Therapeutic Apheresis and Dialysis 2018; 2017; 22(1):79–86 ••(••):••–•• doi: 10.1111/1744-9987.12606 Society forfor Dialysis Therapy © 2017 International Society for Apheresis, Apheresis,Japanese JapaneseSociety Societyfor forApheresis, Apheresis,and andJapanese Japanese Society Dialysis Therapy
Role of Plasmapheresis in the Management of Acute Kidney Injury in Patients With Multiple Myeloma: Should We Abandon It? Vedran Premuzic,1
Josip Batinic,2 Pavle Roncevic,2 Nikolina Basic-Jukic,1 Damir Nemet,2 and Bojan Jelakovic1
Departments of 1Nephrology, Hypertension, Dialysis and Transplantation, 2Haematology, University Hospital Centre Zagreb, Zagreb, Croatia
Abstract: The aim of the current study was to determine whether plasmapheresis in combination with chemotherapy could significantly remove free light chains (FLC) in multiple myeloma (MM) patients with acute kidney injury (AKI) and therefore improve renal recovery and patient survival. During the study period, 29 patients with MM and AKI presented to our unit and were treated with two different therapy modalities (plasmapheresis with chemotherapy or bortezomib). At the end of treatment, a significant decrease of FLCs was present in the group treated with plasmapheresis compared to the bortezomib group. Patients treated with plasmapheresis had similar survival compared to patients
treated with bortezomib. There was a significantly higher decrease of FLCs and longer survival in patients treated with three or more plasmapheresis sessions than in patients treated with two plasmapheresis sessions. Plasmapheresis therapy still remains a useful and effective method in the treatment of AKI in MM patients. Plasmapheresis significantly reduces FLCs compared to bortezomib especially with higher number of plasma exchange sessions but it must be combined with other chemotherapy agents in order to prolong renal recovery and therefore patient survival. Key Words: Acute kidney injury, Bortezomib, Chemotherapy, Free light chains, Plasma exchange.
Acute kidney injury (AKI) is reported in 15–40% of patients with multiple myeloma (MM). An increased serum creatinine at diagnosis is reported in 30–40% of patients with MM and up to 10% of patients require dialysis (1). One of the diagnostic criteria by Hypercalcemia, Renal Impairment, Anemia, and Bone Disease (CRAB) for symptomatic MM requiring therapy is serum creatinine higher than 2.0 mg/dL (2). Reversibility of AKI is associated with improved survival (3). The monoclonal light chains, several thousand times higher than normal, have toxic effects on the kidney as well as dehydration, hypercalcemia and hyperuricemia which results with AKI. Recent work has demonstrated that renal recovery in patients with MM occurs when an early reduction in serum concentration of monoclonal free
light chains (FLCs) is achieved (4). The removal of FLCs with a high-cutoff dialyzer is another alternative approach (5). In additon, recently it has been shown that normalization of FLC values after treatment, which is achieving stringent complete response, also impacts patients’ outcomes in terms of time to progression and overall survival (6). Several studies showed that patients who had high FLC values at baseline had inferior outcomes in terms of event-free and overall survival (7,8). The reduction of serum FLC levels in the first 1 or 2 weeks after diagnosis and initial chemotherapy treatment could be further enhanced by plasma exchange. So far, no studies have shown clear benefits of plasma exchange (9,10) although the likely recovery of renal function with a 50% decrease in serum FLC concentrations is demonstrated by Leung et al. (4). The survival of patients with AKI is improved significantly with the use of novel therapies, which should be initiated as soon as possible. Bortezomib, as one of the novel agents can be administered at
Received April 2017; revised June 2017; accepted July 2017. Address correspondence and reprint requests to Vedran Premuzic, Department of Nephrology, hypertension, dialysis and transplantation, University Hospital Centre Zagreb, Kispaticeva 12, 10 000, Zagreb, Croatia, 10 000 Zagreb. Email:
[email protected]
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the full approved dose and schedule in patients with impaired renal function. Studies indicate that bortezomib is effective and safe in patients with renal insufficiency (11) and additionally, that it can produce improvements in renal function (12). With this new agent and encouraging results in overall patient survival, together with higher rates of renal recovery, the role of nephrologists in treating AKI in MM patients through standard therapies like hemodialysis (HD) and plasmapheresis is fading. The aims of the current study were to determine whether plasmapheresis in combination with chemotherapy could significantly remove FLC in MM patients with AKI and therefore improve renal recovery and patient survival compared to patients treated only with bortezomib and to analyze the aggressive reduction of FLCs in comparison to eGFR levels at baseline as a preferred target point in patients with MM and AKI.
This was a 24-month retrospective, longitudinal follow-up study. Patients ≥18 years old, hospitalized for treatment of newly diagnosed MM and with AKI were enrolled. Renal function was defined as an estimated GFR (eGFR) (mL/min) which was estimated daily using the simplified Modification of Diet in Renal Disease equation (13). AKI was defined by a modified definition of the Kidney Disease: Improving Global Outcomes (KDIGO) AKI Workgroup, harmonizing differences between the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) and the Acute Kidney Injury Network (AKIN) definitions. During the study period, 29 patients with MM and AKI presented to our unit. Only three patients were assessed for the pathogenesis of their renal failure by renal biopsy. All patients had de novo multiple myeloma. There were no patients with prior diabetes and seven patients had arterial hypertension. The MM diagnosis was based on the presence of marrow plasmocytosis in sheets or clusters involving more than 15% of the cells and on the discovery of monoclonal paraprotein in serum and/or urine. Patients were also analyzed for different immunoglobulin types of MM. There were 17 patients with IgG type, seven patients with IgA type and five patients with Bence-Jones type of MM. The International Staging System (ISS) for MM (14) was used for the assessment of patient classification and stratification. Twenty-two patients had an eGFR 30–45 mL/min and seven patients had eGFR 15–29 mL/min. The
nature of AKI was defined by an increase in serum creatinine to ≥1.5 times baseline. This is known or presumed to have occurred within the prior 7 days not reversible by a conservative therapy with the lack of presence of severe infections, dehydration and hyperviscosity. Body weight was used upon admission and after each documented treatment. Each patient underwent a complete clinical and laboratory examination at the time of admission and during hospitalization. The patients were treated with diuretics, intravenous saline, and oral sodium bicarbonate immediately after diagnosis to render the pH of the urine neutral. All patients initially received chemotherapy. The majority of patients (20/29) received CyBorD (or VCD) protocol: bortezomib 1.3 mg/m2 i.v. or s.c., cyclophosphamide 500 mg p.o. or i.v. and dexamethasone 40 mg i.v. on days 1, 8, 15 and 22 in a 28 days cycle. The rest of the patients (9/29) received thalidomide-based regimens: six patients were treated with MPT (melphalan 0.2 mg/kg/day p.o. and prednisolone 2 mg/kg/day p.o. over days 1– 4 and thalidomide 100 mg p.o. days 1 to 42) and three patients were treated with CTD regimen (cyclophosphamide 500 mg p.o. days 1, 8, 15; dexamethasone 40 mg p.o. days 1 to 4 and 12 to 15, thalidomide 100 mg p.o. days 1 to 21). Selection of plasmapheresis as an adjunct to chemotherapy was the choice of the involved nephrologist and hematologist specialists when eGFR level was 35 mL/min. The remaining nine patients with an eGFR level < 35 mL/min were treated with non-bortezomib therapy and plasmapheresis. There were no patients initially treated with nonbortezomib therapy and without plasmapheresis. Plasmapheresis sessions were performed on 15 patients, two sessions in seven patients and three or more in eight patients (three sessions in four patients, four sessions in two patients and five sessions in two patients). FLC removal by plasmapheresis was continued until significant reduction in FLC count or renal recovery. An estimate of plasma volume was determined by using a simplified formula (15). Polypropylene plasma filters were used (Haemoselect L 0.5 Braun) and about 3 to 5.5 L of each patient’s plasma, average of 48 mL per body weight, were removed at each session. Plasmapheresis sessions were using the Diapact
TherApher ApherDial, Dial,Vol. Vol.22, ••,No.1, No. ••, Ther 20182017
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PATIENTS AND METHODS
Plasmapheresis in in Myeloma and Kidney Plasmapheresis Myeloma and Kidney
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system (Braun; Hemosol BO Solutions, Inc, Gambro). This plasma was replaced by saline solution, albumin and when indicated with fresh frozen plasma in equal parts. The patients included in this study were treated with different chemotherapy regiments, according to the patient characteristics, availability of drugs and healthcare insurance policy at the time the diagnosis was established. A patient follow-up continued until the last enrolled patient reached the 730-day time point or until the time of death. Specific causes of death were determined for all deceased patients, namely, sepsis and cardiovascular events like stroke, heart failure and myocardial infarction. Each survived patient underwent the same complete clinical and laboratory examination as during hospitalization with the determination of renal function at the end of follow-up. Partial renal recovery was considered as eGFR 25–60 mL/min while complete as eGFR > 60 mL/min. Patients with eGFR < 25 mL/min eventually ended on chronic hemodialysis. Statistical analysis was performed using SPSS version 23.0 (IBM Corp., Armonk, NY, USA). Normality of data distribution was tested using Kolmogorov–Smirnov test. Preliminary analyses were performed to ensure no violation of the assumptions of normality, linearity and homoscedasticity. Categorical data were expressed as numbers and frequencies. Correlations were obtained using Pearson’s test for normally distributed variables and Spearman’s rank correlation for non-normally distributed variables. Normally distributed variables were presented as means + standard deviations and Student’s t-test for independent samples was used for comparisons between two groups. Non-normally distributed data were presented as median and interquartile range and Mann–Whitney U-test was used in comparing two groups. Baseline-to-Follow-up comparisons were done using Student’s t-test for paired samples and Wilcoxon test. Categorical variables were compared using χ 2 test. The survival analysis was done with Kaplan–Meier curves which were tested with log-rank test. Numbers at risk were calculated for all analyzed subgroups of patients. Multiple linear regression was used to explore the influence of different variables on survival, while logistic regression was used for categorical dependent variables. We constructed three regression models to assess independent associations of multiple independent variables with patient survival. A P-value
