Monoclonal Gammopathies and the Kidney Tibor Nádasdy, MD The Ohio State University, Columbus, OH
Monoclonal gammopathy of renal significance (MGRS) Biopsies at OSU (n=475) between 2007 and 2016 AL or AH amyloidosis (mostly lambda light chain: 136 (28.6%) Myeloma cast nephropathy: 118 (24.8%) Randall type monoclonal immunoglobulin (mostly light [kappa:lambda 7:1], rarely heavy chain) deposition disease: 48 (10.1%) Others: 173 (36.4%)
MGRS (Others) Diseases affecting primarily the glomeruli through direct deposition of monoclonal immunoglobulins Proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMIGD): 64 (13.5%) Type I cryoglobulinemic GN: 17 (3.6%) Immunotactoid GN: 9 (1.9%) Waldenström macroglobulinemia: 3 (0.6%)
PGNMIGD 64 y-o male with hypertension, nephrotic syndrome, AKI (serum Cr 3.6 mg/dl from 1.2) and microscopic hematuria. Serum complement levels normal Autoimmune and hepatitis workup negative Negative for cryoglobulins and RF No evidence of monoclonal gammopathy
Hypercellular lobulated glomerulus (MPGN pattern), H&E
Hypercellular lobulated glomerulus (MPGN pattern). PAS
Strong granular mesangial and granular to ribbon-like glomerular capillary staining for IgG
C1q
C3
Strong staining for Kappa Negative Lambda
There is IgG subclass restriction; usually IgG3 IgG1 IgG2 IgG3 IgG4
Mesangial and subendothelial deposits (arrows)
Higher magnification of mesangial and subendothelial deposits
The deposits may have variegated appearance but have no substructure
PGNMIGD Renal Biopsy Findings Endocapillary proliferative pattern of glomerular injury (usually MPGN pattern), most cases were diagnosed as MPGN in the past. Monoclonal IgG deposits restricted to the glomeruli Unlike in Randall-type monoclonal immunoglobulin deposition disease) 75% IgG3 kappa; rarely IgG1, very rarely IgG2, Mostly kappa; rarely lambda The deposits also contain complement (C3, C1q, C4 EM shows mainly mesangial and subendothelial electron dense immune type deposits without substructure
PGNMIGD Clinical presentation Adults or elderly patients; rarely in young adults. Nephrotic syndrome or nephrotic range proteinuria (70%) Microscopic hematuria Variable degree of AKI in most patients (70%) Hypertension No systemic symptoms
PGNMIGD Laboratory findings Monoclonal gammopathy 25 to 30% Low serum complement (C3 and/or C4): 10 to 20% Negative cryoglobulin test Negative rheumatoid factor Negative autoimmune workup No evidence of alternate complement pathway abnormality
PGNMIGD Clinical Course Slowly progressive, ESRD develops usually in several years unless successfully treated Recurs in renal allografts with exactly the same IgG subclass deposition, usually within one to three years.
PGNMIGD Treatment Perhaps the best treatment option is Rituximab (over 50% remission) Some propose combining Rituximab with cyclophosphamide and dexamethasone or bortezomib, particularly if there is an underlying hematologic malignancy (rare in true PGNMIGD) Other immunosuppressive regimens (steroid, MMF, cyclophosphamide) occasionally may help Rare patients may undergo spontaneous remission.
Example for successful treatment 44-year-old male. ESRD: MPGN Living unrelated renal transplant 16 months before current presentation Nephrotic syndrome with 8.7 g/24h proteinuria, hematuria Serum Cr up to 3.1 mg/dl from 1.7 mg/dl Serum complement levels normal Bx: PGNMIGD with IgG3 kappa deposits
Prominent diffuse global glomerular endocapillary hypercellularity
IgG IgM Kappa Lambda
IgG1 IgG2 IgG3 IgG4
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Clinical Follow-up I Rituximab started No monoclonal protein in the serum or urine. No improvement in the serum creatinine; therefore rebiopsy 4 month later
Mesangial hypercellularity with mostly open capillaries
16-13571 IgG
Kappa Lambda
No deposits on EM
Clinical Follow-up II Four months later proteinuria was down to 1.8 g/24 hour. Serum creatinine was 2.7 mg/dl The patient developed de novo DSA and worsening proteinuria A biopsy 13 months following the first biopsy revealed diffuse peritubular capillary C4d staining and early changes of transplant glomerulopathy but no recurrence of glomerular IgG3 kappa deposits
Type I Cryoglobulinemic GN
Large glomerular capillary deposits with some glomerular capillary hyalin thrombi
IgG IgA IgM
Kappa
IgG1 IgG2 IgG3 IgG4
Microtubules in paracrystalline arrangement on EM
Characteristic Renal Biopsy, Laboratory and Clinical Findings in Cryoglobulinemic Glomerulonephritis Type of Cryoglobulin I II III Glomerular hypercellularity +++ +++ ++ Glomerular capillary hyalin thrombi, large deposits + ++ +/- Vasculitis in the biopsy - + +/- Distribution of deposits Diffuse global Can be focal segmental Diffuse global IgG in deposits Monoclonal +++ Polyclonal ++ to +++ Polyclonal IgM in deposits Monoclonal (there may be some nonspecific entrapment of IgM in IgG +++ (IgM kappa) ++ to +++ Polyclonal monoclonal cases) Substructure in deposits Paracrystalline/crystalline Microtubular Usually none Rheumatoid factor +/- (if IgM) +++ ++ Monoclonal spike in serum ++ +/- - Low serum C3 +/- +/- ++ Low serum C4 +/- +++ ++ Hepatitis C virus - +++ + Infection, acute/active inflammation, autoimmune disease, malignancy B-cell lymphoproliferative disease - - ++ ++ - -
Management of Type I Cryoglobulinemic GN Treat the underlying lymphoproliferative disease (usually B cell lymphoma) Rituximab can be given if the patient has no obvious lymphoma or multiple myeloma only MGUS B cell clone.
Immunotactoid Glomerulonephritis Glomerular deposits with organized substructure Usually microtubules or paracrystalline structure Most of these patients either have cryoglobulinemia or an underlying lymphoproliferative disease If none of these found, we probably did not look carefully enough (occult lymphoma or cryoglobulinemia may be difficult to diagnose) Very rarely, Cryofibrinogenemia may result in glomerular deposits with organized structure
Deposits in a case of type II cryoglobulinemic GN. There are large deposits with microtubular substructure (24 nm). By morphologic criteria the deposits have immunotactoid structure
IgG1 kappa restricted glomerular deposits with a paracrystalline substructure on EM from a patient with B cell lymphoma
Waldenstrom Macroglobulinemia Most patient have lymphoplasmacytic lymphoma with large amount of circulating monoclonal IgM Hyperviscosity syndrome is common; may be associated with AKI. The glomerular capillaries are occluded by precipitated IgM Treatment of the hyperviscosity syndrome and the lymphoma may reverse the renal failure.
Waldenstrom macroglobulinemia: numerous glomerular intracapillary hyalin thrombi
IgM Kappa light chain Lambda light chain
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MGRS Diseases affecting primarily the glomeruli through indirect mechanisms Membranous GN related to B cell lymphoma: 13 (2.7%) Minimal change disease related to B cell lymphoma: 10 (2.1%) C3 GN/Dense deposits disease (DDD) in adults: 20 (4.2%); 11 of them had monoclonal gammopathy
MGRS Diseases affecting primarily the tubulointerstitium through direct deposition of the monoclonal immunoglobulin (light chains) Myeloma cast nephropathy: 118 (24.8%) Lysosomal tubulopathy: 20 (4.2%) Kappa light chain crystalline tubulopathy: 10 (2.1%) light chain restricted lysosomes (usually lambda light chain): 10 (2.1%) Crystal storing histiocytosis: 1 (0.2%)
Kappa light chain crystalline tubulopathy. The tubular epithelium is swollen and granular but obvious crystals are frequently not seen by light microscopy. H&E
Rarely, the crystals are large and visible in H&E or Trichrome stained sections
Routine IF on frozen sections usually is negative for kappa The kappa in the crystals is masked). IF on paraffin sections following protease digestion frequently brings out the kappa staining Kappa Lambda
Numerous small cytoplasmic crystals in a proximal tubule. Such small crystals are usually not visible as crystals by light microscopy
Larger elongated crystals in the proximal tubular epithelium. Such crystals may be visible under the light microscope
Sometimes immuno electron microscopy can reveal the kappa light chain restriction in the crystals. A: Gold conjugated anti kappa antibody. Note the gold particles above the crystals. B: Gold conjugated anti-lambda antibody: no gold particles are visible.
Lambda light chain lysosomal tubulopathy Lambda Kappa
Lambda light chain lysosomal tubulopathy EM shows lysosomes of variable sizes and densities; no crystals are seen
Lambda light chain lysosomal tubulopathy H&E Light microscopy is unremarkable; there is usually some granularity in swollen tubular epithelial cells
Lysosomal Tubulopathies Kappa crystals Many patients slowly progress; others do not. Practically always kappa Most authors agree that treatment is warranted even in the absence of myeloma, particularly if disease progression is evident Light chain restricted lysosomes without crystals Many patients do not progress Mostly lambda light chain Probably the best approach is to watch and follow carefully if the patient has no myeloma. If progression is evident, treatment should be initiated.
MGRS Tubulointerstitial and vascular diseases indirectly induced by monoclonal gammopathies ATN Interstitial nephritis Rarely, thrombotic microangiopathy
Direct infiltration of the renal parenchyma by lymphoma Not truly a MGRS because not all patients with B cell lymphoma have detectable circulating monoclonal immunoglobulin At OSU they were seen in 16 (3.4%) of the MGRS cases (for this lecture I included them among the MGRS cases) May cause progressive renal failure and bilateral renal enlargement but may be an incidental finding. It has to be differentiated from interstitial nephritis
Summary MGRS incudes a large variety of disease pattern, including glomerular, tubulointerstitial and even vascular diseases and the renal disease is frequently only one manifestation of a systemic disease. Patients with renal diseases related to MGUS have to be treated by hematologists for the underlying lymphoproliferative disease. Sometimes (e.g., in most cases of PGNMIGD) circulating monoclonal proteins are not detected; treatment for a lymphoproliferative disease (at least anti CD20) is still warranted
Suggested Reading Motwani SS, et al. Clin J Am Soc Nephrol. 11:2260-2272, 2016. Perry M, et al. Am J Hematol. 89:969-973, 2014. Nasr SH, et al. J Am Soc Nephrol. 20:2055-2064, 2009. Guiard E, et al. Clin J Am Soc Nephrol. 6:1609-1616, 2011. Bhutani G, et al. Mayo Clin Proc. 90:587-596, 2015. Muchtar E, et al. Blood 129:289-298, 2017. Stokes MB, et al. J Am Soc Nephrol. 27:1555-1565, 2016. Leung N, et al. Blood 120:4292-4295, 2012. Sethi S, et al. Curr Opin Nephrol Hypertens. 25:127-137, 2016. Nasr SH, et al. Nephrol Dial Transplant 27:4137-4146, 2012.