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Chronic Kidney Disease (CKD) and cancer constitute two major public health burdens and are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. Potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anti-cancer therapies i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors, and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anti-cancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia, and other metabolic abnormalities because of a decreased GFR. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy (KRT) are very limited and only single cases or small case series are published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists, and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.
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Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.
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Transplante de Rim , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Glomerulonefrite/diagnóstico , Glomerulonefrite/imunologia , Glomerulonefrite Membranoproliferativa/patologia , Glomerulonefrite Membranoproliferativa/etiologia , Rim/patologia , Transplante de Rim/efeitos adversos , Idoso , Idoso de 80 Anos ou maisRESUMO
Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m2 and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period. The primary analysis evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Other efficacy, safety and biomarker parameters were assessed. Baseline characteristics were generally well-balanced across treatment arms. There was a statistically significant dose-response effect, with 23% reduction in UPCR achieved with iptacopan 200 mg bid (80% confidence interval 8-34%) at three months. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). A sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed. Iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN. Thus, our findings support further evaluation of iptacopan in the ongoing Phase 3 trial (APPLAUSE-IgAN; NCT04578834).
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Glomerulonefrite por IGA , Humanos , Glomerulonefrite por IGA/patologia , Resultado do Tratamento , Via Alternativa do Complemento , Fatores Imunológicos/uso terapêutico , Biomarcadores , Método Duplo-CegoRESUMO
RATIONALE & OBJECTIVE: Prior studies have demonstrated the diagnostic potential of urinary chemokines C-X-C motif ligand 9 (CXCL9) and CXCL10 for kidney transplant rejection. However, their benefit in addition to clinical information has not been demonstrated. We evaluated the diagnostic performance for detecting acute rejection of urinary CXCL9 and CXCL10 when integrated with clinical information. STUDY DESIGN: Single-center prospective cohort study. SETTING & PARTICIPANTS: We analyzed 1,559 biopsy-paired urinary samples from 622 kidney transplants performed between April 2013 and July 2019 at a single transplant center in Belgium. External validation was performed in 986 biopsy-paired urinary samples. TESTS COMPARED: We quantified urinary CXCL9 (uCXCL9) and CXCL10 (uCXCL10) using an automated immunoassay platform and normalized the values to urinary creatinine. Urinary chemokines were incorporated into a multivariable model with routine clinical markers (estimated glomerular filtration rate, donor-specific antibodies, and polyoma viremia) (integrated model). This model was then compared with the tissue diagnosis according to the Banff classification for acute rejection. OUTCOME: Acute rejection detected on kidney biopsy using the Banff classification. RESULTS: Chemokines integrated with routine clinical markers had high diagnostic value for detection of acute rejection (n=150) (receiver operating characteristic area under the curve 81.3% [95% CI, 77.6-85.0]). The integrated model would help avoid 59 protocol biopsies per 100 patients when the risk for rejection is predicted to be below 10%. The performance of the integrated model was similar in the external validation cohort. LIMITATIONS: The cross-sectional nature obviates investigating the evolution over time and prediction of future rejection. CONCLUSIONS: The use of an integrated model of urinary chemokines and clinical markers for noninvasive monitoring of rejection could enable a reduction in the number of biopsies. Urinary chemokines may be useful noninvasive biomarkers whose use should be further studied in prospective randomized trials to clarify their role in guiding clinical care and the use of biopsies to detect rejection after kidney transplantation. PLAIN-LANGUAGE SUMMARY: Urinary chemokines CXCL9 and CXCL10 have been suggested to be good noninvasive biomarkers of kidney transplant rejection. However, defining a context of use and integration with clinical information is necessary before clinical implementation can begin. In this study, we demonstrated that urinary chemokines CXCL9 and CXCL10, together with clinical information, have substantial diagnostic accuracy for the detection of acute kidney transplant rejection. Application of urinary chemokines together with clinical information may guide biopsy practices following kidney transplantation and potentially reduce the need for kidney transplant biopsies.
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Nefropatias , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Estudos Transversais , Quimiocina CXCL10/urina , Rejeição de Enxerto/diagnóstico , Nefropatias/etiologia , Biomarcadores/urinaRESUMO
Immune checkpoint inhibitors (ICIs) have significantly altered the treatment landscape for cancer in the last decade. However, their benefits are often offset by therapy-limiting immune-related adverse events (irAEs). Acute interstitial nephritis (AIN) is the most common renal irAE, but the exact mechanisms underlying its development are poorly understood. ICI-induced immune activation against drug-derived antigens, leading to an inflammatory response within the kidney interstitium, has been postulated, evidenced by current observations of a higher incidence of ICI-associated AIN in patients receiving AIN-inducing drugs such as proton pump inhibitors (PPIs). The role of PPIs in this specific context has garnered significant attention, given their ubiquitous use and sometimes misuse. In this issue of CKJ Miao et al. summarise and synthesize the best available evidence to clarify the interactions of PPIs with ICIs in the development of AIN and other adverse kidney outcomes. The sum of evidence provided appear to implicate PPIs in the development of clinically significant short- and long-term kidney-related adverse effects in patients on immune checkpoint blockade, although causality cannot be proven. In this editorial we discuss the key practical implications of these findings and emphasize the need for further quality studies to delineate the true relationship of ICIs and PPIs in the development of AIN.
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We report a case of a 38-year-old man who developed a nephrotic syndrome shortly after the start of guselkumab for the treatment of plaque psoriasis. Renal biopsy showed focal segmental glomerulosclerosis (FSGS). The clinical course of our case is highly suspect for drug-induced FSGS since the nephrotic syndrome resolved after cessation of the drug without relapse (2 years of follow-up). To the best of our knowledge, this is the first case describing FSGS lesions associated with the use of an interleukin-23 inhibitor.
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Systematic screening for BKPyV-DNAemia has been advocated to aid prevention and treatment of polyomavirus associated nephropathy (PyVAN), an important cause of kidney graft failure. The added value of performing a biopsy at time of BKPyV-DNAemia, to distinguish presumptive PyVAN (negative SV40 immunohistochemistry) and proven PyVAN (positive SV40) has not been established. Therefore, we studied an unselected cohort of 950 transplantations, performed between 2008-2017. BKPyV-DNAemia was detected in 250 (26.3%) transplant recipients, and positive SV40 in 91 cases (9.6%). Among 209 patients with a concurrent biopsy at time of first BKPyV-DNAemia, 60 (28.7%) biopsies were SV40 positive. Plasma viral load showed high diagnostic value for concurrent SV40 positivity (ROC-AUC 0.950, 95% confidence interval 0.916-0.978) and the semiquantitatively scored percentage of tubules with evidence of polyomavirus replication (pvl score) (0.979, 0.968-0.988). SV40 positivity was highly unlikely when plasma viral load is below 4 log10 copies/ml (negative predictive value 0.989, 0.979-0.994). In SV40 positive patients, higher plasma BKPyV-DNA load and higher pvl scores were associated with slower viral clearance from the blood (hazard ratio 0.712, 95% confidence interval 0.604-0.839, and 0.327, 0.161-0.668, respectively), whereas the dichotomy positivity/negativity of SV40 immunohistochemistry did not predict viral clearance. Although the pvl score offers some prognostic value for viral clearance on top of plasma viral load, the latter provided good guidance for when a biopsy was unnecessary to exclude PyVAN. Thus, the distinction between presumptive and proven PyVAN, based on SV40 immunohistochemistry, has limited clinical value. Hence, management of BKPyV-DNAemia and immunosuppression reduction should be weighed against the risk of occurrence of rejection, or exacerbation of rejection observed concomitantly.
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Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.
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Rejeição de Enxerto , Rim , Rim/patologia , Transplante Homólogo , Anticorpos , Aloenxertos , Imunidade Inata/genéticaRESUMO
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
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Glomerulonefrite por IGA , Animais , Camundongos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/diagnóstico , Estudo de Associação Genômica Ampla , Imunoglobulina A/genéticaRESUMO
Acute kidney injury is a common and important complication following hematopoietic stem cell transplantation. In the nephrology community, acute kidney injury is no longer viewed as a simple temporary and potentially reversible decline in kidney clearance as acute kidney injury imposes a risk for immediate and future complications. Therefore, stratifying patients for the risk of acute kidney injury following stem cell transplantation would be very helpful to optimize peri-stem cell transplant management and could potentially improve outcomes in this patient population. In the current issue of CKJ, Mancianti et al. report on the testing of the kidney's functional reserve in patients planned for stem cell transplantation and demonstrate that stem cell transplant candidates with a preserved kidney response on a protein load had a higher chance of full kidney recovery after an episode of acute kidney injury. In this editorial, we discuss the kidney's functional reserve test and its limitations.
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In the last decade, immune checkpoint inhibitors (ICI) have become a cornerstone in the treatment of a wide range of malignancies. It is well established that ICI are associated with multiple immune-related adverse events, a spectrum of autoimmune toxicities, that can also affect the kidney. In this issue of Clinical Kidney Journal, Kanbay et al. report the first meta-analysis and systematic review evaluating the impact of ICI-related acute kidney injury (ICI-AKI) on long-term kidney and patient outcomes (including mortality). The authors report a high incidence of ICI-AKI (mostly mild AKI episodes) with high rates of recovery resulting in a good kidney outcomes. However, the occurrence of ICI-AKI has a significant impact on mortality in ICI-treated patients probably related to temporary or definitive cessation of ICI. Additional studies are needed to establish the safety of ICI re-challenging in patients with ICI-AKI, and to determine the optimal treatment strategy for them.
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Besides true acute kidney injury (AKI), the occurrence of pseudo-AKI has been associated with several targeted agents. To improve the management of cancer patients treated with targeted agents, we need to be aware of this and use diagnostic approaches to differentiate between pseudo-AKI and AKI. In an article by Wijtvliet et al. in this issue of CKJ, tepotinib is added to the list of targeted agents associated with pseudo-AKI. In this editorial we discuss the current literature regarding pseudo-AKI and true AKI associated with targeted agents, and subsequently propose a management strategy to monitor kidney function in patients treated with targeted agents.
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Background: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry provides complete population data on kidney disease epidemiology in the region of Flanders (Belgium), as it captures all native kidney biopsies performed in its population of 6.5 million inhabitants. Methods: From 2017 until 2019, 2054 adult kidney biopsies were included from 26 nephrology centers (one biopsy per patient). Data on nephrotic and nephritic syndrome were available in 1992 and 2026 biopsies, respectively. In a subgroup of 898 biopsies containing ≥10 glomeruli from 2018 to 2019, disease chronicity was graded using the Mayo Clinic Chronicity Score (MCCS). The association between clinical variables and MCCS was determined using simple and multiple linear regression models. Results: Nephrotic syndrome (present in 378 patients, 19.0%) was most frequently caused by minimal change disease in younger patients (18-44 years), membranous nephropathy in older patients (45-74 years) and amyloidosis in the elderly (>75 years). Nephritic syndrome (present in 421 patients, 20.8%) was most frequently caused by immunoglobulin A nephropathy (IgAN) in younger patients (18-64 years) and ANCA-associated vasculitis (AAV) in older patients (>64 years). AAV and IgAN were the most frequent underlying diagnoses in biopsies in which crescents were identified. In multivariable analysis, acute and chronic kidney disease and diagnoses of diabetic kidney disease, nephrosclerosis and hyperoxaluria/hypercalcemic nephropathy were associated with the highest MCCS increases. Conclusions: The FCGG registry validates data from previous Western European registries and provides a snapshot of disease chronicity in the whole biopsied Flemish population.
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Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin (MIg) produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end stage kidney disease (ESKD). The diagnosis is typically made by nephrologists through a kidney biopsy. Many distinct pathologies have been identified and they are classified based on the site or composition of the deposited Mig, or according to histological and ultrastructural findings. Therapy is directed towards the identified underlying clonal population and treatment decisions should be coordinated between hematologists and nephrologists in a multidisciplinary fashion, depend on the type of MGRS, the degree of kidney function impairment and the risk of progression to ESKD.
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Nefropatias , Falência Renal Crônica , Gamopatia Monoclonal de Significância Indeterminada , Paraproteinemias , Humanos , Rim/patologia , Paraproteinemias/patologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/patologiaRESUMO
Monoclonal gammopathy of renal significance (MGRS) defines disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin produced by a B-cell or plasma-cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end-stage kidney disease. The current paradigm states that the underlying hematologic condition should be treated and in deep remission before kidney transplantation can be performed because recurrence has been reported for all MGRS-associated kidney diseases. However, we suggest that decisions regarding kidney transplantation in MGRS patients should be individualized considering many factors such as the subtype of MGRS-associated kidney disease, patient age and comorbidity, presence and risk of extrarenal complications, estimated waiting time, the availability of a living kidney donor, and previous hematological treatment and response. Thus, kidney transplantation should be considered even in treatment-naive patients, with hematological treatment initiated after successful kidney transplantation.
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Nefropatias , Falência Renal Crônica , Transplante de Rim , Gamopatia Monoclonal de Significância Indeterminada , Paraproteinemias , Humanos , Transplante de Rim/efeitos adversos , Rim , Paraproteinemias/complicações , Nefropatias/etiologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/cirurgia , Falência Renal Crônica/complicações , Gamopatia Monoclonal de Significância Indeterminada/complicaçõesRESUMO
BACKGROUND: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is a population-based kidney biopsy registry that has been including all native kidney biopsies performed in children in Flanders (Belgium), since 2017. METHODS: From 2017 to 2020, 148 pediatric (< 18 years) native kidney biopsies were included. Each biopsy received a histopathological and final nephrological diagnosis, and concordance between both was assessed. Disease chronicity, summarized by the Mayo Clinic Chronicity Score, was determined on 122 biopsies with > 5 glomeruli. RESULTS: Kidney biopsy rate was high (29.0 biopsies per million children per year), median age was 10.0 years (IQR 5.8-14.7), and boys predominated (56.1% males). A total of 140 biopsies (94.6%) showed a representative pathology result. Glomerular disease was most prevalent, with IgA nephropathy/IgA vasculitis (43 biopsies, 29.1%) and minimal change disease (MCD) (29 biopsies, 19.6%) being the overall most frequent diagnoses. In general, diagnostic concordance was high (80.7%). In Alport syndrome and focal segmental glomerulosclerosis (FSGS), concordance was lower, as the nephrological diagnosis was often determined by results of genetic analysis. Nephrotic syndrome was the most frequent indication for kidney biopsy (31.8%) and was mainly caused by MCD and FSGS. The degree of disease chronicity on kidney biopsies was generally low, although 27.3% of biopsies with a diagnosis of FSGS showed moderate-to-severe chronic damage. CONCLUSIONS: The presented epidemiological findings validate data from previous European registry studies and may inspire kidney biopsy registries worldwide to implement novel features such as clinicopathological concordance and chronicity grading. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Glomerulonefrite por IGA , Glomerulonefrite , Glomerulosclerose Segmentar e Focal , Nefrose Lipoide , Masculino , Criança , Humanos , Feminino , Rim/patologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Glomerulosclerose Segmentar e Focal/patologia , Bélgica/epidemiologia , Glomerulonefrite/patologia , Nefrose Lipoide/patologia , Glomerulonefrite por IGA/patologia , BiópsiaRESUMO
OBJECTIVES: To externally validate the previously published Mayo clinic model for the prediction of early (<30 days) postoperative renal failure, which relies solely on preoperative estimated glomerular filtration rate (eGFR) and develop a novel model for the prediction of long-term (>30 days) renal function after partial nephrectomy (PN) and radical nephrectomy (RN), including patient factors and nephrometry scores. PATIENTS AND METHODS: Retrospective, single-center cohort study on patients who underwent PN or RN for a unilateral renal tumor between 2003 and 2019 with a preoperative eGFR of at least 15 ml/min/1.73m2. Early postoperative renal failure was defined as eGFR <15 ml/min/1.73 m2 or receipt of dialysis within 30 days. We determined the area under the receiver operating characteristics curve (AUC) to assess the Mayo clinic model's discriminative power. We used hierarchical linear mixed models with backward selection of candidate variables to develop a prediction model for long-term eGFR following PN and RN, separately. Their predictive ability was quantified using the marginal and conditional R2GLMM and an internal validation. RESULTS: We included 421 patients (7,548 eGFR observations) who underwent PN and 271 patients (6,530 eGFR observations) who underwent RN. The Mayo clinic model for prediction of early postoperative renal failure following PN and RN showed an AUC of 0.816 (95% CI 0.718-0.920) and 0.825 (95% CI 0.688-0.962), respectively. In multivariable models, long-term eGFR following PN was associated with age, diabetes, the presence of a solitary kidney, tumor diameter and preoperative eGFR, while long-term eGFR following RN was associated with age, body mass index, RENAL nephrometry score and preoperative eGFR. Marginal and conditional R2GLMM were 0.591 and 0.855 for the PN model, and 0.363 and 0.849 for the RN model, respectively. CONCLUSIONS: The Mayo clinic model for short-term renal failure prediction showed good accuracy on external validation. Our long-term eGFR prediction models depend mostly on host factors as opposed to tumor complexity and can aid in decision-making when considering PN vs. RN.