January 2021 — Renal

Sixty-year-old white woman with a history of hypertension, who presented with acute kidney injury, hematuria, and proteinuria (1.9 g/day). Serum creatinine is 2 mg/dL. Serum albumin is 3.9 g/dL. No monoclonal protein was detected on serum or urine protein electrophoresis with immunofixation. A kidney biopsy is performed.

Figure 1: Light Microscopy (LM)
Figure 2: Protocol Immunofluorescence (IF)
Figure 3: IgG subclasses Immunofluorescence (IF)
Figure 4: Electron Microscopy (EM)

What is your diagnosis?

  • Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID)
  • Monoclonal immunoglobulin deposition disease (MIDD)
  • Monoclonal immunotactoid glomerulopathy
  • Membranoproliferative glomerulonephritis (MPGN) with masked monoclonal deposits

The correct answer is...

The correct answer is proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID).

This is a classic case of PGNMID, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. Commonly, it presents in older women as new onset nephrotic syndrome. Approximately 30% of these patients have a detectable monoclonal protein, but multiple myeloma is very rare. The remainder, however, have negative urine and serum protein electrophoresis and bone marrow biopsy. Histologically, PGNMID often presents with an MPGN pattern (like in our case). On LM, you can appreciate mesangial proliferation and matrix expansion (occasionally nodular) along with segmental duplication of the glomerular basement membranes (arrow). Endocapillary hypercellularity (circle) can be present. IF shows granular mesangial and glomerular capillary wall staining for IgG (2+), C1q (1+), C3 (3+), and kappa light chain (1+); lambda is negative. IgG subtypes staining is very important to confirm the diagnosis. About two-thirds of cases of PGNMID show IgG3 subclass restriction (Fig 3), as in this case, and one-fourth show IgG1 restriction. EM shows subepithelial (red arrows), mesangial (green arrow), and subendothelial (yellow arrow) electron dense amorphous deposits (i.e., without substructure). Note that the electron density is not homogenous: indeed, these deposits are characteristically described as variegated (possibly due to partial reabsorption).

Treatment of PGNMID is unclear and depends on multiple factors, including the presence or absence of an underlining clonal disorder as well as the severity of the kidney disease. It may include RAS blockade, immunosuppressive agents (i.e. steroids, mycophenolate mofetil etc.), chemotherapeutic drugs targeting B-cells, such as rituximab, or even antimyeloma agents such as bortezomib or thalidomide. Prognosis is also variable, with nearly one-fourth of patients progressing to end-stage renal disease within 2 ½ years, despite treatment.

Immunotactoid glomerulopathy may show monotypic IgG kappa or lambda IF staining; however, EM would show microtubules.

MPGN with masked monoclonal deposits is incorrect, since the deposits stained positive on standard immunofluorescence on frozen tissue.

MIDD is due to deposition of monoclonal immunoglobulins (light or heavy chains, or bothor) within the glomerular basement membrane, mesangium, and tubular basement membrane. In contrast to MIDD, PGNMID is not characterized by extraglomerular deposits.

1. Nasr SH et al. Proliferative glomerulonephritis with monoclonal IgG deposits. Jasn 2009.
2. Bridoux F et al. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a nephrologist perspective. Nephrol Dial Transplant 2019. ​

Photo of Alessia Buglioni, M.D Alessia Buglioni, M.D.
Resident, Renal Pathology
Mayo Clinic
Assistant Professor of Medicine
Mayo Clinic College of Medicine and Science
Photo of Samih H. Nasr, M.D. Samih Nasr, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
MCL Education (@mmledu)

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