Idiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and therapeutic quandary!

Idiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and... Background: Proteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes. Methods: We retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute. Results: A total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean 6 standard deviation age was 546 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) reg- imen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus. Conclusion: Patients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxic- ity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxic- ities observed in the latter. Key words: diabetes mellitus, membranous nephropathy, nephrotic syndrome Received: November 8, 2016. Editorial decision: April 19, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 iMN in coexistence with diabetes mellitus | 47 statins for hyperlipidemia, dietary salt restriction and diuretics Introduction if edema was present. Membranous nephropathy (MN) is a frequent cause of adult The Modified Ponticelli (MP) regimen was started if the pro- nephrotic syndrome, with a reported incidence of 5–10 cases per teinuria was more than 4 g/day and more than 50% of the base- million population per year in Northern Europe [1]. Studies have line value despite 6 months of supportive treatment, or if there reported an apparent reversal in the trend of the late 20th cen- was an unexplained >30% rise in the serum creatinine levels tury with regard to the frequencies of focal segmental glomerulo- within 6–12 months of treatment initiation. The MP regimen sclerosis and idiopathic membranous nephropathy (iMN) [2–4]. included methyl prednisolone (1 g) given by parenteral route for MN is emerging as the most common cause of adult nephrotic three consecutive days, followed by oral prednisolone (0.5 mg/ syndrome. In about one-third of patients with MN an underlying kg/day) for 27 days (Cycle A). Cycle A was followed by cyclo- cause such as infection, hematological or solid organ malignancy, phosphamide (2 mg/kg/day) orally for 1 month (Cycle B). Cycles systemic autoimmune disease or the use of drugs such as non- A and B were continued at alternate months for three times steroidal anti-inflammatory, penicillamine and intravenous gold each. The total duration of treatment was 6 months. can be identified [5]. In the remaining 70% of patients, the disease If there was no response within 4 months of starting of is regarded as primary or iMN. initial treatment, failure of MP regimen was considered Membranous glomerulopathy is a common cause of primary and alternative therapy including macrolimus and steroids glomerular disease in diabetics [6–8]. It can occur either as an were started. Alternatives such as mycophenolate mofetil isolated lesion or superimposed with diabetic nephropathy (DN). (MMF), rituximab and adrenocorticotropic hormone were con- Nephrotic syndrome occurs late in the course of DN, indicating an sidered if both tacrolimus and the MP regimen failed. advanced stage of glomerular damage [9]. Pathological changes in DN are characterized by mesangial expansion forming nodular glomerulosclerosis, thickening of glomerular basement mem- Definitions brane and arteriolar hyalinization, and in later stages global glo- merulosclerosis and marked interstitial fibrosis. An expeditious Response: achievement of either complete remission or partial onset of the nephrotic syndrome in diabetic patients may result remission from either an accelerated progression of DN or development of Complete remission (CR): a decrease of 24-h urinary protein another primary glomerulopathy such as membranous, minimal excretion to at least 500 mg/day at least 1-month duration with change or IgA nephropathy [9]. Coexistence of diabetes and MN plasma creatinine stable at <1.5 mg/dL. may pose both diagnostic and therapeutic challenges to the treat- Partial remission (PR): a reduction in the rate of urinary pro- ing physician. Both DN and MN can present as proteinuric ill- tein excretion to between 0.5 and 2 g/day for at least 1-month nesses and may be indistinguishable. Steroids and other duration with plasma creatinine stable at <1.5 mg/dL or immunosuppressive drugs such as calcineurin inhibitors used to decrease in proteinuria of >50% from baseline. treat iMN may worsen glycemic control and exacerbate infections Treatment failure/nonresponder: if there is no CR or PR in diabetics. Despite the common occurrence of MN as a nondia- within 4 months of starting of given treatment. betic primary glomerular disease, there is a paucity of data on its Relapse: reappearance of proteinuria of >0.2 g/day in a natural history, management and outcome in diabetics. Hence we patient who had either CR or PR. Renal failure: a persistent dou- performed a retrospective analysis of the clinical profile, diagnos- bling of serum creatinine over the baseline values. tic and therapeutic difficulties encountered in treating this subset of iMN. Results Materials and methods A total of 134 patients with DM were evaluated during the study In this retrospective observational study, we analyzed the data of period and biopsied in suspicion of NDRD. Out of these 134 all diabetics, evaluated for nondiabetic renal disease (NDRD) and patients, 16 patients were found to have iMN in coexistence found to have iMN, between January 2000 and June 2015. The with DM. The duration of follow-up for MN ranged from 15 to study was carried out in a major tertiary care center situated in 75 months. the northern part of India. The demographic profiles, details of illness and hospitalization, management and outcomes of the patients were retrieved from the electronic Hospital Information Demographic and clinical characteristics System. All patients were male with a mean age of 546 11.77 years We included all patients with diabetes mellitus (DM) with (range: 23–69 years) (Table 1). All patients except one had Type iMN and excluded patients with known secondary causes like 2 DM. Indications of kidney biopsy were rapid-onset proteinuria infection with hepatitis B or C virus or HIV, known malignancy, or massive proteinuria, or both. The mean 6 standard deviation positive antibodies to double-stranded DNA, or current treat- proteinuria was 9.4 g6 2.85 g/day. Diabetic retinopathy (DR) was ment with gold or penicillamine. present in only four patients. Other complications of DM such as distal sensory polyneuropathy were present in five patients Management protocol and coronary artery disease was present in 5 of 16 patients. Of Supportive care was given to all patients with iMN with neph- the 16 patients, 11 were stratified as having high risk and 5 as rotic syndrome including angiotensin-converting enzyme an having intermediate risk for progression to end-stage renal inhibitors and/or angiotensin receptor blockers to control pro- disease. Renal histopathology was suggestive of pure MN in 12 teinuria and to maintain blood pressure 130/80 mmHg (protei- of 16 patients while the remaining 4 had MN (Figure 1)in nuria < 1 g/day) or 125/75 mmHg (proteinuria > 1 g/day), coexistence with DN. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 48 | D. Bhadauria et al. Table 1. Demographic and clinical characteristics of patients of iMN in coexistence with DM Patient Age Type Indication DR/other SAlb SCr Anti Risk Renal Follow-up Treatment Outcome no. (years)/ of DM/ of kidney micro/macro mg/dL/ (onset/last) PLA R stratification biopsy duration at last gender duration biopsy vascular UP (g/day) (mg/dL) Ab of iMN diagnosis (months) follow-up (years) complication 1 69/M 2/18 1 DR /CAD 2.1/8.2 0.9/1.5 NA High MN þ DN 19 MP!CNI!MMF Relapse 2 61/M 2/10 1 DR /PN/CAD 1.9/7.5 1.1/1.3 NA Intermediate MN 75 MP PR 3 42/M 2/6 2 DR /None 2.0/12.5 1.0/1.2 NA High MN 29 MP!CNI PR 4 62/M 2/9 1 þ2DR /PN/CAD 1.8/11.6 1.2/1.4 NA High MN 33 MP!CNI!MMF NR 5 45/M 2/4 1 DR /None 2.3/8.5 0.9/1.3 NA High MN 47 MP!CNI!MMF PR 6 69/M 2/13 1 DR /None 2.8/5.4 1.1/1.2 NA Intermediate MN þ DN 23 MP!CNI!MMF CR 7 55/M 2/11 1 þ2DR /PN/CAD 2.3/10.4 1.0/1.4 NA High MN 30 MP!CNI!MMF NR 8 51/M 2/9 2 DR /None 2.0/13.1 1.2/1.6 NA High MN 18 MP!CNI!MMF NR 9 48/M 2/7 1 DR /None 3.0/4.9 0.9/1.3 109.96 Intermediate MN 20 MP CR 10 56/M 2/5 2 DR /None 2.0/12.1 1.1/1.3 NA High MN 26 MP!CNI!MMF CR 11 50/M 2/4 1 þ2DR /None 1.8/11.6 1.2/1.4 NA High MN 29 MP!CNI!MMF PR 12 23/M 1/12 1 DR /None 2.9/6.0 1.1/7 NA Intermediate MN 124 MP!CNI!MMF ESRD 13 67M 2/19 2 DR /PN 2.1/13.0 1.0/1.2 Nil High MN þ DN 24 MP!CNI!MMF CR 14 57/M 2/9 1 DR /None 2.8/5.9 1.1/1.1 106.48 Intermediate MN 16 MP!CNI CR 15 61/M 2/12 1 þ2DR /PN/CAD 2.3/10.6 1.2/1.0 NA High MN þ DN 38 MP!CNI!MMF PR 16 48/M 2/4 1 DR /None 2.2/9.2 1.2/1.3 1.73 High MN 15 MP!CNI CR UP: urinary protein; SAlb: serum albumin; SCr: serum creatinine; Anti PLA R Ab: anti-phospholipase A receptor antibody; M: male; rapid-onset proteinuria¼ 1; massive 2 2 proteinuria¼ 2; PN: distal sensory polyneuropathy; CAD: coronary artery disease; CNI: calcineurin inhibitors; ESRD: end-stage renal disease. Fig. 1. Images from a case of case of MN with early DN. Periodic acidSchiff (A20 and B40) and silver stain (C40) showing argyrophillic spikes (red arrow) and one nodule of exudative lesion (black and blue arrows) characteristic of diabetes. Table 2. Response and adverse effects of different regimens used to treat patients with iMN in coexistence with DM Regimen Responders Relapse Switch to Mean proteinuria Cytopenias Infections Worsening other treatment before TT of diabetes (NR þ IT þ R) MP regimen, N ¼ 16 3 (2 CRþ 1 PR) 1 14 (11 þ 2 þ 1) 9.40 6 3.14 g/day 6 4 7 CNI, N ¼ 14 4 (2 CRþ 2 PR) 1 11 (6 þ 4 þ 1) 10.28 6 2.81 g/day 0 2 11 MMF, N ¼ 11 7 (4 CRþ 3 PR) 1 4 (3 þ 0 þ 1) 8.92 6 2.32 g/day 2 1 0 NR: nonresponder; IT: intolerant; R: relapse; TT: treatment; CNI: calcineurin inhibitors. after treatment with the MP regimen was treated subsequently Management and outcome with tacrolimus and low-dose steroids. All patients (n¼ 16) with iMN were treated with the MP regimen Of the 14 patients who were treated with tacrolimus and after adequate supportive management (Figure 1 and Table 2). low-dose steroids, only 4 patients (28.57%) had responded and Of the 16 patients, only 3 (18%) patients had responded to the the remaining 10 patients (71.43%) were switched to MMF and MP regimen and the remaining 13 (82%) patients were switched low-dose steroids. Of these 10 patients, 4 patients were unable to tacrolimus and low-dose steroids. Persistent cytopenias and to tolerate tacrolimus. They had a persistent worsening of dia- recurrent infections were contributory to poor tolerance and a betes even on insulin therapy. One patient developed ketosis switch in the regimen in two patients. One patient who relapsed during treatment with tacrolimus. One patient relapsed after Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 iMN in coexistence with diabetes mellitus | 49 treatment with tacrolimus and low-dose steroids and was et al. features suggestive of diabetic glomerulosclerosis were treated subsequently with MMF and low-dose steroids. seen in 12 of the 15 patients with MN [15]. Of the 11 patients who were treated with MMF and low-dose The treatment of MN relies on immunosuppression in indi- steroid, 7 patients (63.63%) had responded to treatment. The viduals who have not derived benefit from supportive therapy. remaining three (27.27%) nonresponders were managed with Delaying immunosuppression in patients with iMN categorized supportive treatment and planned for rituximab therapy but as high risk could result in disease progression and may be were lost to follow-up. One patient who relapsed after treat- associated with more frequent and severe adverse effects. ment with MMF and low-dose steroid was treated subsequently There is no published literature examining the response to with supportive management. immunosuppressive medications in iMN patients with diabetes. Current knowledge of immunosuppression is derived from studies on isolated iMN. Alkylating agents with steroids are the Adverse effects of treatment most widely used initial immunosuppressive therapy for iMN. Of the 16 patients of iMN with coexisting DM, 5 patients (31.25%) The response rate to MP regimen is as high as 93% [16]. developed treatment-related side effects significant enough to However, in our study, only 18% of the patients responded to necessitate a regimen switch (Table 2). The most common cause the MP regimen. Calcineurin inhibitors are used in patients who of switch was worsening of diabetes (three patients) followed by are unresponsive to other immunosuppressive medications, cytopenias (one patient) and recurrent infections (one patient). including alkylating agents, with response rates varying from Immunosuppression was not stopped in any patient treated 56% to 85% [17, 18]. The majority of CRs occur after 6 months of with MMF owing to treatment-related toxicity. treatment and the number increases with the duration of ther- apy [17–19]. However, only 28.57% patients responded while similar percentages of patients were intolerant to the Discussion tacrolimus-based regimen. In contrast, however, 63.63% of the patients responded to MMF. Studies examining the role of MMF To the best of our knowledge, we report the largest data set in in the treatment of iMN have produced mixed results [20–22]. the literature to date on the clinical behavior and management Two randomized controlled trials demonstrated a similar effi- of iMN in coexistence with DM. In this study, we have observed cacy of MMF as compared to alkylating agents, with a response that patients with iMN in coexistence with DM responded rate of 65% [20, 21]. A similar response rate to MMF was seen poorly to the MP regimen, which is contrary to our logical belief. in our study. The reason for this poor response to alkylating They had better response to MMF in comparison with the MP agents and tacrolimus and a fair response to MMF remains elu- and tacrolimus-based regimen. Treatment-related toxicity was sive and needs further study. Adverse effects related to treat- also seen less with MMF in comparison with the MP and tacroli- ment were observed with all the regimens. However, adverse mus-based regimen. effects requiring treatment withdrawal were seen only with the The incidence of these NDRDs varies between 18% and 80% MP regimen and tacrolimus, and not MMF. Worsening of the among different studies based on the indication used for renal control of diabetes was the most common adverse effect and biopsy [10, 11]. MN is a common primary glomerular disease was more common in patients treated with tacrolimus. seen in diabetic patients [6–8]. Others include IgA nephropathy, Limitations of our study include its retrospective nature and focal segmental glomerulosclerosis, membranoproliferative glo- the relatively small number of patients. The major strength of merulonephritis and minimal change disease [12]. our study is being largest dataset in the literature to date on The mean age of the patients in our cohort was clinical behavior and management of iMN in coexistence with 546 11.77 years with a striking male predilection similar to the DM. findings observed by Mami et al. [13]. The median duration of In conclusion, our study presents a descriptive account of diabetes was 108 months (range: 48–228 months). The median the clinical course, treatment outcomes and adverse effects of duration of diabetes in the study done by Mami et al. was patients with iMN and diabetes. In this largest series of patients 71.4 months [13]. These findings are in accordance with the with iMN coexisting with DM, an unforeseen poor response to study done by Prakash et al., who concluded that NDRD is more the MP regimen was observed. Treatment-related toxicity was common in patients with short duration of diabetes (<10 years also less common with MMF in comparison with the MP regi- duration) [14]. The indications for renal biopsy in our study men and tacrolimus-based regimen. An a almost similar included rapid-onset proteinuria in 50% of the patients, while response was noted with the MMF and tacrolimus-based regi- the remaining had massive proteinuria or a combination of mens. However, treatment-related toxicities leading to with- both. The mean 6 standard deviation proteinuria was drawal of treatment were observed frequently in tacrolimus- 9.4 6 2.85 g/day. This is contrary to the findings of Mak et al., based regimen. who showed that non-nephrotic range proteinuria is a predictor of NDRD. However, there were no cases of MN in their series [11]. DR was absent in 12 patients (75%) in our cohort. Four patients (25%) with DR had either iMN or a combination of iMN Conflict of interest statement and DN. Prakash et al. showed that DR can be seen in 40% of the patients with non-DN either alone or in combination with DN None declared. [10]. Interestingly, among these four patients who had DR only one patient had DN and it was coexistent with iMN. Among the References four patients who had features of DN in biopsy, only one had DR. These findings are consistent with the observation by 1. McQuarrie EP, Mackinnon B, Stewart GA et al; on behalf of Prakash et al., that, DR is a poor predictor of DN as DN can be the Scottish Renal Biopsy Registry Membranous nephrop- present in 50% of the patients without DR [10]. Twelve patients athy remains the commonest primary cause of nephrotic (75%) had isolated MN and four patients (25%) had a combina- syndrome in a northern European Caucasian population. tion of DN and MN. In the case series reported by Yoshikawa Nephrol Dial Transplant 2010; 25: 1009–1010 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 50 | D. Bhadauria et al. 13. Mami I, Harzallah A, Kaaroud H et al. MP440 membranous 2. Kraus MA, Punj S, Cimbaluk D et al. Resurgence of membra- nous nephropathy in African Americans in inner city glomerulonephritis in patients with type 2 diabetes. Nephrol Chicago. Clin Kidney J 2013; 6: 373–378 Dial Transplant 2016; 31 (Suppl 1): i486 3. Hanko JB, Mullan RN, O’Rourke DM et al. The changing pat- 14. Prakash J, Gupta T, Prakash S et al. Non-diabetic renal dis- tern of adult primary glomerular disease. Nephrol Dial ease in type 2 diabetes mellitus: Study of renal - retinal rela- Transplant 2009; 24: 3050–3054 tionship. Indian J Nephrol 2015; 25: 222–228 4. Changing Incidence of Glomerular Disease in Olmsted County, 15. Yoshikawa Y, Truong LD, Mattioli CA et al. Membranous glo- Minnesota: A 30-Year Renal Biopsy Study. http://cjasn.asnjour merulonephritis in diabetic patients: a study of 15 cases and nals.org/content/1/3/483.abstract?ijkey¼8efcff83b8b2fa review of the literature. Mod Pathol 1990; 3: 36–42 d114a7f50f2ca08be977106972&keytype2¼tf_ipsecsha (26 16. Ponticelli C, Altieri P, Scolari F et al. A randomized study September 2016, date last accessed) comparing methylprednisolone plus chlorambucil versus 5. Glassock RJ. Secondary membranous glomerulonephritis. methylprednisolone plus cyclophosphamide in idiopathic Nephrol Dial Transplant 1992; 7: 64–71 membranous nephropathy. J Am Soc Nephrol 1998; 9: 444–450 6. Jin Kim Y, Hyung Kim Y, Dae Kim K et al. Nondiabetic kidney 17. Chen M, Li H, Li X-Y et al. Tacrolimus combined with cortico- diseases in type 2 diabetic patients. Kidney Res Clin Pract 2013; steroids in treatment of nephrotic idiopathic membranous 32: 115–120 nephropathy: a multicenter randomized controlled trial. Am 7. Nondiabetic Renal Disease in type 2 Diabetes Mellitus Patients: A J Med Sci 2010; 339: 233–238 Clinicopathological Study. https://www.ncbi.nlm.nih.gov/pmc/ 18. Praga M, Barrio V, Juarez GF et al. Grupo Espanol de Estudio articles/PMC3968638/#ref5 (26 September 2016, date last de la Nefropatıa Membranosa. Tacrolimus monotherapy in accessed) membranous nephropathy: a randomized controlled trial. 8. Soni SS, Gowrishankar S, Kishan AG et al. Non diabetic renal Kidney Int 2007; 71: 924–930 disease in type 2 diabetes mellitus. Nephrology (Carlton) 2006; 19. Fritsche L, Budde K, Farber L et al. Treatment of membranous 11: 533–537 glomerulopathy with cyclosporin A: how much patience is 9. Mogensen CE, Christensen CK, Vittinghus E. The stages in required? Nephrol Dial Transplant 1999; 14: 1036–1038 diabetic renal disease. With emphasis on the stage of incipi- 20. Branten AJ, du Buf-Vereijken PW, Vervloet M et al.Mycophe- ent diabetic nephropathy. Diabetes 1983; 32: 64–78 nolate mofetil in idiopathic membranous nephropathy: a clin- 10. Prakash J, Lodha M, Singh SK et al. Diabetic retinopathy is a ical trial with comparison to a historic control group treated poor predictor of type of nephropathy in proteinuric type 2 with cyclophosphamide. Am J Kidney Dis 2007; 50: 248–256 diabetic patients. J Assoc Physicians India 2007; 55: 412–416 21. Chan TM, Lin AW, Tang SC et al. Prospective controlled study 11. Mak SK, Gwi E, Chan KW et al. Clinical predictors of non- on mycophenolate mofetil and prednisolone in the treat- diabetic renal disease in patients with non-insulin depend- ment of membranous nephropathy with nephrotic syn- ent diabetes mellitus. Nephrol Dial Transplant 1997; 12: drome. Nephrology (Carlton) 2007; 12: 576–581 2588–2591 22. Dussol B, Morange S, Burtey S et al. Mycophenolate mofetil 12. Renal Outcomes and Clinical Course of Nondiabetic Renal Diseases monotherapy in membranous nephropathy: a 1-year in Patients with Type 2 Diabetes. https://www.ncbi.nlm.nih. randomized controlled trial. Am J Kidney Dis 2008; 52: 699–705 gov/pmc/articles/PMC3759762/ (2 October 2016, date last accessed) Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Idiopathic membranous nephropathy in patients with diabetes mellitus: a diagnostic and therapeutic quandary!

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Abstract

Background: Proteinuria and renal dysfunction is common in diabetic patients and may occur due to variety of causes. Nondiabetic renal diseases (NDRD) account for 30% of the renal biopsies, and idiopathic membranous nephropathy (iMN) is a common non diabetic glomerular disease that can exist alone or in combination with diabetic nephropathy (DN). Immunosuppressants used in iMN may be associated with complications of worsening glycemic control and recurrent infections. There is a paucity of literature on the clinical course, outcomes and treatment adverse effects of patients with iMN and diabetes. Methods: We retrospectively analyzed the data of all diabetics, evaluated for NDRD and found to have iMN, between January 2000 and June 2015 in our institute. Results: A total of 134 patients with diabetes were biopsied for NDRD and 16 patients had iMN. Mean 6 standard deviation age was 546 11.77 years and the median duration of diabetes was 9.4 years. Twelve patients had isolated iMN and four patients had iMN coexisting with DN. Response rates of 18%, 35.71% and 63.63% were seen with Modified Ponticelli (MP) reg- imen, tacrolimus and mycophenolate mofetil (MMF), respectively. Five patients developed treatment-related adverse effects significant enough to necessitate a treatment change. Worsening glycemic control was the most common side effect. Adverse effects were less with the MMF compared with the MP regimen and tacrolimus. Conclusion: Patients with iMN coexisting with diabetes exhibit a poor response to the MP regimen. Treatment-related toxic- ity is less common with MMF in comparison with the MP regimen and tacrolimus-based regimen. An almost similar response was noted with MMF and tacrolimus-based regimen but there was more withdrawal from treatment due to toxic- ities observed in the latter. Key words: diabetes mellitus, membranous nephropathy, nephrotic syndrome Received: November 8, 2016. Editorial decision: April 19, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 iMN in coexistence with diabetes mellitus | 47 statins for hyperlipidemia, dietary salt restriction and diuretics Introduction if edema was present. Membranous nephropathy (MN) is a frequent cause of adult The Modified Ponticelli (MP) regimen was started if the pro- nephrotic syndrome, with a reported incidence of 5–10 cases per teinuria was more than 4 g/day and more than 50% of the base- million population per year in Northern Europe [1]. Studies have line value despite 6 months of supportive treatment, or if there reported an apparent reversal in the trend of the late 20th cen- was an unexplained >30% rise in the serum creatinine levels tury with regard to the frequencies of focal segmental glomerulo- within 6–12 months of treatment initiation. The MP regimen sclerosis and idiopathic membranous nephropathy (iMN) [2–4]. included methyl prednisolone (1 g) given by parenteral route for MN is emerging as the most common cause of adult nephrotic three consecutive days, followed by oral prednisolone (0.5 mg/ syndrome. In about one-third of patients with MN an underlying kg/day) for 27 days (Cycle A). Cycle A was followed by cyclo- cause such as infection, hematological or solid organ malignancy, phosphamide (2 mg/kg/day) orally for 1 month (Cycle B). Cycles systemic autoimmune disease or the use of drugs such as non- A and B were continued at alternate months for three times steroidal anti-inflammatory, penicillamine and intravenous gold each. The total duration of treatment was 6 months. can be identified [5]. In the remaining 70% of patients, the disease If there was no response within 4 months of starting of is regarded as primary or iMN. initial treatment, failure of MP regimen was considered Membranous glomerulopathy is a common cause of primary and alternative therapy including macrolimus and steroids glomerular disease in diabetics [6–8]. It can occur either as an were started. Alternatives such as mycophenolate mofetil isolated lesion or superimposed with diabetic nephropathy (DN). (MMF), rituximab and adrenocorticotropic hormone were con- Nephrotic syndrome occurs late in the course of DN, indicating an sidered if both tacrolimus and the MP regimen failed. advanced stage of glomerular damage [9]. Pathological changes in DN are characterized by mesangial expansion forming nodular glomerulosclerosis, thickening of glomerular basement mem- Definitions brane and arteriolar hyalinization, and in later stages global glo- merulosclerosis and marked interstitial fibrosis. An expeditious Response: achievement of either complete remission or partial onset of the nephrotic syndrome in diabetic patients may result remission from either an accelerated progression of DN or development of Complete remission (CR): a decrease of 24-h urinary protein another primary glomerulopathy such as membranous, minimal excretion to at least 500 mg/day at least 1-month duration with change or IgA nephropathy [9]. Coexistence of diabetes and MN plasma creatinine stable at <1.5 mg/dL. may pose both diagnostic and therapeutic challenges to the treat- Partial remission (PR): a reduction in the rate of urinary pro- ing physician. Both DN and MN can present as proteinuric ill- tein excretion to between 0.5 and 2 g/day for at least 1-month nesses and may be indistinguishable. Steroids and other duration with plasma creatinine stable at <1.5 mg/dL or immunosuppressive drugs such as calcineurin inhibitors used to decrease in proteinuria of >50% from baseline. treat iMN may worsen glycemic control and exacerbate infections Treatment failure/nonresponder: if there is no CR or PR in diabetics. Despite the common occurrence of MN as a nondia- within 4 months of starting of given treatment. betic primary glomerular disease, there is a paucity of data on its Relapse: reappearance of proteinuria of >0.2 g/day in a natural history, management and outcome in diabetics. Hence we patient who had either CR or PR. Renal failure: a persistent dou- performed a retrospective analysis of the clinical profile, diagnos- bling of serum creatinine over the baseline values. tic and therapeutic difficulties encountered in treating this subset of iMN. Results Materials and methods A total of 134 patients with DM were evaluated during the study In this retrospective observational study, we analyzed the data of period and biopsied in suspicion of NDRD. Out of these 134 all diabetics, evaluated for nondiabetic renal disease (NDRD) and patients, 16 patients were found to have iMN in coexistence found to have iMN, between January 2000 and June 2015. The with DM. The duration of follow-up for MN ranged from 15 to study was carried out in a major tertiary care center situated in 75 months. the northern part of India. The demographic profiles, details of illness and hospitalization, management and outcomes of the patients were retrieved from the electronic Hospital Information Demographic and clinical characteristics System. All patients were male with a mean age of 546 11.77 years We included all patients with diabetes mellitus (DM) with (range: 23–69 years) (Table 1). All patients except one had Type iMN and excluded patients with known secondary causes like 2 DM. Indications of kidney biopsy were rapid-onset proteinuria infection with hepatitis B or C virus or HIV, known malignancy, or massive proteinuria, or both. The mean 6 standard deviation positive antibodies to double-stranded DNA, or current treat- proteinuria was 9.4 g6 2.85 g/day. Diabetic retinopathy (DR) was ment with gold or penicillamine. present in only four patients. Other complications of DM such as distal sensory polyneuropathy were present in five patients Management protocol and coronary artery disease was present in 5 of 16 patients. Of Supportive care was given to all patients with iMN with neph- the 16 patients, 11 were stratified as having high risk and 5 as rotic syndrome including angiotensin-converting enzyme an having intermediate risk for progression to end-stage renal inhibitors and/or angiotensin receptor blockers to control pro- disease. Renal histopathology was suggestive of pure MN in 12 teinuria and to maintain blood pressure 130/80 mmHg (protei- of 16 patients while the remaining 4 had MN (Figure 1)in nuria < 1 g/day) or 125/75 mmHg (proteinuria > 1 g/day), coexistence with DN. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 48 | D. Bhadauria et al. Table 1. Demographic and clinical characteristics of patients of iMN in coexistence with DM Patient Age Type Indication DR/other SAlb SCr Anti Risk Renal Follow-up Treatment Outcome no. (years)/ of DM/ of kidney micro/macro mg/dL/ (onset/last) PLA R stratification biopsy duration at last gender duration biopsy vascular UP (g/day) (mg/dL) Ab of iMN diagnosis (months) follow-up (years) complication 1 69/M 2/18 1 DR /CAD 2.1/8.2 0.9/1.5 NA High MN þ DN 19 MP!CNI!MMF Relapse 2 61/M 2/10 1 DR /PN/CAD 1.9/7.5 1.1/1.3 NA Intermediate MN 75 MP PR 3 42/M 2/6 2 DR /None 2.0/12.5 1.0/1.2 NA High MN 29 MP!CNI PR 4 62/M 2/9 1 þ2DR /PN/CAD 1.8/11.6 1.2/1.4 NA High MN 33 MP!CNI!MMF NR 5 45/M 2/4 1 DR /None 2.3/8.5 0.9/1.3 NA High MN 47 MP!CNI!MMF PR 6 69/M 2/13 1 DR /None 2.8/5.4 1.1/1.2 NA Intermediate MN þ DN 23 MP!CNI!MMF CR 7 55/M 2/11 1 þ2DR /PN/CAD 2.3/10.4 1.0/1.4 NA High MN 30 MP!CNI!MMF NR 8 51/M 2/9 2 DR /None 2.0/13.1 1.2/1.6 NA High MN 18 MP!CNI!MMF NR 9 48/M 2/7 1 DR /None 3.0/4.9 0.9/1.3 109.96 Intermediate MN 20 MP CR 10 56/M 2/5 2 DR /None 2.0/12.1 1.1/1.3 NA High MN 26 MP!CNI!MMF CR 11 50/M 2/4 1 þ2DR /None 1.8/11.6 1.2/1.4 NA High MN 29 MP!CNI!MMF PR 12 23/M 1/12 1 DR /None 2.9/6.0 1.1/7 NA Intermediate MN 124 MP!CNI!MMF ESRD 13 67M 2/19 2 DR /PN 2.1/13.0 1.0/1.2 Nil High MN þ DN 24 MP!CNI!MMF CR 14 57/M 2/9 1 DR /None 2.8/5.9 1.1/1.1 106.48 Intermediate MN 16 MP!CNI CR 15 61/M 2/12 1 þ2DR /PN/CAD 2.3/10.6 1.2/1.0 NA High MN þ DN 38 MP!CNI!MMF PR 16 48/M 2/4 1 DR /None 2.2/9.2 1.2/1.3 1.73 High MN 15 MP!CNI CR UP: urinary protein; SAlb: serum albumin; SCr: serum creatinine; Anti PLA R Ab: anti-phospholipase A receptor antibody; M: male; rapid-onset proteinuria¼ 1; massive 2 2 proteinuria¼ 2; PN: distal sensory polyneuropathy; CAD: coronary artery disease; CNI: calcineurin inhibitors; ESRD: end-stage renal disease. Fig. 1. Images from a case of case of MN with early DN. Periodic acidSchiff (A20 and B40) and silver stain (C40) showing argyrophillic spikes (red arrow) and one nodule of exudative lesion (black and blue arrows) characteristic of diabetes. Table 2. Response and adverse effects of different regimens used to treat patients with iMN in coexistence with DM Regimen Responders Relapse Switch to Mean proteinuria Cytopenias Infections Worsening other treatment before TT of diabetes (NR þ IT þ R) MP regimen, N ¼ 16 3 (2 CRþ 1 PR) 1 14 (11 þ 2 þ 1) 9.40 6 3.14 g/day 6 4 7 CNI, N ¼ 14 4 (2 CRþ 2 PR) 1 11 (6 þ 4 þ 1) 10.28 6 2.81 g/day 0 2 11 MMF, N ¼ 11 7 (4 CRþ 3 PR) 1 4 (3 þ 0 þ 1) 8.92 6 2.32 g/day 2 1 0 NR: nonresponder; IT: intolerant; R: relapse; TT: treatment; CNI: calcineurin inhibitors. after treatment with the MP regimen was treated subsequently Management and outcome with tacrolimus and low-dose steroids. All patients (n¼ 16) with iMN were treated with the MP regimen Of the 14 patients who were treated with tacrolimus and after adequate supportive management (Figure 1 and Table 2). low-dose steroids, only 4 patients (28.57%) had responded and Of the 16 patients, only 3 (18%) patients had responded to the the remaining 10 patients (71.43%) were switched to MMF and MP regimen and the remaining 13 (82%) patients were switched low-dose steroids. Of these 10 patients, 4 patients were unable to tacrolimus and low-dose steroids. Persistent cytopenias and to tolerate tacrolimus. They had a persistent worsening of dia- recurrent infections were contributory to poor tolerance and a betes even on insulin therapy. One patient developed ketosis switch in the regimen in two patients. One patient who relapsed during treatment with tacrolimus. One patient relapsed after Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 iMN in coexistence with diabetes mellitus | 49 treatment with tacrolimus and low-dose steroids and was et al. features suggestive of diabetic glomerulosclerosis were treated subsequently with MMF and low-dose steroids. seen in 12 of the 15 patients with MN [15]. Of the 11 patients who were treated with MMF and low-dose The treatment of MN relies on immunosuppression in indi- steroid, 7 patients (63.63%) had responded to treatment. The viduals who have not derived benefit from supportive therapy. remaining three (27.27%) nonresponders were managed with Delaying immunosuppression in patients with iMN categorized supportive treatment and planned for rituximab therapy but as high risk could result in disease progression and may be were lost to follow-up. One patient who relapsed after treat- associated with more frequent and severe adverse effects. ment with MMF and low-dose steroid was treated subsequently There is no published literature examining the response to with supportive management. immunosuppressive medications in iMN patients with diabetes. Current knowledge of immunosuppression is derived from studies on isolated iMN. Alkylating agents with steroids are the Adverse effects of treatment most widely used initial immunosuppressive therapy for iMN. Of the 16 patients of iMN with coexisting DM, 5 patients (31.25%) The response rate to MP regimen is as high as 93% [16]. developed treatment-related side effects significant enough to However, in our study, only 18% of the patients responded to necessitate a regimen switch (Table 2). The most common cause the MP regimen. Calcineurin inhibitors are used in patients who of switch was worsening of diabetes (three patients) followed by are unresponsive to other immunosuppressive medications, cytopenias (one patient) and recurrent infections (one patient). including alkylating agents, with response rates varying from Immunosuppression was not stopped in any patient treated 56% to 85% [17, 18]. The majority of CRs occur after 6 months of with MMF owing to treatment-related toxicity. treatment and the number increases with the duration of ther- apy [17–19]. However, only 28.57% patients responded while similar percentages of patients were intolerant to the Discussion tacrolimus-based regimen. In contrast, however, 63.63% of the patients responded to MMF. Studies examining the role of MMF To the best of our knowledge, we report the largest data set in in the treatment of iMN have produced mixed results [20–22]. the literature to date on the clinical behavior and management Two randomized controlled trials demonstrated a similar effi- of iMN in coexistence with DM. In this study, we have observed cacy of MMF as compared to alkylating agents, with a response that patients with iMN in coexistence with DM responded rate of 65% [20, 21]. A similar response rate to MMF was seen poorly to the MP regimen, which is contrary to our logical belief. in our study. The reason for this poor response to alkylating They had better response to MMF in comparison with the MP agents and tacrolimus and a fair response to MMF remains elu- and tacrolimus-based regimen. Treatment-related toxicity was sive and needs further study. Adverse effects related to treat- also seen less with MMF in comparison with the MP and tacroli- ment were observed with all the regimens. However, adverse mus-based regimen. effects requiring treatment withdrawal were seen only with the The incidence of these NDRDs varies between 18% and 80% MP regimen and tacrolimus, and not MMF. Worsening of the among different studies based on the indication used for renal control of diabetes was the most common adverse effect and biopsy [10, 11]. MN is a common primary glomerular disease was more common in patients treated with tacrolimus. seen in diabetic patients [6–8]. Others include IgA nephropathy, Limitations of our study include its retrospective nature and focal segmental glomerulosclerosis, membranoproliferative glo- the relatively small number of patients. The major strength of merulonephritis and minimal change disease [12]. our study is being largest dataset in the literature to date on The mean age of the patients in our cohort was clinical behavior and management of iMN in coexistence with 546 11.77 years with a striking male predilection similar to the DM. findings observed by Mami et al. [13]. The median duration of In conclusion, our study presents a descriptive account of diabetes was 108 months (range: 48–228 months). The median the clinical course, treatment outcomes and adverse effects of duration of diabetes in the study done by Mami et al. was patients with iMN and diabetes. In this largest series of patients 71.4 months [13]. These findings are in accordance with the with iMN coexisting with DM, an unforeseen poor response to study done by Prakash et al., who concluded that NDRD is more the MP regimen was observed. Treatment-related toxicity was common in patients with short duration of diabetes (<10 years also less common with MMF in comparison with the MP regi- duration) [14]. The indications for renal biopsy in our study men and tacrolimus-based regimen. An a almost similar included rapid-onset proteinuria in 50% of the patients, while response was noted with the MMF and tacrolimus-based regi- the remaining had massive proteinuria or a combination of mens. However, treatment-related toxicities leading to with- both. The mean 6 standard deviation proteinuria was drawal of treatment were observed frequently in tacrolimus- 9.4 6 2.85 g/day. This is contrary to the findings of Mak et al., based regimen. who showed that non-nephrotic range proteinuria is a predictor of NDRD. However, there were no cases of MN in their series [11]. DR was absent in 12 patients (75%) in our cohort. Four patients (25%) with DR had either iMN or a combination of iMN Conflict of interest statement and DN. Prakash et al. showed that DR can be seen in 40% of the patients with non-DN either alone or in combination with DN None declared. [10]. Interestingly, among these four patients who had DR only one patient had DN and it was coexistent with iMN. Among the References four patients who had features of DN in biopsy, only one had DR. These findings are consistent with the observation by 1. McQuarrie EP, Mackinnon B, Stewart GA et al; on behalf of Prakash et al., that, DR is a poor predictor of DN as DN can be the Scottish Renal Biopsy Registry Membranous nephrop- present in 50% of the patients without DR [10]. Twelve patients athy remains the commonest primary cause of nephrotic (75%) had isolated MN and four patients (25%) had a combina- syndrome in a northern European Caucasian population. tion of DN and MN. In the case series reported by Yoshikawa Nephrol Dial Transplant 2010; 25: 1009–1010 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018 50 | D. Bhadauria et al. 13. Mami I, Harzallah A, Kaaroud H et al. MP440 membranous 2. Kraus MA, Punj S, Cimbaluk D et al. Resurgence of membra- nous nephropathy in African Americans in inner city glomerulonephritis in patients with type 2 diabetes. Nephrol Chicago. Clin Kidney J 2013; 6: 373–378 Dial Transplant 2016; 31 (Suppl 1): i486 3. Hanko JB, Mullan RN, O’Rourke DM et al. The changing pat- 14. Prakash J, Gupta T, Prakash S et al. Non-diabetic renal dis- tern of adult primary glomerular disease. Nephrol Dial ease in type 2 diabetes mellitus: Study of renal - retinal rela- Transplant 2009; 24: 3050–3054 tionship. Indian J Nephrol 2015; 25: 222–228 4. Changing Incidence of Glomerular Disease in Olmsted County, 15. Yoshikawa Y, Truong LD, Mattioli CA et al. Membranous glo- Minnesota: A 30-Year Renal Biopsy Study. http://cjasn.asnjour merulonephritis in diabetic patients: a study of 15 cases and nals.org/content/1/3/483.abstract?ijkey¼8efcff83b8b2fa review of the literature. Mod Pathol 1990; 3: 36–42 d114a7f50f2ca08be977106972&keytype2¼tf_ipsecsha (26 16. Ponticelli C, Altieri P, Scolari F et al. A randomized study September 2016, date last accessed) comparing methylprednisolone plus chlorambucil versus 5. Glassock RJ. Secondary membranous glomerulonephritis. methylprednisolone plus cyclophosphamide in idiopathic Nephrol Dial Transplant 1992; 7: 64–71 membranous nephropathy. J Am Soc Nephrol 1998; 9: 444–450 6. Jin Kim Y, Hyung Kim Y, Dae Kim K et al. Nondiabetic kidney 17. Chen M, Li H, Li X-Y et al. Tacrolimus combined with cortico- diseases in type 2 diabetic patients. Kidney Res Clin Pract 2013; steroids in treatment of nephrotic idiopathic membranous 32: 115–120 nephropathy: a multicenter randomized controlled trial. Am 7. 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Renal Outcomes and Clinical Course of Nondiabetic Renal Diseases monotherapy in membranous nephropathy: a 1-year in Patients with Type 2 Diabetes. https://www.ncbi.nlm.nih. randomized controlled trial. Am J Kidney Dis 2008; 52: 699–705 gov/pmc/articles/PMC3759762/ (2 October 2016, date last accessed) Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/46/3978692 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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