|Year : 2018 | Volume
| Issue : 3 | Page : 219-223
Pleomorphic presentations of IgA nephropathy - postrenal transplantation
Andrew Rajiv, Sampath Kumar Krishnaswamy, Shakti Kumar
Department of Nephrology, Meenakshi Mission Hospital and Research Centre, Madurai, Tamil Nadu, India
|Date of Web Publication||28-Sep-2018|
Dr. Sampath Kumar Krishnaswamy
Department of Nephrology, Meenakshi Mission Hospital and Research Centre, Madurai - 625 107, Tamil Nadu
Source of Support: None, Conflict of Interest: None
IgA nephropathy (IgAN) is a common cause of glomerulonephritis and end-stage renal disease. The recurrence of IgAN postrenal transplant is well documented. IgA recurrence posttransplant manifests as recurrent IgAN, de novo IgAN, and crescentic IgAN. Three cases are described in this article, representing the above-mentioned presentations of IgAN. The first case represents the manifestation of crescentic IgAN in a renal transplant recipient. The patient presented with severe graft dysfunction requiring hemodialysis. Inspite of aggressive immunosuppression and plasmapheresis, the graft kidney could not be salvaged. The second case represents recurrent IgAN. The patient was initiated on antiproteinuric measures and has maintained a stable graft function. The third case presented with de novo IgAN and acute antibody-mediated rejection (AMR). This patient was treated with immunosuppressants and plasmapheresis as per AMR treatment guidelines, following which his graft function improved.
Keywords: Immunoglobulin A, nephropathy, plasmapheresis, recurrence postrenal transplant
|How to cite this article:|
Rajiv A, Krishnaswamy SK, Kumar S. Pleomorphic presentations of IgA nephropathy - postrenal transplantation. Indian J Transplant 2018;12:219-23
|How to cite this URL:|
Rajiv A, Krishnaswamy SK, Kumar S. Pleomorphic presentations of IgA nephropathy - postrenal transplantation. Indian J Transplant [serial online] 2018 [cited 2019 Nov 19];12:219-23. Available from: http://www.ijtonline.in/text.asp?2018/12/3/219/242431
| Introduction|| |
Immunoglobulin A nephropathy (IgAN) is the most common type of glomerulonephritis (GN) globally. Majority of patients with IgAN progress to end-stage renal disease (ESRD), approximately 10% at 10 years and 20% at 20 years. As patients with IgAN are younger thereby having fewer comorbidities, they have higher chances of receiving an allograft when they reach ESRD compared to other types of GN. Published reports of postrenal transplant recurrence rates of IgAN vary widely from 15% to 78% depending on the biopsy policies followed and time since transplant. Few Indian studies have documented the prevalence and recurrence of IgAN, and its effect on graft and patient survival. In this article, we describe the pleomorphic presentations of IgAN in three different patients.
| Case Reports|| |
Case 1: Crescentic immunoglobulin – A nephropathy
A 26 year old male was detected with ESRD in the year 2011 and initiated on hemodialysis. He was on maintenance hemodialysis for 5 months, following which he underwent live-related ABO blood group compatible renal transplantation from his mother with haplomatched human leukocyte antigen (HLA). Graft function was normal and he was on regular follow-up. Five years later, he developed oliguria, pedal edema, and hypertension. History revealed a brief period of drug noncompliance. Evaluation revealed severe graft dysfunction with serum creatinine of 6.2 mg/dl associated with heavy proteinuria and microscopic hematuria. A graft biopsy showed IgAN with cellular crescents [Figure 1] and [Figure 2]. He was pulsed with injection methylprednisolone (500 mg × 3) followed by 6 sessions of plasmapheresis. Intravenous immunoglobulin and injection cyclophosphamide 750 mg were also tried without success. His renal failure progressively worsened and he was initiated on hemodialysis. A repeat graft biopsy was done which showed chronic IgAN with fibrocellular crescents and 30% interstitial fibrosis and tubular atrophy. In view of features of chronicity, the patient was initiated on maintenance hemodialysis. Tacrolimus and prednisolone were tapered to 0.5 mg/day and 5 mg/day, respectively.
|Figure 1: Light microscopy – increase in mesangial and endocapillary cellularity with cellular crescents|
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Case 2: Recurrent immunoglobulin – A nephropathy
A 28-year-old male detected as ESRD (secondary to chronic GN, probably chronic IgAN) on February 2011. He was on maintenance hemodialysis. His sister with a haplomatched HLA system was the renal donor, and he underwent renal transplantation on March 2013. His graft function was normal. He was on triple immunosuppression (tacrolimus, mycophenolate mofetil [MMF], and wysolone). He maintained a normal graft function for the next 3 years. At this time, there was a history of drug noncompliance following which he developed graft dysfunction (creatinine 1.1–1.8 mg/dl). He also developed new-onset hypertension, proteinuria, and microscopic hematuria. Suspecting acute rejection, we pulsed him with methylprednisolone (500 mg) 3 doses. He underwent a graft biopsy which showed IgAN (IgA 3 + over mesangium, MEST score m1, e0, s1, t0) [Figure 3] and [Figure 4]. We suspected recurrence of native disease. The patient was started on angiotensin receptor blockers (ARB's). He has a stable graft function of 1.6 mg/dl and is on regular follow-up.
|Figure 3: Light microscopy-3 glomeruli showing increased mesangial cellularity and matrix with intimal proliferation of arteries. Segmental sclerosis was seen in 2 glomeruli|
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Case 3: De novo immunoglobulin – A nephropathy (native kidney disease anti-glomerular basement membrane disease)
This 33-year-old male was detected as ESRD in 2009 secondary to anti-glomerular basement membrane disease which was resistant to plasmapheresis. He underwent live-related ABO compatible transplant, with his mother as donor in 2010. Baseline graft function was 1.8 mg/dl. He had issues of noncompliance with immunosuppressive medications. He presented 6 years later with graft dysfunction (creatinine 3 mg/dl). Allograft biopsy showed acute antibody-mediated rejection (AMR) with C4d positivity [Figure 5] and [Figure 6]. There was also IgA (2+) over the mesangium with mesangial expansion [Figure 7] and [Figure 8]. Hence, he was diagnosed as acute AMR with de novo IgAN. He was treated with pulse methylprednisolone 500 mg (3 doses), plasmapheresis 3 sessions, intravenous Ig, and injection rituximab 500 mg 2 doses (1 week apart). He was on 4 weeks of hemodialysis after which graft dysfunction improved and his creatinine stabilized at 2.5 mg.
|Figure 5: Light microscopy – mesangial matrix expansion with hypercellularity, interstitial fibrosis, and tubular atrophy <10%|
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|Figure 6: Immunofluorescence – Immunoglobulin A (2+) staining over mesangium|
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|Figure 7: Light microscopy – lymphocytic interstitial infiltration (i1) with peritubular capillaritis|
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| Discussion|| |
According to the USRDS data, 30.2% of IgAN with ESRD received a transplant within 1 year on dialysis compared to only 2.4% of patients who had diabetic nephropathy. IgAN is one of the most common forms of GN to recur posttransplant. A review of the literature showed the incidence of IgAN recurrence to be around 33%, but this varied widely between 9% and 60% in different series. Indications for graft biopsy varied between different studies, as asymptomatic patients with hematuria or proteinuria did not receive a biopsy. Recurrences of IgAN can be either “immunopathologic,” that is, discovered only on a “protocol” renal biopsy in an asymptomatic patient, or “clinical” which is defined by abnormalities in the urine and/or renal function leading to a renal biopsy. Clinical recurrence of IgAN occurs on an average 3 years posttransplant and presents as hematuria and low-grade proteinuria. However, in crescentic IgAN, it can occur earlier with rapid loss of graft function. Recurrence tends to occur more frequently in younger patients and in those who had a rapid progression of the original disease.
There are two donor factors which contribute to recurrence, namely donor source and donor IgA deposits. Studies have shown increased recurrence in recipients of live-related donors compared to deceased donors, although this association has not been conclusively proved. The closer the HLA match, more the recurrence rate. Data from two Australian registries showed lesser incidence of recurrence in those with one or greater mismatches compared to those with zero mismatches. HLA specificity with HLA B35 or DR4 was found to increase the risk of IgAN recurrence. The 10-year graft survival was low in those having increased levels of HLA B8 and DR3 in another series. The presence of IgA deposits in the donor kidney increases risk of IgA recurrence as shown in one Japanese study. Factors linked to the pathogenesis of IgA such as high circulating levels of poorly glycosylated IgA1, circulating anti-glycan antibodies, and low levels of CD89 are associated with an aggressive primary disease and consequent risk of recurrence posttransplant.
The diagnosis of IgA recurrence requires histological evidence of IgA deposits in the transplant kidney in a patient who had biopsy-proven IgAN in their native kidneys. In cases 1 and 2, native kidney biopsies could not be performed as the kidneys were shrunken. Hematuria is not a reliable sign of IgA recurrence being absent in 64% of patients with disease recurrence detected on protocol biopsy. A graft biopsy is, therefore, essential in making a diagnosis. The MEST scoring system based on the Oxford classification though validated in IgAN of the native kidneys has also been applied for transplant kidneys and has provided good prognostic information.
The largest retrospective study of IgAN recurrence is from Australia wherein 526 patients of IgAN recurrence were studied and the estimated 10 year incidence of graft loss was 9.7%. One European study showed that initial graft survival was better with IgAN compared to other GN'S, but after 3 years, they had increased graft loss. The Australian and New Zealand Dialysis and Transplant Registry data showed that IgAN recurrence was a significant cause of graft loss third only to chronic allograft nephropathy, but the overall outcomes at 10 years were similar to other causes of ESRD.
There are no proven specific therapies to treat IgA recurrence. The Kidney Disease: Improving Global Outcomes transplant guidelines recommends treatment of proteinuria and hypertension using angiotensin-converting enzyme inhibitors or ARB. Two small studies have shown this to improve graft survival. Steroid withdrawal has been associated with increased rates of recurrence. The likelihood of IgAN recurrence is not related to any maintenance immunosuppressive drugs. The role of MMF in IgAN recurrence is controversial with some studies indicating that it has a protective role while other studies showing it is a risk factor for recurrence. Single-center retrospective studies have shown that antithymocyte globulin is helpful in preventing recurrence. Tonsillectomy was shown to be of benefit in Japanese studies. Treatment of recurrent IgAN associated with rapidly progressive renal failure and cellular crescents on biopsy (crescentic GN) usually has a poor outcome. In our first case, we tried pulse methylprednisolone, cyclophosphamide, and plasmapheresis, without benefit. De novo IgAN in a patient whose native kidney disease was anti-glomerular basement antibody disease has not been described to the best of our knowledge. Those patients who have lost a graft due to IgAN recurrence can undergo a repeat transplantion, although they are at an increased risk of recurrence for the second transplant also. However, a Korean multicenter study showed that out of 28 patients who underwent second renal transplant following a failed first graft due to IgAN, the condition reappeared only in two patients during a mean follow-up period of 5 years thus providing hope.
| Conclusions|| |
IgAN shows up in the allograft biopsy with myriad presentations.
There are no definitive and effective options available to prevent and treat IgAN recurrence. Inspite of this, the incidence of graft loss due to recurrence of IgAN is low except for crescentic GN which portends a high risk of graft loss.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wyatt RJ, Julian BA. IgA nephropathy. N
Engl J Med 2013;368:2402-14.
Berthoux FC, Mohey H, Afiani A. Natural history of primary IgA nephropathy. Semin Nephrol 2008;28:4-9.
Wyld ML, Chadban SJ. Recurrent IgA nephropathy after kidney transplantation. Transplantation 2016;100:1827-32.
U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2013.
Furness PN, Roberts IS, Briggs JD. Recurrent glomerular disease in transplants. Transplant Proc 2002;34:242.
Ponticelli C, Glassock RJ. Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol 2010;5:2363-72.
Ponticelli C, Traversi L, Banfi G. Renal transplantation in patients with IgA mesangial glomerulonephritis. Pediatr Transplant 2004;8:334-8.
Floege J. Recurrent IgA nephropathy after renal transplantation. Semin Nephrol 2004;24:287-91.
Clayton P, McDonald S, Chadban S. Steroids and recurrent IgA nephropathy after kidney transplantation. Am J Transplant 2011;11:1645-9.
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;12:147-51.
Andresdottir MB, Haasnoot GW, Persijn GG, Claas FH. HLA-B8, DR3: A new risk factor for graft failure after renal transplantation in patients with underlying immunoglobulin A nephropathy. Clin Transplant 2009;23:660-5.
Moriyama T, Nitta K, Suzuki K, Honda K, Horita S, Uchida 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 14:41-8.
Berthelot L, Robert T, Vuiblet V, Tabary T, Braconnier A, Dramé M, et al.
Recurrent IgA nephropathy is predicted by altered glycosylated igA, autoantibodies and soluble CD89 complexes. Kidney Int 2015;88:815-22.
Ortiz F, Gelpi R, Koskinen P, Manonelles A, Räisänen-Sokolowski A, Carrera M, et al.
IgA nephropathy recurs early in the graft when assessed by protocol biopsy. Nephrol Dial Transplant 2012;27:2553-8.
Moroni G, Longhi S, Quaglini S, Gallelli B, Banfi G, Montagnino G, et al.
The long-term outcome of renal transplantation of IgA nephropathy and the impact of recurrence on graft survival. Nephrol Dial Transplant 2013;28:1305-14.
Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. N
Engl J Med 2002;347:103-9.
Andresdottir MB, Haasnoot GW, Doxiadis II, Persijn GG, Claas FH. Exclusive characteristics of graft survival and risk factors in recipients with immunoglobulin A nephropathy: A retrospective analysis of registry data. Transplantation 2005;80:1012-8.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.
Oka K, Imai E, Moriyama T, Akagi Y, Ando A, Hori M, et al.
Aclinicopathological study of IgA nephropathy in renal transplant recipients: Beneficial effect of angiotensin-converting enzyme inhibitor. Nephrol Dial Transplant 2000;15:689-95.
Bumgardner GL, Amend WC, Ascher NL, Vincenti FG. Single-center long-term results of renal transplantation for IgA nephropathy. Transplantation 1998;65:1053-60.
Hauser IA, Renders L, Radeke HH, Sterzel RB, Goppelt-Struebe M. Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion. Nephrol Dial Transplant 1999;14:58-63.
Berthoux F, El Deeb S, Mariat C, Diconne E, Laurent B, Thibaudin L, et al.
Antithymocyte globulin (ATG) induction therapy and disease recurrence in renal transplant recipients with primary IgA nephropathy. Transplantation 2008;85:1505-7.
Kennoki T, Ishida H, Yamaguchi Y, Tanabe K. Proteinuria-reducing effects of tonsillectomy alone in IgA nephropathy recurring after kidney transplantation. Transplantation 2009;88:935-41.
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;20:1214-21.
Baek CH, Lee JG, Park JH, Kim H, Yang WS, Kim YS, et al.
The clinical outcomes of second kidney transplantation in IgA nephropathy: A multicenter retrospective study. Clin Nephrol 2016;86:87-93.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]