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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 800-804
Coexistence of atypical hemolytic uremic syndrome with membranoproliferative glomerulonephritis and antineutrophil cytoplasmic antibodies-associated vasculitis

1 Division of Pediatric Nephrology, Sir H. N. Reliance Foundation Hospital and Research Center, Mumbai, Maharashtra, India
2 Division of Pediatric Nephrology, Jaslok Hospital and Research Center, Mumbai, Maharashtra, India

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Date of Web Publication5-Jul-2016


The simultaneous presence of multiple immune-mediated diseases in a single host is rare. The implications of such coexistence relating to the disease pathogenesis and treatment are not well understood. We describe two cases of renal failure with immune-mediated overlap conditions. We believe, this is the first reported case of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis coexisting with atypical hemolytic uremic syndrome (HUS). Two boys aged eight years (Case 1) and 10 years (Case 2) presenting with renal failure secondary to glomerulonephritis are described. Based on the clinical features, a detailed immunological workup and kidney biopsy was performed to arrive at the diagnosis. Immune-mediated renal dysfunction was present in both cases. Screening for other coexisting autoimmune phenomenon was performed based on suspicious clinical features. Case1 presented with renal failure and D-HUS with low serum C3. Renal biopsy revealed membranoproliferative glomerulonephritis Type 1. The child improved following treatment with plasma infusions and steroids. Case 2 presented with ANCA-positive vasculitis. Renal biopsy was suggestive of focal mesangioproliferative glomerulonephritis. Disease course was further complicated by D-HUS with low serum C3. Factor H antibody was positive. Complete renal recovery was documented following treatment with intravenous rituximab, steroids, cyclophosphamide, and plasmapheresis. Screening for the presence of coexisting autoimmune diseases is imperative to identify covert immune-mediated pathologies and for the successful overall management of such cases.

How to cite this article:
Sathe KP, Mehta KP. Coexistence of atypical hemolytic uremic syndrome with membranoproliferative glomerulonephritis and antineutrophil cytoplasmic antibodies-associated vasculitis. Saudi J Kidney Dis Transpl 2016;27:800-4

How to cite this URL:
Sathe KP, Mehta KP. Coexistence of atypical hemolytic uremic syndrome with membranoproliferative glomerulonephritis and antineutrophil cytoplasmic antibodies-associated vasculitis. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2022 Aug 7];27:800-4. Available from: https://www.sjkdt.org/text.asp?2016/27/4/800/185267

   Introduction Top

Immune mechanisms are central to the pathogenesis of most glomerular diseases. Once diagnosed, further treatment with appropriate immunosuppression is relatively straight forward. However, occasionally we encounter over-lap situations where multiple immune-mediated causes of renal dysfunction coexist in the given host. While the cause may not be apparent, screening for such co-morbidities is essential for optimal management. We report our experience in dealing with two such cases presenting with coexisting renal immune pathologies.

   Case Reports Top

Case 1

An 8-year-old boy, third by order of birth, born to nonconsanguineous parents presented with fever, acute onset pallor, generalized edema, and oliguria over a period of one week. Physical examination revealed hypertension and tender hepatomegaly. Investigations showed hemoglobin (Hb) 4.6 g/dL, total white cell count (TC) 8.9 × 103/μL, platelets 1.35 × 103/μL, peripheral smear showed fragmented red blood cells (RBCs), reticulocyte count 3.2%, blood urea nitrogen 63 mg/dL, serum creatinine 1.9 mg/ dL, serum sodium 123 mEq/L, potassium 7 mEq/L, chloride 99 mEq/L, serum albumin 3.1 g/dL, serum lactate dehydrogenase (LDH) 772 U/L, serum aspartate aminotransferase 134 U/L, and serum alanine aminotransferase 179 U/L. Urinalysis showed albumin 4+ and RBC 30-35/hpf. Urine spot protein: creatinine ratio 8.1. Malaria antigen absent, antistreptolysin O (ASO) titer was normal, antinuclear antibody (ANA) negative, serum complement C3 28.6 mg/dL, C4 was 22 mg/dL, and hepatitis B surface antigen (HbsAg) and anti-hepatitis C virus (HCV) antibody negative. Renal ultrasound showed right kidney size 8.0 cm × 3.5 cm and left kidney, 9.5 cm × 3.5 cm. The diagnosis was consistent with D-HUS. Urgent acute peritoneal dialysis was instituted. Complement mutation studies and factor H antibody assay could not be performed. In view of the nephrotic range proteinuria, renal biopsy was performed. Renal biopsy [Figure 1]a and b revealed glomerular hypertrophy, diffusely thick basement membranes, mesangial proliferation, and neutrophilic infiltration with obliterated capillary loops. Other findings included focal tubular necrosis and atrophy, mild interstitial infiltration, and myointimal vascular thickening with luminal narrowing. Immunofluorescence showed the presence of IgM, C3, and C1q deposits in the mesangium and capil-laries with absent IgA and IgG. Electron microscopy revealed subendothelial electron dense deposits along with mesangial interpositioning in the basement membrane. These findings were consistent with membranoproliferative glomerulonephritis (MPGN) Type 1. The child was treated with plasma infusions along with oral steroids (2 mg/kg/day) and oral mycophenolate mofetil following which there was prompt renal recovery and remission of the HUS activity. However, a few months later, the child developed sepsis with multiorgan dysfunction and succumbed to the illness.
Figure 1:

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Case 2

A 12-year-old boy, second by order of birth, born to nonconsanguineous parents presented with intermittent self-limiting purpuric rash over lower extremities with painful large joint swelling involving wrist and ankle, scrotal edema, and mild intermittent fever over a period of one year. He was adequately grown for age. Investigations revealed Hb 9.8 g/dL, TC 16.3 × 103/μL, platelets 6.2 × 103/μL, erythrocyte sedimentation rate 90 mm and serum creatinine 1.0 mg/dL. Urinalysis showed albumin 2+, RBCs: 35-40/hpf, white blood cell: 6-8/hpf, absent casts. Urine culture did not detect any growth. ANA was weakly positive while ASO was normal. Perinuclear antineutrophil cytoplasmic antibody (P-ANCA) was positive while cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA) was negative; HbsAg and anti-HCV were absent. Renal ultrasound showed right kidney measuring 11.1 cm × 5.6 cm and left kidney 10.5 cm × 6.1 cm. There was a progressive rise in serum creatinine along with low complement C3. Renal biopsy [Figure 2] revealed glomerular hypertrophy, focal mesangial proliferation with partial cellular crescent in one glomerulus, tubular dilation, and necrosis with normal vessels and interstitium. IF was negative for immune deposits which was consistent with a diagnosis of focal proliferative pauci-immune glomerulonephritis. He received six pulses of methylprednisolone followed by oral steroids resulting in normalization of serum creatinine, complement C3, and disappearance of ANCA antibodies from serum. Over the next few months, there was a waxing and waning course with recurrence of gross hematuria and renal dysfunction, which was promptly treated with intravenous (IV) steroid pulses, IV cyclophosphamide, and oral mycophenolate mofetil. About six months since his first presentation, while being on maintenance immunosuppression comprising of oral prednisolone and mycophenolate mofetil, his condition deteriorated with the occurrence of hypertension, gross hematuria, and respiratory distress. Investigations revealed Hb 4.9 mg/dL, thrombocytopenia, fragmented RBCs on peripheral smear, serum creatinine 5.2 mg/dL, serum LDH 930 U/L, C3 52 mg/dL, C4 20.2 mg/dL, and DCT negative. The diagnosis was suggestive of D-HUS. Anti-factor H antibody was positive (titer 1500 AU/mL). Treatment in the form of plasma exchanges (eight sessions), IV steroids, IV rituximab (four doses), and IV cyclophosphamide (six monthly injections) and azathioprine resulted in complete and sustained renal recovery.
Figure 2: Renal biopsy (H and E, ×40) focal proliferation of mesangial cells.

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   Discussion Top

Our understanding of the immune-mediated glomerular diseases is not complete. Traditionally, we have the circulating immune complex nephritis; antibodies directed against the glomerular antigens and ANCA-induced free radical endothelial damage with pauci-immune necrotizing glomerulonephritis as the prototype immune mechanisms contributing to the glomerular damage. Despite this, we rarely encounter autoimmune overlap states coexisting in the same host producing diverse manifestations. It is now argued that in fact these immune mediated diseases may represent part of the same disease spectrum. Uncontrolled activation of the alternate complement pathway resulting from mutations of factor H gene or anti-factor H antibodies which cause atypical HUS can also result in MPGN. [1],[2],[3],[4],[5],[6] The presence of hypocomplementemia supports the presence of such association. The presence of heavy nephrotic range proteinuria in Case 1 suggested an atypical course. This was confirmed on renal biopsy to be resulting from the underlying MPGN Type1. Although there was no evidence of HUS on renal biopsy, the patient responded to the plasma infusions. The presence of hypocomplementemia in Case 2 in the presence of ANCA positivity and pauci-immune glomerulonephritis was secondary to the complement dysregulation resulting from factor H antibody. This also resulted in microangiopathic hemolytic anemia and renal failure. As seen in our experience, both cases presented with distinct pathologies although atypical course mandated screening for additional covert pathologies. This realization was important not only for understanding the future disease course but also for optimal disease management.

   Conclusion Top

While genetic susceptibility seems to be the putative cause, we are yet to conclusively identify the basic step responsible for triggering the production of autoantibody storm acting at different phases of disease course. These genetic tests are expensive and are available at only few centers across the world. Serum samples of the affected cases should be carefully stored which can be used later for genetic evaluation, whenever feasible. While managing such cases, we need to adopt a protocol-based regimen in screening for the possible associations and occult immune dysfunction (Algorithm 1).

   Acknowledgment Top

The authors wish to convey their thanks to Chitale A, Khubchandani S and More V for their valuable contribution in preparing this manuscript.

Conflict of interest: None declared.

   References Top

Servais A, Frémeaux-Bacchi V, Lequintrec M, et al. Primary glomerulonephritis with isolated C3 deposits: A new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 2007;44:193-9.  Back to cited text no. 1
Habbig S, Mihatsch MJ, Heinen S, et al. C3 deposition glomerulopathy due to a functional factor H defect. Kidney Int 2009;75:1230-4.  Back to cited text no. 2
Skerka C, Licht C, Mengel M, et al. Autoimmune forms of thrombotic microangiopathy and membranoproliferative glomerulonephritis: Indications for a disease spectrum and common pathogenic principles. Mol Immunol 2009;46:2801-7.  Back to cited text no. 3
Morizane R, Konishi K, Hashiguchi A, et al. MPO-ANCA associated crescentic glomerulonephritis with numerous immune complexes: Case report. BMC Nephrol 2012;13:32.  Back to cited text no. 4
Hamano Y, Yoshizawa H, Sugase T, et al. Rituximab treatment for PR3-ANCA-positive membranoproliferative glomerulonephritis associated with adult-onset periodic fever syndrome. Case Rep Nephrol Urol 2012;2:92-101.  Back to cited text no. 5
Mehta K, More V, Chitale A, Khubchandani S. Atypical hemolytic uremic syndrome with membranoproliferative glomerulonephritis. Indian Pediatr 2013;50:793-4.  Back to cited text no. 6

Correspondence Address:
Kiran P Sathe
Division of Pediatric Nephrology, Sir H. N. Reliance Foundation Hospital and Research Center, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.185267

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