Prematurity and perinatal stress, such as intrauterine growth restriction (IUGR) and chorioamnionitis, are pathological processes creating an impaired intrauterine environment. These intrauterine factors are associated with the development of proteinuria, hypertension, and chronic kidney disease (CKD) later in life. Initially, this was thought to be secondary to oligonephropathy, subsequent glomerular hypertrophy, and hyperfiltration, leading to glomerulosclerosis, a further decrease in nephron number, and finally CKD. Nowadays, there is increasing evidence that prematurity and perinatal stress affect not only nephron endowment but also the maturation of podocytes and vasculogenesis. IUGR is associated with podocyte damage and an aggravated course of nephrotic syndrome. Moreover, preterm birth and IUGR are known to cause upregulation of the postnatal reninangiotensin system, resulting in hypertension. Chorioamnionitis causes damage to the glomeruli, thereby predisposing to the development of glomerulosclerosis. This review aims to summarize current knowledge on the influence of prematurity, IUGR, and chorioamnionitis on the development of different glomerular structures. After summarizing human and experimental data on low nephron number in general, a specific focus on the current understanding of podocyte and glomerular capillary formation in relation to prematurity and different causes of perinatal stress is presented.

Objective: In most cases of renovascular hypertension in children, the etiology is unclear. The aim of this study was to investigate genetic variation as a factor in the development of renovascular hypertension in children. Methods: In a cohort of 37 unrelated children from a single tertiary referral center, exome sequencing was performed. We assessed variants in recognized and suspected disease genes and searched for novel ones with a gene-based variantburden analysis. Results: In the majority of patients, exome sequencing could not identify causative variants. We found a pathogenic variant in a recognized associated disease gene in five patients (three pathogenic variants in NF1, one in ELN and a deletion of chromosome 7q11.23, consistent with Williams Syndrome). In two other patients, (likely) pathogenic variants were found in putative renovascular hypertension genes (SMAD6 and GLA), with clinical implications for both. Ten additional patients carried variants of uncertain significance (VUS) in known (n=4) or putative (n=6) renovascular hypertension disease genes. Rare variant burden analysis yielded no further candidate genes. Conclusions: Genetic contributors, such as germline mutations in NF1, ELN, 7q11.23del were present in only 5 out of 37 (14%) children with renovascular hypertension. Twelve other children (32%) had potentially causal variants identified, including a pathogenic variant in SMAD6; a vasculopathy gene hitherto unknown to link with renovascular hypertension. Most importantly, our data show that exome sequencing can rarely identify the cause of renovascular hypertension in nonsyndromic children. We suggest that non-genetic factors or somatic genetic variation will play a more important role.

Background Levamisole is frequently used as a steroid-sparing agent in children with steroid-sensitive nephrotic syndrome. Side effects, such as neutropenia, gastro-intestinal upset and skin rash, have been reported. We noted an increase in creatinine in some of our patients, but literature on the effect of levamisole on kidney function is lacking. Methods A retrospective cohort study was conducted, including patients 1–18 years of age, treated for steroid-sensitive nephrotic syndrome with levamisole at Great Ormond Street Hospital for Children between January 2010 and January 2020. Data was collected on clinical observations and serum creatinine values before, during and after treatment. eGFR was calculated using the Schwartz equation. Results In total, 75 children were included in the analysis. The median duration of treatment was 19 (IQR 12–27) months. The median estimated GFR was 134 (IQR 119–160), 101 (IQR 91–113) and 116 (IQR 106–153) ml/min/1.73 m2, respectively, before, during and after treatment with levamisole. The difference between eGFR before and after treatment compared with during treatment was statically significant (P < 0.0001). During the treatment period, the eGFR decrease was not progressive. The median levamisole dose was 2.5 (IQR 2.3–2.6) mg/kg on alternate days, and the dose was not correlated with the decrease in eGFR (r = 0.07, 95% CI − 0.22 to 0.35). Conclusion Levamisole significantly decreases eGFR. However, this decrease is not progressive or irreversible and would not be an indication to discontinue the treatment.