Arginine Depletion Attenuates Renal Cystogenesis in Tuberous Sclerosis Complex Model

Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in mice, indicating the potential therapeutic effects of arginine deprivation for the treatment of TSC-associated kidney disease

Acute Kidney Injury in Very Low Birth Weight Infants: A Major Morbidity and Mortality Risk Factor

Background and objectives: Very low birth weight (VLBW) infants are at high risk of developing acute kidney injury (AKI), presumably secondary to low kidney reserves, stressful postnatal events, and drug exposures. Our study aimed to identify the prevalence, risk factors, and outcomes associated with AKI in VLBW infants. Study design: Records of all VLBW infants admitted to two medical campuses between January 2019 and June 2020 were retrospectively reviewed. AKI was classified using the modified KDIGO definition to include only serum creatinine. Risk factors and composite outcomes were compared between infants with and without AKI. We evaluated the main predictors of AKI and death with forward stepwise regression analysis. Results: 152 VLBW infants were enrolled. 21% of them developed AKI. Based on the multivariable analysis, the most significant predictors of AKI were the use of vasopressors, patent ductus arteriosus, and bloodstream infection. AKI had a strong and independent association with neonatal mortality. Conclusions: AKI is common in VLBW infants and is a significant risk factor for mortality. Efforts to prevent AKI are necessary to prevent its harmful effects

Acute Kidney Injury in Very Low Birth Weight Infants: A Major Morbidity and Mortality Risk Factor

Background and objectives: Very low birth weight (VLBW) infants are at high risk of developing acute kidney injury (AKI), presumably secondary to low kidney reserves, stressful postnatal events, and drug exposures. Our study aimed to identify the prevalence, risk factors, and outcomes associated with AKI in VLBW infants. Study design: Records of all VLBW infants admitted to two medical campuses between January 2019 and June 2020 were retrospectively reviewed. AKI was classified using the modified KDIGO definition to include only serum creatinine. Risk factors and composite outcomes were compared between infants with and without AKI. We evaluated the main predictors of AKI and death with forward stepwise regression analysis. Results: 152 VLBW infants were enrolled. 21% of them developed AKI. Based on the multivariable analysis, the most significant predictors of AKI were the use of vasopressors, patent ductus arteriosus, and bloodstream infection. AKI had a strong and independent association with neonatal mortality. Conclusions: AKI is common in VLBW infants and is a significant risk factor for mortality. Efforts to prevent AKI are necessary to prevent its harmful effects

Molecular Mechanisms of Parathyroid Disorders in Chronic Kidney Disease

Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that induces morbidity and mortality in patients. How CKD stimulates the parathyroid to increase parathyroid hormone (PTH) secretion, gene expression and cell proliferation remains an open question. In experimental SHP, the increased PTH gene expression is post-transcriptional and mediated by PTH mRNA–protein interactions that promote PTH mRNA stability. These interactions are orchestrated by the isomerase Pin1. Pin1 participates in conformational change-based regulation of target proteins, including mRNA-binding proteins. In SHP, Pin1 isomerase activity is decreased, and thus, the Pin1 target and PTH mRNA destabilizing protein KSRP fails to bind PTH mRNA, increasing PTH mRNA stability and levels. An additional level of post-transcriptional regulation is mediated by microRNA (miRNA). Mice with parathyroid-specific knockout of Dicer, which facilitates the final step in miRNA maturation, lack parathyroid miRNAs but have normal PTH and calcium levels. Surprisingly, these mice fail to increase serum PTH in response to hypocalcemia or uremia, indicating a role for miRNAs in parathyroid stimulation. SHP often leads to parathyroid hyperplasia. Reduced expressions of parathyroid regulating receptors, activation of transforming growth factor α-epidermal growth factor receptor, cyclooxygenase 2-prostaglandin E2 and mTOR signaling all contribute to the enhanced parathyroid cell proliferation. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. This review summarizes the current knowledge on the mechanisms that stimulate the parathyroid cell at multiple levels in SHP

Hamartin regulates cessation of mouse nephrogenesis independently of Mtor

Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one Tsc1 allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both Tsc1 al-leles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor

Kidney biopsy findings in children with sickle cell disease: a Midwest Pediatric Nephrology Consortium study

Renal damage is a progressive complication of sickle cell disease (SCD). Microalbuminuria is common in children with SCD, while a smaller number of children have more severe renal manifestations necessitating kidney biopsy. There is limited information on renal biopsy findings in children with SCD and subsequent management and outcome. This is a multicenter retrospective analysis of renal biopsy findings and clinical outcomes in children and adolescents with SCD. We included children and adolescents (age ≤ 20 years) with SCD who had a kidney biopsy performed at a pediatric nephrology unit. The clinical indication for biopsy, biopsy findings, subsequent treatments, and outcomes were analyzed. Thirty-six SCD patients (ages 4-19 years) were identified from 14 centers with a median follow-up of 2.6 years (0.4-10.4 years). The indications for biopsy were proteinuria (92%) and elevated creatinine (30%). All biopsies had abnormal findings, including mesangial hypercellularity (75%), focal segmental glomerulosclerosis (30%), membranoproliferative glomerulonephritis (16%), and thrombotic microangiopathy (2%). There was increased use of hydroxyurea, angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers following renal biopsy. At last follow-up, 3 patients were deceased, 2 developed insulin-dependent diabetes mellitus, 6 initiated chronic hemodialysis, 1 received a bone marrow transplant, and 1 received a kidney transplant. Renal biopsies, while not commonly performed in children with SCD, were universally abnormal. Outcomes were poor in this cohort of patients despite a variety of post-biopsy interventions. Effective early intervention to prevent chronic kidney disease (CKD) is needed to reduce morbidity and mortality in children with SCD