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Acute kidney injury (AKI), either of pre-renal, renal or post-renal origin, is an important complication in cancer patients, resulting in worse prognosis, withdrawal from effective oncological treatments, longer hospitalizations and increased costs. The aim of this article is to provide a literature review of general and cause-specific treatment strategies for AKI, providing a helpful guide for clinical practice. We propose to classify AKI as patient-related, cancer-related and treatment-related in order to optimize therapeutic interventions. In the setting of patient-related causes, proper assessment of hydration status and avoidance of concomitant nephrotoxic medications is key. Cancer-related causes mainly encompass urinary compression/obstruction, direct tumoural kidney involvement and cancer-induced hypercalcaemia. Rapid recognition and specific treatment can potentially restore renal function. Finally, a pre-treatment comprehensive evaluation of risks and benefits of each treatment should always be performed to identify patients at high risk of treatment-related renal damage and allow the implementation of preventive measures without losing the potentialities of the oncological treatment. Considering the complexity of this field, a multidisciplinary approach is necessary with the goal of reducing the incidence of AKI in cancer patients and improving patient outcomes. The overriding research goal in this area is to gather higher quality data from international collaborative studies. ispartof: CLINICAL KIDNEY JOURNAL vol:15 issue:5 pages:873-884 ispartof: location:England status: published

Zi-Shan Lin,1,* Xiao-Juan Yu,1,* Xu Zhang,1,2 Su-Xia Wang,1,2 Xi-Nan Cen,3 Fu-De Zhou,1 Ming-Hui Zhao1,4 1Renal Division, Department of Medicine, Peking University First Hospital; Institute of Nephrology, Peking University, Renal Pathology Center, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, People’s Republic of China; 2Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Hematology, Peking University First Hospital, Beijing, People’s Republic of China; 4Peking-Tsinghua Center for Life Sciences, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fu-De ZhouRenal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University; Renal Pathology Center, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of ChinaTel +86-13501162527Fax +86-10-83575694Email zhoufude1801@vip.sina.comBackground: Monoclonal immunoglobulin-associated renal lesions in patients with newly diagnosed myeloma vary. We aimed to determine the pathological spectrum and analyze associated prognostic factors.Methods: Fifty-six patients with newly diagnosed multiple myeloma and biopsy-proven renal lesions were enrolled. Kidney biopsies were reanalyzed, and the baseline clinical characteristics, treatments and outcomes were recorded.Results: Fifty-one patients had monoclonal immunoglobulin-associated renal lesions, with myeloma cast nephropathy (MCN) being the most common pattern. We divided our cohort into pure MCN, MCN+ other pathologies and non-MCN. Patients with MCN had more severe renal injury than those with non-MCN. In our cohort, none of the patients with pure MCN or MCN + other pathologies presented with nephrotic syndrome. Patients with non-MCN had better renal and overall survival than those with pure MCN but similar survivals to those with MCN + other pathologies. Number of myeloma casts (HR 1.08, p = 0.012) was the only independent prognostic factor for renal survival. Male sex (HR: 3.64; p = 0.015) and number of casts (HR: 1.17; p = 0.001) were independent prognostic factors for overall survival.Conclusion: Patients with MCN had more severe renal injury than those with non-MCN. Patients with non-MCN had better renal and overall outcomes than those with pure MCN, but their outcomes were similar to those with MCN + other pathologies. The independent predictors of overall survival were male sex and number of myeloma casts.Keywords: kidney biopsy, multiple myeloma, myeloma cast nephropathy, monoclonal immunoglobulin, prognosis

Myeloma-related kidney disease has several manifestations; the 2 most common histologic diagnoses are myeloma cast nephropathy and acute tubular necrosis. We describe a case of different kidney pathologies occurring concomitantly in a patient found to have immunoglobulin A κ multiple myeloma. A White woman in her 70s presented with an 8-month history of back pain and was found to have nephrotic-range proteinuria and acute kidney injury. Serum calcium level was 12.6 mg/dL. Kidney biopsy showed κ light chain only proliferative glomerulonephritis with monoclonal immunoglobulin deposits, crystalglobulinemia, light chain proximal tubulopathy with κ light chain deposits, mild tubular atrophy, and interstitial fibrosis. Free κ light chain ratio was >1,000 mg/dL and free κ light chain level was 4,670 mg/dL. Within a week following treatment of hypercalcemia and initiation of chemotherapy, her acute kidney injury and hypercalcemia resolved. This case highlights the many kidney manifestations of multiple myeloma and that prompt management targeting these manifestations, including hypercalcemia, can improve clinical outcomes.

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.

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.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.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.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.Цель.Выявить морфологические и иммуногистохимические предикторы обратимости острого повреждения почек (ОПП) с потребностью в диализе у больных миеломной каст-нефропатией (МКН) на основании исследования биоптатов почек. Материалы и методы.Проведено исследование нефробиоптатов 36 пациентов с МКН и 3-й стадией ОПП (AKIN, 2012) с потребностью в диализе. Исследование биоптатов выполняли полуколичественным и количественным методом с применением компьютерной морфометрии. Иммуногистохимически в клетках эпителия канальцев и интерстиции определяли экспрессию Е-кадгерина, виментина,-гладкомышечного актина. Индукционная терапия 26 пациентам проводилась по бортезомибсодержащим программам, 10 больным использовали другие схемы. Сравнительный анализ морфологических изменений в нефробиоптатах в зависимости от почечного ответа выполнен у пациентов с достигнутой гематологической ремиссией. Результаты.Улучшение функции почек наблюдалось только у пациентов с гематологическим ответом на терапию. Не выявлено различий в количестве склерозированных клубочков, белковых цилиндров, площади клеточной воспалительной инфильтрации, а также степени острого повреждения канальцев у пациентов с почечном ответом и без него. У больных с почечным ответом по сравнению с пациентами без улучшения функции почек площадь интерстициального фиброза меньше (соответственно 24,9 и 45,9%;р=0,001), а площадь экспрессии E-кадгерина больше (соответственно 15,9 и 7,1%;p=0,006). Фиброз интерстиция 40% и более и/или площадь экспрессии Е-кадгерина менее 10% от площади тубулоинтерстиция имеют неблагоприятное прогностическое значение в достижении почечного ответа при МКН. Заключение.При площади фиброза интерстиция 40% и более и площади экспрессии Е-кадгерина менее 10% вероятность отсутствия почечного ответа составляет 93,3% (отношение шансов 24,5) даже при достижении гематологического ответа на индукционную терапию. Количество белковых цилиндров, распространенность острого повреждения канальцев и воспалительной инфильтрации интерстиция не имеют прогностического значения.

Myeloma cast nephropathy (MCN) is a common cause of severe renal impairment in multiple myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m2 (range 1–34). Six patients (5.8%) had an FLC level P = 0.003), 6-months (P = 0.035) and 9-months (P = 0.014); there was no survival benefit observed beyond 12 months (P = 0.146). Serum FLC level at diagnosis was neither associated with renal function recovery nor with OS. This is the largest reported cohort of patients with biopsy-confirmed MCN and prospectively measured serum FLC levels. These results indicate that a serum monoclonal FLC > 500 mg/L should be considered the threshold level associated with the development of MCN.

Introduction: The spectrum of renal disorder in the elderly differs from the younger population. There is a paucity of literature regarding kidney biopsy in elderly. This study aims to highlight the clinical profile and histopathological spectrum of the elderly patient undergoing a renal biopsy. Materials and Methods: This retrospective study included all patients (age ≥60 years) undergoing native renal biopsies from January 2012 to December 2017. The clinical profile, laboratory parameters, and renal biopsy findings of these patients were recorded from the case files. Results: Out of 1656 renal biopsies performed during the study period, 230 (13.9%%) performed on the elderly were included. Mean age was 64.02 ± 7.87 years (Range: 60-87 years), and males were predominant (70.4%). The commonest indication for biopsy was nephrotic syndrome (NS) (49.6%) followed by Rapidly progressive renal failure (RPRF) (20.9%) and Acute Kidney Injury (AKI) (15.7%). The most frequent histological diagnosis was membranous nephropathy (15.2%) followed by amyloidosis (13.9%) and Focal Segmental Glomerulosclerosis (FSGS) (13.0%). The commonest cause of NS was MGN (29.8%) followed by FSGS (24.6%) and amyloidosis (22.8%). The commonest cause of nephritic syndrome was Diffuse Proliferative Glomerulonephritis (29.4%) and Membranoproliferative Glomerulonephritis (29.4%). Hypertensive nephrosclerosis (40.0%) and diabetic nephropathy (26.7%)) were the commonest histological diagnosis in the patients who underwent renal biopsy for clinical Chronic kidney disease. Crescentic GN (35.4%) and Myeloma cast nephropathy 14.6%) were the commonest cause of RPRF while Acute Tubular Necrosis (41.7%) was the commonest cause of AKI. None of the patients had major complications. Conclusion: Renal biopsy is safe in the elderly and provides a wealth of information with regards to the diagnosis and prognosis of renal disorder.

The renal diseases commonly associated with myeloma include primary amyloidosis, cast nephropathy, and light chain deposition disease. Less frequent forms of renal involvement encountered in the course of myeloma are crystalline and non-crystalline proximal tubulopathies, neoplastic plasma cell infiltration, and immunoglobulin crystallization in interstitial histiocytes and glomerular cells including podocytes. Light chain proximal tubulopathy (LCPT) caused by aggregation of non-crystalline and rarely crystalline deposits of monoclonal light chains in the cytoplasm of proximal tubular epithelial cells, accounts for less than 5% of monoclonal gammopathy-associated kidney diseases. We report the case of a 48-year-old Indian woman with multiple myeloma, who presented with acute kidney injury and nephrotic syndrome, in whom the renal biopsy revealed widespread crystalline inclusions in extraglomerular and glomerular compartments. We present illustrative light microscopic (LM) and diagnostic electron microscopic (EM) findings of this case which enabled a diagnosis of crystalline LCPT, crystal storing histiocytosis, and crystalline podocytopathy occurring synchronously with myeloma cast nephropathy. While documenting this unique juxtapositioning of multicompartmental paraproteinemic renal injury in multiple myeloma, diagnosed after EM analysis of the patient's renal biopsy, we discuss the pathogenetic pathways of this condition along with the clinical implications. Due to intrinsic structural properties of the crystals, they frequently escape detection by routine LM, necessitating EM analysis for their diagnosis. Given the prognostic implications of tubulopathies complicating myeloma, LCPT is a critically important diagnosis, highlighting the need for a comprehensive renal biopsy evaluation inclusive of EM for the practice of precision medicine in such scenarios.

Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.

There are several known mechanisms by which monoclonal Igs (MIg) or their subunits can cause kidney disease: (i) deposition in 1 or more kidney compartments, resulting in distinct clinicopathologic lesions, such as Ig-related amyloidosis, monoclonal Ig deposition disease, and a variety of glomerulonephritides, including cryoglobulinemic glomerulonephritis type I and II, immunotactoid glomerulonephritis, and proliferative glomerulonephritis with monoclonal immunoglobulin deposits; (ii) precipitation in tubular lumina (e.g., myeloma cast nephropathy); (iii) activation of the alternative pathway of complement (e.g., C3 glomerulopathy associated with monoclonal gammopathy, thrombotic microangiopathy associated with monoclonal gammopathy); (iv) cytokine activation (e.g., POEMS syndrome); and (v) crystallization in the renal vasculature (e.g., crystalglobulin-induced nephropathy).1, 2 Here, we describe an unusual case of monoclonal gammopathy of renal significance (MGRS)–associated crystalline nephropathy that does not conform to any of the previously described patterns of kidney involvement by monoclonal gammopathy.

Background This study was performed to determine whether the urinary albumin excretion rate (%UAE) could distinguish myeloma cast nephropathy (MCN) without glomerular amyloid deposition from MCN with glomerular amyloid deposition. Materials and methods We retrospectively reviewed clinicopathological data on 16 patients with MCN diagnosed by renal biopsy at Toranomon Hospital from 2004 to 2014. Results A total of 10 patients had pure MCN without glomerular amyloid deposition (group 1), and 6 patients had MCN with glomerular amyloid deposition (group 2). In all 10 patients from group 1, the underlying disease was multiple myeloma (MM), while 4 patients had MM, and 2 patients had lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) in group 2. Total protein did not show a significant difference between the two groups, but serum albumin was significantly higher in group 1 than group 2 (p = 0.0101). Serum-adjusted calcium did not show a significant difference between the groups, while serum creatinine (Cre) was significantly higher in group 1 than group 2 (p = 0.0343). Although urinary protein excretion did not differ significantly between the groups, the %UAE was significantly lower in group 1 than group 2 (p = 0.00198). In group 2, 3 of the 4 patients with MM died within 15 months of diagnosis, but the 2 patients with LPL/WM are alive after 32 months. In group 1, only 1 patient died (of unknown causes) within 15 months after diagnosis. Conclusion In patients with MCN, %UAE may be a useful marker for the detection of coexistence of glomerular lesions, such as amyloidosis, which are associated with a poor outcome.

Summary Background In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). Methods In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6–8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602. Findings Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74–1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group. Interpretation In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients. Funding Gambro, Janssen, and Binding Site.

Crystal-storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of nonneoplastic histiocytes containing intracytoplasmic crystallized immunoglobulins. In most cases, there is an associated underlying lymphoplasmacytic neoplasm expressing Ig kappa light chain. About 131 cases of CSH have been identified. There is a localized and a generalized form of CSH and it can involve several sites including bone marrow, lungs, lymph nodes, liver, spleen, gastrointestinal tract, and kidney. Generalized CSH is less frequent and involves multiple organs and tends to have a worst prognosis than localized CSH. Around 20 cases of renal involvement in CSH have been reported so far. Paraprotein-induced crystalline nephropathy can be divided into two categories based on whether the crystals in the kidney are intracellular (including light chain proximal tubulopathy with crystals and CSH) or extracellular (including the crystalline variant of myeloma cast nephropathy and crystalglobulin-induced nephropathy). The former tends to present with slowly worsening kidney dysfunction and generally has a good prognosis, whereas the latter usually presents with rapidly progressive renal failure and is associated with poor renal outcome. We present a case of generalized CSH associated with extracellular crystalline nephropathy with a fulminant and fatal clinical course. Kappa light-chain crystals were found exclusively extracellularly within the tubular lumen, not within the tubular epithelial cells nor the histiocytes, and the massive presence of those precipitates led to the acute renal failure. Consequently, we review the renal involvement in CSH in the literature and discuss the unique mechanism of renal injury in this case.

A 63-year-old diabetic gentleman with microvascular complications presented with advanced azotemia and anemia. He was stabilized with blood transfusion and hemodialysis. With the probable diagnosis of diabetic nephropathy-related end-stage renal disease, he underwent kidney transplantation. He had delayed graft function. Graft biopsy done on the 2nd postoperative day showed acute tubular necrosis. Graft biopsy repeated after 2 weeks for persistent graft dysfunction showed myeloma cast nephropathy (MCN) and light chain proximal tubulopathy. Work-up for multiple myeloma was positive. He was started on plasmapheresis and chemotherapy. However, he suffered sudden cardiac death during dialysis after 1 week. The presence of MCN in the early graft biopsy implies that it must have been the cause for his native kidney failure. Thus, renal failure in a diabetic should not always be presumed to be due to diabetic nephropathy, and kidney biopsy should be done in diabetics with atypical features.

A 64-year-old African American male presented to the emergency department with subacute low back pain for two weeks and decreased urine output. He was found to have a potassium level of 9.2 mmol/L and was uremic with a creatinine level of 28.5 mg/dL and blood urea nitrogen (BUN) level of 201 mg/dL. He also tested positive for COVID-19. He was then started on continuous renal replacement therapy (CRRT). His urinalysis showed more than 500 mg/dL of protein. A workup for multiple myeloma was also conducted, and urine protein electrophoresis test was positive for free lambda light chains with a level of 17,700 mg/L and free kappa light chains with a level of 88.30 mg/L with a kappa:lambda free light chain ratio of 0.005. Additionally, serum Bence Jones protein level was elevated at 240 mg/dL, and serum beta-2 microglobulin level was elevated at 31.41 mg/L. An immunoglobulin (Ig) panel also showed low levels of IgG, IgA, and IgM. Kidney biopsy for this patient showed definite cast nephropathy and minimal chronic changes, with only one of over 20 glomeruli sclerosed and minimal interstitial deposits. The patient was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).

Applications of machine learning in pathology is an active research area in modern medicine. Here, we presented a classifier for label-free renal histopathology. Three frequently encountered categories of monoclonal gammopathy-associated kidney disease were studied, which included light chain amyloidosis, monoclonal light chain disease deposition (MIDD) and myeloma cast nephropathy. Biopsies with diabetic nephropathy and normal baseline transplant biopsies were used as control. The samples are imaged using a FTIR hyperspectral microscope. More than three million infrared spectra are adopted for the training and evaluation of the computational model. The model recognizes the pixels associated with the glomerulus, and diagnoses the disease based on infrared absorption features.

Onconephrology is a new and evolving field that deals with kidney complications in patients with cancer as well as the management of cancer in patients with preexisting kidney disease. With increasing numbers of patients with cancer with kidney-related complications, the field has garnered increased attention. Thus, an annual Greater Toronto Area Onconephrology Interest Group symposium was held in May 2019. The objective of the meeting was to demonstrate the junctures between oncology and nephrology by highlighting recent data regarding (1) kidney impairment in solid organ malignancies, (2) management and treatment of kidney cancer, (3) kidney impairment in hematologic malignancies, (4) malignancy and kidney transplantation, and (5) hyponatremia in patients with cancer.Through a structured presentation, the group explored key topics discussed at a Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on Onconephrology. Expert opinions, clinical trial findings, and publication summaries were used to illustrate patient and treatment-related considerations in onconephrology.Kidney complications in patients with cancer are a central theme in onconephrology. An estimated 12% to 25% of patients with solid organ malignancies have chronic kidney disease (CKD), although in certain cancers, the prevalence of CKD is higher. Kidney impairment is also a common complication of some hematologic malignancies. The incidence of renal failure in patients with multiple myeloma is estimated at 18% to 56% and light chain cast nephropathy is seen in approximately 30% of these patients. In addition, there appears to be a bidirectional relationship between kidney cancer and CKD, with some data sets suggesting the risk increases as kidney function declines. Cancer is also of concern in patients with preexisting kidney disease. Kidney transplant recipients have a greater risk of cancer and a higher risk of cancer-related mortality. Kidney complications have also been associated with novel cancer therapies, such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. An estimated 2% to 4% of patients initiating an immune checkpoint inhibitor may develop nephrotoxicity, whereas up to 40% of patients on CAR T-cell therapy experience cytokine release syndrome (CRS). Tumor lysis syndrome and electrolyte abnormalities, such as hyponatremia, have also been reported with CAR T-cell therapy. While the incidence and prevalence of hyponatremia vary depending on the cancer type and serum sodium cutoff point, hyponatremia may be seen in up to 46% of patients hospitalized in cancer centers.Onconephrology is a developing field and the themes arising from this meeting indicate a need for greater collaboration between oncologists and nephrologists. Educational symposia and onconephrology fellowship programs may allow for improved cancer care for patients with kidney disease.L’onconéphrologie est une discipline nouvelle et évolutive qui traite les complications néphrologiques chez les patients atteints d’un cancer et assure également la prise en charge des patients soignés en oncologie et présentant une néphropathie préexistante. En mai 2019, le symposium duPar le biais d’une présentation structurée, le groupe s’est penché sur les thèmes clés discutés lors d’une conférence du KDIGO portant sur les controverses entourant l’onconéphrologie. Des avis d’experts, des résultats d’essais cliniques et des résumés de publications ont été utilisés pour illustrer les considérations relatives aux patients et aux traitements en onconéphrologie.Les complications rénales chez les patients atteints d’un cancer sont un thème central en onconéphrologie. On estime qu’environ 12 à 25 % des patients présentant une tumeur maligne touchant les organes solides sont atteints d’insuffisance rénale chronique (IRC), bien que la prévalence soit plus élevée pour certains cancers. L’insuffisance rénale s’avère également une complication fréquente de certaines tumeurs malignes hématologiques. L’incidence d’IRC chez les patients atteints d’un myélome multiple est estimée entre 18 et 56 %, et une néphropathie à chaînes légères est observée chez environ 30 % de ces patients. En outre, on soupçonne l’existence d’une relation bidirectionnelle entre le cancer du rein et l’IRC; certains ensembles de données suggérant que le risque de cancer augmenterait avec le déclin de la fonction rénale. Le cancer est également préoccupant chez les patients ayant une néphropathie préexistante. Enfin, les receveurs d’une greffe rénale présentent un risque accru de cancer et de mortalité liée au cancer. Les complications rénales ont également été associées aux nouveaux traitements contre le cancer, comme les inhibiteurs du point de contrôle immunitaire et les thérapies par cellules CAR T. Environ 2 à 4 % des patients amorçant un traitement par les inhibiteurs de point de contrôle immunitaire pourraient développer une néphrotoxicité, alors que jusqu’à 40 % des patients traités par cellules CAR T présentent un syndrome de relargage de cytokines. Le syndrome de lyse tumorale et des anomalies électrolytiques, comme l’hyponatrémie, ont également été observés chez les patients traités par cellules CAR T. Bien que l’incidence et la prévalence de l’hyponatrémie varient en fonction du type de cancer et du seuil de natrémie, jusqu’à 46 % des patients hospitalisés dans les centres de cancérologie présentent cette anomalie.L’onconéphrologie est une discipline en évolution et les thèmes issus de ce colloque soulignent le besoin d’accroître la collaboration entre les oncologues et les néphrologues. Les symposiums à caractère éducatif et les programmes de bourses d’études et de recherche en onconéphrologie pourraient améliorer les soins oncologiques prodigués aux patients atteints de néphropathies.

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.

Multiple Myeloma (MM) is characterised by clonal B cell proliferation affecting elderly age group and involving various organ systems namely haematological, renal and skeletal system. Kidney may be affected in 50% of cases of MM. Though, Chronic Kidney Disease (CKD) is usually seen in MM, unusual presentations have been documented. The present case is of a 50-year-old female with complains of breathlessness and vague generalised symptoms. Routine tests showed blood urea level of 90 mg/dL and serum creatinine of 8.3 mg/dL. Further investigations revealed 24 hour protein level 48.5 gm/day, Erythrocyte Sedimentation Rate (ESR)-126 mm/1st hour, cast nephropathy in renal biopsy. Immunohistochemical (IHC) study on renal biopsy revealed kappa light chain deposits in tubules, raised kappa light chains (3280.00 mg/L) in serum Free Light Chain (FLC) assay and MM in bone marrow aspiration and biopsy study. So, MM should be considered in differential diagnosis in elderly patients presenting with acute severe renal failure.

PURPOSE We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis. METHODS After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group). RESULTS Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 v 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; P = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; P = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group v 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died. CONCLUSION This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.

Multiple Myeloma is a plasma cell proliferative disorder that commonly involves the kidney. Renal impairment is a serious complication during the course of the disease that is associated with increased morbidity and mortality. Light chain cast nephropathy is the predominant pattern of renal injury in Multiple Myeloma. This review article focuses on the pathophysiology and diagnostic approach of myeloma cast nephropathy. The management of precipitating factors as well as anti-plasma cell treatment modalities in the context of renal impairment are also discussed.

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival.

This report describes a patient with light chain myeloma and acute renal injury. Serum kappa free light chain (FLC) was extremely elevated, >33,000 mg/dL. Treatment with therapeutic plasma exchange (TPE) started day 2 for biopsy-confirmed cast nephropathy. Bortezomib-containing chemotherapy was initiated on day 5, and hemodialysis for tumor lysis syndrome on day 7. TPE alone decreased kappa FLC >70% by day 5, indicating direct FLC removal was successful in this patient. A total of 25 TPE procedures were performed in a 31-day hospitalization. Hemodialysis was discontinued after 3 months, and the patient's renal function and kappa FLC remain stable. Although the use of TPE for FLC removal is controversial, recent evidence supports its use as adjuvant therapy for acute renal injury secondary to myeloma cast nephropathy. TPE can be effective for rapidly reducing FLC; however, several TPE procedures might be required to reduce the risk of hemodialysis dependency.

C3 glomerulonephritis is rare form of membranoproliferative glomerulonephritis, which result from defects in complement regulatory proteins that promotes excessive activation of alternative complement pathway. Kidney disease is common complication of multiple myeloma (MM). Most common renal complications in MM include monoclonal immunoglobulin deposition disease and myeloma cast nephropathy. Moreover, monoclonal Ig, through the interference of the complement alternative pathway has been shown to play the synergistic role towards renal damage. Up to 50% of MM patients present with renal impairment at diagnosis, 20% may present with acute kidney injury, and 10% require dialysis. In this case report, we describe a case of MM with cast nephropathy with mesangial staining for C3 consistent with C3 glomerulopathy, and the interrelationship between MM and complement system that leads to C3 glomerulopathy. A 59-year-old Trinidadian man with a 2-year history of hypertension presented with nausea and vomiting associated with a generalized weakness for the past 3 months. On admission laboratory results were as follows: hemoglobin 9.1 g/dL; red blood count 1.45 × 10 6 /mm 3 ; white cell count 3.2 × 10 3 /mm 3 ; platelet count 94 × 10 3 /mm 3 ; blood urea nitrogen 94 mg/dL; serum creatinine 10.47 mg/dL (patient had a baseline creatinine level of 1.5 mg/dL); sodium 130 mEq/L; potassium 6.2 mEq/L; bicarbonate 14 mEq/L; total protein 7.0 g/dL; albumin 2.9 g/dL; alkaline phosphatase 57; AST and ALT normal; lipase 102 U/L; urine analysis showed 2+ protein with bland urine sediment and microscopic hematuria (3 - 6/HPF). 24-h urine protein was 2 g/day. Renal ultrasound was significant for a right renal 0.6 cm cyst. The patient was admitted to ICU and was subsequently hemodialyzed due to worsening hyperkalemia and acute kidney injury. Serologies were notable for positive anti-dsDNA antibody and low levels of C3 (46 mg/dL) with normal C4 were observed. Immunofixation by electrophoresis showed free lambda. Serum plasma electrophoresis showed two M-spikes: Lambda light chains and IgG Lambda. A renal biopsy was performed and cast nephropathy was identified with mesangial staining for C3. Bone marrow biopsy was performed and showed CD 56-positive plasma cell myeloma. Patient was treated with Velcade, Cytoxan, and dexamethasone. The patient was subsequently discharged on chemotherapy and intermittent hemodialysis therapy. Follow-up evaluation of the alternative complement pathway showed normal activity level. This case illustrated myeloma kidney associated with mesangial C3 deposition in glomeruli and C3 hypocomplementemia. Our hypothesis is that in monoclonal gammopathy induced C3 glomerulopathy; paraprotein itself is acting as a trigger that excessively activates and dysregulates the AC pathway systemically. Thus, it is highly feasible to tailor the treatment to reduce the amount of paraproteins in C3 glomerulopathy associated with myeloma kidney, as opposed to conventional treatment for C3 glomerulopathy such as plasma exchange, rituximab/eculizumab, etc. Recognizing of the association between C3 GN and MM is important because it can be used as potential marker for hematological malignancy as well as the potential effective treatment for C3 G associated MM. World J Nephrol Urol. 2018;7(3-4):73-77 doi: https://doi.org/10.14740/wjnu359w

Chemotherapy and extracorporeal treatment reduce serum free light chains (FLCs) allowing the recovery of acute kidney injury (AKI) caused by myeloma cast nephropathy (MCN). We report the first case of recovery from AKI in a patient with MCN who underwent the removal of FLCs using the PEPA filter, with an undisclosed cut-off, combined with chemotherapy for multiple myeloma (MM).

Monoclonal secretion of light chains can affect the kidney with varied morphologic manifestations. Myeloma cast nephropathy, proximal tubulopathies, monoclonal immunoglobulin deposition disease, amyloidosis, and tubulointerstitial nephritis are often noted in the renal biopsy of these patients. Most often the histopathological manifestations affect only one compartment of the nephron (tubules, capillaries, glomerulus). Case reports of a combination of cast nephropathy and monoclonal light chain deposition disease are also reported in literature. Here we report an unusual case of coexisting cast nephropathy, light chain deposition disease, and deposition of amyloid fibrils in the biopsy of a lady with monoclonal kappa light chain excretion.

Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is due predominantly to paraprotein-mediated nephrotoxicity. AKI occurs in myeloma patients due to a number of causes, including prerenal azotemia, metabolic nephrotoxicity from hypercalcemia and tumor lysis syndrome, proximal tubular injury, cast nephropathy, and drug-related nephrotoxicity. Importantly, AKI may develop in patients with known multiple myeloma or as an initial manifestation of this monoclonal disease. Diagnostic work-up includes the demonstration of monoclonal proteins, the search for the underlying B-cell clone, and a kidney biopsy, in many instances. Myeloma management involves treatment with chemotherapeutic agents to rapidly lower light chain levels, along with supportive measures that optimize volume status, correct metabolic disturbances, reduce proteinuria, and minimize nephrotoxin exposure. Extracorporeal therapies, such as plasma exchange and high-cutoff hemodialysis, have been employed, but their utility remain uncertain. The presence of AKI in myeloma patients appears to be associated with a higher mortality. Partial and full renal recovery are associated with better survival.

International audience; Background - Intensive haemodialysis (IHD) in addition to bortezomib-based chemotherapy might be efficient to rapidly decrease serum immunoglobulin-free light chains removal in patients with multiple myeloma (MM) and to improve renal prognosis and survival. Methods - The aim of this retrospective multi-centre study was to compare the efficacy (renal recovery rate) of IHD and of standard haemodialysis (SHD) in patients with MM and dialysis-dependent acute kidney injury (AKI), concomitantly treated with bortezomib-based chemotherapy. Results - We selected 41 patients with MM and dialysis-dependent AKI, most likely due to myeloma cast nephropathy (MCN), and who were treated in eight French hospitals between January 2007 and June 2011. Patients were classified in two groups according to dialysis regimen: IHD [ = 21, with a mean of 11.3 dialysis sessions all with poly(methyl methacrylate) (PMMA) membranes for 13.2 days] and SHD ( = 20 patients, mostly three times per week, 31% with PMMA membrane). The main outcome was dialysis-independence at 3 months. At 3 months, 15 patients could stop dialysis: 8 (38.1%) in the IHD and 7 (35%) in the SHD group (P = 1). Moreover, 14 (56%) of the 25 patients who did show haematological response and only one of the 16 patients who did not were dialysis-independent (P = 0.002) at 3 months.Conclusions - The results of this retrospective study did not show any clear renal benefit of IHD in patients with MM and MCN compared with SHD. Conversely, they underline the importance of the haematological response to chemotherapy for the renal response and patient prognosis.

The most common kidney presentation in patients with multiple myeloma (MM) is acute kidney injury (AKI) from cast nephropathy. Patients have a poorer 1 year survival compared to patients free of ki...