Jo Abraham MD Division of Nephrology University of Utah

Jo Abraham MD Division of Nephrology University of Utah

68 year old male presented 3 weeks ago with a 3 month history of increasing fatigue He reported a 1 week history of increasing dyspnea with a productive cough Developed worsening respiratory distress and was intubated Developed progressive renal insufficiency Urine analysis was notable for proteinuria

Urine protein/creatinine ratio was 3.2 Urine microalbumin/creatinine ratio was 1.4 Renal biopsy was with acute tubular necrosis and cast nephropathy SPEP/IFE was with a M spike measuring 2.8gm/dL- IgG kappa Kappa/Lambda light chain ratio was elevated Bone Marrow biopsy with 50% plasma cells with kappa light chain restriction Started on CyBorD

71 yr old male presented with severe hypertension and was found to have a creatinine of 1.7 with 13 grams of proteinuria Renal biopsy with MPGN with monoclonal IgG kappa Serum IFE: no monoclonal protein Serum free kappa/lambda light chain ratio 6.7 Bone marrow biopsy < 5% plasma cells, kappa monotypic by flow cytometry Patient was treated with CyBorD Creatinine now 1.1 with < 1gm proteinuria

Renal disease caused by monoclonal immunoglobulin secreted by a non malignant plasma cell or B cell clone Patients meet criteria for MGUS but have renal insufficiency with monoclonal immunoglobulin deposition in the kidney

Multiple myeloma accounts for 13% of the hematological malignancies Renal impairment in MM ranges from 20-50% 70% of patients who secrete more than 10g/d light chain will develop renal impairment 100% renal disease with rare IgD MM Renal impairment in MM is associated with increased mortality Reversibility of myeloma associated renal injury is more predictive of survival than the response to chemotherapy

Pathogenesis: Paraproteinemias can produce a spectrum of renal lesions Free light chains (FLC) are low molecular weight proteins that are normally produced by lymphoid tissue ( ~500mg/day) Readily filtered and reabsorbed in the proximal tubule through endocytosis by the megalin/cubilin receptor system Only 1-10mg of FLC appear in the urine daily

Overproduction of FLCs overwhelms the proximal tubular epithelium resulting in overflow proteinuria- Bence Jones proteinuria Minimal albuminuria with a negative dipstick for proteinuria- leading frequently to a delay in the diagnosis FLCs can accumulate in the proximal tubule and interfere with tubular function FLCs can be degraded and induce pro inflammatory cytokines leading to cell infiltration, matrix deposition and fibrosis

The differential renal handling of paraproteins and the variety of renal lesions in patients with MM reflects the molecular diversity of the paraprotein. Serum FLC`s from 40 patients were injected into mice. Monoclonal FLC`s from patients with renal dysfunction were more likely to deposit in the mice kidneys Renal pathology in mice matched the pathology in humans The site and pathology of renal injury are specific to the physiochemical properties of monoclonal FLC`s. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence Jones proteins. N Engl J Med 324: 1845 1851, 1991

Other mechanisms of pathogenesis: A dimeric monoclonal lambda light chain acts as an auto antibody to complement factor H resulting in uncontrolled activation of the alternate complement pathway causing MPGN Monoclonal light chain may act as a C3 nephritic factor causing C3 GN Monoclonal IgG3kappa targeting phospholipase 2 can cause membranous nephropathy

Cast nephropathy 40-60% of renal disease in MM Risk of renal failure is associated with the level of light chain excretion Renal insufficiency was present in 16% of patients with < 1g/d FLC, 47% with 1-10g/d and 63%with >10g/d Pathological hallmark is intratubular cast Casts are from interaction of FLCs with Tamm Horsfall protein causing obstruction in the distal and collecting tubules Factors that are implicated in cast formation include the type and concentration of Bence Jones protein, hypercalcemia, tubular flow rate, dehydration, furosemide, NSAID and intravenous contrast.

Diagnosis: Serum and urine electrophoresis with immunofixation, kappa/lambda FLC ratio, renal biopsy Prognosis of cast nephropathy: Patients who require dialysis and do not recover renal function have a 50% survival at < 1 yr Patients who are able to discontinue dialysis have a 50% survival at 3 yrs

Treatment General measures Discontinue nephrotoxic medications Volume expansion Avoid IV radio contrast Avoid diuretics Hypercalcemia Volume expansion Bisphosphonates Calcitonin Avoid loop diuretics?denusumab Hyperuricemia Volume expansion Allopurinol Rasburicase

Chemotherapy Early reduction in FLC is associated with the highest rate of renal recovery Significant reduction in FLC by day 21 is associated with renal recovery in 80% of the patients Bortezomib rapidly reduces FLCs and in addition inhibits NF-kB pathways reducing inflammatory cytokines and inducing anti apoptotic pathways Bortezomib is unaffected by renal function- safely administered in patients with renal failure Other chemotherapy: Lenalidomide, Thalidomide, Pomalidomide and Carfilzomib

HSCT is a potentially curative therapy in MM Can be safe and effective even in patients with renal failure 10 yr retrospective study from Mayo in patients with Cr > 3mg/dl ( 50% on dialysis) all patients achieved hematological response although only 1 of 15 was able to discontinue dialysis.

Therapeutic Plasma Exchange RCT failed to show benefit in composite end point of death, dialysis or reduced renal function at 6 months 14 patients with presumed cast nephropathy were treated with bortezomib and TPE, 12 had complete or partial renal response by 6 months TPE in cast nephropathy cannot be recommended on current evidence.

High cutoff (HCO)-HD Not associated with greater recovery of renal function

MIDD 25% of patients Most common form of MIDD is LCDD Extra renal manifestations include cardiac disease and hepatic insufficiency Gi and neurological features less common

Prognosis Median patient survival is 4 years Progression to ESRD occurs in the majority of patients with MIDD Treatment Similar to multiple myeloma Renal transplant has been performed 70% had recurrence Renal transplant should not be performed when hematological remission is not achieved

AL amyloidosis 30% of the patient with MM Proteinuria is a common manifestation Monoclonal protein is present in 90% of the patients Lambda light chains in 80%

Prognosis AL amyloidosis with cardiomyopathy had the poorest prognosis Treatment Melphalan and prednisone ASCT Renal response in 71% of the patients with hematological response Renal transplantation a viable option in patients with successful ASCT

Proliferative GN with monoclonal Ig deposits Paraprotein associated C3 glomerulopathy Paraprotein associated fibrillary GN Immunotactoid glomerulopathy Minimal change disease Membranous GN with masked IgGk Paraprotein associated thrombotic microangiopathy Cryoglobuninemia Fanconi syndrome Proximal tubulopathy

Figure 2 Kidney International 2015 87, 698-711DOI: (10.1038/ki.2014.408) Copyright 2015 International Society of Nephrology Terms and Conditions

Figure 1 Kidney International 2015 87, 698-711DOI: (10.1038/ki.2014.408) Copyright 2015 International Society of Nephrology Terms and Conditions

Paraprotein related kidney disease represent a diverse group of disorders that result from abnormal production of Igs or their components Accurate histo pathological diagnosis is essential for prognostication and treatment A multidisciplinary team consisting of hematologists, oncologists, pathologists and nephrologists who are able to provide a serial long term follow up is ideal for the care for these patients