Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine

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

Rapid corticosteroid taper versus standard of care for immune checkpoint inhibitor induced nephritis: a single-center retrospective cohort study

Background Current guidelines for treatment of immune checkpoint inhibitor (ICI)-induced nephritis are not evidence based and may lead to excess corticosteroid exposure. We aimed to compare a rapid corticosteroid taper to standard of care.Methods Retrospective cohort study in patients with ICI-induced nephritis comparing a rapid taper beginning with 60 mg/day prednisone and tapered to 10 mg within 3 weeks to a historical control group that began 60 mg/day tapered to 10 mg within 6 weeks (standard of care). Renal recovery was defined as creatinine returning to within 1.5-fold baseline. The log-rank test compared the differences in time to renal recovery between the groups. We report rates of renal recovery at 30, 60 and 90 days, and timing and outcomes of ICI rechallenge.Results Thirteen patients received rapid corticosteroid taper and 14 patients received standard of care. Baseline characteristics were similar between groups. The median time to ≤10 mg/day prednisone was 20 days (IQR 15–25) in the rapid-taper group compared with 38 days (IQR 30–58) in the standard-of-care group. There was no significant difference in the time to renal recovery between the groups, though numerically higher numbers of patients recovered by 30 days, 11 (85%) in the rapid-taper arm versus 6 (46%) in the standard of care arm. Exposure to other nephritis-causing medications (proton pump inhibitor or trimethoprim-sulfamethoxazole) during the corticosteroid taper was more common in the standard of care group, 9 (64%) versus rapid-taper group, 2 (15%), and was associated with longer time to renal recovery, 20 days (IQR 14–101) versus 13 days (IQR 7–34) in those that discontinued nephritis-causing medications. Fifteen (56%) of patients were rechallenged with ICIs, and only two (13%) developed recurrent nephritis.Conclusions Patients with ICI-induced nephritis have excellent kidney outcomes when treated with corticosteroids that are tapered over 3 weeks

Adverse kidney outcomes of CDK 4/6 inhibitors for metastatic breast cancer

Abstract Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved overall and progression free survival of patients with metastatic breast cancer, but their effect on short and long-term kidney function is unknown. We found that early, mild estimated glomerular filtration rate (eGFR) decline was common in patients treated with CDK 4/6 inhibitors; however, severe kidney injury is rare and long-term eGFR decline is uncommon

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia >= 1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia >= 10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV >= 10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia >= 10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring

One-Year Outcomes of the Multi-Center StudY to Transplant Hepatitis C-InfeCted kidneys (MYTHIC) Trial

Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to “standard-of-care” at many centers. Nevertheless, most data derive from single centers and provide only short-term follow-up. The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival. Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range [IQR]: 1.02–1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor. The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726 [Display omitted

Acute kidney injury in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. 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. 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. 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