The ERA Registry Annual Report 2021: a summary.

Background: The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper is a summary of the ERA Registry Annual Report 2021, including a comparison across treatment modalities. Methods: Data was collected from 54 national and regional registries from 36 countries, of which 35 registries from 18 countries contributed individual patient data and 19 registries from 19 countries contributed aggregated data. Using this data, incidence and prevalence of KRT, kidney transplantation rates, survival probabilities and expected remaining lifetimes were calculated. Result: In 2021, 533.2 million people in the general population were covered by the ERA Registry. The incidence of KRT was 145 per million population (pmp). In incident patients, 55% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes (22%). The prevalence of KRT was 1040 pmp. In prevalent patients, 47% were 65 years or older, 62% were male, and the most common PRDs were diabetes and glomerulonephritis/sclerosis (both 16%). On 31 December 2021, 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. The kidney transplantation rate in 2021 was 37 pmp, a majority coming from deceased donors (66%). For patients initiating KRT between 2012-2016, 5-year survival probability was 52%. Compared to the general population, life expectancy was 65% and 68% shorter for males and females receiving dialysis, and 40% and 43% shorter for males and females living with a functioning graft.

Kidney-specific methylation patterns correlate with kidney function and are lost upon kidney disease progression.

BACKGROUND: Chronological and biological age correlate with DNA methylation levels at specific sites in the genome. Linear combinations of multiple methylation sites, termed epigenetic clocks, can inform us the chronological age and predict multiple health-related outcomes. However, why some sites correlating with lifespan, healthspan, or specific medical conditions remain poorly understood. Kidney fibrosis is the common pathway for chronic kidney disease, which affects 10% of European and US populations. RESULTS: Here we identify epigenetic clocks and methylation sites that correlate with kidney function. Moreover, we identify methylation sites that have a unique methylation signature in the kidney. Methylation levels in majority of these sites correlate with kidney state and function. When kidney function deteriorates, all of these sites regress toward the common methylation pattern observed in other tissues. Interestingly, while the majority of sites are less methylated in the kidney and become more methylated with loss of function, a fraction of the sites are highly methylated in the kidney and become less methylated when kidney function declines. These methylation sites are enriched for specific transcription-factor binding sites. In a large subset of sites, changes in methylation patterns are accompanied by changes in gene expression in kidneys of chronic kidney disease patients. CONCLUSIONS: These results support the information theory of aging, and the hypothesis that the unique tissue identity, as captured by methylation patterns, is lost as tissue function declines. However, this information loss is not random, but guided toward a baseline that is dependent on the genomic loci. SIGNIFICANCE STATEMENT: DNA methylation at specific sites accurately reflects chronological and biological age. We identify sites that have a unique methylation pattern in the kidney. Methylation levels in the majority of these sites correlate with kidney state and function. Moreover, when kidney function deteriorates, all of these sites regress toward the common methylation pattern observed in other tissues. Thus, the unique methylation signature of the kidney is degraded, and epigenetic information is lost, when kidney disease progresses. These methylation sites are enriched for specific and methylation-sensitive transcription-factor binding sites, and associated genes show disease-dependent changes in expression. These results support the information theory of aging, and the hypothesis that the unique tissue identity, as captured by methylation patterns, is lost as tissue function declines.

Fluctuations in Serum Creatinine Levels During Hospitalization and Long-Term End-Stage Kidney Disease and Mortality.

Importance: Acute kidney injury is associated with poor outcomes, but the clinical implication of reversible serum creatinine level fluctuations during hospitalization not necessarily defined as acute kidney injury is poorly understood. Objective: To investigate the long-term outcomes of patients without previously diagnosed kidney disease who present with decreased kidney function and are subsequently discharged with apparently normal kidney function. Design, Setting, and Participants: A retrospective cohort study was conducted of patients hospitalized in a large tertiary hospital in Israel between September 1, 2007, and July 31, 2022. The study included patients admitted to an internal medicine ward. Patients had not undergone dialysis during the index hospitalization, had at least 3 creatinine tests performed during hospitalization, and had a discharge estimated glomerular filtration rate (eGFR) exceeding 60 mL/min/1.73 m2. Patients with preexisting chronic kidney disease were excluded. Exposure: Glomerular filtration rate was estimated from serum creatinine values using the updated 2022 Chronic Kidney Disease Epidemiology Collaboration formula, and eGFR greater than 60 mL/min/1.73 m2 was regarded as normal. Exposure was defined based on the association between the first and last values determined during hospitalization. Main Outcomes and Measures: All-cause mortality in the year following the index hospitalization and end-stage kidney disease (ESKD) in the 10 years following the index hospitalization. Results: A total of 40 558 patients were included. Median age was 69 (IQR, 56-80) years, with 18 004 women (44%) and 22 554 men (56%). A total of 34 332 patients (85%) were admitted with a normal eGFR and 6226 (15%) with decreased eGFR. Patients with decreased eGFR on presentation had an 18% increased mortality in the year following hospitalization (adjusted hazard ratio [AHR], 1.18; 95% CI, 1.11-1.24) and a 267% increased risk of ESKD in the 10 years following hospitalization (AHR, 3.67; 95% CI, 2.43-5.54), despite having been discharged with apparently normal kidney function. The highest risk was noted in patients who presented to the hospital with an eGFR of 0 to 45 mL/min/1.73 m2. Conclusions and Relevance: The findings of this cohort study suggest that patients who present with decreased kidney function and are discharged without clinically evident residual kidney disease may be at increased long-term risk for ESKD and mortality.

The ERA Registry Annual Report 2020: a summary.

Background: The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with ESKD. This paper is a summary of the ERA Registry Annual Report 2020, also including comparisons among primary renal disease (PRD) groups. Methods: Data were collected from 52 national and regional registries from 34 European countries and countries bordering the Mediterranean Sea: 35 registries from 18 countries providing individual level data and 17 registries from 17 countries providing aggregated data. Using this data, KRT incidence and prevalence, kidney transplantation rates, expected remaining lifetimes and survival probabilities were calculated. Results: A general population of 654.9 million people was covered by the ERA Registry in 2020. The overall incidence of KRT was 128 per million population (p.m.p.). In incident KRT patients, 54% were older than 65 years, 63% were men and the most common PRD was diabetes mellitus (21%). Regarding initial treatment modality in incident patients, 85% received haemodialysis (HD), 11% received peritoneal dialysis (PD) and 4% received a pre-emptive kidney transplant. On 31 December 2020, the prevalence of KRT was 931 p.m.p. In prevalent patients, 45% were older than 65 years, 60% were men and glomerulonephritis was the most common PRD (18%). Of these patients, 58% were on HD, 5% on PD and 37% were living with a kidney transplant. The overall kidney transplantation rate in 2020 was 28 p.m.p., with a majority of kidney grafts from deceased donors (71%). The unadjusted 5-year survival, based on incident dialysis patient from 2011-15, was 41.8%. For patients having received a deceased donor transplant, the unadjusted 5-year survival probability was 86.2% and for patients having received a living donor transplant it was 94.4%. When comparing data by PRD group, differences were found regarding the distribution of age groups, sex and treatment modality received.

Baseline renal function and the risk of cancer among apparently healthy middle-aged adults.

BACKGROUND: The association between mildly impaired renal function with all-site and site-specific cancer risk is not established. We aim to explore this association among apparently healthy adults. METHODS: We followed 25,073 men and women, aged 40-79 years, free of cancer or cardiovascular disease at baseline who were screened annually in preventive healthcare settings. The estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation (CKD-EPI) and classified into four mutually exclusive groups: <60, 60-74, 75-89, ≥90 (mL/min/1.73 m²). The primary outcome was all-site cancer while the secondary outcome was site-specific cancer. Cancer data was available from a national registry. RESULTS: Mean age at baseline was 50 ± 8 years and 7973 (32 %) were women. During a median follow-up of 9 years (IQR 3-16) and 256,279 person years, 2045 (8.2 %) participants were diagnosed with cancer. Multivariable Cox model showed a 1.2 (95 %CI: 1.0-1.4 p = 0.05), 1.2 (95 %CI: 1.0-1.4 p = 0.02), and 1.4 (95 %CI: 1.1-1.7 p = 0.003) higher risk for cancer with eGFR of 75-89, 60-74, and < 60, respectively. Site-specific analysis demonstrated a 1.8 (95 %CI: 1.2-2.6 p = 0.004), 1.7 (95 %CI: 1.2-2.6 p = 0.004) and 2.2 (95 %CI: 1.3-3.6 p = 0.002) increased risk for prostate cancer with eGFR of 75-89, 60-74, and < 60, respectively. eGFR< 60 was associated with a 2.0 (95 %CI: 1.1-3.7 p = 0.03) and 3.7 (95 %CI: 1.1-13.1 p = 0.04) greater risk for melanoma and gynecological caner respectively. CONCLUSIONS: CKD stage 2 and worse is independently associated with higher risk for cancer incidence, primarily prostate cancer. Early intervention and screening are warranted among these individuals in order to reduce cancer burden.

The Prognostic Value of Anti-PLA2R Antibodies Levels in Primary Membranous Nephropathy.

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50-71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35-183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients.

Predictors and Adverse Outcomes of Acute Kidney Injury in Hospitalized Renal Transplant Recipients.

Data about in-hospital AKI in RTRs is lacking. We conducted a retrospective study of 292 RTRs, with 807 hospital admissions, to reveal predictors and outcomes of AKI during admission. In-hospital AKI developed in 149 patients (51%). AKI in a previous admission was associated with a more than twofold increased risk of AKI in subsequent admissions (OR 2.13, p < 0.001). Other major significant predictors for in-hospital AKI included an infection as the major admission diagnosis (OR 2.93, p = 0.015), a medical history of hypertension (OR 1.91, p = 0.027), minimum systolic blood pressure (OR 0.98, p = 0.002), maximum tacrolimus trough level (OR 1.08, p = 0.005), hemoglobin level (OR 0.9, p = 0.016) and albumin level (OR 0.51, p = 0.025) during admission. Compared to admissions with no AKI, admissions with AKI were associated with longer length of stay (median time of 3.83 vs. 7.01 days, p < 0.001). In-hospital AKI was associated with higher rates of mortality during admission, almost doubled odds for rehospitalization within 90 days from discharge and increased the risk of overall mortality in multivariable mixed effect models. In-hospital AKI is common and is associated with poor short- and long-term outcomes. Strategies to prevent AKI during admission in RTRs should be implemented to reduce re-admission rates and improve patient survival.

Dialysis in Israeli Children between 1990 and 2020: Trends and International Comparisons.

BACKGROUND: Childhood kidney failure is a rare condition with worldwide clinical variability. We used a nationwide multicenter analysis to study the pretransplant course of the entire Israeli pediatric kidney failure population over 30 years. METHODS: In this nationwide, population-based, historical cohort study, we analyzed medical and demographic data of all children treated with KRT and reported to the Israeli kidney failure registry in 1990-2020. Statistical analysis was performed with incidence rate corrected for age, ethnicity, and calendar year, using the appropriate age-related general population as denominator. RESULTS: During the last 30 years, childhood incidence of kidney failure decreased. Average incidence in 2015-2019 was 9.1 cases per million age-related population (pmarp). Arab and Druze children exhibited higher kidney failure incidence rates than Jewish children (18.4 versus 7.0 cases pmarp for minorities versus Jews). The most common kidney failure etiologies among Arab and Jewish children were congenital anomalies of the kidney and urinary tract (approximately 27%), followed by cystic kidney diseases among Arab children (13%) and glomerulonephritis among Jewish children (16%). The most common etiology among Druze children was primary hyperoxaluria type 1 (33%). Israel's national health insurance provides access to primary health care to all citizens. Accordingly, waiting time for deceased-donor transplantation was equal between all ethnicities. Living-donor kidney transplantation rates among minority populations remained low in comparison with Jews over the entire study period. Although all patient groups demonstrated improvement in survival, overall survival rates were mainly etiology dependent. CONCLUSIONS: In Israel, Arab and Druze children had a higher incidence of kidney failure, a unique etiological distribution, and a lower rate of living-donor kidney transplantations compared with Jewish children.

Acute Kidney Injury and Hair-Straightening Products: A Case Series.

RATIONALE & OBJECTIVE: Keratin-based hair-straightening treatment is a popular hair-styling method. The majority of keratin-based hair-straightening products in Israel contain glycolic acid derivatives, which are considered safe when used topically. Systemic absorption of these products is possible, and anecdotal reports have described kidney toxicity associated with their use. We report a series of cases of severe acute kidney injury (AKI) following use of hair-straightening treatment in Israel during the past several years. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We retrospectively identified 26 patients from 14 medical centers in Israel who experienced severe AKI and reported prior treatment with hair-straightening products in 2019-2022. FINDINGS: The 26 patients described had a median age of 28.5 (range, 14-58) years and experienced severe AKI following a hair-straightening procedure. The most common symptoms at presentation were nausea, vomiting, and abdominal pain. Scalp rash was noted in 10 (38%) patients. Two patients experienced a recurrent episode of AKI following a repeat hair-straightening treatment. Seven patients underwent kidney biopsies, which demonstrated intratubular calcium oxalate deposition in 6 and microcalcification in tubular cells in 1. In all biopsies, signs of acute tubular injury were present, and an interstitial infiltrate was noted in 4 cases. Three patients required temporary dialysis. LIMITATIONS: Retrospective uncontrolled study, small number of kidney biopsies. CONCLUSIONS: This series describes cases of AKI with prior exposure to hair-straightening treatments. Acute oxalate nephropathy was the dominant finding on kidney biopsies, which may be related to absorption of glycolic acid derivatives and their metabolism to oxalate. This case series suggests a potential underrecognized cause of AKI in the young healthy population. Further studies are needed to confirm this association and to assess the extent of this phenomenon as well as its pathogenesis.

Humoral Response to the Fourth BNT162b2 Vaccination and Link Between the Fourth Dose, Omicron Infection, and Disease Severity in Renal Transplant Recipients.

BACKGROUND: The effectiveness of the fourth BNT162b2 vaccination in reducing the rate and severity of coronavirus disease 2019 (COVID-19) caused by the Omicron variant in renal transplant recipients (RTRs) is unknown. METHODS: Interviews were conducted with 447 RTRs regarding the status and timing of the fourth vaccination, prior vaccinations, and preceding COVID-19 infection. RTRs with polymerase chain reaction-confirmed COVID-19 infection from December 1, 2021, to the end of March 2022 were considered to have been infected with the Omicron variant and were interviewed to determine their disease severity. In a subgroup of 74 RTRs, the humoral response to the fourth dose was analyzed. In 30 RTRs, microneutralization assays were performed to reveal the humoral response to wild-type, Delta, and Omicron variant isolates before and after the fourth dose. RESULTS: Of 447 RTRs, 144 (32.2%) were infected with the Omicron variant, with 71 (49.3%) of the infected RTRs having received the fourth vaccine dose. RTRs who did not receive the fourth dose before the infection had more serious illness. In a subgroup of 74 RTRs, the fourth dose elicited a positive humoral response in 94.6% (70/74), with a significant increase in geometric mean titer for receptor-binding domain immunoglobulin G and neutralizing antibodies ( P < 0.001). The humoral responses to the Omicron variant before and after the fourth dose were significantly lower than the responses to the wild-type and the Delta variants. CONCLUSIONS: Overall, the fourth BNT162b2 dose was effective in reducing the rate and severity of Omicron disease in RTRs, despite the reduced humoral response to the variant.

Optimal peritoneal fluid white blood cell count for diagnosis of peritonitis in peritoneal dialysis patients.

BACKGROUND: The diagnosis of peritonitis among peritoneal dialysis (PD) patients is based on clinical presentation, dialysis effluent white blood cell (WBC) count, and dialysis effluent culture. Peritoneal fluid WBC count is very important in the initial diagnosis of peritonitis. The purpose of this work was to determine the optimal number of peritoneal WBCs with different clinical presentations at admission to define PD-related peritonitis. METHODS: Medical records of chronic PD patients who underwent work-up for suspected peritonitis between 2008 and 2019 were reviewed retrospectively. Results of all peritoneal WBC count tests during this period were collected. Clinical manifestations and follow-up analysis of each peritoneal WBC count were performed. RESULTS: The peritoneal WBC count cutoff of 100/µL recommended by International Society for Peritoneal Dialysis provided specificity of only 35%. Increasing peritoneal WBC count cutoff to 150, 200, and 250/µL provided sensitivity around 98% and gradually increasing specificity. The chi-square automatic interaction detector model of statistical analysis determined that peritoneal WBC count below 230/µL combined with absence of inflammatory markers (fever, increased C-reactive protein) ruled out peritonitis with 99.8% sensitivity. Peritoneal fluid WBC count cutoff of 230/µL provided specificity of 89% and good positive and negative likelihood scores of 8.3 and 0.03, respectively. Peritoneal fluid polymorphonuclear count has lower discriminating ability for peritonitis compared to peritoneal fluid WBC count. CONCLUSION: Increasing peritoneal fluid WBC count cutoff to 230/µL in suspected PD-related peritonitis could improve specificity without compromising the sensitivity of the test.

Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI.

BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

Acute Kidney Injury following Exposure to Formaldehyde-Free Hair-Straightening Products.

Formaldehyde-free hair-straightening products are hair-smoothening solutions widely used by professional beauty salons. Formaldehyde-free hair straighteners do not technically contain formaldehyde; however, they contain other chemicals such as glyoxyloyl carbocysteine which releases formaldehyde upon contact with heat. Moreover, its by-product glyoxylate may convert to oxalate; both compounds have potential nephrotoxic effect. Here, we report a case of a 41-year-old woman who presented to the emergency room with weakness, nausea, vomiting, and stage 3 acute kidney injury (AKI) according to Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury staging shortly after exposure to formaldehyde-free hair-straightening product; other causes of AKI were excluded such as preceding acute illness, drug history, or other nephrotoxic agent exposure. On physical examination, the patient was pale, and her vital signs were normal. The urine microscopy and serologic workup were not indicative. Kidney core biopsy revealed interstitial edema, acute interstitial nephritis, and oxalate crystal nephropathy. Kidney function completely recovered after a short course of steroid therapy. In this case, AKI was a complication caused by exposure to hair-straightening products branded as formaldehyde free but actually containing other chemical products which release formaldehyde and other toxic chemicals when heated during the straightening procedure and may cause systemic toxicity, particularly kidney injury. Different cosmetic products are widely in use, but not all are under tight regulation, and therefore, it is important to raise the awareness among both medical teams and consumers of possible adverse health effects of different cosmetic products.

Treatment of Severe Renal Artery Stenosis with Acute Kidney Injury Requiring Hemodialysis by Percutaneous Transluminal Renal Angioplasty and Stent Implantation.

PURPOSE: To evaluate the outcomes of percutaneous transluminal renal angioplasty with stent implantation (PTRAS) among patients with renal artery stenosis (RAS) who become dialysis-dependent due to acute deterioration of renal function. MATERIALS AND METHODS: This was a single-center retrospective cohort study of all PTRAS procedures performed from 2003 to 2019 in a referral hospital. A total of 109 procedures were performed in 92 patients. Eleven patients (12%) presented with anuric acute kidney injury (AKI) secondary to high-grade RAS (defined as intraluminal stenosis above 70% per angiography) and underwent PTRAS after starting hemodialysis. Data collected included demographic parameters, medical background, creatinine, blood pressure, indication for intervention, procedure characteristics, adverse events, and long-term data including dialysis treatment and mortality. Among the dialysis-dependent AKI group, outcome measures were defined based on the postprocedural improvement in kidney function and discontinuation of dialysis. RESULTS: Following PTRAS, 8 of 11 patients (73%) demonstrated improved kidney function and were able to discontinue dialysis. The median time on dialysis was 18 days (range, 2-35 days) before PTRAS and 4.5 days (range, 1-24 days) to recovery of kidney function after the time of intervention. CONCLUSIONS: Patients with atherosclerotic RAS who develop RAS-related AKI may benefit from PTRAS even after several weeks of anuria and dialysis dependence.

The Peritoneal Membrane-A Potential Mediator of Fibrosis and Inflammation among Heart Failure Patients on Peritoneal Dialysis.

Peritoneal dialysis is a feasible, cost-effective, home-based treatment of renal replacement therapy, based on the dialytic properties of the peritoneal membrane. As compared with hemodialysis, peritoneal dialysis is cheaper, survival rate is similar, residual kidney function is better preserved, fluid and solutes are removed more gradually and continuously leading to minimal impact on hemodynamics, and risks related to a vascular access are avoided. Those features of peritoneal dialysis are useful to treat refractory congestive heart failure patients with fluid overload. It was shown that in such patients, peritoneal dialysis improves functional status and quality of life, reduces hospitalization rate, and may decrease mortality rate. High levels of serum proinflammatory cytokines and fibrosis markers, among other factors, play an important part in congestive heart failure pathogenesis and progression. We demonstrated that those levels decreased following peritoneal dialysis treatment in refractory congestive heart failure patients. The exact mechanism of beneficial effect of peritoneal dialysis in refractory congestive heart failure is currently unknown. Maintenance of fluid balance, leading to resetting of neurohumoral activation towards a more physiological condition, reduced remodeling due to the decrease in mechanical pressure on the heart, decreased inflammatory cytokine levels and oxidative stress, and a potential impact on uremic toxins could play a role in this regard. In this paper, we describe the unique characteristics of the peritoneal membrane, principals of peritoneal dialysis and its role in heart failure patients.

A multidisciplinary nephrogenetic referral clinic for children and adults-diagnostic achievements and insights.

BACKGROUND: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model. METHODS: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team. RESULTS: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing). CONCLUSIONS: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information.

The key role of NLRP3 and STING in APOL1-associated podocytopathy.

Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.

Acute kidney injury in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.