Renal Pathology in Patients with Monoclonal Gammopathy or Multiple Myeloma: Monoclonal Immunoglobulins Are Not Always the Cause
Authors: Kastritis Eftathios , Kanellias Nikolaos , Theodorakakou Foteini , Psimenou Erasmia , Gakiopoulou Charikleia , Marinaki Smaragdi , Roussou Maria , Gavriatopoulou Maria , Migkou Magdalini , Eleutherakis-Papaiakovou Evangelos , Malandrakis Panagiotis , Terpos Evangelos , Dimopoulos Meletios A. 
Published: November 2019

Renal disease in monoclonal gammopathies (MGs) is associated with several different pathologies with prognostic and treatment implications. In symptomatic MM, cast nephropathy is a leading cause of renal dysfunction and acute renal failure (ARF) but in patients with other MGs the diagnoses may be diverse and monoclonal gammopathy of renal significance (MGRS) is well described. Renal biopsy is required in such cases in order to establish the diagnosis, especially if selective Bence Jones proteinuria is absent. MGs are more frequent in the elderly, in which renal diseases are also common, associated with underlying co-morbidities (diabetes, hypertension etc). However, although common, there is limited data on the frequency of monoclonal immunoglobulin (MIg)-unrelated pathologies in patients with a known MG presenting with renal dysfunction. Thus, we evaluated the frequency of non-MIg related renal pathologies in patients with known MGs, in a series of consecutive patients from a single referral center (Department of Clinical Therapeutics, Athens , Greece).
We reviewed our database and identified 79 patients with known MGs that had a renal biopsy for evaluation of renal dysfunction, and which was performed after the diagnosis of MG. We excluded patients in which renal biopsy was performed before the diagnosis of the MG.
At the time of renal biopsy, median age was 69 years (range 39-84), 63% were males, 28% had diabetes, 72% hypertension, 22.5% CAD, 7% an autoimmune disease ; 45% had known symptomatic MM (N=36) and 55% a prior diagnosis of MGUS or SMM. Median eGFR was 33 ml/min/1.73 m2 (range 4-110), 15% required dialysis, median proteinuria was 3.1 gr/d and was >0.5 gr/d in 93%. Abnormal FLC ratio was present in 69.5%, median dFLC level was 85 mg/L and 62% had dFLC>50 mg/L. In urine protein electrophoresis (PEP), median albumin proportion was 40% (range 3-100%) and median urine monoclonal protein was 2% (range 0-97%) of the total urine protein. Reasons leading to renal biopsy included proteinuria (with <50% creatinine increase) in 61% and ARF (with or without proteinuria) in 39%.
Renal pathology revealed a MIg-related diagnosis in 68%, which included cast nephropathy in 13%, MIDD in 25%, AL amyloidosis in 25% and other MGRS in 5%. A non MIg-related diagnosis was established in 32%, and included diabetic nephropathy in 5%, hypertension-associated in 14%, single cases of IgA nephropathy, chinese herb nephropathy, obesity-related GN and in 8% was drug related. Among MM patients, 26/36 were on therapy when renal biopsy was performed, 19/36 (53%) were in hematologic remission. Notably, in 11/19 (58%) of MM patients in remission, renal pathology was not related to MIg vs 6/17 (35%) of those not in remission or at the time of MM diagnosis. Factors that were associated with MIg-related pathology included serum albumin <3 gr/dl (88% vs 60%, p=0.007), proteinuria >1.7 gr/d (82% vs 48%, p=0.004), a positive UIFE (75% vs 33%, p=0.039), urine monoclonal protein >100 mg/d (68% vs 25%, p=0.003), dFLC > 50 mg/L (76% vs 37%, p=0.003) and abnormal FLC ratio (78% vs 53%, p=0.044). The presence of other co-morbidities (diabetes, hypertension, history of CAD, history of autoimmune disease) or the presence of hematuria or the reason leading to renal biopsy (proteinuria or ARF) were not associated with a diagnosis of non MIg-related renal pathology. In multivariate analysis, only urine monoclonal protein >100 mg/d (HR:7.95, 95% CI 1.3-47, p=0.024) was independently associated with a diagnosis of MIg-related pathology. If parameters of urine PEP (urine monoclonal protein, urine IFE) were not included in the analysis, then total proteinuria >1.7 gr/d (HR: 4.5, 95% CI 1.1-18, p=0.036) and dFLC>50 mg/L (HR:5.8, 95% CI 1.15-29, p=0.033) were the only independent predictors. By using these two parameters 7% of those without any vs 30% with any of the two vs 63% with both factors had a MIg related renal pathology.
In conclusion, among patients with known monoclonal gammopathies and renal dysfunction, 32% had a non MIg-related diagnosis, which had implications in their management. Urine protein electrophoresis can help identify those at higher probability of MIg-related renal disease and should be evaluated in all patients with MGs; otherwise, dFLC > 50 mg/L and proteinuria >1.7 gr/d can be used. Renal dysfunction should not attributed to the underlying MIg without careful consideration of the other parameters and of a renal biopsy.

Disclosures
Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Terpos:Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.