Single-Nucleus RNA Sequencing Identifies New Classes of Proximal Tubular Epithelial Cells in Kidney Fibrosis.

BACKGROUND: Proximal tubular cells (PTCs) are the most abundant cell type in the kidney. PTCs are central to normal kidney function and to regeneration versus organ fibrosis following injury. This study used single-nucleus RNA sequencing (snRNAseq) to describe the phenotype of PTCs in renal fibrosis. METHODS: Kidneys were harvested from naïve mice and from mice with renal fibrosis induced by chronic aristolochic acid administration. Nuclei were isolated using Nuclei EZ Lysis buffer. Libraries were prepared on the 10× platform, and snRNAseq was completed using the Illumina NextSeq 550 System. Genome mapping was carried out with high-performance computing. RESULTS: A total of 23,885 nuclei were analyzed. PTCs were found in five abundant clusters, mapping to S1, S1-S2, S2, S2-cortical S3, and medullary S3 segments. Additional cell clusters ("new PTC clusters") were at low abundance in normal kidney and in increased number in kidneys undergoing regeneration/fibrosis following injury. These clusters exhibited clear molecular phenotypes, permitting labeling as proliferating, New-PT1, New-PT2, and (present only following injury) New-PT3. Each cluster exhibited a unique gene expression signature, including multiple genes previously associated with renal injury response and fibrosis progression. Comprehensive pathway analyses revealed metabolic reprogramming, enrichment of cellular communication and cell motility, and various immune activations in new PTC clusters. In ligand-receptor analysis, new PTC clusters promoted fibrotic signaling to fibroblasts and inflammatory activation to macrophages. CONCLUSIONS: These data identify unrecognized PTC phenotype heterogeneity and reveal novel PTCs associated with kidney fibrosis.

The impact of acute kidney injury in diabetes mellitus.

BACKGROUND: Little data exist on outcome of acute kidney injury (AKI) in diabetes. We describe short-term recovery of renal function, patient mortality and progressive renal dysfunction following AKI in diabetic patients. METHODS: Using the diagnosis of either diabetes or no diabetes as the defining variable, AKI episodes were identified from records of a clinical biochemistry department serving a population of 560 000. Patient co-morbidity and mortality were collated from electronic patient records. Outcomes were compared with a non-diabetic cohort with AKI. RESULTS: Acute kidney injury was identified in 101 diabetic and 392 non-diabetic patients. Patients with diabetes had less severe AKI, compared with the non-diabetic cohort (AKI stage 1 76% vs 55%, P = 0.0006). Overall acute mortality, and mortality adjusted for co-morbidity, was comparable in the diabetic and non-diabetic groups. Recovery to baseline renal function was greater in diabetic patients (87% vs 63% P = 0.001), and the proportion of patients developing progressive chronic kidney disease was lower in the (14%) compared with the non-diabetic cohort (48%, P < 0.00001). CONCLUSIONS: Although acute mortality is comparable following an AKI episode in diabetic patients compared with that associated with AKI in a non-diabetic cohort, for those surviving the acute episode, its impact on renal function is significantly less than in a non-diabetic group.

Epidemiology and outcomes in community-acquired versus hospital-acquired AKI.

BACKGROUND AND OBJECTIVE: Compared with AKI in hospitalized patients, little is known about patients sustaining AKI in the community and how this differs from AKI in hospital. This study compared epidemiology, risk factors, and short- and long-term outcomes for patients with community-acquired (CA) and hospital-acquired (HA) AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 15,976 patients admitted to two district general hospitals between July 11, 2011, and January 15, 2012 were studied. Through use of an electronic database and the AKI Network classification, 686 patients with CA-AKI and 334 patients with HA-AKI were identified. Patients were followed up for 14 months, and data were collated on short-term and long-term renal and patient outcomes. RESULTS: The incidence of CA-AKI among all hospital admissions was 4.3% compared with an incidence of 2.1% of HA-AKI, giving an overall AKI incidence of 6.4%. Patients with CA-AKI were younger than patients with HA-AKI. Risks for developing HA and CA-AKI were similar and included preexisting CKD, cardiac failure, ischemic heart disease, hypertension, diabetes, dementia, and cancer. Patients with CA-AKI were more likely to have stage 3 AKI and had shorter lengths of hospital stay than patients with HA-AKI. Those with CA-AKI had better (multivariate-adjusted) survival than patients with HA-AKI (hazard ratio, 1.8 [95% CI, 1.44-2.13; P<0.001] for HA-AKI group). Mortality for the CA-AKI group was 45%; 43.7% of these deaths were acute in-hospital deaths. Mortality for the HA-AKI group was 62.9%, with 68.1% of these deaths being acute in-hospital deaths. Renal referral rates were low across the cohorts (8.3%). Renal outcomes were similar in both CA-AKI and HA-AKI groups, with 39.4% and 33.6% of patients in both groups developing de novo CKD or progression of preexisting CKD within 14 months, respectively. CONCLUSION: Patients with CA-AKI sustain more severe AKI than patients with HA-AKI. Despite having risk factors similar to those of patients with HA-AKI, patients with CA AKI have better short- and long-term outcomes.

Epidemiology and outcome of community-acquired acute kidney injury.

AIMS: Very little data exist regarding community-acquired acute renal injury (CA-AKI). We have identified and characterized a patient cohort with CA-AKI, and documented its impact on renal function and patient mortality. METHODS: Using the database of the Medical Biochemistry Department of the Cardiff and Vale University Health Board we identified all patients with CA-AKI over a 1 month period in 2009. Follow-up biochemical and clinical data were used to determine short-term (3 months) and long-term (3 years) outcomes. Comparisons were made to a random and an age/sex matched group. RESULTS: Patients with CA-AKI were older than a non-AKI cohort (70.3 vs 57.1 years; P < 0.0001), with a 61% male predominance. 38% had pre-existing chronic kidney disease (CKD) compared with 25% in the age- and sex-matched non-CA-AKI cohort (P = 0.007). 54% of CA-AKI were admitted for inpatient care. Admission was associated with a higher incidence of complete recovery of renal function. Mortality at 3 months was 16.5%, and was related to the severity of AKI. Over the 3 years of follow-up 71% of patients with CA-AKI developed progressive CKD which was more likely following incomplete/no recovery of renal function and in the context of pre-existing CKD. Three year mortality was 45%, which was higher than that of the age/sex matched control cohort (15.7%; P < 0.0001), but was not related to the development of progressive CKD. CONCLUSIONS: CA-AKI carries significant implications in terms of both development of progressive renal disease and high long-term patient mortality.

Newborn retinal hemorrhages: a systematic review.

PURPOSE: To systematically review the characteristics, prevalence, evolution, and obstetric associations of retinal hemorrhages (RH) in newborns. METHODS: A systematic review, searching 10 databases (1970-2011), identified 45 studies, which underwent two independent reviews via the use of standardized critical appraisal. Studies meeting the following criteria were included: examination by an ophthalmologist, use indirect ophthalmoscopy, and first examination conducted within 96 hours of birth and before hospital discharge. RESULTS: Thirteen studies were included, representing 1,777 infants. The studies revealed that 25.6% of newborns born via spontaneous vaginal deliveries had RH. In contrast, infants delivered by vacuum extraction had a 42.6% rate of RH (OR, 2.75; 95% CI, 1.32-5.70), and infants delivered by double-instrument deliveries (forceps and vacuum) had a 52% rate of RH (OR, 3.27; 95% CI, 1.68-6.36). The hemorrhages are commonly bilateral (59%), of varying severity, from "mild" (22%-56%) to "severe" (18%-37%), and predominantly intraretinal and in the posterior pole. The majority of RH (83%) resolved within 10 days; isolated cases persisted to 58 days. CONCLUSIONS: Birth-related RH in infants occurs in one-quarter of normal deliveries and are far more common after instrumental deliveries. Commonly bilateral, they were predominantly intraretinal, posterior, resolved rapidly, and very rarely persisted beyond 6 weeks.