Coding variants (named G1 and G2) in Apolipoprotein L1 (APOL1) can explain most excess risk of kidney disease observed in African American individuals. It has been proposed that risk variant APOL1 dose, such as increased risk variant APOL1 level serves as a trigger (second hit) for disease development. The goal of this study was to determine whether lowering risk variant APOL1 levels protects from disease development in a podocyte-specific transgenic mouse disease model. We administered antisense oligonucleotides (ASO) targeting APOL1 to podocyte-specific G2APOL1 mice and observed efficient reduction of APOL1 levels. APOL1 ASO1, which more efficiently lowered APOL1 transcript levels, protected mice from albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and renal failure. Administration of APOL1 ASO1 was effective even for established disease in the NEFTA-rtTA/TRE-G2APOL1 (NEFTA/G2APOL1) mice. We observed a strong correlation between APOL1 transcript level and disease severity. We concluded that APOL1 ASO1 may be an effective therapeutic approach for APOL1-associated glomerular disease.

Background Chronic kidney disease (CKD) causes progressive and irreversible damage to the kidneys. Renal biopsies are essential for diagnosing the etiology and prognosis of CKD, while accurate quantification of tubulo-interstitial injuries from whole slide images (WSIs) of renal biopsy specimens is challenging with visual inspection alone. Methods We develop a deep learning-based method named DLRS to quantify interstitial fibrosis and inflammatory cell infiltration as tubulo-interstitial injury scores, from WSIs of renal biopsy specimens. DLRS segments WSIs into non-tissue areas, glomeruli, tubules, interstitium, and arteries, and detects interstitial nuclei. It then quantifies these tubulo-interstitial injury scores using the segmented tissues and detected nuclei. Results Applied to WSIs from 71 Japanese CKD patients with diabetic nephropathy or benign nephrosclerosis, DLRS-derived scores show concordance with nephrologists’ evaluations. Notably, the DLRS-derived fibrosis score has a higher correlation with the estimated glomerular filtration rate (eGFR) at biopsy than scores from nephrologists’ evaluations. Validated on WSIs from 28 Japanese tubulointerstitial nephritis patients and 49 European-ancestry patients with nephrosclerosis, DLRS-derived scores show a significant correlation with eGFR. In an expanded analysis of 238 Japanese CKD patients, including 167 from another hospital, deviations in eGFR from expected values based on DLRS-derived scores correlate with annual eGFR decline after biopsy. Inclusion of these deviations and DLRS-derived fibrosis scores improve predictions of the annual eGFR decline. Conclusions DLRS-derived tubulo-interstitial injury scores are concordant with nephrologists’ evaluations and correlated with eGFR across different populations and institutions. The effectiveness of DLRS-derived scores for predicting annual eGFR decline highlights the potential of DLRS as a predictor of renal prognosis.

Background: Urinary albumin excretion (UAE) is a risk factor for cardiovascular diseases, metabolic syndrome, chronic kidney disease, etc. Only a few genome-wide association studies (GWAS) for UAE have been conducted in the European population, but not in the Asian population. Here we conducted GWAS and identified several candidate genes harboring single nucleotide polymorphisms (SNPs) responsible for UAE in the Japanese population. Methods: We conducted GWAS for UAE in 7805 individuals of Asian ancestry from health-survey data collected by Tohoku Medical Megabank Organization (ToMMo) and Iwate Tohoku Medical Megabank Organization (IMM). The SNP genotype data were obtained with a SNP microarray. After imputation using a haplotype panel consisting of 2000 genome sequencing, 4,962,728 SNP markers were used for the GWAS. Results: Eighteen SNPs at 14 loci (GRM7, EXOC1/NMU, LPA, STEAP1B/RAPGEF5, SEMA3D, PRKAG2, TRIQK, SERTM1, TPT1-AS1, OR5AU1, TSHR, FMN1/RYR3, COPRS, and BRD1) were associated with UAE in the Japanese individuals. A locus with particularly strong associations was observed on TSHR, chromosome 14 [rs116622332 (p = 3.99 × 10⁻¹⁰)]. Conclusion: In this study, we successfully identified UAE-associated variant loci in the Japanese population. Further study is required to confirm this association.

The authors report a case of a 43-year-old woman who presented with second degree chemical burns to 9% of the total body surface area due to cutaneous contact with cresol. This was associated with acute oliguric kidney injury requiring haemodialysis. In contrast to previous reports of cresol ingestion, the patient did not have evidence of hepatic dysfunction, possibly due to a low cresol concentration in the portal vein and liver. Renal histopathology showed regional accentuated tubular necrosis and disruption of the tubular basement membrane. Renal toxicity was thought to be due to direct tubular toxicity and impaired renal blood flow.