hypoproteinaemia, azotaemia and a high histological grade at initial renal biopsy were independently associated with the risk of ESRD. Mild haematuria predisposed patients to ESRD more than severe haematuria. A scoring system was developed to estimate the 7-year ESRD risk from eight clinical and pathological variables. Actually, this prognostic score accurately classified patients by risk: patients with estimates of 0.0-0.9, 1.0-4.9, 5.0-19.9, 20.0-49.9, and 50.0-100.0% had a 0.2, 2.4, 12.2, 40.2 and 80.8% of ESRD incidence over 7 years, respectively. The corresponding area under the receiver operating characteristic curve was 0.939 [95% confidence interval (CI), 0.921-0.958]. This score was verified in repetitions of the derivation-validation technique.
CONCLUSIONS: Although the quality of some data collected by the mail survey is limited and the influence of therapy could not be considered, this scoring system will serve as a useful prognostic tool for IgA nephropathy in clinical practice.
Reich HN, Troyanov S, Scholey JW, Cattran DC; Toronto Glomerulonephritis Registry.
Remission of proteinuria improves prognosis in IgA nephropathy.
J Am Soc Nephrol. 2007 Dec;18(12):3177-83. doi: 10.1681/ASN.2007050526. Epub 2007 Oct 31.
Abstract/Text
Proteinuria has been shown to be an adverse prognostic factor in IgA nephropathy. The benefit of achieving a partial remission of proteinuria, however, has not been well described. We studied 542 patients with biopsy-proven primary IgA nephropathy in the Toronto Glomerulonephritis Registry and found that glomerular filtration rate (GFR) declined at -0.38 +/- 0.61 ml/min per 1.73 m2/mo overall, with 30% of subjects reaching end-stage renal disease. Multivariate analysis revealed that proteinuria during follow-up was the most important predictor of the rate of GFR decline. Among the 171 patients with <1 g/d of sustained proteinuria, the rate of decline was 90% slower than the mean rate. The rate of decline increased with the amount of proteinuria, such that those with sustained proteinuria >3 g/d (n = 121) lost renal function 25-fold faster than those with <1 g/d. Patients who presented with > or =3 g/d who achieved a partial remission (<1 g/d) had a similar course to patients who had < or =1 g/d throughout, and fared far better than patients who never achieved remission. These results underscore the relationship between proteinuria and prognosis in IgA nephropathy and establish the importance of remission.
Berthoux F, Mohey H, Laurent B, Mariat C, Afiani A, Thibaudin L.
Predicting the risk for dialysis or death in IgA nephropathy.
J Am Soc Nephrol. 2011 Apr;22(4):752-61. doi: 10.1681/ASN.2010040355. Epub 2011 Jan 21.
Abstract/Text
For the individual patient with primary IgA nephropathy (IgAN), it remains a challenge to predict long-term outcomes for patients receiving standard treatment. We studied a prospective cohort of 332 patients with biopsy-proven IgAN patients followed over an average of 13 years. We calculated an absolute renal risk (ARR) of dialysis or death by counting the number of risk factors present at diagnosis: hypertension, proteinuria ≥1 g/d, and severe pathologic lesions (global optical score, ≥8). Overall, the ARR score allowed significant risk stratification (P < 0.0001). The cumulative incidence of death or dialysis at 10 and 20 years was 2 and 4%, respectively, for ARR=0; 2 and 9% for ARR=1; 7 and 18% for ARR=2; and 29 and 64% for ARR=3, in adequately treated patients. When achieved, control of hypertension and reduction of proteinuria reduced the risk for death or dialysis. In conclusion, the absolute renal risk score, determined at diagnosis, associates with risk for dialysis or death.
Copyright © 2011 by the American Society of Nephrology
Goto M, Wakai K, Kawamura T, Ando M, Endoh M, Tomino Y.
A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study.
Nephrol Dial Transplant. 2009 Oct;24(10):3068-74. doi: 10.1093/ndt/gfp273. Epub 2009 Jun 10.
Abstract/Text
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis, and a substantial number of patients succumb to end-stage renal disease (ESRD). However, prediction of the renal outcome in individual patients remains difficult. We have already published a scoring system using the data in a prospective cohort of IgAN patients followed up from 1995 to 2002.
METHODS: The cohort was further followed up until 2005 in 97 clinical units in Japan. The data from 2283 patients were analysed by Cox regression to determine the predictors of ESRD in IgAN, and their beta-coefficients were converted into scores to estimate ESRD risk within 10 years.
RESULTS: During the follow-up (median, 87 months), 252 patients developed ESRD. Male sex, age less than 30 years, family histories of chronic renal failure and chronic glomerulonephritis, hypertension, proteinuria, mild haematuria, hypoalbuminaemia, low glomerular filtration rate and a high histological grade at initial renal biopsy were associated with the risk of ESRD in the multivariable analysis. A scoring system was framed to estimate the 10-year ESRD risk using eight variables significant in both univariable and multivariable models. This prognostic score accurately classified patients by risk: patients with estimates of 0-4.9, 5.0-19.9, 20.0-49.9 and 50.0-100% had an observed incidence of 1.7, 8.3, 36.7 and 85.5%, respectively. The corresponding area under the receiver-operating characteristic curve was 0.942 (95% confidence interval, 0.925-0.958).
CONCLUSION: This validated scoring system to quantitatively estimate ESRD risk during the 10-year follow-up of IgAN patients will serve as a useful prognostic tool in clinical practice.
Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Coppo R, Troyanov S, Camilla R, Hogg RJ, Cattran DC, Cook HT, Feehally J, Roberts IS, Amore A, Alpers CE, Barratt J, Berthoux F, Bonsib S, Bruijn JA, D'Agati V, D'Amico G, Emancipator SN, Emma F, Ferrario F, Fervenza FC, Florquin S, Fogo AB, Geddes CC, Groene HJ, Haas M, Herzenberg AM, Hill PA, Hsu SI, Jennette JC, Joh K, Julian BA, Kawamura T, Lai FM, Li LS, Li PK, Liu ZH, Mezzano S, Schena FP, Tomino Y, Walker PD, Wang H, Weening JJ, Yoshikawa N, Zhang H.
The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.
Kidney Int. 2010 May;77(10):921-7. doi: 10.1038/ki.2010.43. Epub 2010 Mar 3.
Abstract/Text
To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.
Yamamoto R, Nagasawa Y, Shoji T, Iwatani H, Hamano T, Kawada N, Inoue K, Uehata T, Kaneko T, Okada N, Moriyama T, Horio M, Yamauchi A, Tsubakihara Y, Imai E, Rakugi H, Isaka Y.
Cigarette smoking and progression of IgA nephropathy.
Am J Kidney Dis. 2010 Aug;56(2):313-24. doi: 10.1053/j.ajkd.2010.02.351. Epub 2010 May 14.
Abstract/Text
BACKGROUND: Multiple community-based cohort studies of mainly middle-aged and elderly populations have shown that cigarette smoking is a risk factor for chronic kidney disease. However, little information is available about an effect of cigarette smoking on progression of primary kidney diseases, including immunoglobulin A (IgA) nephropathy.
STUDY DESIGN: Retrospective cohort study.
SETTING & PARTICIPANTS: 971 of 1,001 patients with a diagnosis of IgA nephropathy in 3 major nephrology centers in Osaka, Japan, between 1992 and 2005 who enrolled in the Study of Outcome and Practice Pattern of IgA Nephropathy (STOP-IgAN).
PREDICTORS: Smoking status and number of cigarettes smoked at the time of diagnosis using kidney biopsy. Dose-dependent associations between cigarette smoking and outcomes were assessed in multivariate Cox proportional hazards models. Significantly different clinical characteristics between non-/past and current smokers were controlled for using propensity score-based adjustment, stratification, and matching.
OUTCOMES: 50% increase in serum creatinine level as primary outcome. A composite outcome of a 100% increase in serum creatinine level or end-stage renal disease (ESRD) and ESRD alone as secondary outcomes.
RESULTS: During the median 5.8 years (interquartile range, 2.6-10.2) of the observational period, 117 participants progressed to a 50% increase in serum creatinine level and 47 advanced to ESRD. Multivariate Cox proportional hazards models identified current smokers (HR, 2.03 [95% CI, 1.33-3.10] for primary outcome) and number of cigarettes at kidney biopsy (HR, 1.21 [95% CI, 1.06-1.39] per 10 cigarettes per day) as significant predictors of outcomes. Propensity score-based models confirmed these results. Tests for interaction showed that the association of current smoking with adverse outcomes was stronger in those with lower compared with higher estimated glomerular filtration rates.
LIMITATION: Baseline smoking status was not verified using biochemical tests. Smoking status during the observational period was unavailable.
CONCLUSIONS: Cigarette smoking, in a dose-dependent manner, was identified as a key prognostic factor in IgA nephropathy. Smoking cessation should be encouraged as part of the treatment for IgA nephropathy.
Crown Copyright (c) 2010. Published by Elsevier Inc. All rights reserved.
Praga M, Gutiérrez E, González E, Morales E, Hernández E.
Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial.
J Am Soc Nephrol. 2003 Jun;14(6):1578-83. doi: 10.1097/01.asn.0000068460.37369.dc.
Abstract/Text
Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.
Wheeler DC, Toto RD, Stefánsson BV, Jongs N, Chertow GM, Greene T, Hou FF, McMurray JJV, Pecoits-Filho R, Correa-Rotter R, Rossing P, Sjöström CD, Umanath K, Langkilde AM, Heerspink HJL; DAPA-CKD Trial Committees and Investigators.
A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy.
Kidney Int. 2021 Jul;100(1):215-224. doi: 10.1016/j.kint.2021.03.033. Epub 2021 Apr 18.
Abstract/Text
Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m2; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were -3.5 and -4.7 mL/min/1.73m2/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.
Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Reid S, Cawthon PM, Craig JC, Samuels JA, Molony DA, Strippoli GF.
Non-immunosuppressive treatment for IgA nephropathy.
Cochrane Database Syst Rev. 2011 Mar 16;(3):CD003962. doi: 10.1002/14651858.CD003962.pub2. Epub 2011 Mar 16.
Abstract/Text
BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease with approximately 30% to 40% of patients progressing to end-stage kidney disease (ESKD) within 20 years. The most common regimens include immunosuppressive agents, however the risks of long-term treatment often outweigh the potential benefits. Non-immunosuppressive options, including fish oils, anticoagulants, antihypertensive agents and tonsillectomy have also been examined but not reviewed systematically.
OBJECTIVES: To assess the benefits and harms of non-immunosuppressive treatments for treating IgAN in adults and children.
SEARCH STRATEGY: In July 2010 we searched the Cochrane Renal Group's specialised register, CENTRAL (in The Cochrane Library), MEDLINE (from 1966) and EMBASE (from 1980). We also searched reference lists of included studies, review articles and contacted local and international experts.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included.
DATA COLLECTION AND ANALYSIS: Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model.
MAIN RESULTS: We included 56 studies (2838 participants). Antihypertensive agents were the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or combinations of both, versus other antihypertensives and other agents. The benefits of antihypertensive agents, particularly inhibitors of the renin angiotensin system, appear to potentially outweigh the harms in patients with IgAN. The benefits are largely manifest as a reduction in proteinuria, a surrogate outcome. There is no evidence that treatment with any of the antihypertensive agents evaluated affect major renal and/or cardiovascular endpoints or long-term mortality risk beyond the benefit that arises from controlling hypertension in patients with IgAN. The RCT evidence is insufficiently robust to demonstrate efficacy for any of the other non-immunosuppressive therapies evaluated here.
AUTHORS' CONCLUSIONS: IgAN remains a disease in search of adequately powered RCTs to reliably inform clinical practice. More and better evidence is needed to understand the magnitude of benefit and the possible risks of anti-hypertensive or more specifically of ACEi/ARB therapy alone or in combination and which specific types of patients with the IgAN might have the greatest potential for benefit. For other non-immunosuppressive therapies, where neither benefit nor significant harm has yet to be demonstrated, there remains some justification for further exploration of the potential benefits.
Coppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, Stone R, Kirschstein M, Linné T.
IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria.
J Am Soc Nephrol. 2007 Jun;18(6):1880-8. doi: 10.1681/ASN.2006040347. Epub 2007 May 18.
Abstract/Text
This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhibitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (>1 and <3.5 g/d per 1.73 m(2)) and creatinine clearance (CrCl) >50 ml/min per 1.73 m(2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to Benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as >30% decrease of CrCl; secondary outcomes were (1) a composite end point of >30% decrease of CrCl or worsening of proteinuria until > or =3.5 g/d per 1.73 m(2) and (2) proteinuria partial remission (<0.5 g/d per 1.73 m(2)) or total remission (<160 mg/d per 1.73 m(2)) for >6 mo. Analysis was by intention to treat. A single patient (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed a worsening of CrCl >30%. The composite end point of >30% decrease of CrCl or worsening of proteinuria until nephrotic range was reached by one (3.1%) of 32 patients in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients in the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12.5% of ACE-I-treated patients and in none in the placebo group (log-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.
Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G.
Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury.
Am J Kidney Dis. 2000 Jun;35(6):1155-65. doi: 10.1016/s0272-6386(00)70054-0.
Abstract/Text
The Ramipril Efficacy in Nephropathy (REIN) study found that angiotensin-converting enzyme (ACE) inhibitors effectively decreased proteinuria, glomerular filtration rate (GFR) decline (DeltaGFR), and incidence of end-stage renal disease (ESRD) in patients with proteinuric chronic nephropathies. In this study, we prospectively investigated the main clinical determinants of progression and response to treatment in the 352 patients enrolled into the REIN study. Mean DeltaGFR (0.56 +/- 0.05 [SEM] versus 0.21 +/- 0.05 mL/min/1.73 m(2)/mo; P = 0.0001) and incidence of ESRD (30% and 10%; P = 0.0001) were more than twice that in patients with proteinuria of 2 g/24 h or greater of protein compared with those with protein less than 2 g/24 h (relative risk [RR], 4.07; 95% confidence interval [CI], 2.20 to 7.52), as well as in patients with hypertension compared with normotension (mean DeltaGFR, 0.48 +/- 0. 05 versus 0.22 +/- 0.05 mL/min/1.73 m(2)/mon; P = 0.0006; ESRD, 25% versus 10%; P = 0.004; RR, 3.18; 95% CI, 1.38 to 7.32). Hypertension at study entry (P = 0.038), greater mean blood pressure on follow-up (P = 0.002), and urinary protein excretion rate (P = 0.0001) were independent predictors of faster DeltaGFR. DeltaGFR was approximately twofold faster in patients with type 2 diabetes than in those with primary glomerular disease (P = 0.002; including immunoglobulin A [IgA] nephropathy, P = 0.009); nephrosclerosis (P = 0.03), adult polycystic kidney disease (APKD), or chronic interstitial nephritis (P = 0.006). Diabetes at study entry (P = 0. 02) and greater mean blood pressure (P = 0.0001) and urinary protein excretion rate (P = 0.0001) on follow-up were independent predictors of faster DeltaGFR. After correction for baseline covariates, diabetes was also associated with an increased risk for progression to ESRD (RR, 2.39; 95% CI, 1.01 to 5.68; P < 0.05). At multivariate analyses, ramipril significantly decreased DeltaGFR (regression coefficient,-0.23 +/- 0.11 [SEM]; P = 0.036) and ESRD (RR, 2.08; 95% CI, 1.21 to 3.57; P = 0.008) in patients with baseline proteinuria of 2 g/24 h or greater of protein, and the renoprotective effect increased for increasing levels of proteinuria. Ramipril decreased DeltaGFR to a similar extent in normotensive and hypertensive patients (-0.14 +/- 0.11 versus -0.14 +/- 0.09) and significantly limited ESRD in hypertensive patients (RR, 2.03; 95% CI, 1.26 to 3. 26; P = 0.004). DeltaGFR was decreased by 42% in primary glomerular disease (P = 0.017), by 35% in IgA nephropathy, and by 37% in nephrosclerosis, but was not improved in type 2 diabetes, APKD, or interstitial nephritis. At multivariate analyses, ramipril significantly slowed DeltaGFR (-0.24 +/-0.08; P = 0.004) and progression to ESRD (RR, 2.32; 95% CI, 1.36 to 3.96; P = 0.002) in patients without diabetes, but not in patients with diabetes, who tended to have a faster DeltaGFR (+0.62 +/- 0.44) on ramipril therapy. In summary, patients with proteinuria of 2 g/24 h or greater of protein, preexisting hypertension, or type 2 diabetes were faster progressors. Greater blood pressure and degree of proteinuria were the strongest determinants of faster GFR decline. The renoprotective effect of ramipril was similar in patients with normotension and hypertension. Hypertensive patients and those with proteinuria of 2 g/24 h or greater of protein, primary glomerular disease, or nephrosclerosis gained the most from ACE inhibitor treatment. During the study period, those with proteinuria less than 2 g/24 h of protein, type 2 diabetes, or polycystic kidney disease did not benefit by treatment to an appreciable extent.
Li PK, Leung CB, Chow KM, Cheng YL, Fung SK, Mak SK, Tang AW, Wong TY, Yung CY, Yung JC, Yu AW, Szeto CC; HKVIN Study Group.
Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study.
Am J Kidney Dis. 2006 May;47(5):751-60. doi: 10.1053/j.ajkd.2006.01.017.
Abstract/Text
BACKGROUND: Previous studies showed that angiotensin-receptor blocker (ARB) therapy decreased proteinuria and possibly slowed the rate of renal function decline in patients with chronic proteinuric nephropathies. We performed a double-blind, randomized, placebo-controlled, multicenter study on the ARB valsartan in the treatment of patients with immunoglobulin A (IgA) nephropathy.
METHODS: From 6 centers, we recruited 109 patients with IgA nephropathy who had either: (1) proteinuria with protein greater than 1 g/d and serum creatinine level less than 2.8 mg/dL (< 250 micromol/L), or (2) serum creatinine level of 1.4 to 2.8 mg/dL (120 to 250 micromol/L) regardless of degree of proteinuria. Patients were randomly assigned to administration of either valsartan, 80 mg/d (titrated up to 160 mg/d for blood pressure control), or placebo for 104 weeks. Additional antihypertensive therapy was allowed to achieve a target blood pressure of 140/90 mm Hg. The primary end point was doubling of serum creatinine level or dialysis-dependent renal failure. Secondary outcomes included change in proteinuria and decrease in glomerular filtration rate (GFR).
RESULTS: There were 54 patients in the treatment group and 55 patients in the placebo group. Baseline clinical characteristics were similar between groups, although the treatment group had a marginally greater baseline GFR (87 +/- 36 versus 78 +/- 38 mL/min/1.73 m2 [1.45 +/- 0.60 versus 1.30 +/- 0.63 mL/s/1.73 m2];P = 0.29) and less proteinuria (protein, 1.8 +/- 1.2 versus 2.3 +/- 1.7 g/d; P = 0.21) than the placebo group. Average blood pressures during the study were 92.7 +/- 10.6 mm Hg in the treatment group and 100.9 +/- 9.1 mm Hg in the placebo group (P < 0.001). During the study period, 4 patients in the placebo group and 1 patient in the treatment group reached the primary end point (log-rank test, P = 0.18). Proteinuria decreased significantly in the treatment group (protein, 1.8 +/- 1.2 to 1.2 +/- 1.2 g/d; P = 0.03), but did not change in the placebo group. With multiple linear regression models, valsartan treatment resulted in a 33.0% decrease in proteinuria (95% confidence interval, 10.9 to 55.1) after adjusting for other confounding factors. There was a significant decrease in mean rate of GFR decrease in the valsartan-treated group (-5.62 +/- 6.79 mL/min/y [-0.09 +/- 0.11 mL/s/y]) compared with the placebo group (-6.98 +/- 6.17 mL/min/y [-0.12 +/- 0.10 mL/s/y]) throughout the study period after adjustment for average blood pressure and proteinuria (P = 0.014).
CONCLUSION: Valsartan significantly decreases proteinuria and slows renal deterioration in patients with IgA nephropathy after adjustment for confounding factors, notably blood pressure. The long-term benefit of valsartan needs to be confirmed with additional studies.
Kanno Y, Okada H, Yamaji Y, Nakazato Y, Suzuki H.
Angiotensin-converting-enzyme inhibitors slow renal decline in IgA nephropathy, independent of tubulointerstitial fibrosis at presentation.
QJM. 2005 Mar;98(3):199-203. doi: 10.1093/qjmed/hci036.
Abstract/Text
BACKGROUND: Tubulointerstitial fibrosis (TIF) is a marker of progression of diabetic and non-diabetic nephropathy, correlating with creatinine clearance (CCr), and functional outcome. Angiotensin-converting-enzyme inhibitors (ACEIs) slow the rate of decline of renal function in proteinuric patients.
AIM: To examine whether ACEIs affect TIF, directly or indirectly.
DESIGN: Prospective 3-year follow-up study.
METHODS: We enrolled 49 patients with IgA nephropathy (IgAN), treating some with ACE inhibitors (n = 26, 1-2 mg/day temocapril or trandolapril) and some with calcium-channel blockers (CCB, n = 23, 2.5-5 mg/day amlodipine). Blood pressure, serum creatinine, and urinalysis were measured monthly, and 24-h endogenous creatinine clearance (CCr) at least once a year.
RESULTS: In the CCB group, TIF was positively correlated with the rate of decline in CCr (dCCr), consistent with previous observations. In the ACEI group, dCCr was lower (0.02 +/- 0.02 vs. 0.06 +/- 0.03), and the TIF-dCCr correlation was absent.
DISCUSSION: In the absence of post-treatment histological data, it is not possible to say whether ACEIs have an effect on TIF. However, ACEIs appear to slow the progression of renal failure in IgAN, regardless of the degree of TIF at presentation.
Taji Y, Kuwahara T, Shikata S, Morimoto T.
Meta-analysis of antiplatelet therapy for IgA nephropathy.
Clin Exp Nephrol. 2006 Dec;10(4):268-73. doi: 10.1007/s10157-006-0433-8. Epub 2006 Dec 20.
Abstract/Text
BACKGROUND: Antiplatelet agents have been widely used in the management of immunoglobulin A (IgA) nephropathy in the Japanese population. To systematically evaluate the effects of antiplatelet agents for IgA nephropathy, we conducted a meta-analysis of the published studies.
METHODS: Data sources consisted of MEDLINE, EMBASE, the Cochrane Library, Ityu-shi (Japanese medical database), and bibliographies from the studies. The quality of the studies was evaluated from the intention to treat analysis and allocation concealment, as well as by the Jadad method. Meta-analyses were performed on the outcomes of proteinuria and renal function.
RESULTS: Seven articles met the predetermined inclusion criteria. The use of antiplatelet agents showed statistically significant effects on proteinuria and renal function. The pooled risk ratio for proteinuria was 0.61 (95% confidence intervals (CI) 0.39-0.94) and for renal function it was 0.74 (95% CI 0.63-0.87).
CONCLUSIONS: Antiplatelet agents resulted in reduced proteinuria and protected renal function in patients with IgA nephropathy. However, studies of high-quality design were rare, and most studies assessed surrogate outcomes. More properly designed studies are needed to reach a definitive assessment of this matter.
Liu XJ, Geng YQ, Xin SN, Huang GM, Tu XW, Ding ZR, Chen XM.
Antithrombotic drug therapy for IgA nephropathy: a meta analysis of randomized controlled trials.
Intern Med. 2011;50(21):2503-10. doi: 10.2169/internalmedicine.50.5971. Epub 2011 Nov 1.
Abstract/Text
BACKGROUND: Antithrombotic agents, including antiplatelet agents, anticoagulants and thrombolysis agents, have been widely used in the management of immunoglobulin A (IgA) nephropathy in Chinese and Japanese populations. To systematically evaluate the effects of antithrombotic agents for IgA nephropathy.
METHODS: Data sources consisted of MEDLINE, EMBASE, the Cochrane Library, Chinese Biomedical Literature Database (CBM), Chinese Science and Technology Periodicals Databases (CNKI) and Japana Centra Revuo Medicina (http://www.jamas.gr.jp) up to April 5, 2011. The quality of the studies was evaluated from the intention to treat analysis and allocation concealment, as well as by the Jadad method. Meta-analyses were performed on the outcomes of proteinuria and renal function.
RESULTS: Six articles met the predetermined inclusion criteria. Antithrombotic agents showed statistically significant effects on proteinuria (p<0.0001) but not on the protection of renal function (p=0.07). The pooled risk ratio for proteinuria was 0.53, [95% confidence intervals (CI): 0.41-0.68; I(2)=0%] and for renal function it was 0.42 (95% CI 0.17-1.06; I(2)=72%). Subgroup analysis showed that dipyridamole was beneficial for proteinuria (p=0.0003) but had no significant effects on protecting renal function. Urokinase had statistically significant effects both on the reduction of proteinuria (p=0.0005) and protecting renal function (p<0.00001) when compared with the control group.
CONCLUSION: Antithrombotic agents had statistically significant effects on the reduction of proteinuria but not on the protection of renal function in patients with IgAN. Urokinase had statistically significant effects both on the reduction of proteinuria and on protecting renal function. Urokinase was shown to be a promising medication and should be investigated further.
Camara S, de la Cruz JP, Frutos MA, Sanchez P, Lopez de Novales E, Sanchez E, Sanchez de la Cuesta F.
Effects of dipyridamole on the short-term evolution of glomerulonephritis.
Nephron. 1991;58(1):13-6. doi: 10.1159/000186370.
Abstract/Text
The aim of the present study is to evaluate the effect of dipyridamole (300 mg/day) versus placebo in a double-blind randomized trial on membranous glomerulonephritis (M-GMN), mesangial IgA glomerulonephritis (IgA-GMN), and segmentary and focal hyalinosis glomerulonephritis (SFH-GMN) during the first 3 months of treatment. In the case of M-GMN, proteinuria dropped by 60% of the basal value in patients treated with dipyridamole; in the case of IgA-GMN it dropped by 65-70%; and in the case of SFH-GMN it dropped by 40% of the basal value. Inhibition of proteinuria in M-GMN was correlated to platelet response, and above all, to the ADP-induced platelet aggregation in whole blood.
Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, Liu Z.
Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population.
Nephrol Dial Transplant. 2012 Apr;27(4):1479-85. doi: 10.1093/ndt/gfr527. Epub 2011 Sep 29.
Abstract/Text
BACKGROUND: We sought to identify the long-term renal survival rate and related risk factors of progression to renal failure in Chinese adult patients with IgA nephropathy (IgAN) and to quantify the effects of proteinuria during the follow-up on outcome in patients with IgAN.
METHODS: Patients with biopsy-proven primary IgAN in the Nanjing Glomerulonephritis Registry were studied. Renal survival and the relationships between clinical parameters and renal outcomes were assessed.
RESULTS: One thousand one hundred and fifty-five patients were enrolled in this study. The 10-, 15- and 20-year cumulative renal survival rates, calculated by Kaplan-Meier method, were 83, 74 and 64%, respectively. At the time of biopsy, proteinuria>1.0 g/day [hazard ratio (HR) 3.2, P<0.001], estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 (HR 2.6, P<0.001), hypertension (HR 1.9, P<0.001), hypoproteinemia (HR 2.0, P<0.001) and hyperuricemia (HR 2.1, P<0.001) were the independent risk factors. Multivariate Cox analysis showed the time-average proteinuria (TA-P) during follow-up was the most important risk factor of renal failure. Patients with TA-P>1.0 g/day were associated with a 9.4-fold risk than patients with TA-P<1.0 g/day (P<0.001) and 46.5-fold risk than those with TA-P<0.5 g/day (P<0.001). Moreover, patients who achieved TA-P<0.5 g/day benefit much more than those with TA-P between 0.5 and 1.0 g/day (HR 13.1, P<0.001).
CONCLUSIONS: Thirty-six percent of Chinese adult patients with IgAN progress to end stage renal disease within 20 years. Five clinical features-higher proteinuria, hypertension, impaired renal function, hypoproteinemia and hyperuricemia-are independent predictors of an unfavorable renal outcome. The basic goal of anti-proteinuric therapy for Chinese patients is to lower proteinuria<1.0 g/day and the optimal goal is to lower proteinuria to <0.5 g/day.
Pozzi C, Bolasco PG, Fogazzi GB, Andrulli S, Altieri P, Ponticelli C, Locatelli F.
Corticosteroids in IgA nephropathy: a randomised controlled trial.
Lancet. 1999 Mar 13;353(9156):883-7. doi: 10.1016/s0140-6736(98)03563-6.
Abstract/Text
BACKGROUND: IgA nephropathy is progressive in most cases and has no established therapy. In this randomised trial, we assessed the efficacy and safety of a 6-month course of steroids in this disorder.
METHODS: Between July, 1987, and September, 1995, we enrolled 86 consecutive patients from seven renal units in Italy. Eligible patients had biopsy-proven IgA nephropathy, urine protein excretion of 1.0-3.5 g daily, and plasma creatinine concentrations of 133 micromol/L (1.5 mg/dL) or less. Patients were randomly assigned either supportive therapy alone or steroid treatment (intravenous methylprednisolone 1 g per day for 3 consecutive days at the beginning of months 1, 3, and 5, plus oral prednisone 0.5 mg/kg on alternate days for 6 months). The primary endpoint was deterioration in renal function defined as a 50% or 100% increase in plasma creatinine concentration from baseline. Analyses were by intention to treat.
FINDINGS: Nine of 43 patients in the steroid group and 14 of 43 in the control group reached the primary endpoint (a 50% increase in plasma creatinine) by year 5 of follow-up (p<0.048). Factors influencing renal survival were vascular sclerosis (relative risk for 1-point increase in score 1.53, p=0.0347), female sex (0.22, p=0.0163), and steroid therapy (0.41, p=0.0439). All 43 patients assigned steroids completed the treatment without experiencing any important side-effects.
INTERPRETATION: A 6-month course of steroid treatment protected against deterioration in renal function in IgA nephropathy with no notable adverse effects during follow-up. An increase in urinary protein excretion could be a marker indicating the need for a second course of steroid therapy.
Pozzi C, Andrulli S, Del Vecchio L, Melis P, Fogazzi GB, Altieri P, Ponticelli C, Locatelli F.
Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial.
J Am Soc Nephrol. 2004 Jan;15(1):157-63. doi: 10.1097/01.asn.0000103869.08096.4f.
Abstract/Text
Proteinuria plays a causal role in the progression of IgA nephropathy (IgAN). A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN. The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN, examine the trend of proteinuria during follow-up (starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome), and evaluate how histologic scores can influence steroid response. A secondary analysis of a multicenter, randomized, controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 mo was conducted. Ten-year renal survival was significantly better in the steroid than in the control group (97% versus 53%; log rank test P = 0.0003). In the 72 patients who did not reach the end point (doubling in baseline serum creatinine), median proteinuria significantly decreased (1.9 g/24 h at baseline, 1.1 g/24 h after 6 mo, and 0.6 g/24 h after a median of 7 yr). In the 14 progressive patients, proteinuria increased from a median of 1.7 g/24 h at baseline to 2.0 g/24 h after 6 mo and 3.3 g/24 h after a median of 5 yr. Steroids were effective in every histologic class. Cox multivariate regression analyses showed that, in addition to steroids, a low baseline histologic score, a reduction in proteinuria after 6 mo, and no increase in proteinuria during follow-up all were independent predictors of a beneficial outcome. Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN. The histologic picture and proteinuria during early and late follow-up improve the prediction of outcome, but considerable variability remains outside the model.
Manno C, Torres DD, Rossini M, Pesce F, Schena FP.
Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy.
Nephrol Dial Transplant. 2009 Dec;24(12):3694-701. doi: 10.1093/ndt/gfp356. Epub 2009 Jul 23.
Abstract/Text
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common cause of chronic renal failure among primary glomerulonephritis patients. The best treatment for IgAN remains poorly defined. We planned a long-term, prospective, open-label, multicentre, centrally randomized controlled trial to assess whether the combination of prednisone and ramipril was more effective than ramipril alone in patients with proteinuric IgAN.
METHODS: Ninety-seven biopsy-proven IgAN patients with moderate histologic lesions, 24-h proteinuria > or =1.0 g and estimated glomerular filtration rate (eGFR) > or = 50 ml/min/ 1.73 m(2) were randomly allocated to receive a 6-month course of oral prednisone plus ramipril (combination therapy group) or ramipril alone (monotherapy group) for the total duration of follow-up. The primary outcome was the progression of renal disease defined as the combination of doubling of baseline serum creatinine or end-stage kidney disease (ESKD). The secondary outcomes were the rate of renal function decline defined as the eGFR slope over time, and the reduction of 24-h proteinuria.
RESULTS: After a follow-up of up to 96 months, 13/49 (26.5%) patients in the monotherapy group reached the primary outcome compared with 2/48 (4.2%) in the combination therapy group. The Kaplan-Meier analysis showed a significantly higher probability of not reaching the combined outcome in the combination therapy group than in the monotherapy group (85.2% versus 52.1%; log-rank test P = 0.003). In the multivariate analysis, baseline serum creatinine and 24-h proteinuria were independent predictors of the risk of primary outcome; treatment with prednisone plus ramipril significantly reduced the risk of renal disease progression (hazard ratio 0.13; 95% confidence interval 0.03-0.61; P = 0.01). The mean rate of eGFR decline was higher in the monotherapy group than in the combination therapy group (-6.17 +/- 13.3 versus -0.56 +/- 7.62 ml/min/ 1.73 m(2)/year; P = 0.013). Moreover, the combined treatment reduced 24-h proteinuria more than ramipril alone during the first 2 years.
CONCLUSIONS: Our results suggest that the combination of corticosteroids and ramipril may provide additional benefits compared with ramipril alone in preventing the progression of renal disease in proteinuric IgAN patients in the long-term follow-up.
Lv J, Zhang H, Chen Y, Li G, Jiang L, Singh AK, Wang H.
Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial.
Am J Kidney Dis. 2009 Jan;53(1):26-32. doi: 10.1053/j.ajkd.2008.07.029. Epub 2008 Oct 19.
Abstract/Text
BACKGROUND: Recent studies have shown that both steroids and angiotensin-converting enzyme (ACE) inhibitors improve kidney survival and decrease proteinuria in patients with immunoglobulin A nephropathy. In this study, we aim to investigate whether the addition of steroids to ACE-inhibitor therapy produces a more potent antiproteinuric effect and better protection of kidney function than an ACE inhibitor alone.
STUDY DESIGN: Randomized controlled trial.
SETTING & PARTICIPANTS: Patients with biopsy-proven immunoglobulin A nephropathy with proteinuria of 1 to 5 g/d of protein.
INTERVENTION: 63 patients were randomly assigned to either cilazapril alone (ACE-inhibitor group; n = 30) or steroid plus cilazapril (combination group; n = 33).
OUTCOMES & MEASUREMENTS: The primary end point was kidney survival, defined as a 50% increase in baseline serum creatinine level.
RESULTS: After follow-up for up to 48 months, 7 patients in the ACE-inhibitor group (24.1%) reached the primary end point compared with 1 patient (3%) in the combination group. Kaplan-Meier kidney survival was significantly better in the combination group than the ACE-inhibitor group after 24 and 36 months (96.6% versus 75.7%, 96.6% versus 66.2%; P = 0.001). Urine protein excretion significantly decreased in patients in the combination group compared with the ACE-inhibitor group (time-average proteinuria, 1.04 +/- 0.54 versus 1.57 +/- 0.86 g/d of protein; P = 0.01). Multivariate analysis showed that combination treatment (hazard ratio, 0.1; 95% confidence interval, 0.014 to 0.946) and time-average proteinuria (hazard ratio, 14.3; 95% confidence interval, 2.86 to 71.92) were independent predictors of kidney survival.
LIMITATIONS: Small sample size, a single center, and slight imbalances at baseline.
CONCLUSIONS: Our results suggest that the addition of steroid to ACE-inhibitor therapy provided additional benefit compared with an ACE inhibitor alone. However, this was a pilot study with a small number of participants achieving the end points, and thus further validation is necessary.
Katafuchi R, Ikeda K, Mizumasa T, Tanaka H, Ando T, Yanase T, Masutani K, Kubo M, Fujimi S.
Controlled, prospective trial of steroid treatment in IgA nephropathy: a limitation of low-dose prednisolone therapy.
Am J Kidney Dis. 2003 May;41(5):972-83. doi: 10.1016/s0272-6386(03)00194-x.
Abstract/Text
BACKGROUND: No accepted therapy has been established for progressive immunoglobulin A (IgA) nephropathy.
METHODS: A prospective, randomized, controlled trial of low-dose prednisolone therapy was performed in patients with IgA nephropathy with moderate histological characteristics. Forty-three patients in the steroid group and 47 patients in the control group were included in the study. The initial dose of prednisolone was 20 mg/d, gradually tapered to 5 mg/d during 2 years.
RESULTS: Baseline urine protein-creatinine ratio (UP-UCR) was significantly greater in the steroid group than in controls. Follow-up duration was 65 +/- 25 months in the steroid group and 64 +/- 23 months in controls. Changes in UP-UCR from baseline, ie, UP-UCR at last follow-up minus UP-UCR at baseline, were significantly lower in the steroid group than in controls (steroid group, -0.84 +/- 1.78; controls, 0.26 +/- 1.65; P = 0.0034). Kidney survival was similar in both groups. Patients were divided into two subgroups according to clinical course. There were 28 improved patients and 15 unimproved patients in the steroid group and 27 improved patients and 20 unimproved patients in the control group. In the steroid group, UP-UCR was significantly greater in the unimproved than improved subgroup (3.1 +/- 2.6 versus 1.8 +/- 1.5).
CONCLUSION: These data suggest that our protocol had an antiproteinuric effect, but could not improve kidney survival. Because the effect of steroid therapy to prevent the progression of IgA nephropathy is believed to be linked closely to reduction in urinary protein, an insufficient dose of prednisolone in our protocol may be the reason for the discrepancy between the effect on proteinuria and kidney survival.
Koike M, Takei T, Uchida K, Honda K, Moriyama T, Horita S, Ogawa T, Yoshida T, Tsuchiya K, Nitta K.
Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center.
Clin Exp Nephrol. 2008 Aug;12(4):250-255. doi: 10.1007/s10157-008-0036-7. Epub 2008 Feb 21.
Abstract/Text
BACKGROUND/AIM: No accepted therapy has been established for progressive IgA nephropathy (IgAN). The purpose of the present study was to assess low-dose steroid therapy in the treatment of patients with IgAN.
METHODS: A prospective trial of low-dose steroid therapy was performed in patients with IgAN with mild histological activities. Twenty-four patients in the steroid group and 24 patients in the control group were included in this study. The initial dose of prednisolone was 0.4 mg/kgBW/day (20-30 mg/day), gradually tapered to 5-10 mg/day over 24 months. The patients with mild active inflammatory lesions were treated with prednisolone. The patients assigned to the control group were treated with dipyridamole or zilazep hydrochloride in a dose of 150 or 300 mg/day.
RESULTS: In all of the patients studied, serum creatinine levels did not significantly change over 24 months. However, daily proteinuria significantly reduced after 24 months of steroid therapy (0.97 +/- 0.75 vs. 0.31 +/- 0.51 g/day, P = 0.0012), even if did not change after 24 months of anti-platelet drugs (0.89 +/- 0.49 vs. 0.68 +/- 0.69 g/day, P = 0.2289), respectively. In addition, the grade of hematuria significantly reduced after 24 months of steroid therapy (35.6 +/- 36.3 RBC/HPF vs. 13.7 +/- 28.4 RBC/HPF, P = 0.0249) and 24 months of anti-platelet drugs (30.1 +/- 37.1 RBC/HPF vs. 12.4 +/- 20.3 RBC/HPF, P = 0.0465), respectively. Systolic and diastolic blood pressures did not significantly change during treatment with steroid or anti-platelet drugs. Vascular changes (0.63 +/- 0.73) in the steroid group were lower than those (1.08 +/- 0.88) in the control group (P = 0.008).
CONCLUSION: Our data suggested that low-dose steroid therapy for IgAN patients with mild inflammatory lesions could reduce the amount of urinary protein excretion and prevent deterioration of renal function, provided the histological findings in the renal biopsies showed mild vascular lesions.
Hogg RJ, Lee J, Nardelli N, Julian BA, Cattran D, Waldo B, Wyatt R, Jennette JC, Sibley R, Hyland K, Fitzgibbons L, Hirschman G, Donadio JV Jr, Holub BJ; Southwest Pediatric Nephrology Study Group.
Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: report from the Southwest Pediatric Nephrology Study Group.
Clin J Am Soc Nephrol. 2006 May;1(3):467-74. doi: 10.2215/CJN.01020905. Epub 2006 Apr 12.
Abstract/Text
This randomized, placebo-controlled, double-blind trial evaluated the role of prednisone and omega 3 fatty acids (O3FA) in patients with IgA nephropathy. Entry criteria were (1) biopsy-proven IgA nephropathy, (2) estimated GFR > or = 50 ml/min per 1.73 m2, and (3) moderate to severe proteinuria. Thirty-three patients were randomly assigned to receive prednisone 60 mg/m2 every other day for 3 mo, then 40 mg/m2 every other day for 9 mo, then 30 mg/m2 every other day for 12 mo (prednisone group); 32 were randomly assigned to receive O3FA 4 g/d for 2 yr (1.88 g eicosapentaenoic acid, 1.48 g docosahexaenoic acid; O3FA group); and 31 were randomly assigned to receive placebo (placebo group). Most (73%) patients completed 2 yr of treatment. Randomly assigned patients who were hypertensive were given enalapril 2.5 to 40 mg/d. The primary end point was time to failure, defined as estimated GFR <60% of baseline. An overall significance level of 0.10 was used. The three groups were comparable at baseline except that the O3FA group had higher urine protein to creatinine (UP/C) ratios than the placebo group (P = 0.003). Neither treatment group showed benefit over the placebo group with respect to time to failure, with 14 patient failures overall (two in the prednisone group, eight in the O3FA group, and four in the placebo group). The primary factor associated with time to failure was higher baseline UP/C ratios (P = 0.009). Superiority of prednisone or O3FA over placebo in slowing progression of renal disease was not demonstrated in this study. However, the relatively short follow-up period, inequality of baseline UP/C ratios, and small numbers of patients precludes definitive conclusions.
Ballardie FW, Roberts ISD.
Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy.
J Am Soc Nephrol. 2002 Jan;13(1):142-148. doi: 10.1681/ASN.V131142.
Abstract/Text
In a single-center, multiple-referral source study, 38 patients with progressive IgA nephropathy and controlled hypertension were randomized to treatment with prednisolone and cytotoxic agents, to therapy with low-dose cyclophosphamide then azathioprine, and to control groups. The follow-up period lasted 2 to 6 yr. Renal survival, as assessed by Kaplan-Meier analysis annually to 5 yr, showed significant preservation of function from 3 yr in the treatment group and 82, 82, 72, and 72% for 2, 3, 4, and 5 yr, respectively, compared with 68, 47, 26, and 6% in controls. Rate of loss of renal function, evaluated objectively by least-squares analyses of reciprocal serum creatinine, was reduced-and in one-third of the patients, arrested-during immunosuppressive treatment. Proteinuria, present in all patients at the time of entry into the trial, was reduced by treatment from 12 mo, compared with pretreatment levels or controls; erythrocyturia was reduced from 6 mo. Histologic activity and chronicity indexes were determined in renal biopsies performed at trial entry. Multivariate analysis demonstrated that mesangial cell proliferation and matrix scores were highest in those patients with more rapidly progressive disease. No morphologic variable or residual renal function predicted response to immunosuppressive therapy at entry. Mean arterial pressures did not differ significantly between treatment and control groups. There was thus no explanation other than treatment for the improved outcome in patients who received immunosuppressive therapy. Morbidity attributable to treatment or to renal failure occurred in both groups; an audit showed that benefits of therapy outweighed expected or minor side effects of drugs in this population at risk of end-stage renal failure. Patients selected for moderately progressive IgA nephropathy benefit from treatment with prednisolone and cytotoxic agents; results are consistent with modulation of systemic immune response or nephritic injury, thus explaining improved outcome, and indicate that this therapy has an acceptably low risk of side effects.
Pozzi C, Andrulli S, Pani A, Scaini P, Del Vecchio L, Fogazzi G, Vogt B, De Cristofaro V, Allegri L, Cirami L, Procaccini AD, Locatelli F.
Addition of azathioprine to corticosteroids does not benefit patients with IgA nephropathy.
J Am Soc Nephrol. 2010 Oct;21(10):1783-90. doi: 10.1681/ASN.2010010117. Epub 2010 Jul 15.
Abstract/Text
The optimal treatment for IgA nephropathy (IgAN) remains unknown. Some patients respond to corticosteroids, suggesting that more aggressive treatment may provide additional benefit. We performed a randomized, multicenter, controlled trial to determine whether adding azathioprine to steroids improves renal outcome. We randomly assigned 207 IgAN patients with creatinine ≤2.0 mg/dl and proteinuria ≥1.0 g/d to either (1) a 3-day pulse of methylprednisolone in months 1, 3, and 5 in addition to both oral prednisone 0.5 mg/kg every other day and azathioprine 1.5 mg/kg per day for 6 months (n = 101, group 1) or (2) steroids alone on the same schedule (n = 106, group 2). The primary outcome was renal survival (time to 50% increase in plasma creatinine from baseline); secondary outcomes were changes in proteinuria over time and safety. After a median follow-up of 4.9 years, the primary endpoint occurred in 13 patients in group 1 (12.9%, 95% CI 7.5 to 20.9%) and 12 patients in group 2 (11.3%, CI 6.5 to 18.9%) (P = 0.83). Five-year cumulative renal survival was similar between groups (88 versus 89%; P = 0.83). Multivariate Cox regression analysis revealed that female gender, systolic BP, number of antihypertensive drugs, ACE inhibitor use, and proteinuria during follow-up predicted the risk of reaching the primary endpoint. Treatment significantly decreased proteinuria from 2.00 to 1.07 g/d during follow-up (P < 0.001) on average, with no difference between groups. Treatment-related adverse events were more frequent among those receiving azathioprine. In summary, adding low-dose azathioprine to corticosteroids for 6 months does not provide additional benefit to patients with IgAN and may increase the risk for adverse events.
Maes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, Van Damme B, Vanrenterghem YF.
Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study.
Kidney Int. 2004 May;65(5):1842-9. doi: 10.1111/j.1523-1755.2004.00588.x.
Abstract/Text
BACKGROUND: Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF).
METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis.
RESULTS: Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d.
CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.
Tang S, Leung JC, Chan LY, Lui YH, Tang CS, Kan CH, Ho YW, Lai KN.
Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy.
Kidney Int. 2005 Aug;68(2):802-12. doi: 10.1111/j.1523-1755.2005.00460.x.
Abstract/Text
BACKGROUND: Mycophenolate mofetil (MMF) is increasingly used to treat primary glomerulopathies. Its effectiveness in IgA nephropathy (IgAN) remains unclear.
METHODS: Forty IgAN patients with persistent proteinuria (>1 g/24 hours) despite conventional treatment with blockers of the renin-angiotensin system were randomized to receive MMF for 24 weeks (group 1) or continue conventional therapy (group 2), and followed for 72 weeks. The primary end point was reduction of proteinuria by 50% or more over entry level.
RESULTS: Sixteen patients (80%) in group 1 versus six patients (30%) in group 2 reached the primary end point (P= 0.0019). Time-averaged change in proteinuria showed a significant decline in group 1, while control subjects displayed a modest rise (P= 0.003). By 72 weeks, the mean proteinuria was 62.0 +/- 7.7% (P= 0.003) and 120.5 +/- 14.1% (P= 0.351) that of the corresponding baseline value in group 1 and group 2, respectively. There was concomitant increase in serum albumin and decrease in serum IgA levels in group 1 but not group 2 patients. Baseline histologic grades, blood pressure control, and the rates of change in serum creatinine and creatinine clearance were not different between the two groups. Normalization in binding of polymeric IgA to cultured mesangial cells and serum interleukin-6 (IL-6) levels, which sustained to study end, was observed in group 1 but not group 2 subjects.
CONCLUSION: In selected patients with IgAN, MMF is effective in lowering proteinuria and ameliorating some of the putative pathogenetic abnormalities.
Frisch G, Lin J, Rosenstock J, Markowitz G, D'Agati V, Radhakrishnan J, Preddie D, Crew J, Valeri A, Appel G.
Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial.
Nephrol Dial Transplant. 2005 Oct;20(10):2139-45. doi: 10.1093/ndt/gfh974. Epub 2005 Jul 19.
Abstract/Text
BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Up to 40% progress to end-stage renal disease (ESRD) over 10-20 years. Currently, treatment is limited. We studied the use of mycophenolate mofetil (MMF) vs placebo in a group of North American IgAN patients at high risk for progressive disease.
METHODS: Included were 32 patients aged 18-75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors: (i) male sex; (ii) hypertension >150/90 mmHg or requiring antihypertensive medications; (iii) creatinine clearance, measured by 24 h urine collection, <80 and >20 ml/min at time of enrolment; and (iv) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy. Patients were randomized to either 1 year of MMF, titrated up to a dose of 1000 mg bid, or placebo. Total follow-up was 2 years. All patients received angiotensin inhibition medication. The primary outcome was a 50% increase in baseline serum creatinine (SCr). Secondary outcomes were an increase of 0.5 mg/dl SCr, ESRD and a 50% reduction in proteinuria.
RESULTS: The mean baseline SCr was 2.4 mg/dl. No statistically significant differences were observed for any outcome. Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50% increase in SCr (P = 0.4). In both groups, all patients who reached the primary outcome also reached ESRD. Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr (P = 0.7) Only three MMF and two placebo patients had a 50% reduction in 24 h proteinuria. No serious adverse events occurred in either group.
CONCLUSION: No benefit was seen in patients who received MMF in this high risk group, probably reflecting the relatively advanced stage of disease of our population. We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency.
Roccatello D, Ferro M, Coppo R, Giraudo G, Quattrocchio G, Piccoli G.
Report on intensive treatment of extracapillary glomerulonephritis with focus on crescentic IgA nephropathy.
Nephrol Dial Transplant. 1995 Nov;10(11):2054-9.
Abstract/Text
UNLABELLED: PURPOSE AND DESIGN OF STUDY: In this retrospective analysis the effects of combined treatment with steroid pulses, cyclophosphamide and plasma exchange on six crescentic IgA glomerulonephritis (IgAGN) patients, selected on a histological basis, were examined. The histological criteria included involvement of more than 40% of glomeruli by cellular crescents. The effects of this treatment were compared to those observed in three untreated crescentic IgAGN patients and 12 treated patients who had extracapillary glomerulonephritis of different origins, i.e. ANCA-associated systemic or renal-limited vasculitis. All patients, except the three crescentic untreated IgAGN patients, received the same 2-month treatment according to a standardized protocol: steroid boli 15 mg/kg methylprednisolone for 3 consecutive days by intravenous infusion, followed by prednisone per os (1 mg/kg/day for 4 weeks, 0.75 mg/kg/day for 4 more weeks), cyclophosphamide per os 2.5 mg/kg/day for 8 weeks, and plasma exchange.
RESULTS: After this 2-month course of therapy, substantial clinical improvement was observed in both IgAGN and vasculitis patients. However, a second biopsy revealed that florid crescents persisted in IgAGN patients and, unlike the vasculitis group, during the long-term the initial clinical amelioration disappeared in one-half of the treated IgAGN cases. Nevertheless, even in the progressive cases, intensive treatment seemed to substantially delay the onset of dialysis.
CONCLUSIONS: Despite some clinical benefits of therapy, short-term reversal of active crescents appears less likely to occur in crescentic IgAGN than in vasculitis-associated crescentic GN. Intensive treatment seems sufficient to arrest, but inadequate to reverse, phlogistic lesions in IgAGN before development of chronic changes.
McIntyre CW, Fluck RJ, Lambie SH.
Steroid and cyclophosphamide therapy for IgA nephropathy associated with crescenteric change: an effective treatment.
Clin Nephrol. 2001 Sep;56(3):193-8.
Abstract/Text
BACKGROUND: IgA nephropathy is the most common form of idiopathic glomerulonephritis. There is no current consensus on treatment for this condition. We report on the effect of immunosuppression with corticosteroids and cyclophosphamide for the treatment of IgA nephropathy associated with crescenteric change.
METHODS: The effect of oral prednisolone (0.8 mg/kg initially, reducing to 0.4 mg/kg after 4 weeks) and cyclophosphamide (1.5 mg/kg) given until a plateau of response was obtained was studied in 9 patients with IgA nephropathy associated with severe inflammatory change and crescents. The initial diagnostic renal biopsies of these patients revealed 25-70% of the glomeruli effected with active cellular crescents. When response to therapy, plateaued cyclophosphamide was discontinued and prednisolone reduced from 0.4 mg/kg. Follow-up renal biopsy was performed in 8 of the 9 patients. Patients were maintained on prednisolone (5- 7.5 mg) and azathioprine (1 mg/kg) for further 2 years.
RESULTS: The mean time until discontinuation of cyclophosphamide was 17.8 weeks (+/-1.23, range 12-25 weeks). There were no serious complications of therapy. There was an improvement in renal function in all patients with serum creatinine falling from a mean of 149.6+/-16.5, range 81-227 micromol/l to 116.4+/-8.6, range 80-158 micromol/l, p=0.01. Creatinine clearance improved from a mean of 57.1+/-9.9, range 21-104 ml/min to 87.2+/-10.1, range 39-125 ml/min, p=0.004. 24-hour urinary total protein fell over the same time m period from a mean of 4.54+/-1.1, range 1.0-11.27 g to 1.2+/-0.27, range 0.01-2.65 g, p=0.004. There were no significant differences in blood pressure during this time. Repeat renal biopsies showed significant degrees of histological improvement with healing of crescents and a reduction in acute inflammatory change in all except one patient. The mean period of follow-up after cessation of cyclophosphamide was 17.4+/-2.8 months, range 10-36 months. There was no significant change over this period in serum creatinine, creatinine clearance or urinary protein losses.
CONCLUSION: These data suggest that IgA nephropathy associated with severe inflammatory and crescenteric change can be effectively and safely treated with a low-cost regime based on oral corticosteroids and cyclophosphamide tailored to a plateau of treatment response in individual patients.
Tumlin JA, Lohavichan V, Hennigar R.
Crescentic, proliferative IgA nephropathy: clinical and histological response to methylprednisolone and intravenous cyclophosphamide.
Nephrol Dial Transplant. 2003 Jul;18(7):1321-9. doi: 10.1093/ndt/gfg081.
Abstract/Text
BACKGROUND: IgA nephropathy is an immune-complex glomerulopathy that can result in capillary or extra-capillary proliferation. Previous attempts to correlate specific histological findings including cellular crescents or endocapillary proliferation, with clinical outcomes, have produced conflicting results.
METHODS: We conducted a prospective open-labelled trial of 12 patients with crescentic, proliferative IgA nephropathy and clinically progressive disease and treated them with pulse steroids and intravenous cyclophosphamide. Therapy included pulse solumedrol at 15 mg/kg/day for 3 days, followed by monthly intravenous cyclophosphamide at 0.5 g/m(2) body surface area for 6 months. Clinically significant proteinuria (>1.0 g/24 h) was present in all patients, while nephrotic-range proteinuria (>3.0 g/24 h) was observed in eight of 12 patients. All patients were hypertensive (BP >140/90 mmHg).
RESULTS: After 6 months of treatment, the mean serum creatinine was reduced from a maximum of 2.65+/-0.39 to 1.51+/-0.10 mg/dl (P<0.03), while proteinuria was reduced from 4.04 to 1.35 g/24 h (P<0.01). The mean slope of 1/serum creatinine increased from -0.0398+/-0.02 to 0.0076+/-0.01 after 6 months of therapy, but this trend did not reach statistical significance (P<0.08). A repeat kidney biopsy was performed in all treated patients. Endocapillary proliferation, cellular crescents and karyorrhexis were eliminated in all 12 patients after 6 months of therapy, while interstitial fibrosis and tubule dropout remained unchanged. To determine the long-term efficacy of the treatment, treated patients were compared to 12 historical controls matched for severity of IgA on initial biopsy. After 36 months, the rate of end-stage renal disease in the treated group was lower (1/12) than in the historical controls (5/12).
CONCLUSIONS: We conclude that steroids and intravenous cyclophosphamide reduce proliferative lesions, reduce proteinuria and stabilize renal function in patients with crescentic IgA nephropathy.
Kawamura T, Yoshimura M, Miyazaki Y, Okamoto H, Kimura K, Hirano K, Matsushima M, Utsunomiya Y, Ogura M, Yokoo T, Okonogi H, Ishii T, Hamaguchi A, Ueda H, Furusu A, Horikoshi S, Suzuki Y, Shibata T, Yasuda T, Shirai S, Imasawa T, Kanozawa K, Wada A, Yamaji I, Miura N, Imai H, Kasai K, Soma J, Fujimoto S, Matsuo S, Tomino Y; Special IgA Nephropathy Study Group.
A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy.
Nephrol Dial Transplant. 2014 Aug;29(8):1546-53. doi: 10.1093/ndt/gfu020. Epub 2014 Mar 3.
Abstract/Text
BACKGROUND: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN).
METHODS: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria.
RESULTS: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission.
CONCLUSIONS: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.
Hirano K, Matsuzaki K, Yasuda T, Nishikawa M, Yasuda Y, Koike K, Maruyama S, Yokoo T, Matsuo S, Kawamura T, Suzuki Y.
Association Between Tonsillectomy and Outcomes in Patients With Immunoglobulin A Nephropathy.
JAMA Netw Open. 2019 May 3;2(5):e194772. doi: 10.1001/jamanetworkopen.2019.4772. Epub 2019 May 3.
Abstract/Text
IMPORTANCE: Immunoglobulin A nephropathy is a major cause of end-stage renal disease worldwide; previous methods of medical management, including use of renin-angiotensin system inhibitors and corticosteroids, remain unproven in clinical trials.
OBJECTIVE: To investigate the possible association between tonsillectomy and outcomes in patients with IgA nephropathy.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 1065 patients with IgA nephropathy enrolled between 2002 and 2004 and divided into 2 groups, those who underwent tonsillectomy and those who did not. Initial treatments (renin-angiotensin system inhibitors or corticosteroids) within 1 year after renal biopsy were also evaluated. A 1:1 propensity score matching was performed to account for between-group differences and 153 matched pairs were obtained. Follow-up concluded January 31, 2014. Analysis was conducted between September 11, 2017, and July 31, 2018.
EXPOSURE: Tonsillectomy.
MAIN OUTCOMES AND MEASURES: The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine level from baseline or dialysis initiation. Secondary outcomes included additional therapy with renin-angiotensin system inhibitors or corticosteroids initiated 1 year after renal biopsy and adverse events.
RESULTS: In 1065 patients (49.8% women; median [interquartile range] age, 35 [25-52] years), the mean (SD) estimated glomerular filtration rate was 76.6 (28.9) mL/min/1.73 m2 and the median (interquartile range) proteinuria was 0.68 (0.29-1.30) g per day. In all, 252 patients (23.7%) underwent tonsillectomy within 1 year after renal biopsy and 813 patients (76.3%) did not undergo tonsillectomy. The primary outcome was reached by 129 patients (12.1%) during a median (interquartile range) follow-up of 5.8 (1.9-8.5) years. In matching analysis, tonsillectomy was associated with primary outcome reduction (hazard ratio, 0.34; 95% CI, 0.13-0.77; P = .009). In subgroup analyses, benefit associated with tonsillectomy was not modified by baseline characteristic differences. Those undergoing tonsillectomy required fewer additional therapies 1 year following renal biopsy (adjusted hazard ratio, 0.37; 95% CI, 0.20-0.63; P < .001) without increased risks for adverse events, except transient tonsillectomy-related complications.
CONCLUSIONS AND RELEVANCE: This study found that tonsillectomy was associated with a lower risk of renal outcomes in patients with IgA nephropathy. The potential role of tonsillectomy should be considered for preventing end-stage renal disease in patients with IgA nephropathy.
Hotta O, Miyazaki M, Furuta T, Tomioka S, Chiba S, Horigome I, Abe K, Taguma Y.
Tonsillectomy and steroid pulse therapy significantly impact on clinical remission in patients with IgA nephropathy.
Am J Kidney Dis. 2001 Oct;38(4):736-43. doi: 10.1053/ajkd.2001.27690.
Abstract/Text
We conducted a retrospective investigation of renal outcome in 329 patients with immunoglobulin A (IgA) nephropathy with an observation period longer than 36 months (82.3 +/- 38.2 months) in our renal unit between 1977 and 1995. Clinical remission, renal progression, and the impact of covariates were estimated by Kaplan-Meier analysis and a Cox regression model. In 157 of 329 patients (48%), disappearance of urinary abnormalities (clinical remission) was obtained. None of these 157 patients showed progressive deterioration, defined as a 50% increase in serum creatinine (Scr) level from baseline, during the observation period. Conversely, in patients without clinical remission, the Kaplan-Meier estimate of probability of progressive deterioration was 21% +/- 5% at 10 years. In the multivariate Cox regression model with 13 independent covariates, initial Scr level, histological score, tonsillectomy, and high-dose methylprednisolone therapy had a significant impact on clinical remission, whereas proteinuria, age, sex, levels of hematuria, blood pressure, conventional steroid therapy, angiotensin-converting enzyme inhibitor therapy, and cyclophosphamide therapy had no significant effect. These findings indicate that interventions aimed at achieving clinical remission have provided encouraging results applicable to managing patients with IgA nephropathy.
Komatsu H, Fujimoto S, Hara S, Sato Y, Yamada K, Kitamura K.
Effect of tonsillectomy plus steroid pulse therapy on clinical remission of IgA nephropathy: a controlled study.
Clin J Am Soc Nephrol. 2008 Sep;3(5):1301-7. doi: 10.2215/CJN.00310108. Epub 2008 May 28.
Abstract/Text
BACKGROUND AND OBJECTIVES: Few well-designed investigations have examined how tonsillectomy plus steroid pulse therapy affects IgA nephropathy. A prospective, controlled study therefore was performed to compare the effects of combined therapy with those of steroid pulse alone in patients with IgA nephropathy.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-five patients were followed up for 54.0 +/- 21.2 mo. Thirty-five of them underwent tonsillectomy and steroid pulse therapy (group C), and 20 received steroid pulse monotherapy (group M). Both groups received methylprednisolone intravenously, followed by oral prednisolone (initial dosage 0.5 mg/kg per d) for 12 to 18 mo. Primary evaluation items were a 100% increase in serum creatinine from baseline levels or the disappearance of urinary protein (UP) and/or occult blood (UOB) indicating clinical remission.
RESULTS: At 24 mo after the initial treatment, the ratios of the UP and UOB disappearance were higher in group C than in group M, and the therapeutic effect persisted until the final observation. None of group C achieved a 100% increase in serum creatinine from the baseline level, whereas one patient in group M developed ESRD during the observation period. The histologic findings of repeated biopsy specimens from 18 patients revealed that mesangial proliferation and IgA deposition were significantly more reduced in group C than in group M. The Cox regression model showed that the combined therapy was approximately six-fold more effective in causing the disappearance of UP than steroid pulse monotherapy.
CONCLUSION: Tonsillectomy combined with steroid pulse treatment can induce clinical remission in patients with IgA nephropathy.
Kawaguchi T, Ieiri N, Yamazaki S, Hayashino Y, Gillespie B, Miyazaki M, Taguma Y, Fukuhara S, Hotta O.
Clinical effectiveness of steroid pulse therapy combined with tonsillectomy in patients with immunoglobulin A nephropathy presenting glomerular haematuria and minimal proteinuria.
Nephrology (Carlton). 2010 Feb;15(1):116-23. doi: 10.1111/j.1440-1797.2009.01147.x.
Abstract/Text
AIM: The effectiveness of steroid pulse therapy combined with tonsillectomy (ST) has been shown in immunoglobulin A nephropathy (IgAN) patients with moderate or severe urinary abnormalities. The present study aimed to clarify whether the effectiveness may be extrapolated to IgAN with minor urinary abnormalities, and whether the effectiveness may depend on the histological severity with minor urinary abnormalities.
METHODS: Data on 388 IgAN patients diagnosed by renal biopsies between 1987 and 2000 in Sendai Shakaihoken Hospital, who presented glomerular haematuria and minimal proteinuria (RESULTS: During a median follow up of 24 months, we observed 170 CR cases. Patients receiving ST were younger and showed a better case-mix profile. Patients with ST had a significantly higher rate of CR than patients without tonsillectomy or steroid pulse in an unadjusted (hazard ratio (HR) = 5.51, 95% confidence interval (CI) = 3.33-9.12, P < 0.001) or adjusted Cox model (HR = 4.65, 95% CI = 2.43-8.88, P < 0.001). Less severe histological findings were substantially associated with higher CR rate in ST group. Adjusting for confounding by treatment indication showed an attenuated but still significant effect of ST (HR = 3.10, 95% CI = 2.02-4.77, P < 0.001).
CONCLUSION: ST significantly increased the probability of CR in IgAN patients with glomerular haematuria and minimal proteinuria, and it was more effective in those with less severe histological findings.
Miura N, Imai H, Kikuchi S, Hayashi S, Endoh M, Kawamura T, Tomino Y, Moriwaki K, Kiyomoto H, Kohagura K, Nakazawa E, Kusano E, Mochizuki T, Nomura S, Sasaki T, Kashihara N, Soma J, Tomo T, Nakabayashi I, Yoshida M, Watanabe T.
Tonsillectomy and steroid pulse (TSP) therapy for patients with IgA nephropathy: a nationwide survey of TSP therapy in Japan and an analysis of the predictive factors for resistance to TSP therapy.
Clin Exp Nephrol. 2009 Oct;13(5):460-466. doi: 10.1007/s10157-009-0179-1. Epub 2009 May 19.
Abstract/Text
BACKGROUND: Tonsillectomy and steroid pulse (TSP) therapy was proposed as a curative treatment for IgA nephropathy by Hotta et al. (Am J Kidney Dis 38:736-742, 2001) based on data that about 50% of patients achieved clinical remission (CR) of urinary abnormalities.
MATERIALS AND METHODS: As a primary survey, we sent a questionnaire and letter to 848 hospitals in Japan, each of which employed a Fellow of the Japanese Society of Nephrology between October and December of 2006, in order to gather information about the prevalence and efficacy of TSP therapy for patients with IgA nephropathy. As a secondary survey, we collected data from both low- and high-CR-rate groups to determine which factors predicted resistance to TSP therapy.
RESULTS: A total of 2,746 patients received TSP therapy between 2000 and 2006. The CR rates, calculated by measuring urinary criteria 6 and 12 months after TSP therapy, were 32.0% (347/1,085) and 45.6% (452/991), respectively. Analysis of the 30 hospitals in which TSP therapy had been performed on at least ten patients revealed that the CR rates varied from below 10% to 100%. A secondary survey of ten hospitals revealed that, after correction of the CR rate from each hospital, patients could be categorized into three groups: those with a low CR rate (122 patients in four hospitals), a middle CR rate (78 patients in four hospitals), and a high CR rate (103 patients in two hospitals). The CR rate of all patients (N = 303) was 54.1%. A comparison of patient data between the low- and high-CR-rate groups showed a significant difference in age at onset (years; P = 0.05), amount of proteinuria (g/day; P = 0.02), total protein (g/dl; P = 0.02), pathological grade (P = 0.009), and prognostic score as described by Wakai et al. [Nephrol Dial Transplant 21:2800-2808, 2006, (P = 0.04)]. Univariate analysis revealed that there was a significant difference between non-CR and CR subgroups in duration from diagnosis until TSP therapy (6.9 +/- 6.8 versus 5.3 +/- 5.2 years; P = 0.02), amount of proteinuria (1.5 +/- 1.6 versus 0.8 +/- 0.8 g/day; P < 0.0001), serum creatinine (0.99 +/- 0.40 versus 0.87 +/- 0.34 mg/dl; P = 0.006), pathological grade (P = 0.0006), and Wakai et al.'s prognostic score (37.4 +/- 17.8 versus 28.1 +/- 15.1; P < 0.0001). A multivariate logistic analysis demonstrated that resistance to TSP therapy depends on age at onset, amount of proteinuria, hematuria grade, and pathological grade, and a score predicting resistance to TSP therapy could be derived by the formula: [(-0.0330) x (age) + (0.4772) x log (amount of proteinuria) - (0.0273) x (hematuria grade: 0, 1, 2, and 3) + (0.7604) x (pathological grade: 1, 2, 3, and 4) - 0.1894]. A receiver operating characteristic (ROC) curve showed that patients with a resistance score of greater than -0.02 easily resist TSP therapy (sensitivity 69%, specificity 75%, positive likelihood ratio 2.76).
CONCLUSION: TSP therapy shows promise as a treatment that can bring about CR of urinary abnormalities, but unfortunately the average CR rate is about 50% at 1 year after treatment. Predictive factors for resistance to TSP therapy are age at onset, amount of proteinuria, hematuria grade, and pathological grade. The present study suggests that patients with either early-stage or mild to moderate IgA nephropathy easily achieve CR following TSP therapy, whereas patients with late-stage or severe disease are prone to TSP therapy resistance.
Chen Y, Tang Z, Wang Q, Yu Y, Zeng C, Chen H, Liu ZH, Li LS.
Long-term efficacy of tonsillectomy in Chinese patients with IgA nephropathy.
Am J Nephrol. 2007;27(2):170-5. doi: 10.1159/000100431. Epub 2007 Mar 1.
Abstract/Text
BACKGROUND: To investigate the clinical efficacy of tonsillectomy on long-term clinical remission and renal survival of immunoglobulin A nephropathy (IgAN) patients in China.
METHODS: We performed a 130-month retrospective case-control study of 112 patients with idiopathic biopsy-diagnosed IgAN from 1983 to 1999. Fifty-four patients underwent tonsillectomy and 58 patients did not. The clinical remission rate during follow-up and variables to predict clinical remission were estimated by chi2 test and multivariate Cox regression analysis; renal survival was evaluated by Kaplan-Meier analysis.
RESULTS: Up to 2006, the follow-up period lasted 130 +/- 50.3 months (60-276 months). The clinical remission rate was 46.3% in patients with tonsillectomy and 27.6% in those without tonsillectomy during follow-up. Multivariate analysis demonstrated that tonsillectomy was not an independent impact factor for renal clinical remission (p = 0.386). By Kaplan-Meier analysis, there was no significant difference in renal survival rate between patients with tonsillectomy and those without tonsillectomy (p = 0.059).
CONCLUSION: The clinical remission rate in IgAN patients with tonsillectomy was higher than that in patients without tonsillectomy during follow-up. But within 130 months, it was difficult to find statistical difference in renal survival between IgAN patients with and without tonsillectomy.
Copyright 2007 S. Karger AG, Basel.
Xie Y, Nishi S, Ueno M, Imai N, Sakatsume M, Narita I, Suzuki Y, Akazawa K, Shimada H, Arakawa M, Gejyo F.
The efficacy of tonsillectomy on long-term renal survival in patients with IgA nephropathy.
Kidney Int. 2003 May;63(5):1861-7. doi: 10.1046/j.1523-1755.2003.00935.x.
Abstract/Text
BACKGROUND: Little information has been available until now about the clinical efficacy of tonsillectomy on long-term renal survival of patients with idiopathic immunoglobulin A nephropathy (IgAN).
METHODS: To investigate the effect of tonsillectomy on long-term renal survival, we reviewed the clinical course of 118 patients with idiopathic biopsy-diagnosed IgAN from 1973 to 1980. Of those, 48 patients received tonsillectomy and 70 patients did not. The starting point of observation was defined as the time of the diagnostic renal biopsy, and the end point as when requiring the first dialysis. Up to 2001, the mean observation time was 192.9 +/- 74.8 months (48-326 months). Renal survival and impact of covariates were evaluated by Kaplan-Meier analysis and Cox proportional hazards regression model.
RESULTS: Age, gender, amount of urinary protein excretion, serum creatinine, serum IgA, blood pressure, and histopathologic findings at the time of renal biopsy and treatments during the observation period were not significantly different between patients with and without tonsillectomy. Five (10.4%) of the patients with tonsillectomy and 18 (25.7%) of the patients without tonsillectomy finally required dialysis therapy (chi-square test, P = 0.0393). By Kaplan-Meier analysis, renal survival rates were 89.6% and 63.7% at 240 months in the patients with and without tonsillectomy, respectively, and were significantly different (log-rank test, P = 0.0329). In the multivariate Cox regression model, tonsillectomy (hazard ratio, 0.22; 95% CI, 0.06 to 0.76; P = 0.0164) had a significant effect on renal outcome.
CONCLUSION: These results indicate that tonsillectomy has a favorable effect on long-term renal survival in patients with IgAN.
Rasche FM, Schwarz A, Keller F.
Tonsillectomy does not prevent a progressive course in IgA nephropathy.
Clin Nephrol. 1999 Mar;51(3):147-52.
Abstract/Text
BACKGROUND: IgA nephropathy, or Berger's disease, is a primary mesangioproliferative glomerulonephritis, usually with a favourable prognosis.
PATIENTS AND METHODS: To investigate the effect of tonsillectomy we conducted a retrospective investigation on renal outcome in 55 patients with IgA nephropathy in an outpatient university clinic between 1968 and 1994. Established risk factors for progressive IgA nephropathy were equally distributed in 16 patients subjected to tonsillectomy and in 39 patients without tonsillectomy. Renal survival and impact of risk factors were estimated by Kaplan-Meier analysis and Cox regression model.
RESULTS: Seen in terms of the bivariate Kaplan-Meier analysis the probability of renal survival 10 years after biopsy was 0.37 for the 16 patients with tonsillectomy and 0.63 for the 39 patients without tonsillectomy (log-rank test p = 0.49, not significant). In the multivariate Cox regression model with 6 independent clinical covariates, initially high serum creatinine concentration had the strongest impact on renal outcome (p = 0.002), with a hazard ratio of 8.9 (95% CI: 2.3-35.0). Tonsillectomy had no significant influence in the Cox model (p = 0.37), displaying a hazard ratio of 1.7 (95% CI: 0.5-5.7).
CONCLUSION: In conclusion, tonsillectomy does not reduce the risk of developing renal failure or prevent a progressive course of IgA nephropathy.
Bennett WM, Kincaid-Smith P.
Macroscopic hematuria in mesangial IgA nephropathy: correlation with glomerular crescents and renal dysfunction.
Kidney Int. 1983 Feb;23(2):393-400. doi: 10.1038/ki.1983.32.
Abstract/Text
One hundred and eighty-six renal biopsy specimens from 79 adult patients with mesangial IgA nephropathy were examined and correlated with clinical data at the time of biopsy. Forty patients (group 1) with a history of macroscopic hematuria were compared with 39 patients (group 2) without such a history. Group 1 patients had a higher serum creatinine, 240 +/- 20 mumoles/liter vs. 140 +/- 10 mumoles/liter (P less than 0.01), lower creatinine clearance 69 +/- 36 ml/min vs. 87 +/- 30 ml/min (P less than 0.05), and a higher percentage of patients presenting with serum creatinine greater than 300 mumoles/liter, 22.5% vs. 5.1% (P less than 0.05). Fourteen biopsies were performed in 11 patients during an episode of macroscopic hematuria (group 1A). One hundred percent of these biopsy specimens showed crescents. Ninety-one percent of 11 biopsy specimens from ten patients (group 1B), taken 3 to 27 days following an episode but at a time when urinary red cells were less than 1,000,000/ml, also showed crescent formation. Of 14 biopsy specimens from 13 patients without macroscopic hematuria, but with greater than 1,000,000 red cells/ml in the urine just prior to biopsy (group 2A), 79% had crescents. In conclusion, macroscopic hematuria in adult patients with mesangial IgA nephropathy is associated with a high likelihood of crescents on renal biopsy specimens and worse renal function. Careful quantitative assessment of the urine for renal bleeding may help to better define the activity of disease in these patients.
Praga M, Gutierrez-Millet V, Navas JJ, Ruilope LM, Morales JM, Alcazar JM, Bello I, Rodicio JL.
Acute worsening of renal function during episodes of macroscopic hematuria in IgA nephropathy.
Kidney Int. 1985 Jul;28(1):69-74. doi: 10.1038/ki.1985.120.
Abstract/Text
The appearance of renal failure during episodes of macroscopic hematuria (EMH) in IgA nephropathy (IgAN) has been described as very unusual. The results of a prospective investigation on the effect of EMH on renal function in IgAN are presented. During a 3-year period, 29 episodes of EMH occurring in 21 patients with IgAN have been studied. A derangement of renal function (increase of serum creatinine by more than 0.5 mg/dl) was observed in 11 episodes (37.9%) with peak creatinine values ranging from 1.2 to 6.7 mg/dl. The worsening of renal function was accompanied by a longer duration of EMH (4.8 +/- 1.3 vs. 3.5 +/- 1.5 days; P less than 0.05) but not by arterial hypertension or edema. A complete recovery of renal function was observed in every patient 1 to 2 months after the start of EMH. The histological survey disclosed that the decrease of renal function correlated closely with the presence of red blood cell casts in as much as 50% of the tubular lumen and with findings of tubular necrosis. We conclude that a worsening of renal function can be observed frequently during the EMH. Tubular damage and obstruction by red blood cell casts may play a significant role in the pathogenesis of this complication.
Delclaux C, Jacquot C, Callard P, Kleinknecht D.
Acute reversible renal failure with macroscopic haematuria in IgA nephropathy.
Nephrol Dial Transplant. 1993;8(3):195-9.
Abstract/Text
Macroscopic haematuria is common in IgA nephropathy, but its significance and influence on prognosis remains uncertain. We compared the clinical and pathological features of 11 adult patients with primary IgA nephropathy who had had a renal biopsy during or shortly after a bleeding episode. Six patients developed transient acute renal failure (ARF) (group 1) and five did not (group 2). Patients of group 1 had a higher percentage of tubular red-blood-cell (RBC) casts (P < 0.05) and of glomerular crescents (P < 0.001). However, crescents were focal and involved less than 50% of glomeruli. Acute tubular necrosis was only present in patients of group 1, and ARF was attributed to the acute tubular changes rather than to the glomerular lesions. Despite a prolonged duration of ARF (mean: 38 days), further outcome did not differ in patients of both groups. We suggest that acute tubular damage and/or tubular obstruction by RBC casts should be considered in any patient who develops ARF soon after a haematuric episode.
Kveder R, Lindic J, Ales A, Kovac D, Vizjak A, Ferluga D.
Acute kidney injury in immunoglobulin A nephropathy: potential role of macroscopic hematuria and acute tubulointerstitial injury.
Ther Apher Dial. 2009 Aug;13(4):273-7. doi: 10.1111/j.1744-9987.2009.00723.x.
Abstract/Text
The aim of our retrospective study was to analyze the clinical course and outcome of patients with immunoglobulin A (IgA) nephropathy who presented with macroscopic hematuria and acute kidney injury (AKI). During the period from 1990 to 2005, seven out of 584 adult patients with IgA nephropathy (1.2%) fulfilled the criteria for macroscopic hematuria-induced AKI. There was an equal gender distribution among our patients, and a rather high average age at presentation (55.7 +/- 10.9 years). Four patients who were oliguric upon admission to hospital needed hemodialysis treatment. The average serum creatinine at the time of kidney biopsy was 429.8 +/- 377 micromol/L (median value 378). The percutaneous kidney needle biopsies showed focal proliferative crescentic glomerulonephritis of subclass III, according to the Haas scheme, associated with prominent red blood cell tubular casts and acute tubulointerstitial nephritis. Four patients with the most prominent crescents and tubulointerstitial involvement were treated with methylprednisolone. All patients, treated and untreated, recovered their kidney function (the serum creatinine at a median follow-up of 15 months was 111.7 +/- 38 micromol/L). In conclusion, AKI in IgA nephropathy accompanied by macroscopic hematuria appears to have been a reversible condition in our series of patients. Regarding pathogenesis, the kidney biopsy study points to the important role of glomerular bleeding with consequent, widespread obstructive red blood cell tubular casts accompanied by tubular injury and interstitial nephritis.
Gutiérrez E, González E, Hernández E, Morales E, Martínez MA, Usera G, Praga M.
Factors that determine an incomplete recovery of renal function in macrohematuria-induced acute renal failure of IgA nephropathy.
Clin J Am Soc Nephrol. 2007 Jan;2(1):51-7. doi: 10.2215/CJN.02670706. Epub 2006 Nov 29.
Abstract/Text
Acute renal failure that is associated with macroscopic hematuria (ARF-MH) is a widely known complication of IgA nephropathy (IgAN). Although spontaneous recovery of renal function after cessation of MH has been described, no long-term outcome studies have been performed. The outcome of patients who had biopsy-proven IgAN and presented an ARF-MH episode in the period 1975 through 2005 was studied. Thirty-six episodes of ARF-MH that occurred in 32 patients were identified. A complete recovery of baseline renal function after cessation of MH was observed in 27 (group 1); in the remaining nine episodes (25%; group 2), estimated GFR (eGFR) did not reach the baseline value. Final eGFR was 89 +/- 28 ml/min per 1.73 m(2) in group 1 patients and 38 +/- 12 ml/min per 1.73 m(2) in group 2 patients (P = 0.0005). The duration of MH was significantly longer in group 2 patients: 33.7 +/- 25.3 versus 15.4 +/- 18.4 d (P = 0008). A high proportion of tubules that were filled by red blood cell casts and had signs of acute tubular necrosis were the most striking histologic abnormalities. In conclusion, a significant proportion (25%) of ARF-MH in IgAN did not recover the baseline renal function after the disappearance of MH. Duration of MH longer than 10 d, age >50 yr, decreased baseline eGFR, absence of previous episodes of MH, and the severity of tubular necrosis were significant risk factors for an incomplete recovery of renal function.
Tang Z, Wu Y, Wang QW, Yu YS, Hu WX, Yao XD, Chen HP, Liu ZH, Li LS.
Idiopathic IgA nephropathy with diffuse crescent formation.
Am J Nephrol. 2002 Sep-Dec;22(5-6):480-6. doi: 10.1159/000065281.
Abstract/Text
OBJECTIVE: To investigate the clinicopathological features and outcome of idiopathic IgA nephropathy with diffuse crescent formation in Chinese patients.
METHODS: Twenty-five patients with diffuse crescentic IgA nephropathy (DCIgAN), 15 males and 10 females with median age of 28.5, and median disease duration of 5.1 months, were studied. Their clinical, laboratory and pathological features and outcome were investigated. Twenty-one were administered pulse immunosuppressive therapy, and 15 were followed up for more than 6 months.
RESULTS: 1.14% had total IgA nephropathy, and 16.4% total diffuse crescentic glomerulonephritis. Clinically, most of patients (88%) showed rapidly progressive glomerulonephritis associated with a high level of serum creatinine (418 +/- 264 micromol/l). Gross hematuria was noted in 72%, hypertension in 64%, and nephrotic syndrome in 48%. Pathologically, except for diffuse crescent formation (a median 65% and range 50-95%), we observed segmental necrosis of glomerular capillaries in 60%, glomerular infiltrating cells in 48%, endothelial cells proliferation in 32%, and rupture of Bowmans' capsule in 24%. Severe tubular interstitial damage was also found, tubular atrophy in 64%, interstitial fibrosis in 60%, diffuse interstitial infiltrating cells in 74%, and interstitial vasculitis in 40%. Immunopathologically, four phenotypes were observed; however, IgA associated with IgM deposition was higher than that in patients with general IgA nephropathy (IgAN). In addition, the infiltrating CD4+, CD8+, CD68+ and PCNA+ cells in renal tissue were significantly high compared with that in controls. In a follow-up study, 66.7% of patients had life-sustaining renal function, 4 of them had normal range of serum creatinine (<124 micromol/l), and only 5 were dialysis-dependent.
CONCLUSIONS: The patients with crescentic IgA nephropathy mostly show rapidly progressive nephritis associated with more severe pathological changes including glomerular, tubular interstitial and vascular lesions than in patients with general IgAN. The infiltrates in glomeruli may contribute to the crescentic formation, and the intensive immune suppressing treatment is useful to improve renal damage in patients with DCIgAN.
Copyright 2002 S. Karger AG, Basel
Abuelo JG, Esparza AR, Matarese RA, Endreny RG, Carvalho JS, Allegra SR.
Crescentic IgA nephropathy.
Medicine (Baltimore). 1984 Nov;63(6):396-406. doi: 10.1097/00005792-198411000-00005.
Abstract/Text
We report five cases of crescentic IgA nephropathy. All are males, 16-60 years of age. One case each came to medical attention with uremia, nephrotic syndrome, and gross hematuria; two cases presented with microhematuria and proteinuria on routine urinalysis. All had hypertension, azotemia (serum creatinine 1.6-9.4 mg/dl), proteinuria (greater than 6 g/24 hr in four cases), hypoalbuminemia (less than 3 g/dl), and hematuria (gross in two cases). All progressed to end-stage renal failure renal failure ending in dialysis (three cases) or death from unrelated causes (two cases). Prednisone, 60 mg/day for 1 month in two patients (with two 1-g doses of iv methylprednisolone in 1 case) did not improve the serum creatinine level, but one patient subsequently experienced a less rapid fall in renal function. A crescentic glomerulonephritis was present in all biopsies (crescents in 31-80% of glomeruli; mean, 50%). The size and stage of the crescents were variable. Numerous glomeruli had focal or diffuse sclerosis. In all cases, there was a 3 or 4+ deposition of IgA. Low-intensity staining for IgG and IgM was noted in four and three patients, respectively. On electron microscopy, dense granular mesangial deposits were noted in all cases and in four patients capillary subepithelial deposits were also observed. This form of IgA nephropathy is not common, but some studies indicate that it may occur in about 5% of patients with IgA nephropathy.
Chambers ME, McDonald BR, Hall FW, Rabetoy GM.
Plasmapheresis for crescentic IgA nephropathy: a report of two cases and review of the literature.
J Clin Apher. 1999;14(4):185-7. doi: 10.1002/(sici)1098-1101(1999)14:4<185::aid-jca6>3.0.co;2-k.
Abstract/Text
Idiopathic IgA nephropathy is widely regarded as a slowly progressive disease that not infrequently results in end-stage renal failure. Only a minority of patients present with either a rapidly progressive form of glomerulonephritis, or with end-stage renal failure. Anecdotal reports of improved renal function after treatment with plasmapheresis have been published, but the efficacy of this therapy remains controversial. We describe the course of two young males presenting with uremia, hypertension, nephrotic-range proteinuria, and crescentic glomerulonephritis on renal biopsy. Both patients underwent therapy with steroids, immunosuppressive agents, and plasmapheresis without an appreciable improvement in renal function. A review of the literature does not offer any conclusive data to support the role of plasmapheresis in the treatment of rapidly progressive glomerulonephritis due to IgA nephropathy and points out the need to define criteria that may identify subsets of patients with this disorder who may potentially benefit from plasma exchange therapy. J. Clin. Apheresis 14:185-187, 1999. Published 1999 Wiley-Liss, Inc.
Bazzi C, Rizza V, Raimondi S, Casellato D, Napodano P, D'Amico G.
In crescentic IgA nephropathy, fractional excretion of IgG in combination with nephron loss is the best predictor of progression and responsiveness to immunosuppression.
Clin J Am Soc Nephrol. 2009 May;4(5):929-35. doi: 10.2215/CJN.05711108. Epub 2009 Apr 30.
Abstract/Text
BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the relationship between proteinuric markers (urinary excretion of IgG, alpha2-macroglobulin, alpha1-microglobulin) and serum creatinine (sCr), histologic lesions, progression, and immunosuppression responsiveness in crescentic IgA nephropathy.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fractional excretion of IgG (FEIgG) and of alpha1-microglobulin and urinary excretion of alpha2-macroglobulin were evaluated in 37 patients, 23 treated with steroids and cyclophosphamide. For assessment of the effective tubular load of proteins in surviving nephrons, new markers that take into account not only the absolute excretion value but also nephron loss were obtained dividing proteinuric markers for percentage of nonobsolescent glomeruli (surviving glomeruli [SG]). For each parameter, low- and high-risk groups were defined according to cutoffs with the highest sensitivity and specificity for progression (ESRD/doubling sCr) assessed by receiver operating characteristic analysis; follow up was 60 +/- 40 mo.
RESULTS: FEIgG/SG is the most powerful progression predictor: 5 versus 83% in all patients; in treated patients, 0 versus 89%, increased to 0 versus 100% by sCr and FEIgG/SG in combination (low risk: both markers or only one below cutoff (n = 15); high risk: both markers above cutoff (n = 8). The nonprogressors showed at last observation 65% proteinuria reduction and 10% sCr reduction.
CONCLUSIONS: In crescentic IgA nephropathy, FEIgG/SG, which evaluates altered size selectivity in relation to nephron loss, is the best progression predictor. In treated patients, progression prediction was increased by FEIgG/SG and sCr in combination. Treatment may be restricted to low-risk patients.
Lai KN, Lai FM, Leung AC, Ho CP, Vallance-Owen J.
Plasma exchange in patients with rapidly progressive idiopathic IgA nephropathy: a report of two cases and review of literature.
Am J Kidney Dis. 1987 Jul;10(1):66-70. doi: 10.1016/s0272-6386(87)80014-8.
Abstract/Text
Primary IgA nephropathy is generally considered an indolent disease, but progression to chronic renal failure is not uncommon, and a rapidly progressive course is observed in some cases, especially when extensive fibrocellular crescents are present. The therapeutic benefit of immunosuppression and plasma exchange remains controversial. We described two patients with primary IgA nephropathy and rapidly progressive renal failure. Both patients showed extensive glomerulosclerosis and crescent formation in their renal biopsies. Corticosteroid and immunosuppressive therapy failed to control the progression of the disease, and plasma exchanges were performed. In both cases, the serum creatinine and creatinine clearance initially improved with plasma exchange and the rapid progression of renal failure was apparently halted. In one patient, the serum creatinine rose when treatment was discontinued and fell again when plasma exchange was recommenced. Nevertheless, the long-term benefit of plasma exchange in crescentic IgA nephropathy was unsatisfactory as the renal function continued to deteriorate in the following 12 months despite an initial stabilization.
Welch TR, McAdams AJ, Berry A.
Rapidly progressive IgA nephropathy.
Am J Dis Child. 1988 Jul;142(7):789-93. doi: 10.1001/archpedi.1988.02150070103038.
Abstract/Text
Five children had rapidly progressive glomerulonephritis, determined by biopsy specimen and terminating in end-stage renal disease. All had mesangial deposition of IgA and C3 in the pattern typically seen with IgA nephropathy (Berger's disease). These children ranged in age from 7 to 13 years; four were boys. Severe hypertension was present in all, and three had a nephrotic syndrome. Other than hypertension and findings related to renal insufficiency or nephrotic syndrome, no clinical or laboratory finding was a consistent marker distinguishing these patients from those with uncomplicated IgA nephropathy, and no therapy proved useful in halting the rapid decline in renal function. The disease has not recurred in the kidney transplant of any of the five children.
Harper L, Ferreira MA, Howie AJ, Savage CO, Richards NT, Michael J, Adu D.
Treatment of vasculitic IgA nephropathy.
J Nephrol. 2000 Sep-Oct;13(5):360-6.
Abstract/Text
BACKGROUND: Patients with IgA nephropathy and histological vasculitic/crescentic lesions have a poor prognosis. We performed a retrospective study to assess whether treatment with steroids and immunosuppressants would preserve renal function by healing these lesions and thereby prevent progression to glomerular sclerosis and renal failure.
METHODS: Sixteen patients with IgA nephropathy and a vasculitic/crescentic glomerulonephritis diagnosed by renal histology were treated with a reducing course of prednisolone (initial dose 60 mg/day). Six patients also received cyclophosphamide (2 mg/kg/day) for three months followed by azathioprine (100 mg/day) in five patients. Ten patients received azathioprine (100 mg/day) in addition to prednisolone. The median duration of treatment was 12 months (range 5-30 months). At the end of treatment each patient had a second renal biopsy.
RESULTS: Following treatment there was a significant reduction in the proportion of glomeruli with acute vasculitic lesions from a median of 17.4% (range 4.8-57.5%) to 0 (range 0-15.8%) (p=0.001). There was an increase in the proportion of globally sclerosed glomeruli from a median of 13.4% (range 0-44.4%) to 21.5% (range 0-90%) after treatment but this did not significantly differ from baseline (p=0.24). The proportion of renal cortex with chronic tubular atrophy increased from 2.55% (0.4-57.7%) to 11.3% (0.3-61%) (p=0.09). The median duration of follow-up was 30 months (inter-quartile range 6-30 months). At both 12 and 24 months there was no significant increase in serum creatinine. Four patients, however, developed end-stage renal failure between 24 and 81 months.
CONCLUSION: In this retrospective study we show that treatment with steroids and immunosuppressants leads to healing of vasculitic lesions and may thus arrest progression of glomerular scarring.
Nicholls K, Walker RG, Dowling JP, Kincaid-Smith P.
"Malignant" IgA nephropathy.
Am J Kidney Dis. 1985 Jan;5(1):42-6. doi: 10.1016/s0272-6386(85)80134-7.
Abstract/Text
Most patients with mesangial IgA nephropathy who run a progressive course usually do so over a period of 10 to 20 years. This paper describes the course of three young men with similar presenting features and biopsy findings who progressed to end-stage renal failure in less than 4 years from presentation, even though initially all had serum creatinine levels that were in the normal range. They presented with macroscopic hematuria, which has previously been regarded as an indicator of a favorable prognosis, and all three had loin pain, constantly elevated urinary erythrocyte counts, and crescents in renal biopsies. In two cases, treatment appeared to be associated with stabilization of renal function, but deterioration to end-stage renal failure occurred rapidly after treatment was ceased.
Coppo R, Basolo B, Roccatello D, Giachino O, Lajolo D, Martina G, Rollino C, Amore A, Costa M, Piccoli G.
Plasma exchange in progressive primary IgA nephropathy.
Int J Artif Organs. 1985 Jul;8 Suppl 2:55-8.
Abstract/Text
Five patients with progressive primary IgA nephropathy (PIgAGN) were treated by plasma-exchange (PE) combined with immunosuppressive drugs. Circulating IgA-containing immune complexes (IgAIC), detected by a specific conglutinin solid phase assay, were monitored. Two patients with acute nephritic syndrome and rapidly progressing course, crescent formations and high levels of IgAIC had substantial lasting clinical improvement after several PE, with a fall in IgAIC levels. Another rapidly progressive case with marked sclerotic changes and a longer history of nephritic syndrome, but with normal levels of IgAIC, did not show any clinical improvement after PE. Two patients with a PIgAGN diagnosed several years before and presenting slowly evolutive course had no substantial clinical benefit from PE treatment. IgAIC levels, very high before PE temporarily decreased, but returned to the previous values after the end of the treatment. We conclude that PE combined with immunosuppressive treatment may be of clinical benefit for cases with acute nephritic syndrome of recent onset who still have high levels of IgAIC, even when important crescent formations are present.
