Neurodevelopmental profile of infants and toddlers awaiting a kidney transplant.

BACKGROUND: Infants and toddlers with kidney failure are susceptible to neurodevelopmental delays due to medical comorbidities and rapid brain development in early childhood. However, research on the neuropsychological development of this patient population has been limited over the past 10 years. METHODS: We performed a retrospective study to evaluate the neurodevelopmental functioning of infants/toddlers with kidney failure who completed the Bayley Scales of Infant and Toddler Development (3rd and 4th Edition) as part of a pretransplant evaluation between 2010 and 2022 (n = 23; Mage = 18 months, SD = 8.53; 16 males) using t-tests, linear model, and Pearson correlations. RESULTS: Mean Bayley scores of participants were below normative means for cognition (M = 86.74, 95% CI = 80.53-92.94, p < 0.001), language (M = 79.20, 95% CI = 73.32-85.08, p < 0.001), and motor (M = 78.00, 95% CI = 70.15-85.85, p < 0.001) domains. After adjusting for prematurity and epilepsy, patients on dialysis had significantly lower cognitive (78.7 vs. 93.8; p = 0.001) and motor scores (67.1 vs. 85.5; p = 0.01) compared to no dialysis. Pretransplant cognitive scores were positively correlated with posttransplant Full-Scale IQ (r(8) = 0.65 p = 0.04), verbal comprehension (r(8) = 0.75 p = 0.02), and fluid reasoning (r(7) = 0.68 p = 0.045). Similarly, pretransplant language scores were positively correlated with posttransplant Full-Scale IQ (r(7) = 0.74 p = 0.03) and verbal comprehension (r(7) = 0.73 p = 0.03). Of the 16 participants who reached age > 5 years during the study period, seven were diagnosed with a neurodevelopmental disorder, including three with autism spectrum disorder. CONCLUSIONS: Infants and toddlers with kidney failure are at risk of developmental delays and later neurodevelopmental disorders. Dialysis is associated with cognitive and motor delays independent of prematurity and epilepsy.

Use of kidney failure risk equation as a tool to evaluate referrals from primary care to specialist nephrology care.

BACKGROUND: With rising costs and burden of chronic kidney disease (CKD), timely referral of patients to a kidney specialist is crucial. Currently, Kidney Health Australia (KHA) uses a 'heat map' based on severity and not future risk of kidney failure, whereas the kidney failure risk equation (KFRE) score predicts future risk of progression. AIMS: Evaluate whether a KFRE score assists with timing of CKD referrals. METHODS: Retrospective cohort of 2137 adult patients, referred to tertiary hospital outpatient nephrologist between 2012 and 2020, were analysed. Referrals were analysed for concordance with the KHA referral guidelines and, with the KFRE score, a recommended practice. RESULTS: Of 2137 patients, 626 (29%) did not have urine albumin-to-creatinine ratio (UACR) measurement at referral. For those who had a UACR, the number who met KFRE preferred referral criteria was 36% less than KHA criteria. If the recommended KFRE score was used, then fewer older patients (≥40 years) needed referral. Positively, many diabetes patients were referred, even if their risk of kidney failure was low, and 29% had a KFRE over 3%. For patients evaluated meeting KFRE criteria, a larger proportion (76%) remained in follow-up, with only 8% being discharged. CONCLUSIONS: KFRE could reduce referrals and be a useful tool to assist timely referrals. Using KFRE for triage may allow those patients with very low risk of future kidney failure not be referred, remaining longer in primary care, saving health resources and reducing patients' stress and wait times. Using KFRE encourages albuminuria measurement.

Arteriovenous Access for Hemodialysis: A Review.

Importance: Hemodialysis requires reliable vascular access to the patient's blood circulation, such as an arteriovenous access in the form of an autogenous arteriovenous fistula or nonautogenous arteriovenous graft. This Review addresses key issues associated with the construction and maintenance of hemodialysis arteriovenous access. Observations: All patients with kidney failure should have an individualized strategy (known as Patient Life-Plan, Access Needs, or PLAN) for kidney replacement therapy and dialysis access, including contingency plans for access failure. Patients should be referred for hemodialysis access when their estimated glomerular filtration rate progressively decreases to 15 to 20 mL/min, or when their peritoneal dialysis, kidney transplant, or current vascular access is failing. Patients with chronic kidney disease should limit or avoid vascular procedures that may complicate future arteriovenous access, such as antecubital venipuncture or peripheral insertion of central catheters. Autogenous arteriovenous fistulas require 3 to 6 months to mature, whereas standard arteriovenous grafts can be used 2 to 4 weeks after being established, and "early-cannulation" grafts can be used within 24 to 72 hours of creation. The prime pathologic lesion of flow-related complications of arteriovenous access is intimal hyperplasia within the arteriovenous access that can lead to stenosis, maturation failure (33%-62% at 6 months), or poor patency (60%-63% at 2 years) and suboptimal dialysis. Nonflow complications such as access-related hand ischemia ("steal syndrome"; 1%-8% of patients) and arteriovenous access infection require timely identification and treatment. An arteriovenous access at high risk of hemorrhaging is a surgical emergency. Conclusions and Relevance: The selection, creation, and maintenance of arteriovenous access for hemodialysis vascular access is critical for patients with kidney failure. Generalist clinicians play an important role in protecting current and future arteriovenous access; identifying arteriovenous access complications such as infection, steal syndrome, and high-output cardiac failure; and making timely referrals to facilitate arteriovenous access creation and treatment of arteriovenous access complications.

A Predictive Model for Kidney Failure After Nephrectomy for Localized Kidney Cancer: The Kidney Cancer Risk Equation.

RATIONALE & OBJECTIVE: Nephrectomy is the mainstay of treatment for individuals with localized kidney cancer. However, surgery can potentially result in the loss of kidney function or in kidney failure requiring dialysis/kidney transplantation. There are currently no clinical tools available to preoperatively identify which patients are at risk of kidney failure over the long term. Our study developed and validated a prediction equation for kidney failure after nephrectomy for localized kidney cancer. STUDY DESIGN: Population-level cohort study. SETTING & PARTICIPANTS: Adults (n=1,026) from Manitoba, Canada, with non-metastatic kidney cancer diagnosed between January 1, 2004, and December 31, 2016, who were treated with either a partial or radical nephrectomy and had at least 1 estimated glomerular filtration rate (eGFR) measurement before and after nephrectomy. A validation cohort included individuals in Ontario (n=12,043) with a diagnosis of localized kidney cancer between October 1, 2008, and September 30, 2018, who received a partial or radical nephrectomy and had at least 1 eGFR measurement before and after surgery. NEW PREDICTORS & ESTABLISHED PREDICTORS: Age, sex, eGFR, urinary albumin-creatinine ratio, history of diabetes mellitus, and nephrectomy type (partial/radical). OUTCOME: The primary outcome was a composite of dialysis, transplantation, or an eGFR<15mL/min/1.73m2 during the follow-up period. ANALYTICAL APPROACH: Cox proportional hazards regression models evaluated for accuracy using area under the receiver operating characteristic curve (AUC), Brier scores, calibration plots, and continuous net reclassification improvement. We also implemented decision curve analysis. Models developed in the Manitoba cohort were validated in the Ontario cohort. RESULTS: In the development cohort, 10.3% reached kidney failure after nephrectomy. The final model resulted in a 5-year area under the curve of 0.85 (95% CI, 0.78-0.92) in the development cohort and 0.86 (95% CI, 0.84-0.88) in the validation cohort. LIMITATIONS: Further external validation needed in diverse cohorts. CONCLUSIONS: Our externally validated model can be easily applied in clinical practice to inform preoperative discussions about kidney failure risk in patients facing surgical options for localized kidney cancer. PLAIN-LANGUAGE SUMMARY: Patients with localized kidney cancer often experience a lot of worry about whether their kidney function will remain stable or will decline if they choose to undergo surgery for treatment. To help patients make an informed treatment decision, we developed a simple equation that incorporates 6 easily accessible pieces of patient information to predict the risk of reaching kidney failure 5 years after kidney cancer surgery. We expect that this tool has the potential to inform patient-centered discussions tailored around individualized risk, helping ensure that patients receive the most appropriate risk-based care.

TAFRO syndrome: A disease that known is half cured.

Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is rare in clinical practice. It is a systemic inflammatory disease caused by a cytokine storm. Its clinical manifestations include thrombocytopenia, systemic edema, fever, bone marrow fibrosis, renal insufficiency, and organ enlargement. The high mortality rate of TAFRO syndrome is due to the difficulty of acquiring biopsy samples for diagnosis and the rapid disease progression. This disease is poorly understood by clinicians. Early detection, accurate diagnosis, and timely treatment play key roles in prolonging the survival of the patients. This review summarizes the latest progress in the pathogenesis, diagnostic criteria, and treatment regimens of TAFRO syndrome, aiming to help clinicians better understand TAFRO syndrome and improve its diagnosis and treatment.

Biallelic variants in NUDCD2 associated with a multiple malformation syndrome with cholestasis and renal failure.

NudC-like protein 2 (NUDCD2) is a 4-exon protein-coding gene at 5q34. The protein appears to act in concert with other genes regulating cell migration and microtubule extension. Early studies in model organisms show associations with LIS1, HERC2, and cohesin subunits via a co-chaperone function with Heat shock protein 90 (Hsp90). It is a candidate gene for human pathology. We present two unrelated patients with biallelic variants in NUDCD2. Their phenotypes comprise similar dysmorphic facies, midline brain hypoplasia, hypothyroidism, pulmonary and aortic valve stenosis, severe dysfunction of the liver and kidneys, profound hypotonia, and early death. The cellular analysis demonstrates the absence of the NUDCD2 protein in fibroblasts of one patient with biallelic loss-of-function variants. The data suggest that NUDCD2 deficiency causes this recognizable syndrome that has features of a ciliopathy with additional complications.

Rapidly progressive renal failure to reveal LCAT deficiency in an Algerian family.

Lecithin-cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder that can reveal two different diseases: a very interesting nephrological picture of complete enzyme deficiency characterized by the association of dyslipidemia, corneal opacities, anemia, and progressive nephropathy; and a partial form (fish-eye disease) with dyslipidemia and progressive corneal opacities only. We report herein the case of a 35-year-old man who presented hypertension, renal symptomatology of rapidly progressive glomerulonephritis associates: nephrotic proteinuria, severe renal failure, in combination with annular corneal opacities, anemia, and dyslipidemia. The diagnosis of familial LCAT deficiency was confirmed by clinical examination, characteristic dyslipidemia, undetectable LCAT levels in plasma, and positive family history.

Misdiagnosed Branchio-Oto-Renal syndrome presenting as proteinuria and renal insufficiency with insidious signs since early childhood: a report of three cases.

BACKGROUND: Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited. CASE PRESENTATION: Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m2. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying. CONCLUSIONS: BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.

A man in his seventies with fatigue and renal failure. / En mann i 70-årene med utmattelse og nyresvikt.

A man in his seventies underwent routine heart examinations as part of workup for kidney transplantation. Unexpected findings led to more extensive investigations and revealed two rare systemic diseases as causes of his heart failure.

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.

Nephrology Referral Based on Laboratory Values, Kidney Failure Risk, or Both: A Study Using Veterans Affairs Health System Data.

RATIONALE & OBJECTIVE: Current guidelines for nephrology referral are based on laboratory criteria. We sought to evaluate whether nephrology referral patterns reflect current clinical practice guidelines and to estimate the change in referral volume if they were based on the estimated risk of kidney failure. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: Retrospective study of 399,644 veterans with chronic kidney disease (October 1, 2015 through September 30, 2016). EXPOSURE: Laboratory referral criteria based on Veterans Affairs/Department of Defense guidelines, categories of predicted risk for kidney failure using the Kidney Failure Risk Equation, and the combination of laboratory referral criteria and predicted risk. OUTCOME: Number of patients identified for referral. ANALYTICAL APPROACH: We evaluated the number of patients who were referred and their predicted 2-year risk for kidney failure. For each exposure, we estimated the number of patients who would be identified for referral. RESULTS: There were 66,276 patients who met laboratory indications for referral. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year. The median 2-year predicted risk of kidney failure was 1.5% (interquartile range, 0.3%-4.7%) among all patients meeting the laboratory referral criteria. If referrals were restricted to patients with a predicted risk of ≥1% in addition to laboratory indications, the potential referral volume would be reduced from 66,276 to 38,229 patients. If referrals were based on predicted risk alone, a 2-year risk threshold of 1% or higher would identify a similar number of patients (72,948) as laboratory-based criteria with median predicted risk of 2.3% (interquartile range, 1.4%-4.6%). LIMITATIONS: Missing proteinuria measurements. CONCLUSIONS: The current laboratory-based guidelines for nephrology referral identify patients who are, on average, at low risk for progression, most of whom are not referred. As an alternative, referral based on a 2-year kidney failure risk exceeding 1% would identify a similar number of patients but with a higher median risk of kidney failure.

Immunoglobulin light-chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease.

Light chain (LC) deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin LC, leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse immunoglobulin κ locus, ensuring its production by all plasma cells (PCs). High free LC levels were achieved after backcrossing with mice presenting increased PC differentiation and no immunoglobulin heavy chain production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria, and finally kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on PCs demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function but also partially reversed kidney lesions. Finally, transcriptome analysis of presclerotic glomeruli revealed that proliferation and extracellular matrix remodeling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.

The effect of suprarenal graft fixation during endovascular aneurysm repair on short- and long-term renal function.

OBJECTIVE: The effect of suprarenal fixation (SR) compared with infrarenal fixation (IR) on renal function during endovascular aneurysm repair (EVAR) remains controversial. This study aims to compare the renal outcomes between fixation types in short- and long-term follow-up. METHODS: Patients undergoing EVAR for infrarenal abdominal aortic aneurysm between 2005 and 2013 were included. The estimated glomerular filtration rate (eGFR) was measured at baseline and during a follow-up of 5 years. A decline in renal function was defined as a 20% or greater decrease in the eGFR. Changes in the eGFR were compared between SR and IR groups at 1 to 7 days, 30 days, and 1 to 5 years postoperatively. Preoperative renal insufficiency was defined as an eGFR of less than 60 mL/min/1.73 m2, and those patients were included in the subanalyses. RESULTS: A total of 358 patients were included. Among these, 267 (74.6%) had SR and 91 (25.4%) had IR fixation. A decrease in renal function occurred more commonly after SR than after IR in 1 to 7 days postoperatively (P = .009), but no difference was noticed at 30 days and 1 to 5 years. Regardless of the fixation method, renal function steadily decreased steadily over time after EVAR (estimate -3.13 per a year; 95% confidence interval, -3.40 to -2.85; P < .001). Patients with preexisting renal insufficiency were included in subgroup analyses, and those with SR were more often found to have a decline in eGFR 5 years postoperatively than their counterparts with IR (59.5% vs 20.0%; P = .036). CONCLUSIONS: An immediate postoperative decrease in renal function was seen more often after SR fixation than IR fixation but this difference was transient. SR fixation is a safe method for patients with normal renal function. Long-term results seems to favor IR over SR in patients with preexisting renal insufficiency.

One case of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome featuring an incomplete and mild phenotype.

BACKGROUND: Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare disease with a high mortality rate caused by VPS33B or VIPAS39 mutations. ARC syndrome typically presents with arthrogryposis, renal tubular leak and neonatal cholestatic jaundice, and most patients with this disease do not survive beyond one year. CASE PRESENTATION: Here, we report the case of a 13-year-old girl with ARC featuring an incomplete and mild phenotype with novel compound heterozygous mutations of VPS33B. The patient presented with arthrogryposis (claw-shaped limbs), ichthyosis, jaundice, and pruritus. Laboratory tests revealed highly evaluated levels of total bilirubin (TB), direct bilirubin (DB), and total bile acid (TBA) as well as normal levels of gamma-glutamyltransferase (GGT). However, signs of renal dysfunction, as well as other manifestations of ARC syndrome, including nervous system abnormalities, deafness, and failure to thrive, were not observed. The patient's clinical symptoms of jaundice and pruritus were significantly alleviated by administration of ursodeoxycholic acid. Whole-exome sequencing (WES) revealed novel compound heterozygous mutations of VPS33B, c.1081 C > T (p.Q361X,257)/c.244 T > C (p.C82R). Both variants were predicted to be pathogenic in silico and have never been reported previously. To date, the patients' cholestatic jaundice has been well controlled with continuous treatment of ursodeoxycholic acid. CONCLUSIONS: We report the case of a Chinese female with ARC including novel compound heterozygous mutations of VPS33B and an incomplete and mild phenotype. Early diagnosis and suitable symptomatic therapies are critical for the management of ARC patients with mild manifestations and prolonged lifespan.

Nomogram to predict rapid kidney function decline in population at risk of cardiovascular disease.

BACKGROUND: To develop a reliable model to predict rapid kidney function decline (RKFD) among population at risk of cardiovascular disease. METHODS: In this retrospective study, key monitoring residents including the elderly, and patients with hypertension or diabetes of China National Basic Public Health Service who underwent community annual physical examinations from January 2015 to December 2020 were included. Healthy records were extracted from regional chronic disease management platform. RKFD was defined as the reduction of estimated glomerular filtration rate (eGFR) ≥ 40% during follow-up period. The entire cohort were randomly assigned to a development cohort and a validation cohort in a 2:1 ratio. Cox regression analysis was used to identify the independent predictors. A nomogram was established based on the development cohort. The concordance index (C-index) and calibration plots were calculated. Decision curve analysis was applied to evaluate the clinical utility. RESULTS: A total of 8455 subjects were included. During the median follow-up period of 3.72 years, the incidence of RKFD was 11.96% (n = 1011), 11.98% (n = 676) and 11.92% (n = 335) in the entire cohort, development cohort and validation cohort, respectively. Age, eGFR, hemoglobin, systolic blood pressure, and diabetes were identified as predictors for RKFD. Good discriminating performance was observed in both the development (C-index, 0.73) and the validation (C-index, 0.71) cohorts, and the AUCs for predicting 5-years RKFD was 0.763 and 0.740 in the development and the validation cohort, respectively. Decision curve analysis further confirmed the clinical utility of the nomogram. CONCLUSIONS: Our nomogram based on five readily accessible variables (age, eGFR, hemoglobin, systolic blood pressure, and diabetes) is a useful tool to identify high risk patients for RKFD among population at risk of cardiovascular disease in primary care. Whereas, further external validations are needed before clinical generalization.

Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study.

RATIONALE & OBJECTIVE: Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. OBSERVATIONS: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2). LIMITATIONS: The relatively small size of this series from a single country, potentially limiting generalizability. CONCLUSIONS: Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.

Risk of renal failure and death when renal arteries are involved in endovascular aortic aneurysm repair.

OBJECTIVE: Endovascular abdominal aortic repair can involve the incorporation of renal arteries. Revascularization after intentional or unintentional renal artery (RA) coverage is not always technically successful, and the loss of a single RA may result in the need for postoperative dialysis. Thus, we compared the outcomes after endovascular aneurysm repair (EVAR) stratified by RA involvement (RAI). METHODS: Patient data from the Vascular Quality Initiative from 2009 to 2018 registry were analyzed. The exclusion criteria were preoperative dialysis, missing RAI data, and repair above the superior mesenteric artery. The repair type cohorts were defined as (1) no RAI (NRAI), (2) RAI with revascularization (RAI-R), and (3) RAI with no revascularization (RAI-NR). A sensitivity analysis was performed by excluding ruptured presentations. The primary outcome was the need for postoperative dialysis. The secondary outcomes were 30-day mortality, dialysis at follow-up, postoperative renal function, and 2-year survival. Multivariate analysis was used to determine the independent predictors for postoperative dialysis. The 2-year survival analysis was performed using Kaplan-Meier log-rank test. RESULTS: Of 54,020 patients in the EVAR and TEVAR (thoracic EVAR)/complex EVAR modules in the Vascular Quality Initiative, 25,724 met the criteria for inclusion (NRAI, n = 24,879; RAI-R, n = 733; RAI-NR, n = 112). The demographics and comorbidities were similar among the three groups. The RAI-NR group had more frequently had ruptured or symptomatic aneurysms. The postoperative dialysis requirement was higher in the RAI-NR group (NRAI, 0.7%; RAI-R, 2.2%; RAI-NR, 17%; P < .0001), as were the 30-day mortality and dialysis requirement at follow-up. On multivariate analysis, RAI-R (odds ratio [OR], 2.2; P = .03) and RAI-NR (OR, 5.9; P < .0001) were independent predictors of postoperative dialysis and remained so after excluding ruptured presentations (RAI-R: OR, 3; P = .003; RAI-NR: OR, 22.3; P < .0001). Other independent predictors of the need for postoperative dialysis were worse preoperative renal function, a symptomatic presentation, any preoperative or intraoperative blood transfusion, and larger blood loss (≥200 mL). Excluding those with rupture, the overall survival at 2 years on Kaplan-Meier analysis was lower for the RAI-NR group (NRAI, 92%; RAI-R, 89%; RAI-NR, 80%; P = .004). CONCLUSIONS: RAI is highly predictive of the need for postoperative and permanent dialysis after EVAR. RAI-NR was associated with lower overall survival. These risks should be considered when planning and performing EVAR and should be weighed against the risks of open repair when considering the treatment options.

Inherited intragenic PBX1 deletion: Expanding the phenotype.

PBX1 encodes the pre-B cell leukemia homeobox transcription factor, a three amino acid loop extension (TALE) homeodomain transcription factor, which forms nuclear complexes with other TALE class homeodomain proteins that ultimately regulate target genes controlling organ patterning during embryogenesis. Heterozygous de novo pathogenic variants in PBX1 resulting in haploinsufficiency are associated with congenital anomalies of the kidneys and urinary tract, most commonly renal hypoplasia, as well as anomalies involving the external ear, branchial arch, heart, and genitalia, and they cause intellectual disability and developmental delay. Affected individuals described thus far have had de novo variants. Here, we report three related individuals with an inherited pathogenic intragenic PBX1 deletion with variable clinical features typical for this syndrome.

Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.