Role of adjunct plasma exchange or high cut-off hemodialysis in the management of myeloma cast nephropathy: A systematic review.

e20032 Background: Renal impairment by cast nephropathy is a common complication in multiple myeloma. Tubulointerstitial injury results from precipitation of filtered free light chains (FLC) with Uromodulin in the distal convoluted tubules. Rapid reduction in serum FLC levels has shown to improve renal function in modeling studies. Extracorporeal light chain removal techniques such as plasma exchange (PEX) and high cut-off hemodialysis (HCO-HD) have been explored as potential adjunct treatment options for cast nephropathy in various clinical trials. Methods: PubMed, Cochrane library, and Clinicaltrials.gov were searched systematically for the use of plasma exchange and/or hemodialysis with chemotherapy in the treatment of myeloma cast nephropathy using their MeSH words and keywords. PRISMA guidelines were followed for screening and 5 out of 866 studies were finalized (N = 342). Results: Zucchelli et al. 1988 (n = 29) reported a dramatic reduction in Bence Jones protein (BJP) levels of 0.81 ± 0.46 g/day (P value < 0.01) and 1-year survival rate of 66% in the PEX group and decrease in BJP of 3.25 +/- 0.21 g/day (P-value < 0.05) with a survival rate of 28% in the control group. Clark et al. 2005 (n = 104) reported a primary composite response (patient alive at 6 months + dialysis independence + serum creatinine improvement of 50% at 6 months) in 57.9% of patients in the PEX group and 69.2% in the control group [95% CI, -8.3% to 29.1%]; P = 0.36. Johnson et al. 1990 (n = 21) reported a mean change of 880 μmol /L ± 260(SD) in serum creatinine in the PEX group and 570 μmol /L +/-240 in the control group. HD independence at 3 months was reported as 41.3% (n = 19) in the HCO-HD group and 33.3% (n = 16) in the conventional HD group (95% CI -12%–27.9%; P = 0.42) in the MYRE trial 2017 (n = 98). The EuLITE trial 2019 (n = 90) compared the efficacy of the high cut-off vs high flux hemodialysis (HF-HD) technique and concluded that there was no clinical benefit of one over the other. Independence from HD was achieved in 56% (n = 24) in the HCO-HD cohort vs 51% (n = 24) in HF-HD cohort (relative risk [RR] 1.09, 95% CI 0.74–1.61; P = 0.81). Conclusions: The use of high cut-off hemodialysis and plasma exchange as adjunct therapy did not show any significant survival benefit or improvement in clinical outcome. The role of routine use of PEX/HCO-HD in the management of cast nephropathy is still unclear and the decision to use these modalities should be made on an individual basis.

MO670EXPANDED HEMODIALYSIS REDUCES THE CONCENTRATION OF FREE LIGHT CHAINS IN PATIENTS WITH ACUTE KIDNEY INJURY IN MYELOMA CAST NEPHROPATHY

Background and Aims The myeloma cast nephropathy is largely associated with the production of intact immunoglobulin and free light chains (FLC) by a plasma cells monoclone. The use of high-flux hemodiafiltration (HDF) contributes to a decrease in the concentration of FLC. However, it is not always possible to achieve the required substitute volume with acute kidney injury (AKI) emergency treatment. An alternative to HDF could be the usage of membranes with a medium cut-off (expanded hemodialysis (HD), Expanded HD). The aim of this study was to compare the degree of reduction in FLC concentration using conventional HD, HDF and Expanded HD. Method The study includes patients with newly diagnosed multiple myeloma who presented indications for HD therapy start. Procedures were performed on a daily basis from the moment when indications for HD therapy were identified. The duration of the first three procedures was 2 hours. Consistently for each patient the first procedure was carried out using a standard low-flow filter, the second - using a high-flow dialyzer and HDF (substitute volume 9 liters for 2 hours), the third - using a Theranova 400 filter (Baxter, Germany). The concentrations of FLC (kappa and lambda) and albumin were determined every 30 minutes of each treatment. Chemotherapy was prescribed according to the local clinical recommendations in combination with the ongoing renal replacement therapy. Results The study included 7 patients with cast nephropathy, mean age 68±8 years. Average concentration before treatment: kappa FLC 876±727 μg/ml (norm 3.25-15.81 μg/ml), lambda FLK 84±112 μg/ml (norm 3.23-28.05 μg/ml), albumin 34±1 g/l (norm 40-50 g/l). After 2 hours of treatment, there was a decrease in kappa FLC concentration with HDF (-34±33%, p=0.01) and with Expanded HD (-31±12%, p&lt;0.001), but not with conventional HD (-1±7, p=0.79, Fig 1). The lambda FLC concentration also decreased with HDF (-41±29%, p=0.01) and with Expanded HD (-28±22%, p=0.01), but not with conventional HD (-3±12, p=0.65, Fig 2). Albumin concentrations did not change significantly with any of the treatments. Conclusion Expanded HD, as well as high-flow HDF, helps to reduce the FLC concentration in patients with cast nephropathy without loss of albumin, which may have a positive effect on the multiple myeloma prognosis. Further studies are needed regarding possibilities of using Expanded HD in the complex therapy for patients with AKI in myeloma cast nephropathy.

Myeloma cast nephropathy with diffuse amyloid casts without systemic amyloidosis: two cases report

Background Multiple myeloma (MM) is a plasma-cell derived hematologic malignant disease. The malignant proliferating plasma cells secrete massive monoclonal immunoglobulins which lead to various pathologic types of renal injury. Myeloma cast nephropathy (MCN) is the most common histopathologic lesion with the worst renal prognosis. Rarely, the free light chains in the protein casts can form amyloid fibrils. Here, we reported two rare cases of MCN with diffuse amyloid casts. Case presentation Case 1: A 54-year-old Chinese man presented with a 4-year history of multiple myeloma, proteinuria and hematuria. He had monoclonal IgAλ plus free λ spike in both serum and urine. He had been on chemotherapy for 4 years and maintained normal serum creatinine until 11 months ago. Then, his renal function deteriorated and he went on hemodialysis 4 months before admission. Renal biopsy showed diffuse amyloid casts in the tubular lumens, without any obvious amyloid deposits in other kidney compartments or signs of extra-renal amyloidosis. The amyloid fibrils formed around mononuclear cells which were CD68 negative. According to the morphology and location, these mononuclear cells were considered as tubular epithelial cells. The patient was maintained on chemotherapy and hemodialysis. He died 8 months after renal biopsy. Case 2: A 58-year-old Chinese man presented with a one-and-a-half-year history of proteinuria and slowly rising serum creatinine. He had monoclonal IgDλ spike in both serum and urine. Amyloid casts were observed in the tubular lumens and mononuclear cells could be identified in the center of some casts. There were no amyloid deposits in other kidney compartments and no sign of systemic amyloidosis. The patient also had fine granular deposits along the tubular basement membrane with λ linear staining along tubular basement membrane suggesting light chain deposition disease. He was treated with bortezomib-based chemotherapy followed by lenalidomide-based chemotherapy and achieved very good partial remission (VGPR). After 27 months of follow-up, the patient still showed no signs of systemic amyloidosis. Conclusions These 2 cases of MCN with diffuse amyloid casts have different histopathologic characteristics from the usual myeloma casts and tubular epithelial cells might play important roles in the pathogenesis.

Effect of high cut-off dialysis for acute kidney injury secondary to cast nephropathy in patients with multiple myeloma: a systematic review and meta-analysis

ABSTRACT Background Acute kidney injury (AKI) caused by cast nephropathy is associated with increased morbidity and mortality among patients with multiple myeloma (MM). High cut-off haemodialysis (HCO-HD) has proven to be effective in the removal of serum light chains but the effect on clinical outcomes, especially renal recovery, remains uncertain. Methods A systematic review and meta-analysis were performed examining all randomized controlled trials (RCTs) and observational studies (OBSs) assessing the effect of HCO-HD on clinical outcomes of patients with MM complicated by cast nephropathy–induced severe AKI. The primary outcome was all-cause mortality at the end of the study. The secondary outcomes included all-cause mortality at 12 months, HD independence and serum kappa and lambda light chain reduction. Pooled analysis was performed using random effects models. Results We identified five studies, comprising two RCTs and three retrospective cohort studies, including 276 patients with a mean follow-up of 18.7 months. The majority of the studies were of suboptimal quality and underpowered. Compared with patients treated with conventional HD, HCO-HD was not associated with a survival benefit at 12 months {five studies, 276 patients, relative risk [RR] 1.02 [95% confidence interval (CI) 0.76–1.35], I2 = 33.9%} or at the end of the studies at an average of 34 months [five studies, 276 patients, RR 1.32 (95% CI 0.71–2.45), I2 = 62.0%]. There was no difference in HD independence at 90 days [two trials, 78 patients, RR 2.23 (95% CI 1.09–4.55)], 6 months [two studies, 188 patients, RR 1.19 (95% CI 0.68–2.06)] or 12 months [two studies, 188 patients, RR 1.14 (95% CI 0.58–2.26)]. Patients receiving HCO dialysis, however, had a greater reduction in serum kappa [two studies, 188 patients, weighted mean difference (WMD) 46.7 (95% CI 38.6–54.7), I2 = 52.0%] and lambda [two studies, 188 patients, WMD 50.3 (95% CI 21.4–79.3), I2 = 95.1%] light chain levels. Conclusion Current evidence from RCTs and OBSs suggests HCO dialysis is able to reduce serum free light chains but makes no significant improvement in all-cause mortality and renal outcomes compared with conventional HD for patients with myeloma cast nephropathy. However, there is a trend towards better renal outcomes with the use of HCO dialysis. The lack of long-term data and the small sample sizes of the included studies limit this analysis. Therefore further large-scale RCTs with longer follow-up are needed to assess the effect of HCO dialysis on clinical outcomes in patients with myeloma cast nephropathy.

Clinicopathologic Predictors of Reversibility Dialysis Dependent Acute Kidney Injury in Patients with Myeloma Cast Nephropathy

Introduction: Myeloma cast nephropathy (MCN) is a main cause of acute kidney injury (AKI) at multiple myeloma (MM) onset. Wherein 5-9% of newly diagnosed MM patients are dialysis dependent. The introduction of novel agents has provided the achievement of rapid and deep hematologic response in most patients. However, the renal response in patients on dialysis is only 38-62.5%. The predictors of AKI reversibility in patients with MCN remain not enough studied. Aim: to determine clinical, morphological and immunohistochemical predictors of reversibility dialysis dependent AKI in patients with MCN. Materials and methods: 36 patients aged 38 to 74 years (median age=57 years) with newly diagnosed MM and dialysis dependent AKI stage 3 (AKIN, 2012) due to MCN were enrolled into the study from January 2006 till November 2019. The diagnosis of MM, hematologic and renal response were established according to the 2016 IMWG criteria. MCN was determined by renal biopsy performed prior to induction therapy. The assessment degree of acute tubular injury, tubular atrophy and interstitial fibrosis (IF/TA) were semi-quantitatively evaluated. The number of sclerotic glomerular were calculated manually. The median number of casts was defined by all casts in a section divided by number of fields observed (х100). Additionally, square of interstitial fibrosis, interstitial inflammation, expression of Immunohistochemical markers (E-cadherin, α-smooth muscle actin (α-SMA), vimentin) were measured by computerized quantitatively image analysis using the digital module Leica (Germany). The time from diagnosis of AKI to start of induction therapy did not exceed 3 months. Bortezomib based first line treatment regimen was used in 25 (69%) of patients; 9 (25%) patients received chemotherapeutic agents only, 2 (6%) dead before a start of induction therapy. Statistical software package SAS 9.4 was applied for calculations. Overall survival according to renal response was compared by using Kaplan-Meier curves. Also frequency, logistic, discriminant and ROC analysis were used. All estimates are shown with a 95%CI. Results: Hematologic partial response or better occurred in 19 (53%) of patients, median of 32 (13-129) days. Renal response - in 14 (39%). In 3 (8%) cases renal function improved after correction of dehydration before start of antimyeloma therapy, in the remaining 11 (30%) patients only when hematologic response was achieved (p = 0.001). The frequency of renal response was depending on start of antimyeloma therapy before and after 4 weeks from diagnosis of AKI and was 83% and 17%, respectively (p &lt;0.05). In patients with renal response there was not a single fatal outcome; without renal response 3-year OS was 68% ± 13%. Patients with hematologic response were divided into two groups (Tab.). The main pathological findings associated with renal response were less frequent mild to severe IF/TA in patients with and without renal response (moderate 45% vs 75%, respectively, p=0.008), less area of interstitial fibrosis (24.9% vs 44.7%, respectively, p=0.001), percentage of proximal tubules with save epithelial phenotype and less area of expression E-cadherin at interstitium (15.9% vs 7.1%, respectively, p=0.006). The median number of casts per field was the same (6.4 and 6.3, p=0.64) as well as the percentage of tubule lumen obstruction by casts (13.6% and 15.1%, p=0.81). Statistically significant correlation between the expression area of E-cadherin and interstitial fibrosis was not found (Rs= -0.335, p= 0.065). Therefore, a combination of these factors can be used to predict renal response in the onset of AKI due to MCN (area under the ROC curve is 0.84). The prognostic model and logical rule allow to define groups of renal outcomes (Fig.). If expression area of E-cadherin is less than 10% and / or area of interstitial fibrosis is more than 40% of the interstitium, a renal response is unlikely (OR = 24.5) and will not be achieved in almost 90% of cases, despite hematological response. Discussion. Reversibility of dialysis dependent AKI due to MCN rely on the achievement of hematological response and the time from diagnosis of AKI to start of antimyeloma therapy. There are predictors of renal response of these patients determined by the severity of morphological changes: degree of IFTA, quantitative area of interstitial fibrosis and E-cadherin expression. Disclosures No relevant conflicts of interest to declare.

Morphological and immunohistochemical predictors of renal response to therapy patients with myeloma cast nephropathy and dialysis-dependent acute kidney injury

Aim.Reveal morphological and immunohistochemical predictors of reversibility of dialysis-dependent acute kidney injury (AKI) in patients with myeloma cast nephropathy (MCN) based on the study of kidney biopsy. Materials and methods.Renal pathological findings were studied in 36 patients with MCN and dialysis-dependent stage 3 AKI (AKIN, 2012). The study of biopsy samples was performed by a semi-quantitative and quantitative analysis using computer morphometry. The expression of E-cadherin, vimentin and-smooth muscle actin was determined immunohistochemically in the tubular cells and interstitium. Induction therapy for 26 patients was carried out to bortezomib-based programs; in 10 patients other schemes were used. A comparative analysis of morphological changes in nephrobiopathy depending on the renal response was performed in patients with achieved hematologic remission. Results.Improved renal function was observed only in patients with hematologic response to therapy. There were no differences in the number of sclerotic glomeruli, protein casts, the area of inflammatory interstitial infiltration, and the degree of acute tubular damage in patients with and without renal response. In patients with renal response compared with patients without improving renal function, the area of interstitial fibrosis was less (24.9% and 45.9%, respectively;p=0.001), and the area of E-cadherin expression was larger (15.9% and 7.1%, respectively;p=0.006). Interstitial fibrosis of 40% or more and/or the area of expression of E-cadherin less than 10% of the area of tubulo-interstitium have an unfavorable prognostic value in achieving a renal response in MCN. Conclusion.If the interstitial fibrosis area is 40% or more and the expression area of E-cadherin is less than 10%, the probability of the absence of a renal response is 93.3% (OR=24.5) even when a hematological response to induction therapy is achieved. The number of protein casts, the prevalence of acute tubular damage and inflammatory interstitial infiltration have not prognostic value.