Clinical Kidney Journal, 2018, 1–6 doi: 10.1093/ckj/sfy031 Exceptional Case EX C EPT I O NA L C A S E Membranous nephropathy due to chronic mercury poisoning from traditional Indian medicines: report of five cases Manan Doshi, Rajeev A. Annigeri, Prakash C. Kowdle, Budithi Subba Rao and Mahendran Varman Department of Nephrology, Apollo Hospitals, Chennai, Tamil Nadu, India Correspondence and offprint requests to: Rajeev A. Annigeri; E-mail: firstname.lastname@example.org ABSTRACT Mercury contained in traditional medicines can cause chronic poisoning, which can cause membranous nephropathy (MN). We report ﬁve cases of nephrotic syndrome caused by MN with evidence of chronic mercury poisoning due to consumption of traditional Indian medicines such as Siddha and Ayurveda, which to our knowledge are the ﬁrst such reports. All patients were seronegative for antibodies against phospholipase A2 receptor (PLA2R). Two patients, who had severe nephrotic syndrome, had received Siddha medicine for prolonged period and oral chelation with dimercaptopropane-1-sulfonic acid was successful in eliminating mercury, resulting in an improvement in nephrotic state in these patients. We suggest that mercury poisoning should be entertained in patients with anti-PLA2R antibody-negative MN, with history of consumption of traditional Indian medicines. Keywords: dimercaptopropane-1-sulfonic acid, membranous nephropathy, mercury, nephrotic syndrome, traditional Indian medicine INTRODUCTION several systems of traditional medicines. Chronic heavy metal exposure following environmental or medicinal exposure is an Membranous nephropathy (MN) is the leading cause of ne- important, but under-recognized cause of renal damage. phrotic syndrome in adults. It is characterized by basement Renal manifestations due to mercury toxicity are acute membrane thickening with minimal or no cellular proliferation kidney injury due to acute tubular necrosis, tubulointerstitial and the presence of immune deposits on the epithelial side of nephritis, and glomerulonephritis due to MN and minimal the glomerular capillary wall . MN most often is primary (idio- change disease . pathic), which accounts for 75% of cases, while the remaining We present five cases of nephrotic syndrome due to MN, cases may be associated with various secondary causes . proven by renal biopsy. All cases were investigated for second- For centuries, mercury was an essential part of many differ- ent systems of medicine and was used as a diuretic, antibacte- ary causes of MN, since they were negative for anti- phospholipase A2 receptor (PLA2R) antibodies and enquiry rial agent and laxative. Currently, mercury is no longer used in revealed that they had been consuming traditional Indian medi- the allopathic system of medicine due to its recognized toxicity. However, heavy metals including mercury are still being used in cines such as Siddha and Ayurveda. The association between Received: 7.10.2017. Editorial decision: 14.3.2018 V C The Author(s) 2018. 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 email@example.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy031/5032560 by Ed 'DeepDyve' Gillespie user on 07 June 2018 2| M. Doshi et al. the use of mercury-containing skin-lightening creams as well 5 months. She had noticed a lump in her left breast in 2011, as Chinese traditional medicines and MN has been described which she ignored, which was later diagnosed as carcinoma of previously , but such an association has not been reported the breast in 2015. She opted for Siddha medicine for carcinoma previously in patients taking traditional Indian medicines. We of the breast, which she took for 12 months starting January present these cases to emphasize the importance of MN caused 2016. She developed oral ulcerations and bilateral pedal edema by mercury contained in traditional medicines, a reversible 9 months after initiation of the treatment. On evaluation, she cause of the nephrotic syndrome, which can be easily over- was detected to have proteinuria (dipstick 3þ) and microscopic looked unless a careful drug history is taken. hematuria (6–8 red blood cells/high power field). The laboratory results at presentation are shown in Table 1. Renal biopsy showed 20 glomeruli that were enlarged and there was mild in- Case 1 (index case) crease in mesangial cellularity with underlying patent capillar- A 47-year-old male with a history of diabetes and hypertension ies and uniformly thickened capillary basement membrane for 5 years, well controlled on oral drugs, presented in (BM). Eight glomeruli showed segmental endothelial prolifera- September 2016, with a history of gradual onset of edema and tion with infiltration by numerous neutrophils (Figure 2A). Few reduced urine output of 1 week duration. On evaluation, he had glomeruli showed segmental sclerosis and one showed partial anasarca, ascites and no evidence of diabetic retinopathy. The fibroepithelial crescent (Figure 2B). Immunofluorescence stain- laboratory results at presentation are shown in Table 1. A renal ing showed peripheral fine granular deposits of IgG and C3c and biopsy was done, which showed enlarged glomeruli with widely minimal C1q in the glomeruli. Electron microscopy (EM) study patent capillary loops. The capillary walls were uniformly thick- showed uniformly thickened BM and subepithelial electron ened (Figure 1A) and silver staining showed fine linear spikes dense deposits (Figure 3) and no electron dense deposits else- on capillary walls (Figure 1B). Tubulointerstitium was unre- where, which was consistent with MN. markable. Immunofluorescence showed peripheral granular Based on our previous experience with the index case, we deposits of immunoglobulin G (IgG) and C3c in the glomeruli suspected mercury poisoning causing MN, which was con- suggestive of MN. There was no evidence of underlying malig- firmed by the presence of very high levels of mercury in the nancy. He was started on a combination of steroid and cytotoxic urine (Table 1). The patient received oral prednisolone, which drug therapy for MN and received oral prednisolone and one in- was discontinued after 2 weeks in view of intolerance and un- travenous pulse of cyclophosphamide (500 mg/m ). He received certainty about the efficacy of steroid in mercury-induced MN. telmisartan intermittently, but did not tolerate it well. On en- She was initiated on Dimaval at a dose of 300 mg/day and the quiry about the intake of medicines, a month after initial pre- dose was increased to 400 mg/day, which was well tolerated. sentation, he admitted to taking Siddha medicine for 6 months She received a total of 12 g of Dimaval over 6 weeks. There was a for sinusitis, which he had stopped recently before renal biopsy. 20-fold increase in urinary mercury excretion following oral A chemical analysis of the Siddha medicine consumed by him chelation therapy, confirming the efficacy of the drug. The urine showed a very high concentration of mercury (132.95 mg/kg) mercury had reduced to an insignificant level (2.66 lg/L and and no trace of lead or arsenic. His urine mercury was markedly 4.79 lg/day) after the completion of Dimaval therapy. There was elevated (Table 1). He was initiated on oral chelation therapy a significant improvement in nephrotic state after chelation with dimercaptopropane-1-sulfonic acid (DMPS), available as therapy, with improvement in serum albumin to 3.0 g/dL and V R 100 mg tablets of Dimaval . He initially received 800 mg of proteinuria (urine PCR: 0.9 g/g of creatinine). Dimaval daily in three divided doses, which was reduced to 400 mg/day due to gastrointestinal intolerance. He received a to- Case 3 tal of 8 g (80 tablets) of Dimaval over 3 weeks. There was more than a 100-fold increase in urine mercury excretion while re- A 41-year-old female presented with leg edema for 4 months in ceiving Dimaval, which confirmed the efficacy of the drug to March 2017. She was detected to have hypertension 1 month chelate and remove mercury. He had multiple infections such prior to presentation. She had skin rashes for 10 years with in- termittent flares, which were treated with topical Ayurveda as cellulitis and viral pneumonitis following the initiation of steroid therapy, necessitating hospitalization on several occa- medicine. She was evaluated elsewhere and found to have ne- sions. Oral steroid was given intermittently and irregularly and phrotic syndrome and was started empirically on oral predniso- was eventually discontinued after 3 months. He remained se- lone. The laboratory results at presentation are summarized in verely nephrotic and developed severe bilateral upper abdomi- Table 1. Renal biopsy showed features typical of MN. The urine nal pain, 4 months after the initial presentation. He was found analysis showed a mildly elevated mercury level (Table 1). She to have bilateral renal vein thrombosis on computed tomogra- was advised to stop topical Ayurveda medicine and steroid was phy and he received oral anticoagulation with coumarin for stopped. She was counselled about chelation therapy in case 6 months. He recovered well from renal vein thrombosis and nephrotic syndrome did not improve. However, after initial received no further immunosuppression. Serial urine mercury evaluation, there was no follow-up. excretion measurements showed a decline and eventual disap- pearance over a period of 1 year. He showed gradual, but sus- Case 4 tained improvement in symptoms. At 18 months, he had no A 48-year-old male, known to have diabetes mellitus for 4 years significant leg edema, serum creatinine was 1.2 mg/dL, serum and hypertension for 1 month, presented with fever and arthral- albumin was 3.6 g/dL and urine protein/creatinine ratio (PCR) gia and foamy urination in December 2016. He had mild edema was 5.5 g/g of creatinine. on examination. The laboratory results at presentation are shown in Table 1. Renal biopsy showed 28 glomeruli, which Case 2 showed features typical of MN. The patient gave a history of con- A 47-year-old female with no comorbidities presented in sumption of Ayurveda medicine for bronchial asthma during the January 2017, with a history of bilateral pedal edema for past 2 months. Blood mercury level was mildly elevated at 24 lg/L Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy031/5032560 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Cases of mercury-induced MN | 3 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy031/5032560 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 1. Summary of cases Parameter Case 1 Case 2 Case 3 Case 4 Case 5 Age (years) 47 47 41 48 70 Type of alternative medication Siddha Siddha Ayurveda Ayurveda Ayurveda Route of administration Oral Oral Topical Oral Oral Duration of traditional medication 5 months 1 year 10 years 2 months 2 months Clinical syndrome Nephrotic Nephrotic Nephrotic Nephrotic Nephrotic syndrome syndrome syndrome syndrome syndrome Serum creatinine (normal: 0.6–1.1 for women, 0.9 0.52 0.5 0.7 1.02 0.8–1.3 for men; mg/dL) Serum albumin (normal: 3.5–5.2 g/dL) 2.1 2.3 3.4 3.4 2.2 Proteinuria (g/g of creatinine) 11.6 10.3 6.21 13.7 8.58 Renal biopsy MN MN with focal MN MN MN proliferation and 1/20 ﬁbroepithelial crescent Immunoﬂuorescence Peripheral granular Peripheral granular Peripheral granular Peripheral granular No glomeruli deposits of IgG, C3c deposits of IgG, deposits of IgG deposits of IgG, C3c with lesser amount C3c with minimal and moderate and C1q with of C1q amount of C1q amounts of IgA peripheral and and C3c mesangial IgA Anti-PLA2R antibody assay Negative Negative Negative Negative Negative ANA Negative Positive Negative NA NA Serology for HBV, HCV, HIV Negative Negative Negative Negative Negative Urine mercury (lg/L) (normal <10 lg/L) 68 183.7 16.88 NA 97.35 (68.15 lg/day) Blood mercury levels (lg/L) (normal <11 lg/L) NA NA NA 24 NA Treatment Oral DMPS Oral DMPS None Tacrolimus None Outcomes Improved Improved Lost to follow-up Remission Improved DMPS, dimercaptopropane-1-sulfonic acid; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeﬁciency virus; MN, membranous nephropathy; NA, not available; PLA2R, phospholipase A2 receptor. At presentation. 4| M. Doshi et al. FIGURE 1: Periodic acid–Schiff staining of renal biopsy specimen showing uniformly thickened capillary walls (A) and silver staining of renal biopsy specimen from in- dex case showing ﬁne linear spikes (B). hypertension 1 month prior to presentation. The laboratory results at presentation are summarized in Table 1. Renal biopsy showed 18 glomeruli, which showed features consistent with MN. Renal tissue subjected to immunofluorescence did not have any glomeruli. The urinary mercury level was markedly el- evated (Table 1). He was treated with losartan 50 mg/day and Ayurveda medicine was discontinued. At last follow-up in June 2017, his urine PCR had reduced to 4.37 g/g creatinine and renal function remained normal. DISCUSSION Clinical presentation Very few cases of mercury-induced MN have been reported in the literature so far. Miller et al.  reviewed the English litera- ture up to November 2010 and reported 15 cases of mercury-in- duced MN. Subsequently, Li et al. reported a series of 11 cases of mercury-induced MN from China, of which 5 had received traditional Chinese medicine, 4 were due to skin-lightening creams and 1 each due to vapor inhalation containing mercury and hair dye containing mercury. In addition, Priya et al. and Chakera et al. reported a case each of mercury-induced MN following the injection of mercury and use of skin creams, re- spectively. We report five cases of mercury-induced MN in patients taking traditional Indian medicines such as Siddha (two patients) and Ayurveda (three patients). The index patient received oral Siddha medicine for sinusitis for 5 months, whereas another received it for breast cancer for 12 months. They developed severe nephrotic syndrome, 5 and 9 months af- ter the consumption of Siddha medicine, respectively. The pa- FIGURE 2: Hematoxylin and eosin staining showing segmental endothelial pro- tient who received topical Ayurveda medicine intermittently, liferation (arrow) with inﬁltration by numerous neutrophils and uniform thick- for skin lesions for 10 years, developed a lesser degree of ne- ening of capillary basement membrane (A) and Periodic acid–Schiff staining phrotic state, indicating lower level of toxicity. The other two showing partial ﬁbroepithelial crescent (arrow) from renal biopsy of Case 2 (B). patients who received Ayurveda medicine for 2 months for bronchial asthma had severe nephrotic syndrome. The timeline (normal:<11 lg/L). He was advised to stop Ayurveda medicine to develop mercury-induced MN appears to be variable and probably depends upon the amount of mercury contained in and was treated with tacrolimus 3 mg/day along with losartan the medicine, in addition to duration of toxicity. Li et al. also 125 mg/day. At last follow-up in May 2017, his urine PCR was reported a wide variation in duration of mercury exposure from 0.79 g/g creatinine and renal function remained normal. 2 to 60 months in 11 patients with mercury-induced MN. A chemical analysis of the Siddha medicines consumed by the in- Case 5 dex case showed a very high concentration of mercury An elderly male aged 70 years presented in May 2017, with com- (132.95 mg/kg), which was far above the permissible limit of plaints of bilateral pedal edema and foamy urination for the 0.1 lg/kg . We made efforts to exclude other secondary causes past 15 days. He had received Ayurveda medication for bron- of MN in our patients. Case 2 had breast cancer and positive chial asthma for the past 2 months. He was detected to have anti-nuclear antibody (ANA), which raised the possibility of Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy031/5032560 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Cases of mercury-induced MN | 5 anti-PLA2R antibody. Histochemical staining of renal tissue is more sensitive than serum assay to determine anti-PLA2R- related MN [11, 12]. We did not perform the tissue staining for anti-PLA2R antibodies due to lack of availability. One of our patients had a positive ANA, but negative anti-dsDNA and a simi- lar finding was reported in 4 of 11 cases reported by Li et al.. These experimental and clinical observations indicate that mer- cury causes MN by mechanisms other than antibody formation against PLA2R. However, the nature of autoantibodies in the cau- sation of mercury-induced MN in humans remains unclear. Treatment The optimal treatment of mercury-induced MN is unclear. It is essential to withdraw the medicines suspected to contain mer- cury, which was done in all our cases. It is desirable to analyze the content in order to determine the concentration of mercury to assess the degree of poisoning. The levels in the blood or FIGURE 3: EM picture from Case 2, showing subepithelial electron dense deposits. urine do not reflect the true degree of chronic mercury poison- ing, since mercury tends to deposit in the tissues. In case of mild disease, withdrawal of mercury-containing medicines may malignancy-induced MN and lupus nephritis (LN). The absence of suffice, whereas in case of severe MN with clear evidence of anti-dsDNA antibody, full-house immune deposits on immunoflu- mercury poisoning, chelation would facilitate the removal of orescence stain and mesangial and subendothelial deposits was mercury, which may hasten the recovery of MN. A few authors inconsistent with LN. Malignancy-related MN could not be ex- have reported successful use of chelating agents such as DMPS cluded, though the time interval between consumption of Siddha  and dimercaptopurine [13, 14] in mercury-induced MN. We medicine and evolution of MN and subsequent improvement with demonstrated that oral DMPS markedly increased the excretion chelation therapy favored mercury-induced MN. ANA was not of mercury in two of our cases, proving their efficacy. Both of done forCase4, and theabsence of full-house immune deposits these patients showed clinical improvement after DMPS chela- on immunofluorescence did not favor the diagnosis of LN. tion despite not receiving substantial immunosuppression, which indicated that chelation hastened recovery. Oral chelat- Histopathology and pathogenesis ing agents such as DMPS are the drug of choice in chronic mer- Mercury-induced MN may show mesangial proliferation and cury poisoning, which is generally well tolerated. However, it acute tubulointerstitial injury on light microscopy, in addition should be used cautiously if renal function is impaired, since to typical membrane thickening [2, 3]. Case 2 showed focal en- these chelating agents are essentially excreted in urine . The dothelial proliferation and a rare fibro-epithelial crescent, outcome in mercury-induced MN is generally good, as indicated whereas the rest of the four patients showed typical features of in our cases. Li et al. reported improvement in proteinuria in MN on renal histology. Li et al. reported that in addition to all 11 cases and 9 patients reached complete remission on granular IgG and C3, mercury-induced MN showed deposits of follow-up, after withdrawal from mercury exposure. C4 and C1q, which are not common in idiopathic MN. Also, they reported that IgG1 subtype was the predominant IgG deposit as Traditional medicines and mercury-induced MN against the commonly observed IgG4 subtype in idiopathic MN. Mercury has been an ingredient in several traditional medicines Three of our cases showed weak positive staining for C1q on im- such as Ayurveda, Unani, Siddha, Tibetan and Chinese medi- munofluorescence and we did not perform subtyping of subepi- cines [16–18]. Traditional Indian medicines have been used for thelial IgG deposits. EM study of Case 2 showed deposits millennia in India, and with globalization, several of these tradi- localized to subepithelial space and no deposits in mesangial or tional medicines are sold over the Internet and have found a subendothelial space. Li et al. reported subepithelial deposits global market. However, the drugs sold by traditional medicine on EM study in all 11 patients, of which 5 had additional mesan- gial deposits, but no subendothelial deposits. manufacturers are not rigorously tested for the contents and their sale is not regulated. Saper et al. randomly analyzed The precise pathogenesis of mercury-induced MN is uncer- tain. Bariety et al. induced MN by several successive subcuta- Ayurvedic herbs and medicines sold over the Internet in the neous injections of mercury chloride in rat experiments. Their USA and found that 4.1% of them contained mercury above the permissible limits . The content of mercury was more in findings of subepithelial deposits support the hypothesis of an immune complex disease probably initiated by mercuric chloride. rasayan shastra preparations (9.5%) compared with non- The autoimmune nature of mercury-induced MN is supported by rasayan shastra Ayurvedic medicines. However, despite the widespread consumption of traditional Indian medicines by the animal experiments. In rat models, mercury chloride was shown to induce autoimmunity due to a T-cell-dependent B-cell poly- population, no renal toxicity has been reported thus far and to clonal activation, resulting in production of numerous autoanti- our knowledge ours is among the first reported cases of tradi- bodies . In mercury-induced MN rat models, anti-laminin tional Indian medicines containing mercury causing MN. It is antibodies were eluted from the BM . Anti-PLA2R antibodies possible that it is underreported due to a lack of awareness among physicians and nephrologists. We identified within a were negative in all of our five patients. The discovery of anti-PLA2R antibodies is recent  and previous reports of mer- span of 24 months, five cases of mercury-induced MN, cury-induced MN did not perform this test, except a recent case who were anti-PLA2R antibody negative. We emphasize the report by Chakera et al., who reported negative serology for need to suspect and evaluate for mercury-induced MN when Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy031/5032560 by Ed 'DeepDyve' Gillespie user on 07 June 2018 6| M. Doshi et al. 8. Hua J, Pelletier L, Berlin M et al. Autoimmune glomerulone- anti-PLA2R antibody is negative and a history of consumption of traditional Indian medicines is present or suspected. phritis induced by mercury vapour exposure in the Brown Norway rat. Toxicology 1993; 79: 119–129 9. Icard P, Pelletier L, Vial MC et al. Evidence for a role of CONCLUSION antilaminin-producing B cell clones that escape tolerance in We report five cases of mercury-induced MN due to traditional the pathogenesis of HgCl2-induced membranous glomerul- Indian medicines, which to our knowledge is the first such re- opathy. Nephrol Dial Transplant 1993; 8: 122–127 port. We suggest that MN with anti-PLA2R antibody negative 10. Beck LH Jr, Bonegio RGB, Lambeau G et al. M-type phospholi- cases should be evaluated for mercury-induced MN in patients pase A2 receptor as target antigen in idiopathic membra- consuming traditional Indian medicines. We showed that oral nous nephropathy. N Engl J Med 2009; 361: 11–21 chelation by DMPS is effective and should be used as first-line 11. Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomer- therapy in severe cases of mercury-induced MN. ular deposits in membranous nephropathy. N Engl J Med 2011; 364: 689–690 12. Segarra-Medrano A, Jatem-Escalante E, Quiles-Pe ´ rez MT CONFLICT OF INTEREST STATEMENT et al. Prevalence, diagnostic value and clinical characteristics None declared. associated with the presence of circulating levels and renal deposits of antibodies against the M-type phospholipase A2 receptor in idiopathic membranous nephropathy. Nefrologia REFERENCES 2014; 34: 353–359 1. Wasserstein AG. Membranous glomerulonephritis. J Am Soc 13. Blanusa M, Varnai VM, Piasek M et al. Chelators as antidotes Nephrol 1997; 8: 664–674 of metal toxicity: therapeutic and experimental aspects. 2. Miller S, Pallan S, Gangji AS et al. 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Clinical Kidney Journal – Oxford University Press
Published: Jun 3, 2018
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