Nephroquiz 6: A 67-Year-Old Kidney Transplant Recipient With Nephrotic-Range Proteinuria

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1 NEPHROQUIZ Nephroquiz 6: A 67-Year-Old Kidney Transplant Recipient With Nephrotic-Range Proteinuria Pedram Ahmadpoor, Fatemeh Pour-Reza-Gholi, Mohsen Nafar, Mahmood Parvin, Fariba Samadian, Shiva Samavat, Saeed Amirkhanloo Departments of Nephrology and Pathology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran IJKD 2011;5: Nephroquiz CASE A 67-year-old female kidney transplant recipient with nephrotic-range proteinuria was admitted for kidney biopsy. She had undergone living unrelated kidney transplantation in 1999 due to kidney failure of unknown cause after being on hemodialysis for 8 months. Her donor was a 23-year-old female who was homozygous for human leukocyte antigen (HLA) B5, DR 52, DQ 1, and CW 4. The patient s HLA type was A2, B5, B35, DR11, DR52, DQ1, and CW4. Immunosuppressive therapy consisted of cyclosporine, azathioprine, and steroids. Two months after transplantation, she had developed an episode of acute allograft dysfunction due to calcineurin toxicity which had responded to dose reduction. Her high blood pressure had been treated with atenolol, to which enalapril had been added 2 years later. Six years after transplantation, azathioprine had been converted to mycophenolate mofetil. Her clinical course was uneventful until a year after conversion when she developed progressive proteinuria without hematuria or worsening of graft function. She was admitted with a 24-hour urine protein excretion of 4030 mg and stable allograft function. On admission, her immunosuppressive regimen consisted of cyclosporine, 100 mg/d; mycophenolate mofetil, 1000 mg/d; and prednisolone, 5 mg/d. She was also receiving enalapril, 5 mg twice daily; metoprolol, 50 mg/d; and atorvastatin, 20 mg/d. Her test results at admission are shown in the Table. Kidney biopsy was performed, which revealed marked mesangial matrix expansion and hypercellularity in 6 glomeruli with focal synechiae and segmental scar in one of them, and about 30% tubular atrophy and interstitial Patient s Laboratory Data on Admission Laboratory Study Value Biochemistry Fasting blood glucose, mg/dl 100 Blood urea nitrogen, mg/dl 40 Creatinine, mg/dl 1.46 Triglyceride, mg/dl 142 Cholesterol, mg/dl 165 Albumin, g/dl 3.5 Total protein, g/dl 6 Asparate aminotransferase, U/L 18 Alanine aminotransferase, U/L 17 Calcium 9.5 Phosphorus 3.8 Complete blood count Leukocyte, 10 9 /L 7 Hemoglobin, g/dl 9.8 Hematocrit, % 31 Mean corpuscular volume, fl 86 Platelet, 10 9 /L 242 Urinalysis Protein ++ Blood Leukocyte 0 to 2 Erythrocyte 0 to 2 Urine culture Immunology C-reactive protein, mg/l 1 Complement 3, mg/l 125 Complement 4, mg/l 24 CH50, mg/l 140 Antinuclear antibody Anti-double stranded DNA P-antineutrophil cytoplasmic antibody C-antineutrophil cytoplasmic antibody Anti-Glomerular basement membrane Citrulinated pro.ab fibrosis (M1, S1, E0, and T1). Features of benign nephrosclerosis were present in the background 278

2 Figure 1. Left, Mesangial expansion with hypercellularity and segmental scar (hematoxylin-eosin, 400). Right, Mesangial expansion with hypercellularity and segmental scar (PAD, 400). Figure 2. Left, Mesangial deposition of IgA (FITC Anti-human IgA, 400). Right, Mesangial deposition of C3c (FITC Anti-human C3c, 400). (Figure 1). Immunoflurescence examination showed depositions of immunoglobulin A (IgA) antibody and complement 3 (C3) on the mesangium and no C4d deposition in peritubular capillaries (Figure 2). The diagnosis of IgA nephropathy class IV was made and mycophenolate mofetil dosage was increased to 2000 mg/d. QUIZ Can we predict recurrence of Immunoglobulin A nephropathy in a transplanted kidney? Posttransplant IgA nephropathy can occur as de novo IgA nephropathy, recurrent IgA nephropathy, or transmitted from the donor. 1 Recurrent IgA nephropathy after transplantation is being reported in 13% to 60% of patients depending on the duration of follow-up and the biopsy protocol in the transplant center. 2,3 The diagnosis of recurrent IgA nephropathy requires characterization of glomerulonephritis in the native kidneys and histologic findings of mesangioproliferative glomerulonephritis with IgA deposition in transplanted kidney, although most series lack the first criteria like our patients. Clinical manifestations of recurrent IgA nephropathy are persistent microhematuria and proteinuria more than 500 mg per day, but usually remaining below the nephrotic range. 1 Disease recurrence contributes to graft dysfunction in 5% to 30% of cases. 3-5 Progressive allograft dysfunction and decreased graft survival prompt physicians to identify patients who are at higher risk of 279

3 recurrence. Articles are not unanimously agreed on risk factors of recurrence. Assessing the role of demographic factors as a risk, there are reports that show younger recipient and male gender are prone to recurrence. 5-7 Several reports have found increased risk of recurrence in those with related living donors, 3,5,8-10 although there are no significant change in graft survival, probably due to better matched donor and decreased prevalence of chronic allograft nephropathy. 5 On the other hand, some analyses showed no greater risk for recurrence with living related donors. 3,6,11-13 The likelihood of HLA affecting the risk of recurrence of IgA nephropathy is discussed in 2 separate areas of the effect of specific HLA and the effect of HLA matching. A protective role for HLA-A2 and HLA-B46 against IgA nephropathy recurrence has been reported. 3 Other studies found an association between increased susceptibility to recurrent IgA nephropathy and HLA-DR4 or B35. 14,15 The importance of HLA matching on recurrence and the graft survival is reported in several studies. Wang and colleagues and Bumgardner and colleagues reported a trend toward a greater IgA nephropathy recurrence rate for HLA-identical versus non HLA-identical allografts from living related donors and decreased graft survival with zero mismatched donors. 3,7,11 Increased serum level of IgA is one of the proposed risk factors. In a study, serum IgA levels were significantly greater for patients with recurrence of IgA nephropathy compared with those without recurrence. It also demonstrated significantly increased binding of circulating IgA to type IV collagen in patients with recurrent IgA nephropathy. 3 Coppo and coworkers found the difference in amounts of circulating aberrantly glycosylated IgA1 between patients with recurrent and nonrecurrent disease and also showed that patients with polymorphisms of tumor necrosis factor-α (-308 AG/ AA genotype), and interleukin-10 (-1082, -819, -592 ACC/ATA genotype ) which downregulate the T helper 2 subset, experienced less recurrence of IgA nephropathy. 16 Several other risk factors have been proposed such as glomerular crescents on the original renal biopsy, 7 a short duration of the disease until endstage renal disease, 8 latent IgA deposition from the donor of the kidney, 17 high plasma creatinine and proteinuria values at 6 months, 6 and greater number of rejections. 7 In respect of immunosuppressive regimens effect on recurrence of IgA nephropathy, data are limited and controversial. Mycophenolate mofetil was proposed to prevent recurrence of IgA nephropathy via 2 mechanisms: inhibition of lymphocytes proliferation, synthesis of antibody, generation of cytotoxic T cells and recruitment of leukocytes to sites of inflammation, 14 and a direct antiproliferative effect on mesangial cells. 18 Some preliminary data suggest that mycophenolate mofetil could affect the clinical course of recurrent IgA nephropathy, 19 but long-term data are lacking. Ponticelli and colleagues reported a lower risk of recurrence in patients given mycophenolate mofetil in comparison to sirolimus, although small number of cases made it difficult to reach a firm conclusion. 6 Later reports failed to demonstrate any advantage in using mycophenolate mofetil. Mycophenolate mofetil failed to prevent the development of recurrent IgA nephropathy, to improve graft survival after recurrence or to delay clinical or histological recurrence of IgA nephropathy. It is assumed that lower doses of glucocorticoids have permitted more glomerular damage in allografts with IgA mesangial deposits despite mycophenolate mofetil usage. 13 No significant difference has been observed in the incidence of IgA nephropathy comparing the pre- and postcyclosporine eras. 11,20 There are case reports of occurrence of IgA nephropathy in transplanted kidney after conversion from calcineurine inhibitors to sirolimus, which responded to reinstitution of calcineurine inhibitors by decline in proteinuria. 21 How can we treat recurrent immunoglobulin A nephropathy in a transplanted kidney? As with the risk factors, data on treatment are also controversial and limited. Like native kidneys, there are evidences of hyperfiltration and glomerular hypertension in transplanted kidney with IgA nephropathy that make using angiotensin-converting enzyme (ACE) inhibitors logical. Some studies reported favorable effects of ACE inhibitors in treatment and graft outcome in recurrent IgA nephropathy, 4,22 and Namba and associates demonstrated an association between progressive graft failure and not using ACE inhibitors at the time of allograft biopsy in IgA 280

4 nephropathy. 23 In another study of transplant recipients with recurrent IgA nephropathy, 5-year graft survival was higher in those prescribed ACE inhibitors or angiotensin II receptor blockers (ARBs) therapy compared with those who were not. 24 While Ponticelli and colleagues recommended use of these drugs as evidenced by their retrospective study, 25 Chandrakantan and coworkers study failed to show significant decrease in the amount of proteinuria after diagnosis of recurrence using ACE inhibitors and/or ARBs. 13 Although 2 case reports suggested that fish oil improves proteinuria in patients who developed recurrent IgA nephropathy, 26,27 no clinical trial has been done yet. Tonsillectomy is proposed as treatment in primary IgA nephropathy. In a case report, Sakai and colleagues reported clinical remission of recurrent IgA nephropathy after transplantation following tonsillectomy and prescription of valsartan with pathologic progression. 2 There is a case report of treating a patient with posttransplantation IgA nephropathy and severe proteinuria despite ACE inhibition, with low-molecular weight heparin which led to significant decline in protein excretion. 28 Changes in immunosuppressive regimen have been the center of attention for years, but firm information is still lacking. Conversion from azathioprine to mycophenolate mofetil or increasing mycophenolate mofetil is not proven to be effective. 2,14,29 In a report, conversion from cyclosporine to tacrolimus stabilized graft function. 30 Early administration of angiotensin system blockade seems to be a wise step in treatment of recurrent IgA nephropathy, and further treatment options need to be evaluated by a well-designed clinical trial with appropriate follow-up period. REFERENCES 1. Koselj M, Rott T. Immunoglobulin A nephropathy in renal transplant recipients. Transplant Proc. 1992;24: Sakai K, Saneshige M, Takasu J, et al. Clinical remission and pathological progression after tonsillectomy in a renal transplant patient with recurrent IgA nephropathy. Clin Transplant. 2009;23 Suppl 20: Wang AY, Lai FM, Yu AW, et al. Recurrent IgA nephropathy in renal transplant allografts. Am J Kidney Dis. 2001;38: Oka K, Imai E, Moriyama T, et al. A clinicopathological study of IgA nephropathy in renal transplant recipients: beneficial effect of angiotensin-converting enzyme inhibitor. Nephrol Dial Transplant. 2000;15: Han SS, Huh W, Park SK, et al. Impact of recurrent disease and chronic allograft nephropathy on the longterm allograft outcome in patients with IgA nephropathy. Transpl Int.23: Ponticelli C, Traversi L, Feliciani A, Cesana BM, Banfi G, Tarantino A. Kidney transplantation in patients with IgA mesangial glomerulonephritis. Kidney Int. 2001;60: Stack A, Campbell E, Browne O, Saran R, Dorman T, Donohoe J. Prevalence and predictors of recurrent IgA nephropathy following renal transplantation. Ir J Med Sci. 2000;169: Freese P, Svalander C, Norden G, Nyberg G. Clinical risk factors for recurrence of IgA nephropathy. Clin Transplant. 1999;13: Andresdottir MB, Hoitsma AJ, Assmann KJ, Wetzels JF. Favorable outcome of renal transplantation in patients with IgA nephropathy. Clin Nephrol. 2001;56: Choy BY, Chan TM, Lo SK, Lo WK, Lai KN. Renal transplantation in patients with primary immunoglobulin A nephropathy. Nephrol Dial Transplant. 2003;18: Bumgardner GL, Amend WC, Ascher NL, Vincenti FG. Single-center long-term results of renal transplantation for IgA nephropathy. Transplantation. 1998;65: Kim YS, Moon JI, Jeong HJ, et al. Live donor renal allograft in end-stage renal failure patients from immunoglobulin A nephropathy. Transplantation. 2001;71: Chandrakantan A, Ratanapanichkich P, Said M, Barker CV, Julian BA. Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil. Nephrol Dial Transplant. 2005;20: Matsugami K, Naito T, Nitta K, et al. [A clinicopathological study of recurrent IgA nephropathy following renal transplantation]. Nippon Jinzo Gakkai Shi. 1998;40: Brensilver JM, Mallat S, Scholes J, McCabe R. Recurrent IgA nephropathy in living-related donor transplantation: recurrence or transmission of familial disease? Am J Kidney Dis. 1988;12: Coppo R, Amore A, Chiesa M, et al. Serological and genetic factors in early recurrence of IgA nephropathy after renal transplantation. Clin Transplant. 2007;21: Moriyama T, Nitta K, Suzuki K, et al. Latent IgA deposition from donor kidney is the major risk factor for recurrent IgA nephropathy in renal transplantation. Clin Transplant. 2005;19 Suppl 14: Floege J. Recurrent IgA nephropathy after renal transplantation. Semin Nephrol. 2004;24: Nowack R, Birck R, van der Woude FJ. Mycophenolate mofetil for systemic vasculitis and IgA nephropathy. Lancet. 1997;349: Schwarz A, Krause PH, Offermann G, Keller F. Recurrent and de novo renal disease after kidney transplantation with or without cyclosporine A. Am J Kidney Dis. 1991;17: Dittrich E, Schmaldienst S, Soleiman A, Horl WH, Pohanka E. Rapamycin-associated post-transplantation 281

5 glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int. 2004;17: Jeong HJ, Kim YS, Kwon KW, et al. Segmental glomerulosclerosis in IgA nephropathy after renal transplantation: relationship with proteinuria and therapeutic response to enalapril. Clin Transplant. 2003;17: Namba Y, Oka K, Moriyama T, et al. Risk factors for graft loss in patients with recurrent IGA nephropathy after renal transplantation. Transplant Proc. 2004;36: Courtney AE, McNamee PT, Nelson WE, Maxwell AP. Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy? Nephrol Dial Transplant. 2006;21: Ponticelli C, Traversi L, Banfi G. Renal transplantation in patients with IgA mesangial glomerulonephritis. Pediatr Transplant. 2004;8: Butani L, Palmer J. Effect of fish oil in a patient with posttransplantation IgA nephropathy. Nephrol Dial Transplant. 2000;15: Ng R. Fish oil therapy in recurrent IgA nephropathy. Ann Intern Med. 2003;138: Krzossok S, Birck R, Koeppel H, et al. Treatment of proteinuria with low-molecular-weight heparin after renal transplantation. Transpl Int. 2004;17: Woodroffe A, Clarkson A. Recurrence of IgA nephropathy in renal transplants. Nephrology. 2002;7:S Manu MA, Tanabe K, Ishikawa N, et al. Tacrolimus rescue for resistant rejection, chronic rejection, and immunoglobulin A nephropathy of renal allografts under primary cyclosporine A immunosuppression. Transplant Proc. 1999;31: Correspondence to: Shiva Samavat, MD Department of Internal Medicine, Shahid Labbafinejad Medical Center, 9th Boustan St, Pasdaran Ave, Tehran, Iran Tel: Fax: sh_samavat@yahoo.com 282