Management of IgA nephropathy: contemporary views

Management of IgA nephropathy: contemporary views MBBS, MD, PhD, MRCP (UK), FHKCP, FHKAM (Medicine) Associate Consultant and Honorary Associate Professor, Department of Medicine, University of Hong Kong, Queen Mary Hospital Prof. Kar-neng Lai MD, DSc, FRCPath, FRCP (Lond, Edin & Glas), FRACP, FACP, FAMS, FHKCP, FHKAM (Medicine) Head and Chief of Service, Department of Medicine, University of Hong Kong, Queen Mary Hospital Prof. Kar-neng Lai This article has been selected by the Editorial Board of the Hong Kong Medical Diary for participants in the CME programme of the Medical Council of Hong Kong (MCHK) to complete the following self-assessment questions in order to be awarded one CME credit under the programme upon returning the completed answer sheet to the Federation Secretariat on or before 31 May 2006. Ever since its first description in 1968 by the French pathologist, J. Berger 1, IgA nephropathy (IgAN) has remained the commonest primary glomerulonephritis worldwide 2. In Hong Kong, the commonest renal manifestation is microscopic haematuria which is often synpharyngitic 3. The disease is unique among g l o m e r u l o p a t h i e s i n b e i n g d e f i n e d b y immunohistochemical findings of mesangial deposition of IgA (Figure 1), rather than by light microscopy in which mesangial cell proliferation is the commonest feature (Figure 2). Another hallmark of the disease is its indolent progressive nature. Between 15% and 40% of adults and children will eventually progress to end stage renal disease 4;5. Approximately 15 to 20% develop ESRD within 10 years, and 30 to 35% develop ESRD within 20 years of onset. Proteinuria, elevated serum creatinine, and hypertension predict progression 6, as does renal biopsy demonstrating focal proliferative glomerulonephritis with crescents, diffuse proliferative glomerulonephritis, or advanced, chronic lesions of tubulointerstitial fibrosis 7. Until recently, there was no effective treatment available for patients with IgAN. Although there remains no cure, treatment options that slow disease progression are becoming available. In this update I will review the current armamentarium in the management of IgAN. Conservative treatment For patients with normal renal function, normotension and only minor urinary abnormalities, such as isolated microhaematuria, and/or low grade proteinuria, the general consensus is not to offer specific treatment but to keep such patients under review. Up to 23% of patients will have a spontaneous complete remission. Blockers of the renin-angiotensin system Reduction in proteinuria is considered to be the hallmark of effective treatment in preserving renal function in nondiabetic renal diseases. Angiotensinconverting enzyme inhibitors (ACEi), and more recently angiotensin II type 1 receptor blockers (ARB), are widely used to control blood pressure and proteinuria, both of which are considered modifiable risk factors for progressive disease, in IgAN subjects with significant proteinuria with or without hypertension. They are superior to other antihypertensives in lowering proteinuria by virtue of their capacity to reduce intraglomerular pressure. Response to ACEi in IgAN has been reported to be related to the ACE genotype, with more favourable outcome in subjects with the DD genotype over those with ID or II genotypes 8. Limited data are available on the effects on proteinuria of combination therapy with ACEi/ARB. In a small trial, the combination of losartan and enalapril appeared to have an additive effect on the reduction of urinary protein excretion, whereas doubling the dose of monotherapy had no effect 9. In the COOPERATE study 10 in which half of the subjects had IgAN, combination treatment safely retarded progression of non-diabetic renal disease compared with monotherapy. One of the precautions in prescribing monotherapy or dual therapy is refractory hyperkalaemia particularly in subjects with significant renal impairment. Another precaution is the precipitation of acute renal failure in subjects with bilateral renovascular disease. Corticosteroids Corticosteroids have been used for over 20 years in the treatment of IgAN because of their antiinflammatory and immunosuppressive properties, and are usually confined to patients considered at risk of progressive renal failure. A meta-analysis of six available trials of sufficient quality suggested that corticosteroid therapy may be effective in reducing proteinuria, although the impact on protecting renal function is less clear 11. In an RCT from Italy, treatment with steroids (1 g/d of intravenous methylprednisolone for 3 d at the beginning of months 1, 3, and 5, plus 0.5 mg of oral prednisone/kg BW on alternate days for 6 m) was shown to lower proteinuria by 50% after 6 months and to reduce the risk of a 50% increase in the serum creatinine level by 36% after five years 12. The long-term follow-up data from this study showed impressive benefits of corticosteroid treatment in reducing proteinuria and preventing ESRD 13. Although several 3

other studies have shown beneficial results in small numbers of patients treated with daily or alternate-day steroid early in their illness, long-term efficacy in controlling disease progression has not been validated in Chinese patients, and therapy is only beneficial to selected groups of patients with IgAN and nephrotic syndrome 14. Another recent RCT of corticosteroids showed only a modest reduction in proteinuria with no protection of GFR amongst Japanese patients 15. At this juncture, steroid does not appear to consistently offer any beneficial effect other than modest amelioration of proteinuria. The only exception is found in children with IgA deposition in the setting of minimal change nephrotic syndrome. Such patients respond to corticosteroid promptly 16. In adults, in view of the toxicities associated with steroid therapy, it should be considered only when proteinuria persists >1 g/24 h despite optimal BP control and maximum RAS blockade. Fish oil (n-3 Polyunsaturated Fatty Acids) supplementation The first landmark report on the efficacy of dietary fish-oil supplements was published in 1994 from the Mayo Clinic 17. The rationale of using fish oil in IgAN is based on the premise that ω-3 polyunsaturated fatty acids alter the production or action of cytokines and eicosanoids evoked by the initial or by repeated immunological renal injury, thereby alleviating ongoing renal inflammation and glomerulosclerosis, both being hallmarks of progressive renal disease. However, a meta-analysis of 5 controlled trials failed to substantiate the efficacy of fish oil in IgAN 18. The mean effect to indicate that treatment was superior to control was not statistically significant. Despite this, the Mayo investigators published their long-term data in 1999 to conclude that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgAN 19. Locally, a study performed in the late 1980s on 11 patients with IgAN given dietary fish oil supplement showed either no demonstrable or an unpredictable effect 20. The preliminary report of a more recent RCT showed no benefit of 2 years of treatment with fish oil compared with corticosteroids and placebo 21. Hence, the clinical benefit of fish oil supplementation in IgAN cannot be established at this point, and primary treatment of IgAN with fish oil is not recommended. Cyclophosphamide Only one study suggested efficacy of cyclophosphamide followed by azathioprine in conjunction with high-dose prednisolone in patients who are at very high risk for progression (ESRD predicted in all cases within 5 yr) 22. However, these are only a small minority of patients encountered in clinical practice. Thus, there is insufficient evidence to justify the use of such cytotoxic agent in IgAN except in crescentic IgAN with rapidly progressive renal failure. Mycophenolate mofetil (MMF) The rationale for employing MMF to treat IgAN stems from its selective suppressive effects on lymphocyte proliferation and antibody formation 23. Four clinical trials have been published so far which together gave no conclusion. We provided evidence that a 6-month course of MMF (0.75 to 1 g b.d.) can induce lasting remission (up to 72 weeks of follow up thus far) of proteinuria in at-risk patients (i.e. those with persistent proteinuria >1g/day despite full RAS inhibition and normal BP, but had histology that did not reveal advanced sclerosis) 24. Similarly, another report from Beijing suggested that MMF is more effective than prednisone in reducing proteinuria in patients with urine protein > 2 g/d 25. Conversely, lack of efficacy was reported from Belgium (MMF for 3 years in 21 patients with histologic unfavourable criteria, arterial hypertension, and inulin clearance between 21 and 69 ml/min) 26 and North America (MMF for 1 year as a "salvage" therapy in 16 patients with advanced renal insufficiency) 27. Such discrepancies likely arise from a difference in race, and our selection of patients with less advanced disease. It would be reasonable at this point to recommend MMF to at-risk patients without advanced sclerosis who can afford this expensive drug. Kidney transplantation Kidney transplantation offers the best potential for full rehabilitation in ESRD from IgAN. Disease recurrence in the allograft typically is slowly progressive. Available evidence indicates at 5 years a 5% risk for graft failure due to recurrence, a 13% risk for significant graft dysfunction, and at least 50% risk for IgA deposition. Local data suggest that around 20% of patients developed recurrence by 5 years after transplantation 28. The risk for graft loss increases markedly to 25% when a first graft was lost to recurrence. There is no consistent evidence that these risks differ between living and cadaveric donors 29. Into the future Short of an effective cure of IgAN, future therapeutic attempts should target the prevention of mesangial IgA deposition and the amelioration of the ensuing downstream inflammatory injury induced by infiltrating neutrophils and the released cytokines 30. Based on pathogenetic insights derived from experimental studies, antagonism of platelet-derived growth factor and transforming growth factor provides an attractive and possibly more specific therapeutic alternative to immunosuppression. At present, the development of other novel therapeutic approaches is greatly hampered by the lack of animal models that resemble human IgAN. 4

Figure 1 Predominant or co-dominant deposition of IgA in the mesangium is the defining hallmark in IgAN. IgG, IgM, and C3 deposition may also accompany IgA. Magnification x 200 Figure 2 Classical mesangial cell proliferation in IgAN. PAS staining, magnification x 200 References 1. Berger J, Hinglais N: [Intercapillary deposits of IgA-IgG]. J Urol Nephrol (Paris) 74:694-695, 1968 2. D'Amico G: The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 64:709-727, 1987 3. Lai KN, Mac-Moune LF, Li PK, Chan KW, Au TC, Tong KL: The clinicopathological characteristics of IgA nephropathy in Hong Kong. Pathology 20:15-19, 1988 4. Tang S, Lai KN: IgA nephropathy: 30 years on. Medical Progress 26:814, 1999 5. Wyatt RJ, Kritchevsky SB, Woodford SY, Miller PM, Roy S, III, Holland NH, Jackson E, Bishof NA: IgA nephropathy: long-term prognosis for pediatric patients. J Pediatr 127:913-919, 1995 6. D'Amico G: Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis 36:227237, 2000 7. Coppo R, D'Amico G: Factors predicting progression of IgA nephropathies. J Nephrol 18:503-512, 2005 8. Tang S, Lai KN: Gene polymorphism in IgA nephropathy. Nephrology 6:63-70, 2001 9. Russo D, Minutolo R, Pisani A, Esposito R, Signoriello G, Andreucci M, Balletta MM: Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis 38:18-25, 2001 10. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T: Combination treatment of angiotensin-ii receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361:117-124, 2003 11. Samuels JA, Strippoli GF, Craig JC, Schena FP, Molony DA: Immunosuppressive treatments for immunoglobulin A nephropathy: a meta-analysis of randomized controlled trials. Nephrology 9:177-185, 2004 12. Pozzi C, Bolasco PG, Fogazzi GB, Andrulli S, Altieri P, Ponticelli C, Locatelli F: Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet 353:883-887, 1999 13. 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 15:157-163, 2004 14. Lai KN, Lai FM, Ho CP, Chan KW: Corticosteroid therapy in IgA nephropathy with nephrotic syndrome: a long-term controlled trial. Clin Nephrol 26:174-180, 1986 15. 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 41:972-983, 2003 16. Lai KN, Lai FM, Chan KW, Ho CP, Leung AC, Vallance-Owen J: An overlapping syndrome of IgA nephropathy and lipoid nephrosis. Am J Clin Pathol 86:716-723, 1986 17. Donadio JV, Bergstralh EJ, Offord KP, Spencer DC, Holley KE, The Mayo Nephrology Collaborative Group: A Controlled Trial of Fish Oil in IgA Nephropathy. N Engl J Med 331:1194-1199, 1994 18. Dillon JJ: Fish oil therapy for IgA nephropathy: efficacy and interstudy variability. J Am Soc Nephrol 8:1739-1744, 1997 19. Donadio JV, Jr., Grande JP, Bergstralh EJ, Dart RA, Larson TS, Spencer DC: The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. J Am Soc Nephrol 10:1772-1777, 1999 20. Cheng IK, Chan PC, Chan MK: The effect of fish-oil dietary supplement on the progression of mesangial IgA glomerulonephritis. Nephrol Dial Transplant 5:241-246, 1990 21. Hogg, R. J., Lee, J., Narelli, N., Cattran, D. C., Hirschman, G., and Julian, B. A. Multicenter placebo-controlled trial of alternate day prednisolone or daily omega-3 fatty acids in children and young adults with IgA nephropathy. Report from the Southwest Pediatric Nephrology Study Group. Journal of the American Society of Nephrology 14, 751A. 1-9-2003. 22. Ballardie FW, Roberts IS: Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 13:142-148, 2002 23. Allison AC, Eugui EM: Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 10:77-84, 1996 24. 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 68:802-812, 2005 25. Chen X, Chen P, Cai G, Wu J, Cui Y, Zhang Y, Liu S, Tang L: [A randomized control trial of mycophenolate mofeil treatment in severe IgA nephropathy]. Zhonghua Yi Xue Za Zhi 82:796-801, 2002 26. Maes BD, Oyen R, Claes K, Evenepoel P, Kuypers D, Vanwalleghem J, Damme BV, Vanrenterghem YF: Mycophenolate mofetil in IgA nephropathy: Results of a 3-year prospective placebo-controlled randomized study. Kidney Int 65:1842-1849, 2004 27. 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 20:2139-2145, 2005 28. Choy BY, Chan TM, Lo SK, Lo WK, Lai KN: Renal transplantation in patients with primary immunoglobulin A nephropathy. Nephrol Dial Transplant 18:2399-2404, 2003 29. Floege J: Recurrent IgA nephropathy after renal transplantation. Semin Nephrol 24:287-291, 2004 30. Lai KN: Future directions in the treatment of IgA nephropathy. Nephron 92:263-270, 2002 5

MCHK CME Programme Self-assessment Questions Please read the article entitled "Management of IgA nephropathy: contemporary views" by and complete the following self-assessment questions. Participants in the MCHK CME Programme will be awarded 1 CME credit under the Programme for returning completed answer sheet via fax (2865 0345) or by mail to the Federation Secretariat on or before 31 May 2006. Answers to questions will be provided in the next issue of The Hong Kong Medical Diary. Questions 1-10: Please choose the best answer. 1. What investigation is needed to make a definitive diagnosis of IgAN? a. Serum IgA level b. Urine RBC c. Renal biopsy d. 24-hour Urine protein 2. What is the confirmatory histologic feature in IgAN? a. Mesangial proliferation b. Concomitant IgA deposition c. Double contouring of glomerular basement membrane d. Predominant or codominant mesangial IgA deposit 3. What is the commonest mode of presentation? a. Microscopic haematuria (often incidentally found) b. Hypertension c. Nephrotic syndrome d. Gross haematuria 4. Which is not a modifiable risk factor for progression to ESRD in IgAN a. Proteinuria b. Haematuria c. Hypertension 5. Which is the drug of first choice for patients with significant proteinuria regardless of blood pressure? a. Ca channel blocker b. MMF c. ACEi and/or ARB d. Corticosteroid 6. Which of the following is not a potential adverse effect of RAS blockade a. Hyponatraemia b. Hyperkalaemia in patients with CRF c. Acute renal failure in subjects with bilateral renal artery stenoses d. Dry cough 7. Is corticosteroid a standard form of treatment for IgAN? a. No b. Yes 8. When should corticosteroid be considered in IgAN? a. In gross haematuria b. In proteinuria c. In microscopic haematuria d. In crescentic IgAN 9. When should mycophenolate be considered in IgAN? a. Advanced renal insufficiency b. Refractory proteinuria despite full RAS blockade in the absence of significant kidney fibrosis c. Before renal transplantation d. Recurrent synpharyngitic haematuria 10. What may be a peculiar feature in patients who undergo renal transplantation due to ESRD resulting from IgAN? a. Acute allograft rejection b. Recurrent IgAN c. Graft thrombosis d. Polycythaemia 6

ANSWER SHEET FOR MAY 2006 Please return the completed answer sheet to the Federation Secretariat on or before 31 May 2006 for documentation. 1 CME point will be awarded for answering the MCHK CME programme (for non-specialists) self-assessment questions. Management of IgA nephropathy: contemporary views MBBS, MD, PhD, MRCP (UK), FHKCP, FHKAM (Medicine) Associate Consultant and Honorary Associate Professor, Department of Medicine, University of Hong Kong, Queen Mary Hospital 1 2 3 4 5 6 7 8 9 10 Name: HKID No. - X X (x) Signature: Contact Tel No.: Answers to April 2006 issue Management of First Epileptic Seizure 1. D 2. E 3. C 4. D 5. B 6. E 7. D 8. E 9. D 10. E CALL FOR SUBMISSION OF ARTICLES FOR PUBLICATION IN THE HONG KONG MEDICAL DIARY The Editorial Board of the Hong Kong Medical Diary invites you to send in your interesting articles for publication in the Hong Kong Medical Diary (500-1,500 words per article). Abstracts from recent local or international meetings/symposia are also welcome. You can send in your manuscript by facsimile at 2865 0345, through mail or via email at sue.cheng@fmshk.com.hk. The Editorial Board of the Hong Kong Medical Diary will give you a prompt reply. 7