KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantation
Authors: Jolanta Małyszko, Aristotelis Bamias, Farhad R. Danesh, Alicja Dębska-Ślizień, Maurizio Gallieni, Morie A. Gertz, Jan T. Kielstein, Petra Tesarova, Germaine Wong, Michael Cheung, David C. Wheeler, Wolfgang C. Winkelmayer, Camillo Porta, Ali K. Abu-Alfa, Hatem Amer, Gernot Beutel, Jeremy Chapman, Xiaohong Chen, Jerzy Chudek, Laura Cosmai, Romano Danesi, Filippo De Stefano, Kunitoshi Iseki, Edgar A. Jaimes, Kenar D. Jhaveri, Artur Jurczyszyn, Rümeyza Kazancioğlu, Abhijat Kitchlu, Christian Kollmannsberger, Amit Lahoti, Yang Li, Manuel Macía, Takeshi Matsubara, Dionysios Mitropoulos, Eisei Noiri, Mark A. Perazella, Pierre Ronco, Mitchell H. Rosner, Maria Jose Soler Romeo, Ben Sprangers, Walter M. Stadler, Paul E. Stevens, Vladimír Tesař, Verônica Torres da Costa e Silva, David H. Vesole, Anitha Vijayan, Ondřej Viklický, Biruh T. Workeneh, Motoko Yanagita, Elena Zakharova
Journal: Kidney International (2020)

The bidirectional relationship between cancer and chronic kidney disease (CKD) is complex. Patients with cancer, particularly those with hematological malignancies such as multiple myeloma and lymphoma, are at increased risk of developing acute kidney injury and CKD. On the other hand, emerging evidence from large observational registry analyses have consistently shown that cancer risk is increased by at least 2- to 3-fold in kidney transplant recipients, and the observed increased risk occurs not only in those who have received kidney transplants but also in those on dialysis and with mild- to moderate-stage CKD. The interactions between cancer and CKD have raised major therapeutic and clinical challenges in the management of these patients. Given the magnitude of the problem and uncertainties, and current controversies within the existing evidence, Kidney Disease: Improving Global Outcomes (KDIGO) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology to identify key management issues in nephrology relevant to patients with malignancy. This report covers the discussed controversies in kidney disease in hematological malignancies, as well as cancer after kidney transplantation. An overview of future research priorities is also discussed. The bidirectional relationship between cancer and chronic kidney disease (CKD) is complex. Patients with cancer, particularly those with hematological malignancies such as multiple myeloma and lymphoma, are at increased risk of developing acute kidney injury and CKD. On the other hand, emerging evidence from large observational registry analyses have consistently shown that cancer risk is increased by at least 2- to 3-fold in kidney transplant recipients, and the observed increased risk occurs not only in those who have received kidney transplants but also in those on dialysis and with mild- to moderate-stage CKD. The interactions between cancer and CKD have raised major therapeutic and clinical challenges in the management of these patients. Given the magnitude of the problem and uncertainties, and current controversies within the existing evidence, Kidney Disease: Improving Global Outcomes (KDIGO) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology to identify key management issues in nephrology relevant to patients with malignancy. This report covers the discussed controversies in kidney disease in hematological malignancies, as well as cancer after kidney transplantation. An overview of future research priorities is also discussed. Cancer is becoming recognized as a major complication in patients with chronic kidney disease (CKD). The magnitude of the increased risk varies based on CKD severity, with the greatest risk among kidney transplant recipients. Convincing evidence from longitudinal observational analyses has suggested the excess risk of cancer and cancer-related death in kidney transplant recipients is at least 2-fold greater than the sex- and age-matched general population.1Vajdic C.M. McDonald S.P. McCredie M.R. et al.Cancer incidence before and after kidney transplantation.JAMA. 2006; 296: 2823-2831Crossref PubMed Scopus (790) Google Scholar,2Au E. Wong G. Chapman J.R. Cancer in kidney transplant recipients.Nat Rev Nephrol. 2018; 14: 508-520Crossref PubMed Scopus (49) Google Scholar Specifically, the excess risk of viral-related cancers such as lymphoproliferative disease and Kaposi sarcoma is more than 10-fold.1Vajdic C.M. McDonald S.P. McCredie M.R. et al.Cancer incidence before and after kidney transplantation.JAMA. 2006; 296: 2823-2831Crossref PubMed Scopus (790) Google Scholar Hematological or oncological malignancy is also associated with a plethora of kidney problems, such as CKD, acute kidney injury (AKI), electrolyte disturbances, glomerulonephritis, and thrombotic thrombocytopenic purpura. Both CKD and AKI can be caused either by processes related to malignancy or treatments for it.3Malyszko J. Kozlowski L. Kozlowska K. et al.Cancer and the kidney: dangereoux liasons or price paid for the progress in medicine?.Oncotarget. 2017; 8: 66601-66619Crossref PubMed Scopus (14) Google Scholar In patients with hematological malignancies, CKD can result from direct injury by cancer cells or indirect injury via immunologically mediated mechanisms, such as occurs with membranous nephropathy.4Jhaveri K.D. Shah H.H. Calderon K. et al.Glomerular diseases seen with cancer and chemotherapy: a narrative review.Kidney Int. 2013; 84: 34-44Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar AKI in patients with malignancy can be caused by lymphomatous infiltration of the kidneys, cast nephropathy in multiple myeloma and monoclonal gammopathies, and tumor lysis syndrome (TLS), and these occur mainly in malignancies with high tumor burden and rapid cell turnover.4Jhaveri K.D. Shah H.H. Calderon K. et al.Glomerular diseases seen with cancer and chemotherapy: a narrative review.Kidney Int. 2013; 84: 34-44Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 5Pierson-Marchandise M. Gras V. Moragny J. et al.The drugs that mostly frequently induce acute kidney injury: a case-noncase study of a pharmacovigilance database.Br J Clin Pharmacol. 2017; 83: 1341-1349Crossref PubMed Scopus (33) Google Scholar, 6Lam A.Q. Humphreys B.D. Onco-nephrology: AKI in the cancer patient.Clin J Am Soc Nephrol. 2012; 7: 1692-1700Crossref PubMed Scopus (65) Google Scholar In patients treated with hematopoietic cell transplantation, there are several unique causes of both AKI and CKD.7Renaghan A.D. Jaimes E.A. Malyszko J. et al.Acute kidney injury and CKD associated with hematopoietic stem cell transplantation.Clin J Am Soc Nephrol. 2020; 15: 289-297Crossref PubMed Scopus (5) Google Scholar The risk of AKI can be potentiated by several factors: dehydration due to vomiting, diarrhea, obstruction of the urinary tract, fluid and electrolyte disturbances, contrast agent administration, nonsteroidal anti-inflammatory drugs, nephrotoxic antibiotics, and renal toxicity of chemotherapeutic or targeted drugs.4Jhaveri K.D. Shah H.H. Calderon K. et al.Glomerular diseases seen with cancer and chemotherapy: a narrative review.Kidney Int. 2013; 84: 34-44Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 5Pierson-Marchandise M. Gras V. Moragny J. et al.The drugs that mostly frequently induce acute kidney injury: a case-noncase study of a pharmacovigilance database.Br J Clin Pharmacol. 2017; 83: 1341-1349Crossref PubMed Scopus (33) Google Scholar, 6Lam A.Q. Humphreys B.D. Onco-nephrology: AKI in the cancer patient.Clin J Am Soc Nephrol. 2012; 7: 1692-1700Crossref PubMed Scopus (65) Google Scholar The incidence of AKI in patients with high-grade hematological malignancy has been estimated to be as high as 68.5% using RIFLE criteria (risk, injury, failure, loss of function, end-stage kidney disease [ESKD]), with >90% of cases resulting from hypoperfusion, acute tubular necrosis, TLS, nephrotoxins, or hemophagocytic lymphohistiocytosis.8Canet E. Zafrani L. Lambert J. et al.Acute kidney injury in patients with newly diagnosed high-grade hematological malignancies: impact on remission and survival.PLoS One. 2013; 8e55870Crossref PubMed Scopus (68) Google Scholar Improved cancer outcomes through better diagnostics and personalized therapies such as selective genome- and immune-targeted drugs have resulted in a growing population of cancer survivors9Torre L.A. Siegel R.L. Ward E.M. Jemal A. Global cancer incidence and mortality rates and trends—an update.Cancer Epidemiol Biomarkers Prev. 2016; 25: 16-27Crossref PubMed Scopus (1818) Google Scholar who are at increased risk for kidney disease. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, transplantation medicine, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise to convene a controversies conference on onco-nephrology in Milan, Italy, in December 2018. This report addresses the renal-related issues in hematological malignancies and discusses the burden of cancer in kidney transplant recipients. TLS is a hemato-oncologic emergency resulting from spontaneous or chemotherapy-induced tumor cell death. It can be classified as a laboratory or clinical form in which metabolic disturbances can overwhelm homeostatic capacity and have severe clinical consequences. The development of new oncology drugs has outpaced investigations concerning TLS, and thus the incidence and prevalence of TLS are not well defined. TLS risk is influenced by tumor type, tumor burden, patient characteristics, and type of therapy. The commonly used definition of TLS10Cairo M.S. Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification.Br J Haematol. 2004; 127: 3-11Crossref PubMed Scopus (594) Google Scholar contains an outdated kidney injury component that should be updated to reflect the current KDIGO AKI definition.11Kellum J.A. Lameire N. KDIGO AKI Guideline Work GroupDiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1).Crit Care. 2013; 17: 204Crossref PubMed Scopus (942) Google Scholar To evaluate risk of TLS, electrolytes (sodium, potassium, phosphorus, magnesium, and calcium), estimated glomerular filtration rate (eGFR), and uric acid should be measured in all patients at baseline. The frequency of laboratory measurements depends on the risk profile. The predictive role of baseline uric acid for TLS is currently unknown. With the expanded availability of several novel targeted molecular and immune cell–based agents, such as monoclonal antibodies, cyclin-dependent kinase inhibitors, proteasome inhibitors, pro-apoptotic agents, and chimeric antigen receptor (CAR)–T cells, the spectrum of neoplasms with a risk of TLS is expanding and now includes chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, and several solid tumors.12Howard S.C. Jones D.P. Pui C.H. The tumor lysis syndrome.N Engl J Med. 2011; 364: 1844-1854Crossref PubMed Scopus (456) Google Scholar,13McBride A. Trifilio S. Baxter N. et al.Managing tumor lysis syndrome in the era of novel cancer therapies.J Adv Pract Oncol. 2017; 8: 705-720PubMed Google Scholar Xanthine oxidase inhibitors (XOIs) are the drug class of choice for preventing TLS, although the dose and target level of uric acid has not been defined (Table 114Voelker R. Another warning for febuxostat.JAMA. 2019; 321: 1245Google Scholar, 15Bridoux F. Chevret S. Fermand J.P. High cutoff haemodialysis in myeloma cast nephropathy: further investigation is needed.Lancet Haematol. 2019; 6: e347Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 16Mazali F.C. Johnson R.J. Mazzali M. Use of uric acid-lowering agents limits experimental cyclosporine nephropathy.Nephron Exp Nephrol. 2012; 120: e12-e19Crossref PubMed Scopus (23) Google Scholar).17Bellos I. Kontzoglou K. Psyrri A. Pergialiotis V. Febuxostat administration for the prevention of tumour lysis syndrome: a meta-analysis.J Clin Pharm Ther. 2019; 44: 525-533PubMed Google Scholar For established TLS patients with normal kidney function, allopurinol is the preferred XOI. Febuxostat is an alternative for lowering uric acid; in the FLORENCE trial, 1 fixed dose of febuxostat started 2 days prior to chemotherapy initiation and continued for only 7 to 9 days achieved a significantly superior serum uric acid control compared with allopurinol, with comparable kidney function preservation and safety profile. For longer treatments (as with gout), febuxostat's safety profile remains uncertain. Short febuxostat administration may be a good alternative, especially considering that a quick response of serum uric acid is achievable.14Voelker R. Another warning for febuxostat.JAMA. 2019; 321: 1245Google Scholar,18Spina M. Nagy Z. Ribera J.M. et al.FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk.Ann Oncol. 2015; 26: 2155-2161Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Although febuxostat is now generic and its cost has decreased, it is still more expensive than allopurinol, making cost a factor in many regions. Alternatively, rasburicase is a very effective treatment for TLS,19Vadhan-Raj S. Fayad L.E. Fanale M.A. et al.A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome.Ann Oncol. 2012; 23: 1640-1645Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar although its optimal dose and frequency are not known, and availability and cost can be prohibitive. Recent reports indicate that single-dose rasburicase is efficient in preventing and managing TLS,20Nauffal M. Redd R. Ni J. et al.Single 6-mg dose of rasburicase: the experience in a large academic medical center.J Oncol Pharm Pract. 2019; 25: 1349-1356Crossref PubMed Scopus (4) Google Scholar which could broaden accessibility. Sequential therapy of rasburicase and an XOI has been shown to be effective.21Cortes J. Moore J.O. Maziarz R.T. et al.Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone—results of a multicenter phase III study.J Clin Oncol. 2010; 28: 4207-4213Crossref PubMed Scopus (122) Google ScholarTable 1Research priorities for kidney disease in hematological malignanciesResearch prioritiesTumor lysis syndrome•Define the optimal dosing of xanthine oxide inhibitors for preventing tumor lysis syndrome and define the target level of uric acid•Increase the knowledge base on the role of phosphorous and xanthine in tumor lysis syndrome•Evaluate how febuxostat compares with allopurinol in onset of action, effectiveness in lowering uric acid, and safety in the medium and long-term14Voelker R. Another warning for febuxostat.JAMA. 2019; 321: 1245Google ScholarMultiple myeloma•Explore whether therapeutic plasma exchange improves kidney or overall outcomes in multiple myeloma patients with high serum free light chain levels○Determine whether there is a threshold level for serum free light chains•Investigate combining efficient free light chain removal techniques with effective but tolerable chemotherapy15Bridoux F. Chevret S. Fermand J.P. High cutoff haemodialysis in myeloma cast nephropathy: further investigation is needed.Lancet Haematol. 2019; 6: e347Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar•Examine whether bisphosphonate is associated with adverse risks (thrombotic microangiopathy, nephrotic syndrome) in hemodialysis and peritoneal dialysis with multiple myelomaCast nephropathy•Investigate biomarkers for predicting risk of cast nephropathyMGRS•Determine whether clonal deposits in the kidney are sufficient cause to start treatment○Develop a registry to help determine the number needed to harm vs. the number needed to treat•Determine the percentage of light chain staining in kidney biopsies•Determine how (and whether) to find the clone as a target of chemotherapyKT in patients with myeloma and amyloidosis on dialysis•Determine the optimal duration of remission of myeloma and amyloidosis prior to transplantation•Develop a registry of transplant patients to determine the following:○How to diagnose extrarenal organ dysfunction of amyloid○Whether there is a benefit of parallel bone marrow transplantation and kidney transplantation○Whether it is possible to expand the kidney donor poolDosing cytotoxic agents in CKD G3b–G5D•Conduct postmarketing studies to generate data on dosing in CKD G3b–G5D•Investigate whether there is a clinically relevant difference between dosing based on creatinine clearance vs. eGFR•Determine how the dialysis session should be adapted for drug administration•Explore whether there are specific preventive strategies to avoid renal toxicity of cytotoxic agents or calcineurin inhibitors16Mazali F.C. Johnson R.J. Mazzali M. Use of uric acid-lowering agents limits experimental cyclosporine nephropathy.Nephron Exp Nephrol. 2012; 120: e12-e19Crossref PubMed Scopus (23) Google ScholarNovel sorbent devices in hematology/oncology•Determine whether adsorbent devices offer a benefit over anti–IL-6 therapy approaches•Determine whether there is an indication for using new adsorbent devices in the setting of AKI stage 3 with need for kidney replacement therapyESAs in hematological cancer and CKD patients•Generate data on safety of ESAs in CKD patients with hematological cancer•Determine target hemoglobin levels in CKD patients with hematological cancer•Evaluate newer oral ESAs in CKD patients with hematological cancerAKI, acute kidney injury; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; eGFR, estimated glomerular filtration rate; IL, interleukin; KT, kidney transplantation; MGRS, monoclonal gammopathy of renal significance. Open table in a new tab AKI, acute kidney injury; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; eGFR, estimated glomerular filtration rate; IL, interleukin; KT, kidney transplantation; MGRS, monoclonal gammopathy of renal significance. Evidence regarding the prevention of TLS is limited. In trials of acute leukemias, reported TLS rates were 42% and 53% with alvocidib (with sequential cytarabine and mitoxantrone) and 15% with dinaciclib. Venetoclax has the highest associated risk for inducing TLS in chronic lymphocytic leukemia (8.3% and 8.9% in 2 trials), whereas TLS incidence is ≤5% with brentuximab vedotin (for anaplastic large cell lymphoma), carfilzomib and lenalidomide (for multiple myeloma), dasatinib (for acute lymphoblastic leukemia), and oprozomib (for various hematologic malignancies).22Howard S.C. Trifilio S. Gregory T.K. et al.Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review.Ann Hematol. 2016; 95: 563-573Crossref PubMed Scopus (58) Google Scholar Although the predictive role of baseline uric acid for TLS is still debated, the guidelines for pediatric and adult TLS suggest that the risk of developing TLS and renal events is increased by 1.75- and 2.21-fold, respectively, for every mg/dl increase in serum uric acid.23Coiffier B. Altman A. Pui C.H. et al.Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review.J Clin Oncol. 2008; 26: 2767-2778Crossref PubMed Scopus (454) Google Scholar If extracorporeal treatments are used, levels of serum free light chains (FLCs) will need to be monitored. High levels of FLCs are associated with lower event-free and overall survival,24Snozek C.L. Katzmann J.A. Kyle R.A. et al.Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system.Leukemia. 2008; 22: 1933-1937Crossref PubMed Scopus (132) Google Scholar whereas rapid reduction of FLC leads to improved kidney and overall survival.25van Rhee F. Bolejack V. Hollmig K. et al.High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis.Blood. 2007; 110: 827-832Crossref PubMed Scopus (149) Google Scholar Supportive measures and chemotherapy should always be started as soon as possible, before therapeutic plasma exchange (TPE) or high cut-off hemodialysis (HCO-HD). It is unknown whether TPE improves kidney or overall outcome in multiple myeloma patients with high FLC (Table 1). Most trials investigating TPE in cast nephropathy are from the pre-bortezomib era, and it is unclear whether newer agents lead to a lower integral of FLC concentration over time. In a trial published in 1988 including 29 participants, TPE demonstrated efficiency in removing light chains from circulation and improving outcomes.26Zucchelli P. Pasquali S. Cagnoli L. Gerrari G. Controlled plasma exchange trial in acute renal failure due to multiple myeloma.Kidney Int. 1988; 33: 1175-1180Abstract Full Text PDF PubMed Scopus (174) Google Scholar However, in a larger patient population undergoing chemotherapy prior to bortezomib introduction (n = 104), TPE failed to improve the composite endpoint of death, dialysis dependence, or glomerular filtration rate <30 ml/min per 1.73 m2 at 6 months.27Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial.Ann Intern Med. 2005; 143: 777-784Crossref PubMed Google Scholar Anecdotal data with high-volume selective plasma exchange are encouraging.28Kanda M. Sanada S. Kowata H. et al.Renal improvement with molecular-selective plasma exchange in a patient with Bence-Jones Type multiple myeloma.Ther Apher Dial. 2016; 20: 420-422Crossref PubMed Scopus (1) Google Scholar Extracorporeal elimination of FLC is not indicated in patients with normal kidney function. Hyperviscosity syndrome is an indication for TPE, irrespective of other treatment goals. The role of FLC levels for initiating or discontinuing extracorporeal treatments is unknown. HCO-HD can effectively remove light chains29Mene P. Giammarioli E. Fofi C. et al.Serum free light chains removal by HFR hemodiafiltration in patients with multiple myeloma and acute kidney injury: a case series.Kidney Blood Press Res. 2018; 43: 1263-1272Crossref PubMed Scopus (8) Google Scholar and has been shown to remove cytotoxic agents30Eden G. Kühn-Velten W.N. Hafer C. Kielstein J.T. Enhanced elimination of cyclophosphamide by high cut-off haemodialysis: single-dose pharmacokinetics in a patient with cast nephropathy.BMJ Case Rep. 2018; (bcr-2017-221735)Crossref PubMed Scopus (1) Google Scholar and analgesics.31Arelin V. Schmidt J.J. Kayser N. et al.Removal of methadone by extended dialysis using a high cut-off dialyzer: implications for the treatment of overdose and for pain management in patients undergoing light chain removal.Clin Nephrol. 2016; 85: 353-357Crossref PubMed Scopus (2) Google Scholar Data from uncontrolled trials suggest that using HCO-HD can lead to improvement in renal endpoints.32Gerth H.U. Pohlen M. Görlich D. et al.Impact of high-cut-off dialysis on renal recovery in dialysis-dependent multiple myeloma patients: results from a case-control study.PLoS One. 2016; 11 (e0154993)Crossref Scopus (16) Google Scholar,33Buus N.H. Rantanen J.M. Krag S.P. et al.Hemodialysis using high cut off filters in light chain cast nephropathy.Blood Purif. 2015; 40: 223-231Crossref PubMed Scopus (7) Google Scholar However, in a study of patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of HCO-HD compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months.34Bridoux F. Carron P.L. Pegourie B. et al.Effect of high-cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: a randomized clinical trial.JAMA. 2017; 318: 2099-2110Crossref PubMed Scopus (59) Google Scholar During a 2-year follow-up of 90 patients enrolled in the open-label, phase 2, randomized controlled EuLITE trial,35Hutchison C.A. Cockwell P. Moroz V. et al.High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial.Lancet Haematol. 2019; 6: e217-e228Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar 98 and 82 serious adverse events were reported in the HCO-HD and high-flux hemodialysis (HF-HD) groups, respectively. The most common serious adverse events were infections, cardiovascular and thrombotic events, and events related to the musculoskeletal systems. During the first 90 days, 26 infections (including 14 lung) were reported in the HCO-HD group, and 13 infections (including 3 lung) were reported in the HF-HD group.35Hutchison C.A. Cockwell P. Moroz V. et al.High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial.Lancet Haematol. 2019; 6: e217-e228Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Together these results do not support initiation of HCO-HD phase 3 studies. Given the need to improve therapeutic strategies in myeloma cast nephropathy, combining efficient FLC removal techniques with effective but tolerable chemotherapy warrants further investigation.15Bridoux F. Chevret S. Fermand J.P. High cutoff haemodialysis in myeloma cast nephropathy: further investigation is needed.Lancet Haematol. 2019; 6: e347Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar A 2012 report from animal models identified a competitive inhibitor cyclized peptide that interferes with the binding of the light chains with Tamm-Horsfall protein,36Ying W.Z. Wang P.X. Sanders P.W. Pivotal role of apoptosis signal-regulating kinase 1 in monoclonal free light chain-mediated apoptosis.Am J Pathol. 2012; 180: 41-47Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar possibly paving the way for eliminating the need for extracorporeal elimination. However, human studies are yet to be conducted. Although bisphosphonates are contraindicated in patients with advanced kidney disease, single-dose (30 mg) pamidronate for hypercalcemia does not require dose adjustment if eGFR is >30 ml/min per 1.73 m2. Twelve-month study data indicate pamidronate may also be used in hemodialysis patients.37Torregrosa J.V. Moreno A. Mas M. et al.Usefulness of pamidronate in severe secondary hyperparathyroidism in patients undergoing hemodialysis.Kidney Int Suppl. 2003; 85: S88-S90Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar For newly diagnosed multiple myeloma, denosumab is non-inferior to zoledronic acid in time to skeletal-related events and has a lower renal toxicity.38Raje N. Terpos E. Willenbacher W. et al.Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study.Lancet Oncol. 2018; 19: 370-381Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar There are, however, limited data supporting non-inferiority of denosumab safety relative to alendronate in hemodialysis patients, especially regarding risk of severe hypocalcemia.39Iseri K. Watanabe M. Yoshikawa H. et al.Effects of denosumab and alendronate on bone health and vascular function in hemodialysis patients: a randomized, controlled trial.J Bone Miner Res. 2019; 34: 1014-1024Crossref PubMed Scopus (21) Google Scholar Anecdotal data suggest the same is true for peritoneal dialysis.40Bhanot R.D. Kaur J. Bhat Z. Severe hypocalcemia and dramatic increase in parathyroid hormone after denosumab in a dialysis patient: a case report and review of the literature.Case Rep Nephrol. 2019; : 3027419PubMed Google Scholar Whether bisphosphonate is associated with adverse risks needs to be examined (Table 1). In recipients of allogeneic stem cell transplants, tacrolimus is associated with a lower likelihood of AKI relative to cyclosporine. Drug blood levels should be measured at regular intervals. It is unknown if lowering calcineurin inhibitor levels to reduce the risk of AKI elevates the risk of graft-versus-host disease. However, cyclosporine levels >195 μg/l on post-transplant day 10 have been associated with significantly reduced likelihood of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.41Bianchi M. Heim D. Lengerke C. et al.Cyclosporine levels > 195 μg/L on day 10 post-transplant was associated with significantly reduced acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.Ann Hematol. 2019; 98: 971-977Crossref PubMed Scopus (4) Google Scholar It is unclear whether there is any role for kidney biopsy in patients with AKI who take calcineurin inhibitors. Because calcineurin inhibitors can cause transplant-associated thrombotic microangiopathy, cases of hypertension, thrombocytopenia, and elevated lactate dehydrogenase should prompt suspicion of thrombotic microangiopathy. Kidney biopsy is strongly recommended to confirm cast nephropathy in AKI after chemotherapy initiation. Therapy should not be delayed while waiting for biopsy results. Any concern that there is an increased bleeding risk in this patient population is not supported by the literature.42Fish R. Pinney J. Jain P. et al.The incidence of major hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies.Clin J Am Soc Nephrol. 2010; 5: 1977-1980Crossref PubMed Scopus (45) Google Scholar The proportion of noncast nephropathy in patients with suspected cast nephropathy is unknown. Investigating whether there are biomarkers that can be used to predict the probability of developing cast nephropathy may be worthwhile. The 2014 International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma defined light chain cast nephropathy as a myeloma defining event and identified validated biomarkers of malignancy.43Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of m