Nephrotic syndrome is associated with increased plasma K+ concentration, intestinal K+ losses, and attenuated urinary K+ excretion: a study in rats and humans.

The present study tested the hypotheses that nephrotic syndrome (NS) leads to renal K+ loss because of augmented epithelial Na+ channel (ENaC) activity followed by downregulation of renal K+ secretory pathways by suppressed aldosterone. The hypotheses were addressed by determining K+ balance and kidney abundance of K+ and Na+ transporter proteins in puromycin aminonucleoside (PAN)-induced rat nephrosis. The effects of amiloride and angiotensin II type 1 receptor and mineralocorticoid receptor (MR) antagonists were tested. Glucocorticoid-dependent MR activation was tested by suppression of endogenous glucocorticoid with dexamethasone. Urine and plasma samples were obtained from pediatric patients with NS in acute and remission phases. PAN-induced nephrotic rats had ENaC-dependent Na+ retention and displayed lower renal K+ excretion but elevated intestinal K+ secretion that resulted in less cumulated K+ in NS. Aldosterone was suppressed at day 8. The NS-associated changes in intestinal, but not renal, K+ handling responded to suppression of corticosterone, whereas angiotensin II type 1 receptor and MR blockers and amiloride had no effect on urine K+ excretion during NS. In PAN-induced nephrosis, kidney protein abundance of the renal outer medullary K+ channel and γ-ENaC were unchanged, whereas the Na+-Cl- cotransporter was suppressed and Na+-K+-ATPase increased. Pediatric patients with acute NS displayed suppressed urine Na+-to-K+ ratios compared with remission and elevated plasma K+ concentration, whereas fractional K+ excretion did not differ. Acute NS is associated with less cumulated K+ in a rat model, whereas patients with acute NS have elevated plasma K+ and normal renal fractional K+ excretion. In NS rats, K+ balance is not coupled to ENaC activity but results from opposite changes in renal and fecal K+ excretion with a contribution from corticosteroid MR-driven colonic secretion.

An evaluation of phase angle, bioelectrical impedance vector analysis and impedance ratio for the assessment of disease status in children with nephrotic syndrome.

BACKGROUND: Oedema, characterized by accumulation of extracellular water (ECW), is one of the major clinical manifestations in children suffering from nephrotic syndrome (NS). The lack of a simple, inexpensive and harmless method for assessing ECW may be solved by the use of the bioelectrical impedance analysis (BIA) technique. The aims of this study were to examine whether phase angle (PA), bioelectrical impedance vector analysis (BIVA) and the impedance ratio (IR) reflect change in disease status in children with NS. METHODS: Eight children (age range: 2-10 years) with active NS (ANS group) were enrolled. In five of these (ANS* subgroup), impedance was also measured at remission (NSR group). Thirty-eight healthy children (age range: 2-10 years) were included as healthy controls (HC group). Whole-body impedance was measured with a bioimpedance spectroscopy device (Xitron 4200) with surface electrodes placed on the wrist and ankle. RESULTS: Values of PA, BIVA and IR were found to be significantly lower (p-value range < 0.001 to < 0.01) in the ANS patients compared to the HC and NSR groups. No significant differences were observed between the NSR and HC groups. CONCLUSION: The studied parameters can be used to assess change in disease status in NS patients. Data were consistent with NS being associated with expansion of ECW.

Acute intravenous acyl ghrelin infusion induces thirst but does not affect sodium excretion: two randomized, double-blind, placebo-controlled crossover studies in hypopituitary patients.

OBJECTIVE: Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies. The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients. DESIGN: Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double-blind and placebo-controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analog Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis and urinary excretion of sodium and creatinine were measured. RESULTS: In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time × treatment analysis of variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water. CONCLUSIONS: We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

Childhood onset steroid-sensitive nephrotic syndrome continues into adulthood.

BACKGROUND: Childhood steroid-sensitive nephrotic syndrome (SSNS) has previously been assumed to be a disease of childhood. This has been challenged by few studies reporting that some patients with childhood SSNS may continue to relapse into adulthood. The aim of this study was to investigate the long-term outcome of childhood SSNS presenting data from an unselected well-defined cohort of Danish patients. METHODS: We conducted a retrospective study of the clinical outcome from a population of patients consecutively admitted to the pediatric departments in the central and northern region of Denmark from 1998 to 2015. Patients were followed until August 2017. Data were collected from the patient's medical records. RESULTS: Long-term outcome was studied in 39 adult patients with childhood onset SSNS. A total of 31% (12/39) had active disease in adulthood. Univariate analysis showed that more severe forms of SSNS (e.g., steroid dependent/frequent relapsing (SD/FR) nephrotic syndrome) in childhood were associated with active disease in adulthood. Comparing adult patients with SD/FR showed a significantly higher number of relapses/patient/year from late childhood and adolescence in the group with active disease vs. non-active disease (1.06 (95%CI: 0.32-1.81) vs. 0.19 (95%CI: 0.06-0.31, p = 0.005). CONCLUSION: In general, one third of all patients with SSNS during childhood continue to have active disease during early adulthood, in particular patients with SD/FR continue to suffer from active disease. The present data illustrates that SSNS is not just a disease of childhood but persists in adulthood in a significant number of patients.

Plasma and urine proteomic profiles in childhood idiopathic nephrotic syndrome.

PURPOSE: Idiopathic nephrotic syndrome (NS) is characterized by proteinuria, edema, and hypoalbuminemia. The aim of the study was to identify differentially expressed proteins in urine and plasma during NS compared with remission. EXPERIMENTAL DESIGN: Plasma and urine samples were collected during NS and at remission. Proteomic profiling was performed by iTRAQ labeling followed by nano-LC-MS/MS to yield data on relative protein amounts. Protein validation was performed by ELISA. RESULTS: A total of 388 and 425 proteins were detected in plasma and urine, respectively. In total, 18 plasma and 38 urinary proteins were significantly altered (p <0.05). E-cadherin was one of the proteins with reduced urinary concentration during NS, a finding validated by ELISA. The slit diaphragm protein P-cadherin was identified by nano-LC-MS/MS and shown to be reduced in urine during NS by ELISA. CONCLUSIONS AND CLINICAL RELEVANCE: The present study identified more than 50 differentially altered proteins comparing NS with remission. Several proteins were found to be linked to the major clinical symptoms of NS, and further studies must elucidate if P-cadherin is involved in proteinuria during NS, and if low urinary E-cadherin level is linked to altered epithelial cell to cell contact in the distal part of the nephron.

Reduced anti-diuretic response to desmopressin during wet nights in patients with monosymptomatic nocturnal enuresis.

OBJECTIVE: To investigate why not all children with monosymptomatic nocturnal enuresis (MNE) treated with desmopressin give an adequate response. MATERIALS AND METHODS: We included 114 children with MNE aged 5-15 years (9.8 ± 0.2 years) who experienced at least 1 wet night and more than 2 dry nights during desmopressin treatment. The patients made home recordings for 2 weeks as baseline and for 2-4 weeks of desmopressin titration. Nocturnal urine production during wet and dry nights, and maximum voided volumes (MVVs) were documented in all patients. RESULTS: Sixty-four patients were desmopressin non-responders, 29 were either partial responders or responders, while 21 patients were full responders. Desmopressin reduced nocturnal urine production dramatically during dry nights compared with pre-treatment wet nights. Nocturnal urine production during desmopressin treatment was significantly greater during wet nights compared to dry nights (243 ± 9.32 vs 176 ± 5.31 ml, P < 0.001). There was a highly significant correlation between individual nocturnal urine output and MVV, and dry nights were characterized by nocturnal urine output/MVV ratios well below 1.0. CONCLUSION: The anti-enuretic response to desmopressin seems to be dependent upon the degree of reduction in nocturnal urine production. Research on desmopressin bioavailability in children is needed.

Early age at debut is a predictor of steroid-dependent and frequent relapsing nephrotic syndrome.

The purpose of this study was to identify characteristics of patients with steroid-sensitive nephrotic syndrome (SSNS) that point to a high risk of frequent relapsing (FR) or steroid-dependent (SD) SSNS. A retrospective analysis of 54 consecutive patients with SSNS was performed. In this cohort, the incidence of idiopathic NS was 1.9/100,000, age at debut was 5.5 years, and the mean follow-up was 4.0 years. A total of 56% (30/54) of our patients were classified with FR/SD SSNS. FR/SD patients were significantly younger at debut than non-FR/SD patients (3.5 vs. 8.5 years, respectively; p < 0.002). Males were overrepresented in the FR/SD group (69 vs. 38%; p = 0.03). No differences were found in terms of haematuria, hypoalbuminaemia, or days to achieve remission. In total, 31 and 23 patients were on a 6 + 6-week (pred-long) and 4 + 4-week (pred-short) steroid treatment regimen, respectively. There was a reduction in the number of FR/SD patients in the pred-long group relative to the pred-short group (38 vs. 80%, respectively). In the pred-long group, the 12 FR/SD patients were younger than the 19 non-FR/SD patients (4.4 +/- 3.1 vs. 8.4 +/- 4.1 years; p<0.005). Low age at debut and male gender was associated with a high risk of SD/FR in this unselected series of SSNS patients despite the prolongation of the steroid course at debut of SSNS.