| Abstract|| |
Renal dysfunction is encountered in 20-25% of patients with multiple myeloma (MM) at the time of diagnosis. There is often a precipitating event. Several biochemical and clinical correlations with renal failure in MM have been reported. Renal failure in MM is associated with worse outcome of the disease. We retrospectively analyzed the medical records of 64 patients with MM admitted to our institution during the period January 1992 to December 2012. Abnormal renal function was observed in 24 (37.5%) patients and 17 (26.6%) of them had renal failure; 14 of the 17 (82.4%) of patients with renal failure had Stage III MM. Urine Bence- Jones protein was positive in ten (58.8%) patients with renal failure versus ten (21.3%) patients without renal failure (P = 0.004). Potential precipitating factors of renal failure were determined in nine patients. Renal function normalized in 11 patients with simple measures, while six patients required hemodialysis; one remained dialysis dependent till time of death. Early mortality occurred in five (29.4%) patients with renal failure as compared with two (4.3%) patients in the group without renal failure (P = 0.005). In conclusion, renal failure is associated with a higher tumor burden and Bence-Jones proteinuria in patients with MM. It is reversible in the majority of patients; however, early mortality tends to be higher in patients with persistent renal failure.
|How to cite this article:|
Almueilo SH. Renal failure in patients with multiple myeloma. Saudi J Kidney Dis Transpl 2015;26:482-8
| Introduction|| |
Multiple myeloma (MM) is a rare hematological malignancy. It is characterized by uncontrolled proliferation of plasma cells in the bone marrow. The incidence of MM is about three to four per 100,000 population. It comprises about 10% of all hematological malignancies.  Common presenting features of MM include bone pain and bone fractures, anemia, increased susceptibility to infections, hypercalcemia, neurological manifestations, hyperviscosity syndrome, and renal failure. ,
Renal failure is a fairly common finding in patients presenting with MM. ,, Renal failure complicates MM in about 20-25% of patients, but more than half of all myeloma patients show some renal abnormalities. ,,,, The most common renal lesion is myeloma cast nephropathy, characterized by the presence of large tubular casts. These tubular casts form as a result of aggregation of light chain immunoglobins and Tamm-Horsfall protein, a glycoprotein produced by cells in the loop of Henle. These casts result in tubular damage due to its toxicity and obstructive nature.  The obstruction could be worsened by volume depletion.  Less-frequent varieties of renal lesions of MM include light chain deposition disease and primary amyloidosis.  Several factors may predispose MM patients to develop renal failure, such as volume depletion, hypotension, sepsis, hypercalcemia, hyperuricemia and exposure to intravenous radiocontrast material or other potentially nephrotoxic agents such as nonsteroidal anti-inflammatory drugs. ,
Renal failure in MM patients has been associated with poor prognosis. It is associated with higher mortality, in part because renal failure also limits some treatment options.  The prognosis of MM patients, however, is dependent on multiple factors such as the estimated tumor load and response to chemotherapy. Renal failure is often reversible with simple measures such as rehydration, removal of offending drugs and correction of hypercalcemia. The reversibility of renal failure has a positive impact on the prognosis. ,,
The aim of this study was to evaluate patients with MM in the presence of renal failure at time of diagnosis and the association of renal failure with other laboratory and clinical correlates and their impact on early survival of patients.
| Patients and Methods|| |
The medical records of all patients with a diagnosis of MM admitted to our hospital during the period January 1992 to December 2012 were retrospectively analyzed. The diagnosis of MM was based on the presence of two of the following criteria: Bone marrow plasma cells more than 30%, serum or urinary monoclonal protein and osteolytic bone lesions on skeletal radiological survey. The plasma cell tumor load was determined as low, moderate or high according to the criteria proposed by Durie and Salmon.  The patients' data were reviewed with respect to age, sex, nationality, presenting symptoms and signs, hematological and chemical parameters and the level of monoclonal protein in the serum and urine. Abnormal renal function was defined as a serum creatinine concentration ≥133 μmol/L (1.5 mg/dL) at the time of diagnosis, whereas renal failure was defined as a serum creatinine ≥177 μmol/L (2 mg/dL) at the time of presentation. The estimated glomerular filtration rate (eGFR) was calculated using the four-variable Modification of Diet in Renal Disease (MDRD) equation.  Renal failure was staged as per practice guidelines proposed by the National Kidney Foundation for staging chronic kidney disease (CKD).  When possible, the precipitating factor of renal failure was determined from the clinical and laboratory information available. The course of the disease in the patients was monitored with respect to renal function recovery, need of dialysis support and early mortality. Early mortality was defined as death within three months from the time of diagnosis.
| Statistical Analysis|| |
Data were expressed as mean values with standard deviation (SD). Comparison between patients with and without renal failure was performed by using the unpaired Student's "t" test for numerical variables. The chi-square test was used for comparing nominal variables. P-values <0.05 were considered as statistically significant.
| Results|| |
During the study period, a total of 64 patients were diagnosed as MM; the mean (±SD) age of the patients was 62.2 ± 12.1 years (range 36-84 years) and 49 (76.6%) patients were male and 46 (71.9%) patients were Saudi nationals.
[Table 1] shows that the most common presenting symptoms were bone pain and fatigue, and they were present in 65.6% and 26.6% of the patients, respectively. Weight loss was present in 18.8% of the patients and anemia (Hb <100 g/L) was present in 57.8% of the patients. Osteolytic bone lesions and plasmacytoma were observed in 20.3% and 18.8% of the patients, respectively.
|Table 1: Clinical and laboratory findings at pre-sentation in 43 patients with multiple myeloma.|
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Abnormal renal function, defined as serum creatinine ≥133 μmol/L at the time of diagnosis, was observed in 24 (37.5%) patients while renal failure, defined as a serum creatinine ≥177 μmol/L, was observed in 17 (26.6%) patients; five patients had CKD stage 3, with eGFR 34.2 ± 3.4 mL/min/1.73 m 2 , nine patients had CKD stage 4 with eGFR 21.2 + 5.04 mL/min/1.73 m 2 and three patients had CKD stage 5 with eGFR 11.3 + 2.1 mL/min/1.73 m 2 . The patients with stage 3 were significantly younger (59.6 + 11.8 years) than those with higher stages of CKD (70.6 + 8.2 years) (P = 0.04).
[Table 2] compares patients with and without renal failure with respect to several clinical and laboratory variables. The two groups were similar in age, gender distribution, serum calcium and lactic dehydrogenase (LDH) levels. There was a tendency for lower hemoglobin level in patients with renal failure, but it did not reach statistical significance. Fourteen of 17 (82.4%) patients with renal failure at presentation had a Stage III MM compared with 20 of 47 (42.6%) patients without renal failure (P = 0.005). Positive urine Bence-Jones protein was significantly associated with renal failure at presentation [ten (58.8%) patients with renal failure vs. ten (21.3%) patients without renal failure, P = 0.004].
|Table 2: Comparison of clinical and laboratory findings in patients with and without renal failure at presentation.|
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[Table 3] shows the potential precipitating factors of renal failure determined in nine patients. No precipitating factor could be ascertained in the remaining eight (47%) renal failure patients. Renal function normalized in 11 patients with simple measures such as intravenous hydration, treatment of infection and removal of potential offending drugs, in addition to chemotherapy. However, renal function remained abnormal, but stable, in four patients, and six patients required hemodialysis treatment to control uremia; one of these six patients remained dialysis dependent till the time of death four months after the diagnosis of MM. Kidney biopsy was performed in two renal failure patients, and both revealed histological findings consistent with myeloma cast nephropathy.
|Table 3: Potential precipitating factors for renal failure in 17 patients.|
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Treatment for the study patients included a combination of prednisolone and melphalan in 33 (51.6%) patients and a combination of vincristine, adriamycin and dexamethasone in 12 (18.8%) patients. In addition, six patients required radiation therapy for localized severe pain due to the osteolytic lesions, three patients were treated with thalidomide and one patient was referred for stem cell transplantation.
However, the treatment in the patients with renal failure included a combination of melphalan and prednisolone in nine patients (six of whom had improved renal function) and a combination of vincristine, adriamycin and dexamethasone in seven patients (four had improved renal function). Melphalan and prednisolone in conjunction with thalidomide were used in one patient whose renal function also improved. Early mortality, defined as death within three months from diagnosis, occurred in five (29.4%) patients with renal failure compared with two patients (4.3%) in the group without renal failure (P = 0.005).
| Discussion|| |
According to the results of our study, abnormal renal function was observed in 37.2% of our patients with MM and renal failure was observed in 25.6% of patients. Patients with renal failure tended to have higher tumor burden and Bence-Jones proteinuria. Renal failure was reversible in the majority of patients; however, there was a tendency for higher early mortality in MM patients with renal failure.
The prevalence of renal failure at the time of presentation in our study was similar to that reported in the medical literature. Kyle et al  reported a 19% prevalence of renal failure with serum creatinine >177 μmol/L. Knudsen et al reported a 15% prevalence of severe renal failure with plasma creatinine >200 μmol/L. Renal impairment was mainly seen in patients with hypercalcemia, stage III MM disease and a high level of Bence-Jones proteinuria. Renal impairment at the time of diagnosis was associated with poorer survival.  In our study, renal failure was reversible in 63.6%, dialysis was required in 27.3% and permanent till death in one patient (9.1%). Reversibility of renal failure is associated with improved survival.  Because of the small number of our patients with renal failure, it was difficult to correlate between the type of MM therapy and the outcome of renal dysfunction.
Several precipitating events have been implicated in aggravating cast nephropathy. These include dehydration, use of non-steroidal antiinflammatory drugs, hypercalcemia and exposure to radiocontrast agent, particularly the ionic high osmolar form. ,,, In a series of patients with severe renal failure and myeloma, a precipitant of renal failure was identified in 43% of patients, most commonly hypercalcemia and the consumption of nonsteroidal anti-inflammatory drugs. 
Management of patients with MM complicated by renal failure is difficult. The standard treatment of myeloma often consists of highdose chemotherapy with autologous peripheral stem cell transplantation in patients younger than 70 years.  However, in many cases, the presence of severe renal failure precludes such an approach. ,, Stem cell transplantation is associated with higher mortality in patients with renal failure,  and the response rate to chemotherapy in patients with renal failure is 29-50%, which lowers the survival rate. ,
More recently, several workers had reported encouraging strategies in managing the MM patients with renal failure. ,, Vigneau et al used a single intermediate dose of melphalan (25 mg/m 2 ) IV for treating 45 patients with MM and renal failure. The overall median survival was 45 months after diagnosis. For the Stage III MM patients, survival was the same, irrespective of whether renal insufficiency was present or not.  Tosi et al treated 20 consecutive patients with Stage III relapsed or refractory MM and renal failure. Three patients were undergoing chronic hemodialysis. Eight patients were treated with thalidomide as a single agent and 12 patients were treated with thalidomide and dexamethasone for four consecutive days every four weeks. Good response was achieved in nine patients (45%). Furthermore, recovery of normal renal function was observed in 12 of 15 responsive patients.  Badros et al presented data on 81 MM patients with renal failure at the time of autologous stem cell transplantation, including 38 patients on dialysis. At a median follow-up of 31 months, 30 (37%) patients died, 21 (26%) patients had complete remission after the first stem cell transplantation, 31 (38%) patients had remission after tandem stem cell transplantation and two patients discontinued dialysis. 
Because cast nephropathy is related to the excretion of large amounts of free light chains that overwhelm the absorptive capacity of the proximal tubules, the removal of free light chains by plasma exchange was beneficial in renal recovery and discontinuation of dialysis therapy. , Recently, however, a larger multicenter controlled trial raised serious doubts about the benefit of plasma exchange in patients with MM and renal failure.  Plasma exchange was performed in one of our study patients who had hyperviscosity syndrome.
A protocol consisting of chemotherapy and extended high cut-off hemodialysis may be effective in reducing the light chain levels and improving kidney function. Hutchison et al in an open-label study, treated 19 MM patients with renal failure using a combination of standard chemotherapy and high cut-off hemodialysis. Sustained reduction in serum-free light levels was achieved in 13 (68%) patients. These patients became dialysis independent at a median of 27 days. Survival of patients who recovered kidney function significantly improved. 
Recent studies suggest that bortezomib, a reversible proteasome inhibitor, alone or in combination with other chemotherapeutic agents is beneficial in MM patients with renal failure.  In a study by Ludwig et al, 68 patients with light chain-induced acute renal failure and GFR <50 mL/min received a combination of bortezomib, doxorubicin and dexamethasone. Results by intent-to-treat analysis showed a renal response of 62%. However, survival did not differ between patients with and without renal response. 
Limitations of our study include its retrospective nature, small size and short-term follow-up.
We conclude from our study that renal failure is present in 25% of MM at the time of diagnosis. Renal failure is associated with a higher tumor burden and Bence-Jones proteinuria and is reversible in many patients after correction or removal of the precipitating factors and myeloma therapy. Finally, early mortality is higher in MM patients with than without renal failure.
Conflict of interest: None declared
| References|| |
Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:2133.
Barlogie B, Epstein J, Selvanayagam P, Alexanian R. Plasma cell myeloma: New biological insights and advances in therapy. Blood 1989;73:865-79.
Blade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma: Presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998;158:1889-93.
Knudsen L, Hippe E, Hjorth M, Holmberg E, Westin J. Renal function in newly diagnosed multiple myeloma: A demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol 1994;53:207-12.
Alexanian R, Barlogie B, Dixon D. Prognosis of asymptomatic multiple myeloma. Arch Int Med 1988;148:1963-5.
Hamblin TJ. The kidney in myeloma. Br Med J 1986;292:2-3.
Sanders PW, Booker BB. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992;89:630-9.
Winearls CG. Acute myeloma kidney. Kidney Int 1995;48:1347-61.
Hill GS, Morel-Maroger L, Mery JP, Brouet JC, Mignon F. Renal lesions in multiple myeloma: Their relationship to associated protein abnormalities. Am J Kidney Dis 1983; 2:423-38.
Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990;150:1693-5.
Bernstein SP, Humes HD. Reversible renal insufficiency in multiple myeloma. Arch Intern Med 1982;142:2083-6.
Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 1975;36:842-54.
Levey AS, Coresh J, Greene T, et al; Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-54.
Levey AS, Coresh J, Blake E, et al. National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 2003;139:13747.
Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: Reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eur J Haematol 2000;65:175-81.
Sanders PW. Pathogenesis and treatment of myeloma kidney. J Lab Clin Med 1994;124: 484-8.
Smolens P, Barnes JL, Kreisberg R. Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins. J Lab Clin Med 1987; 110:460-5.
Morgan C, Hammack WJ. Intravenous urography in multiple myeloma. N Engl J Med 1966;275:77-9.
Irish AB, Winearls CG, Littlewood T. Presentation and survival of patients with severe renal failure and myeloma. Q J Med 1997;90:77380.
Anderson KC, Kyle RA, Dalton WS, et al. Multiple Myeloma: New Insights and Therapeutic Approaches. Hematology Am Soc Hematol Educ Program 2000;147-65.
Carlson K, Hjorth M, Knudsen LM; Nordic Myeloma Study Group. Toxicity in standard melphan-prednisone therapy among myeloma patients with renal failurea retrospective analysis and recommendations for dose adjustment. Br J Haematol 2005;128:631-5.
San Miguel JF, Lahuerta JJ, Garcia-Snaz R, et al. Are myeloma patients with renal failure candidates for autologous stem cell transplantation? Hematol J 2000;1:28-36.
Knudsen LM, Nielsen B, Gimsing P, Geisler C. Autologous stem cell transplantation in multiple myeloma: Outcome in patients with renal failure. Eur J Hematol 2005;75:27-33.
Vigneau C, Ardiet C, Bert M, et al. Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure. J Nephrol 2002;15:684-9.
Tosi P, Zamagni E, Cellini C, et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 2004;73:98-103.
Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol 2001;114:822-9.
Zucchelli P, Pasquali S, Cagnoli L, Ferreri G. Contolled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 1988;33:1175-80.
Moist L, Nesrallah G, Kortas C, Espirtu E, Ostbye T, Clark WF. Plasma exchange in rapidly progressive renal failure due to multiple myeloma. A retrospective case series. Am J Nephrol 1999;19:45-50.
Clark WF, Stewart AK, Rock GA, et al, and the Canadian Apheresis Group. Plasma exchange when myeloma presents as acute renal failure: A randomized, controlled trial. Ann Intern Med 2005;143:777-84. Erratum in: Ann Intern Med 2007;146:471.
Hutchison CA, Bradwell AR, Cook M, et al. Treatment of Acute Renal Failure Secondary to Multiple Myeloma with Chemotherapy and Extended High Cut-Off Hemodialysis. Clin J Am Soc Nephrol 2009;4:745-54.
Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: A multicenter retrospective study. Blood 2007;109:2604-6.
Ludwig H, Adam Z, Hajek R, et al. Light Chain-Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study. J Clin Oncol 2010;28:4635-41.
Dr. Samir H Almueilo
Department of Internal Medicine and Nephrology, King Fahd Hospital of the University, University of Dammam, P. O. Box 40154, Alkhobar 31952
[Table 1], [Table 2], [Table 3]