Defining the Incidence, Pathology and Clinical Outcomes of Kidney Disease Related to Waldenstrom's Macroglobulinemia and IgM MGUS

Background While kidney disease (KD) is a well described complication of multiple myeloma (MM), occurring in up to 40% of patients, the incidence, pathological manifestations, and clinical correlations associated with KD in patients with Waldenström’s Macroglobulinemia (WM) or IgM MGUS remain to be clarified.

Methods Out of 1,738 patients with consensus criteria defined WM (N=1,655) or IgM MGUS (N=83) diagnosis who were evaluated in the WM clinic at our institution from 2001-2015, we selected those individuals with at least one of the following abnormalities: serum creatinine ≥1.3; estimated GFR (eGFR) <60; or proteinuria. Patients with non-WM/IgM MGUS related KD were excluded.

Results Renal impairment and/or proteinuria were present in 259 patients. In 183 cases, KD was not related to WM/IgM MGUS (mainly diabetic and/or hypertensive nephropathy). Fifteen patients with kidney or bladder carcinoma, and 4 patients with peri-renal diffuse large B-cell lymphoma (N=3) or lymphoplasmacytic lymphoma (N=1) were also excluded. Therefore, a clinical diagnosis of WM/IgM MGUS associated KD was made in 57 (53 WM; 4 IGM MGUS) patients, of whom 41 had a confirmatory renal biopsy. The crude incidence of WM/IgM MGUS-associated KD in this cohort was 3.3% (2.4% for renal biopsy confirmed cases). Renal pathology in the 41 cases showed: amyloid deposition (N=10; 24%); parenchymal lymphoplasmacytic infiltrate (N=7; 17%); monoclonal light chain deposition (N=6; 15%); cryoglobulin deposition (N=6; 15%); light chain cast nephropathy (N=4; 10%); monoclonal IgM deposition (N=3; 7%), thrombotic microangiopathy (N=3; 7%), and minimal change disease (N=2; 5%). In 11 (27%) of these cases, multiple abnormalities were present in the renal biopsy. For patients who underwent renal biopsy, the median age was 66 (range 46-81 years), serum IgM was 2,053 (range 178-5,870 mg/dL), and eGFR was 30 (range 4-99 ml/min/1.73m²). Nephrotic syndrome was present in 13 (31%) of these patients. Four (10%) patients presented with hemoglobin ≤10 g/dL, while none had hypercalcemia. The median follow-up for these patients was 17 (range 1-162 months). A synchronous diagnosis of WM and KD was made in 17 patients (41%), while in the remaining 24 patients the median time to KD following the diagnosis of WM was 29 (range 5-88 months).

KD was diagnosed in mainly untreated patients (N=29; 70%), while for the remaining 12 patients, KD occurred after a median of 2 prior therapies. Thirty-six patients received treatment associated with WM/IgM MGUS related KD as follows: proteasome-inhibitor based (N=19; 46%); alkylator based (N=11; 27%); nucleoside analogues (N=4; 10%); and rituximab monotherapy (N=2; 5%). Plasmapheresis was employed in 12 (31%) patients. Treatment responses based on consensus criteria were as follows: CR (N=1; 3%), VGPR (N=4; 11%), PR (N=27; 75%), MR (N=1; 3%) progressive disease (N=1; 3%), or unevaluable (N=5; 14%). Renal outcomes for the 36 treated patients based on at least a 10 ml/min/1.73m2 change in eGFR were as follows: improved (N=14; 34%); stable (N=12; 29%); decreased (N=9; 22%) and unknown (N=1; 2%). Patients with either amyloid or light chain deposition (N=16) showed worse outcomes: 1 died of refractory nephrotic syndrome; 5 went on to dialysis. None of the patients with other renal pathology either died of renal complications or required dialysis.

Conclusions In contrast to MM, KD is uncommon and shows a different spectrum of renal pathology (including multiple pathological findings) in WM/IgM MGUS patients. Patients with amyloid or light chain deposition disease show worse outcomes, including the requirement for dialysis. While treatment is associated with either improved or stable renal function in most patients, the optimal approach to the management of WM/IgM MGUS related KD remains to be determined.