Growth hormone in pediatric chronic kidney disease: more than just height.

Recombinant human growth hormone therapy, which was introduced in the 1980s, is now routine for children with advanced chronic kidney disease (CKD) who are exhibiting growth impairment. Growth hormone usage remains variable across different centers, with some showing low uptake. Much of the focus on growth hormone supplementation has been on increasing height because of social and psychological effects of short stature. There are, however, numerous other changes that occur in CKD that have not received as much attention but are biologically important for pediatric growth and development. This article reviews the current knowledge about the multisystem effects of growth hormone therapy in pediatric patients with CKD and highlights areas where additional clinical research is needed. We also included clinical data on children and adults who had received growth hormone for other indications apart from CKD. Ultimately, having robust clinical studies which examine these effects will allow children and their families to make more informed decisions about this therapy.

The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort.

INTRODUCTION: Although diabetic kidney disease (DKD) is responsible for more than half of all chronic and end-stage kidney disease (ESKD), the association of light (LM) and electron microscopic (EM) structural changes with clinical parameters and prognosis in DKD is incompletely understood. METHODS: This is an interim analysis of 62 patients diagnosed with biopsy-confirmed DKD from the multicenter TRIDENT (Transformative Research in Diabetic Nephropathy) study. Twelve LM and 8 EM descriptors, representing changes in glomeruli, tubulointerstitium, and vasculature were analyzed for their relationship with clinical measures of renal function. Patients were followed every 6 months. RESULTS: Multivariable linear regression analysis revealed that estimated glomerular filtration rate (eGFR) upon enrollment correlated the best with interstitial fibrosis. On the other hand, the rate of kidney function decline (eGFR slope) correlated the most with glomerular lesions including global glomerulosclerosis and mesangiolysis. Unbiased clustering analysis based on histopathologic data identified 3 subgroups. The first cluster, encompassing subjects with the mildest histologic lesions, had the most preserved kidney function. The second and third clusters had similar degrees of kidney dysfunction and structural damage, but differed in the degree of glomerular epithelial cell and podocyte injury (podocytopathy DKD subtype). Cox proportional hazard analysis showed that subjects in cluster 2 had the highest risk to reach ESKD (hazard ratio: 17.89; 95% confidence interval: 2.13-149.79). Glomerular epithelial hyperplasia and interstitial fibrosis were significant predictors of ESKD in the multivariate model. CONCLUSION: The study highlights the association between fibrosis and kidney function and identifies the role of glomerular epithelial changes and kidney function decline.

Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney.

BACKGROUND: Microscopic analysis of urine sediment is probably the most commonly used diagnostic procedure in nephrology. The urinary cells, however, have not yet undergone careful unbiased characterization. METHODS: Single-cell transcriptomic analysis was performed on 17 urine samples obtained from five subjects at two different occasions, using both spot and 24-hour urine collection. A pooled urine sample from multiple healthy individuals served as a reference control. In total 23,082 cells were analyzed. Urinary cells were compared with human kidney and human bladder datasets to understand similarities and differences among the observed cell types. RESULTS: Almost all kidney cell types can be identified in urine, such as podocyte, proximal tubule, loop of Henle, and collecting duct, in addition to macrophages, lymphocytes, and bladder cells. The urinary cell-type composition was subject specific and reasonably stable using different collection methods and over time. Urinary cells clustered with kidney and bladder cells, such as urinary podocytes with kidney podocytes, and principal cells of the kidney and urine, indicating their similarities in gene expression. CONCLUSIONS: A reference dataset for cells in human urine was generated. Single-cell transcriptomics enables detection and quantification of almost all types of cells in the kidney and urinary tract.

Unravelling the complex genetics of common kidney diseases: from variants to mechanisms.

Genome-wide association studies (GWAS) have identified hundreds of loci associated with kidney-related traits such as glomerular filtration rate, albuminuria, hypertension, electrolyte and metabolite levels. However, these impressive, large-scale mapping approaches have not always translated into an improved understanding of disease or development of novel therapeutics. GWAS have several important limitations. Nearly all disease-associated risk loci are located in the non-coding region of the genome and therefore, their target genes, affected cell types and regulatory mechanisms remain unknown. Genome-scale approaches can be used to identify associations between DNA sequence variants and changes in gene expression (quantified through bulk and single-cell methods), gene regulation and other molecular quantitative trait studies, such as chromatin accessibility, DNA methylation, protein expression and metabolite levels. Data obtained through these approaches, used in combination with robust computational methods, can deliver robust mechanistic inferences for translational exploitation. Understanding the genetic basis of common kidney diseases means having a comprehensive picture of the genes that have a causal role in disease development and progression, of the cells, tissues and organs in which these genes act to affect the disease, of the cellular pathways and mechanisms that drive disease, and of potential targets for disease prevention, detection and therapy.

Ethnic/racial determinants of glycemic markers in a UK sample.

OBJECTIVE: To investigate possible causes for previously reported glycemia-independent South Asian-white differences in HbA1c. METHODS: Demographic and laboratory data on non-diabetic patients from primary care were analyzed. Linear regression models measured the association between race/ethnicity and three glycemic measures (HbA1c, fructosamine and fasting plasma glucose), adjusted for a range of hematological, biochemical and demographic factors. RESULTS: Nine hundred and forty-eight patients consisting of 711 white subjects (407 women) and 237 South Asian subjects (138 women) were studied. Unadjusted bivariate analysis showed that South Asians had higher HbA1c concentrations [41 (5.9 %) vs. 40 (5.8 %) mmol/mol (p = 0.011), coefficient 1.21, 95 % CI 0.27, 2.17 (p = 0.011)] similar fructosamine [228.4 vs. 226.7 mmol/L (p = 0.352), coefficient 3.93, 95 % CI 0.79, 7.08 (p = 0.014)] and fasting plasma glucose [5.1 vs. 5.2 mmol/L (p = 0.154), coefficient -0.09, 95 % CI -0.22, -0.04 (p = 0.156)] concentrations than whites. South Asians also had lower hemoglobin, ferritin and vitamin B12 concentrations than whites. After adjustment for independent variables, South Asian ethnicity was associated with higher HbA1c concentrations [0.89, 95 % CI 0.06-1.72 (p = 0.035)], higher fructosamine levels [3.93, 95 % CI 0.79, 7.08 (p = 0.014)] and lower fasting plasma glucose concentrations [-0.12, 95 % CI -0.26, -0.02 (p = 0.026)] compared to white race. CONCLUSIONS: The increased prevalence of hematological abnormalities in South Asians and their higher adjusted HbA1c and fructosamine but lower fasting glucose levels compared to white subjects suggest that ethnic differences in glycation markers may, in part, be due to a combination of erythrocyte factors and glycemia-independent glycation.