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Objective: To determine the effects of low-dose dopamine on urine output (UOP) in very low birth weight premature neonates., Study Design: Retrospective cohort study of all low-dose (3-5 μg kg(-1) per min) dopamine infusions >24-h duration in neonates 1500 g and 32 weeks gestation from August 2009 through September 2011. Linear regression was used to estimate the impact of covariates on UOP., Result: We identified 91 episodes of low-dose dopamine use in 65 neonates. Increased UOP occurred in 64% of episodes. Low-dose dopamine use was associated with a 0.6 ml kg(-1) h(-1) increase in UOP (P<0.001) and a 1.3 ml kg(-1)h(-1) increase when baseline UOP was <1.5 ml kg(-1) h(-1) (P<0.001). The improvement remained statistically significant after controlling for medications (diuretics and hydrocortisone) and fluid intake., Conclusion: Low-dose dopamine use was associated with increased UOP in very low birth weight neonates.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

The administration of growth hormone (GH) in conjunction with calcitriol in uremia may increase urinary calcium and decrease renal phosphate excretion, which could have an adverse effect on the kidney in chronic renal insufficiency. The effect of 40 d of ovine GH, calcitriol, and the combination of GH and calcitriol on mineral excretion was studied in rapidly growing uremic rats. Uremia was produced by 75% nephrectomy, and the animals were fed a diet containing 8% protein with equal quantities of calcium (0.6%) and phosphate (0.6%). The uremic rats treated with ovine GH were significantly longer and heavier than the uremic control rats and the uremic rats treated with calcitriol alone. However, the combination of calcitriol and GH abolished the beneficial effect of GH on growth and increased urinary calcium excretion 4-fold over uremic controls whether expressed as calcium excretion per 100 g body weight, urine calcium to creatinine ratio, or as fractional calcium excretion. Calcitriol therapy alone also significantly increased calcium excretion, but not to the extent that the combination therapy did. This increased urinary calcium excretion in the GH plus calcitriol group was not associated with an increase in calcium and sodium intake, plasma ionized calcium, or urinary sodium excretion. The calcium content of the femurs from all uremic rat groups was significantly lower than that of the sham control rats; however, there was also no further decrease in bone calcium content in the GH plus calcitriol group compared with uremic controls. This indicated that bone was not the source of this excess urinary calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular levels of cysteine (CSH) and reduced glutathione (GSH) in the kidney and liver of rats from the newborn to the adult period have been determined using a sensitive high performance liquid chromatography method. In the kidney, the intracellular level of free CSH increased 4-fold from 1 to 4 nmol/mg protein with GSH levels which ranged from 20 to 25 nmol/mg protein from the 10th to 21st postnatal day, respectively. In contrast, intracellular free hepatic CSH showed a biphasic pattern with development. Intracellular free hepatic GSH, on the other hand, increased 2-fold over the 3- to 21-day postnatal period. In adult tissues, intracellular levels of free CSH and GSH decreased as compared with levels in 21-day postnatal animals. When ratios of CSH to GSH were compared between tissues from the 3-day-old postnatal and adult rat, CSH:GSH increased approximately 4-fold in the kidney and decreased 2- to 3-fold in the liver.

Although the mechanisms underlying the inhibitory effects of chronic renal insufficiency on growth are poorly understood, large doses of growth hormone (GH) have been used to improve growth. The present study examines the effects of rat GH and a reduced (8%) protein diet on 75% nephrectomized weanling rats by measuring changes in growth parameters, food utilization, serum albumin concentration, and muscle water content. Significantly greater improvement in growth was found in the GH-treated uremic rats compared with the uremic controls. The mean percent change in wt, length (nose to tail tip), and cranial biparietal diameter was significantly increased in the GH-treated uremic rats, compared with the uremic controls, but foot length and femur length showed only moderate improvement. Food utilization efficiency and serum albumin concentration were significantly higher in GH-treated uremic rats compared with uremic controls, achieving levels that were not different from sham-operated rats. Muscle water content was not significantly different between GH-treated uremic rats, uremic controls, and sham-operated rats. Thus, rat GH treatment administered at an early age in mild renal insufficiency significantly improved overall growth, food efficiency, and serum albumin concentrations, despite a low protein diet, suggesting that further evaluation of this form of therapy for growth failure of uremia is warranted.

Developmental changes in cystine transport by the canine kidney were examined both in vivo and in vitro. Renal clearance studies indicated that cystine was one of the more incompletely reabsorbed amino acids at birth, but its reabsorption approaches adult levels by 21 days. Concomitantly, cystine uptake by isolated renal cortical tubule fragments from immature dogs was slower than that by renal tubules from adult dogs. Both age groups rapidly metabolized the transported cystine. This metabolism was principally to cysteine, but also small amounts of reduced glutathione were formed from the transported cystine. Concentration dependence studies indicated two transport systems for cystine uptake in both the immature and the adult dog. Both transport systems in the 1-wk-old dog had a somewhat greater affinity for cystine than the corresponding system in the adult, but this was offset by the markedly lower maximal transport rates for these systems in the 1-wk-old dog. The high affinity system was inhibited by lysine in tubules from both age groups. In the dog, the rise in the tubular reabsorption of cystine with maturation could, in part, be explained by an increase in the number of transport sites for cystine.

alpha-Methyl-D-glucoside (AMG) uptake was examined in isolated renal cortical tubules from newborn, 3-month-old, and adult dogs. All three age groups demonstrated active sugar transport. The initial rate of AMG uptake was similar in the 3-month-old and adult tubules which was twice that of the newborn. At steady-state, the adult and newborn tubules had achieved a similar intracellular AMG concentration which was 45% greater than that of the 3-month-old. Determination of the flux constants of these uptake patterns revealed that there was an age-dependent increase in both the net flux and the fractional influx rate constant. However, the 3-month-old had the highest fractional efflux rate constant and the newborn the lowest value with the adult in between. Kinetic analysis of AMG uptake showed a single saturable transport system for each age group. The newborn and adult had similar Km values but the 3-month-old had a value that was 60% higher. The 3-month-old tubules had the highest Vmax and the newborn tubules the lowest with the adult value in between. AMG uptake by tubules from each age group demonstrated a similar pattern of inhibition in a low sodium buffer and by glucose and phlorizin. This indicated that, aside from kinetic changes with maturation, the saturable transport system for AMG is similar in each age group.