Membranoproliferative glomerulonephritis case study one

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A 60-year-old man was presented with a 1-week history of bilateral pedal edema, worsening hypertension, and a rise in serum creatinine from 111 μmol/L to 213 μmol/L over 2 weeks. He had microscopic hematuria and proteinuria quantified at 24 grams/day . His serum albumin was 24 g/L compared with 35 g/L 2 weeks earlier. Other relevant investigations included negative hepatitis B and C serology, weakly positive speckled antinuclear antibody (ANA) titer of 160 (normal <40) with double-stranded deoxyribonucleic acid (DNA) of 0 IU/mL (normal <7), normal ratio of serum free light chains, negative cryoglobulin screen, negative serum protein electrophoresis, and a normal C3 of 1.77 g/L and C4 of 0.38 g/L.

Background

He had a background history of hypertension, and a 5-year history of colorectal carcinoma with hepatic metastasis. His initial treatment included neoadjuvant chemotherapy with capecitabine and bevacizumab, and 26 fractions of radiotherapy. He then underwent a right hemicolectomy and a partial right hemihepatectomy, followed by 6 months of capecitabine and bevacizumab. He was recommenced on capecitabine, bevacizumab, and cetuximab, and continued on this treatment until presentation with nephrotic syndrome.

Renal Biopsy

A renal biopsy was diagnostic of MPGN type I. Functioning glomeruli showed mesangial hypercellularity, endocapillary proliferation, and double contours in capillary loops. No hyaline deposits were noted in the capillary loops and no segmental sclerosis was seen. There was interstitial fibrosis and tubular atrophy together with lymphocytes, plasma cells, and eosinophils in the scarred interstitium. Immunofluorescence showed moderate granular deposition of IgG and C3 in the mesangial areas and around the capillary loops. Electron microscopy showed deposits in the mesangial, paramesangial, and subendothelial regions. Focal duplication of the glomerular basement membrane was seen and there was mild expansion of mesangial matrix.

Curative therapy for the malignancy was not possible, so treatment was commenced with prednisolone for the renal disease. Four months later, his proteinuria had reduced to 1.4 grams/day, creatinine had improved to 155 μmol/L, and albumin returned to baseline of 31 g/L.

Discussion

This case highlights that MPGN can be associated with malignancy.

Hypothesis

There are two main hypotheses which have been proposed to explain the pathogenesis of the association between MPGN and malignancy.

  • First, an undiagnosed malignancy associated with immune complex deposition may cause a glomerular disease-like paraneoplastic syndrome. While data are limited in MPGN, studies have shown that paraneoplastic membranous nephropathy is characterized by an increased number of inflammatory cells in the glomeruli compared with that of idiopathic membranous nephropathy. There is a greater prominence of the subtypes of IgG1 and IgG2 in the renal biopsy samples of patients with paraneoplastic membranous nephropathy compared with idiopathic membranous nephropathy.
  • Second, viral infection may have induced both glomerulopathy and cancer by intrinsic viral oncogenic activity. It is possible that disrupted renal clearance of biological mediators may be associated with oncogenesis. However, the most likely explanation for the connection between virus latency and tumorigenesis is that replicating viruses may initiate cell death. When latent viruses produce virions, virus replication generates pathogen-associated molecular patterns from partially synthesized viral chromosomes, double-stranded ribonucleic acid (RNAs) and empty capsids that trigger cellular DNA damage responses and innate immune signaling. Toll-like receptor and interferon signaling by virus infection is subsequently activated, amplifying the innate response. The prognosis of MPGN in the setting of malignancy is uncertain. The presence of hypertension at presentation, severe nephrotic syndrome, and renal insufficiency are known poor prognostic factors among non-malignancy-associated nephrotic syndrome.

Conclusions

In summary, we report a case of an association between MPGN and metastatic colorectal cancer. Clinicians need to be vigilant about the possible paraneoplastic nature of MPGN. Initial treatment of the underlying malignancy should be the primary management in patients presenting with kidney disease which is suspected to be paraneoplastic in etiology, although prednisolone is an appropriate therapy if cure of the cancer is not feasible.

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