Renal Involvement in Monoclonal Gammopathy :

The amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of the most frequent sites of amyloid deposition in AL, AA, and several of the hereditary amyloidoses. Amyloid fibril formation begins with the misfolding of an amyloidogenic precursor protein. The misfolded variants self-aggregate in a highly ordered manner, generating protofilaments that interact to form fibrils. The fibrils have a characteristic appearance by electron microscopy and generate birefringence under polarized light when stained with Congo red dye. Advances in elucidating the mechanisms of amyloid fibril formation, tissue deposition, and tissue injury have led to new and more aggressive treatment approaches for these disorders. This article reviews the pathogenesis, diagnosis, clinical manifestations, and treatment of the amyloidoses, focusing heavily on the renal aspects of each of these areas.

To better define the clinical-pathologic spectrum and prognosis of monoclonal immunoglobulin deposition disease (MIDD), this study reports the largest series. Characteristics of 64 MIDD patients who were seen at Mayo Clinic are provided. Of 64 patients with MIDD, 51 had light chain deposition disease, 7 had heavy chain deposition disease, and 6 had light and heavy chain deposition disease. The mean age at diagnosis was 56 years, and 23 patients (36%) were ≤50 years of age. Clinical evidence of dysproteinemia was present in 62 patients (97%), including multiple myeloma in 38 (59%). M-spike was detected on serum protein electrophoresis in 47 (73%). Serum free light chain ratio was abnormal in all 51 patients tested. Presentation included renal insufficiency, proteinuria, hematuria, and hypertension. Nodular mesangial sclerosis was seen in 39 patients (61%). During a median of 25 months of follow-up (range, 1-140) in 56 patients, 32 (57%) had stable/improved renal function, 2 (4%) had worsening renal function, and 22 (39%) progressed to ESRD. The mean renal and patient survivals were 64 and 90 months, respectively. The disease recurred in three of four patients who received a kidney transplant. Patients with MIDD generally present at a younger age than those with light chain amyloidosis or light chain cast nephropathy. Serum free light chain ratio is abnormal in all MIDD patients, whereas only three-quarters have abnormal serum protein electrophoresis. The prognosis for MIDD is improving compared with historical controls, likely reflecting earlier detection and improved therapies.

Controversy surrounds the relatedness of fibrillary glomerulonephritis (FGN) and immunotactoid glomerulonephritis (IT). To better define their clinicopathologic features and outcome, we report the largest single center series of 67 cases biopsied from 1980 to 2001, including 61 FGN and 6 IT. FGN was defined by glomerular immune deposition of Congo red-negative randomly oriented fibrils of or = 30 nm (mean, 38.2 +/- 5.7 nm). FGN comprised 0.6% of total native kidney biopsies and IT was tenfold more rare (0.06%). Deposits in FGN were immunoglobulin G (IgG) dominant and polyclonal in 96%. IgG subtype analysis in 19 FGN cases showed monotypic deposits in four (two IgG1 and two IgG4) and oligotypic deposits in 15 (all combined IgG1 and IgG4). In IT, deposits were IgG dominant in 83% and monoclonal in 67% (three IgG1 kappa and one IgG1 lambda). FGN patients were a mean age of 57 years, 92% were Caucasian, and 39% were male. At biopsy, FGN patients had the following clinical characteristics (mean, range): creatinine 3.1 mg/dL (0.5 to 14), proteinuria 6.5 g/day (0.8 to 25), 60% microhematuria, and 59% hypertension. Histologic patterns of FGN were diverse, including diffuse proliferative glomerulonephritis (DPGN) (nine cases), membranoproliferative glomerulonephritis (MPGN) (27 cases), mesangial proliferative/sclerosing (MES) (13), membranous glomerulonephritis (MGN) (four), and diffuse sclerosing (DS) (eight). The more proliferative (MPGN and DPGN) and sclerosing (DS) forms presented with a higher creatinine and greater proteinuria compared to MES and MGN. Median time to end-stage renal disease (ESRD) was 24.4 months for FGN and mean time to ESRD varied by histologic subtype: DS 7 months, DPGN 20 months, MPGN 44 months, compared to MES 80 months and MGN 87 months. There was no statistically significant effect of immunosuppressive therapy (given to 36% of FGN patients). By Cox regression (hazard ratio, confidence interval, P value), independent predictors of progression to ESRD were creatinine at biopsy [2.05 (1.55 to 2.72) P < 0.001] and severity of interstitial fibrosis [2.01 (1.05 to 3.85) P = 0.034]. Although IT had similar presentation, histologic patterns, and outcome compared to FGN, it had a greater association with monoclonal gammopathy (P = 0.014), underlying lymphoproliferative disease (P = 0.020), and hypocomplementemia (P = 0.032). FGN is an idiopathic condition characterized by polyclonal immune deposits with restricted gamma isotypes. Most patients present with significant renal insufficiency and have a poor outcome despite immunosuppressive therapy, and outcome correlates with histologic subtype. By contrast, IT often contains monoclonal IgG deposits and has a significant association with underlying dysproteinemia and hypocomplementemia. Differentiation of FGN from the much more rare entity IT appears justified on immunopathologic, ultrastructural, and clinical grounds.