Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative Study Group of Pubertal development in Chronic Renal Failure.

To elucidate the endocrine mechanisms underlying the pubertal growth failure observed in patients with chronic renal failure (CRF), we used deconvolution analysis to estimate the rates of GH secretion and elimination in nighttime plasma GH profiles of peripubertal boys with CRF and after renal transplantation (Tx). Forty-three boys with advanced CRF (conservative treatment with glomerular filtration rate < 25 mL/min.1.73 m2 or dialysis; CT/D group), 38 boys after Tx, and 40 healthy control boys were studied. The estimated plasma GH half-life (mean +/- SEM) was significantly higher (P < 0.05) in CRF (25 +/- 1.8 min) than in Tx patients (21 +/- 1.6 min) and controls (20 +/- 0.5 min). In the pre- and early pubertal CT/D boys, the calculated GH secretion rate was low normal or reduced when expressed in absolute numbers or normalized per unit distribution volume or body surface. In late puberty, whereas body surface-corrected GH secretion was double the prepubertal value in normal boys (389 +/- 56 vs. 868 +/- 113 micrograms/m2.11 h; P < 0.01), it did not differ significantly from the prepubertal rate in CT/D boys (281 +/- 59 vs. 389 +/- 56 micrograms/m2.11 h). GH hyposecretion resulted from a decrease in the mass of GH released within each burst, whereas burst frequency was unchanged. In the Tx group, GH secretion rates were significantly reduced in the prepubertal (221 +/- 39 micrograms/m2.11 h; P < 0.05) and late pubertal period (266 +/- 64 micrograms/m2.11 h; P < 0.01). The mass of hormone secreted per burst was significantly reduced at each pubertal stage, whereas GH secretory burst frequency tended to be increased (significant in prepubertal group, P < 0.05). The GH secretion rate was positively correlated with plasma testosterone levels (r = 0.58; P < 0.0001) in controls, but not in CT/D or Tx patients. GH secretion rates were lower than expected at each level of plasma testosterone in both patient groups except CT/D boys with plasma testosterone below 0.9 nmol/L. In the Tx group, GH secretion rate was positively correlated with relative height (r = 0.31; P < 0.05). The dosage of corticosteroids administered for immunosuppression was negatively correlated with GH burst mass (r = -0.42; P < 0.01) and GH secretion rate (r = -0.29; P = 0.08) and positively correlated with GH burst frequency (r = 0.49; P < 0.01). We conclude that in peripubertal boys with CRF, a state of GH hyposecretion is associated with an increase in the apparent plasma half-life of GH.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum erythropoietin levels in children with chronic renal failure.

Serum erythropoietin (EPO) was measured in 64 children with chronic renal failure (CRF) by means of the fetal mouse liver cell assay. The results were compared with two control groups consisting of 20 healthy children and 10 with nonrenal anemia. EPO was analyzed according to the mode of treatment and the degree of uremia, anemia, hypoxemia, hyperparathyroidism, and body iron load. Mean EPO was 36 U/liter on conservative treatment (CT) (N = 30), similar to that in healthy children (35 U/liter) and in 15 children with renal transplants (TP, 39 U/liter), but significantly higher than that in 19 patients on regular dialysis (RDT; 16 U/liter) and lower than that in children with nonrenal anemia but with similar hemoglobin (230 U/liter). On CT, EPO was higher with severe uremia (SCr greater than 4 mg/dl) compared with moderate CRF and was inversely correlated with hemoglobin, but on a lower level compared with control, whereas on RDT the correlation became positive. By serial measurements, the decrease of EPO from CT to RDT was confirmed. An inverse relationship between EPO and p50 or the oxygen transport index was detected only on CT and after TP. EPO was inversely correlated with serum ferritin levels on HD. Between EPO and PTH, no correlation was found. Data demonstrate a negative feedback between EPO and the degree of hypoxia in children with CRF. On CT, this regulatory mechanism of erythropoiesis is acting on a lower level than it does in control subjects and is lost on RDT.

Nocturnal blood pressure elevation in transplanted pediatric patients.

Ambulatory blood pressure monitoring during 24 hours was applied in 34 pediatric patients aged 6.3 to 24.3 (median 14.0) years who had been transplanted 0.3 to 8.4 years previously. The mean arterial blood pressure levels measured during the daytime and at night correlated positively (r = 0.70), but 14 of the 28 patients with nocturnal hypertension were normotensive during the day. A reduced nocturnal dip (< 5.5%) of mean arterial blood pressure was detected in 11 of 34 patients. In the first year post-transplantation 4 of 7 patients had an attenuated dip without any obvious cause. Beyond the first year a reduced dip was always associated with a renal pathology. In conclusion, a high prevalence of nocturnal hypertension was detected in grafted pediatric patients, even in presence of normal daytime blood pressures. An attenuated nocturnal dip was found in association with an underlying renal pathology or within the first post-transplant year.

Prediction of adult height in children with chronic renal insufficiency.

The ability to accurately predict adult height (AH) has important implications for the management of children with chronic renal insufficiency (CRI). Serial predictions of AH were performed for 22 pediatric patients with CRI of variable duration and severity using the Tanner predictive method. The patients were followed until completion of growth. At the first predictions, the prediction error (PE) was within an acceptable range of +/- 2 cm in 59% of the patients. The mean size of the PE was 2.7 cm. It was larger in 7 patients with a bone age up to 11 years (4.9 cm) as compared to 15 patients with more advanced bone age (1.7 cm) and also larger in males (3.4 cm) than in females (2.4 cm). There was no correlation between size or direction of PE and (1) mode of treatment and (2) time elapsed between the first prediction and age at AH. A significant association was found between the direction of PE and the relative change in body height from the first prediction to adult age. Patients with decreasing SD scores were overpredicted and those with increasing SD scores were underpredicted at the initial assessment. Serial predictions gave large variations only in 2 girls who presented with unusual growth patterns. These results indicate that the method applied allows a reliable prognosis of future growth in most children with CRI.

Taurine metabolism in experimental renal failure.

Taurine is important for the regulation of ionic fluxes in excitable tissues, especially in heart where it is the most abundant amino acid. To investigate a possible role of taurine in uremia, we measured the taurine concentrations in plasma, liver, muscle, heart, and brain tissues of young male Wistar rats. Two groups of rats were studied: (1) rats with acute renal failure (ARF) 12, 24, and 48 hours after bilateral nephrectomy and (2) rats with chronic renal failure (CRF) studied 3 weeks after 5/6 nephrectomy. In ARF animals, taurine increased in plasma and liver two to three times the normal levels, remained unchanged in muscle and brain, but decreased in heart tissue; this decrease (-20%) was significantly correlated with the concomitant increase of BUN and plasma creatinine. In CRF animals, taurine was unchanged in plasma, liver, muscle, and heart, but was increased by 70% in brain accompanied by a high content of gamma-aminoisobutyric acid. The data suggest that in uremia accumulation of taurine is counteracted by increased hepatic elimination and/or decreased synthesis. The depletion of taurine in cardiac muscle might be related to the development of uremic heart disease. The increased concentrations of brain taurine might represent a compensation for the increased neuroexcitability in CRF.

Hypothalamo-pituitary-gonadal axis in children with chronic renal failure.

Delayed puberty in children with chronic renal failure (CRF) may be due to gonadal dysfunction, increased plasma binding of gonadal hormones, or changes of the hypothalamo-pituitary axis. Plasma androgens were studied in 17 prepubertal boys with preterminal CRF. In addition, the response of luteinizing and follicle-stimulating hormones (LH, FSH) to luteinizing-releasing hormone (LHRH) was followed in the plasma of these boys and of 12 prepubertal girls with CRF. Plasma testosterone (T) was significantly lower in the CRF boys than it was in the controls (mean, 9 vs. 22 ng/ml) and concerned also the free T fraction (2.5% in both groups). Dihydro-T was similarly reduced in CRF, resulting in a normal T/DHT ratio. Basal plasma LH levels were significantly elevated in boys (1.0 vs. 0.5 ng/ml) and in girls with CRF (1.4 vs. 0.4 ng/ml), whereas mean basal FSH values were similar to controls. After LHRH administration, peak levels of LH and FSH were not different in CRF and control children; however, the absolute differences from basal to peak values were lower in CRF. These findings may indicate that Leydig cell dysfunction in CRF already occurs before the onset of puberty. The blunted LH and FSH responses to LHRH suggest an additional disturbance at the hypothalamo-pituitary level.

Vasoactive hormones in children with chronic renal failure.

Plasma renin activity (PRA), aldosterone, vasopressin and catecholamines were measured in 15 children (ages 7.3 to 16.2 years) with chronic renal failure (CRF) before and after one session of hemodialysis and in 15 control children. Basal levels of PRA and aldosterone in children with CRF did not differ significantly from control values, but showed a wider range. Uremic patients with nephronophthisis showed the highest basal PRA and aldosterone levels. In children with CRF, basal vasopressin levels were significantly higher (9.7 +/- [SEM] 2.0 ng/liter) than control values (3.2 +/- 0.8 ng/liter). Plasma noradrenalin and adrenalin concentrations were similar in children with CRF and controls. During hemodialysis, a fall in blood pressure and a rise in heart rate was observed in all children. PRA and catecholamines increased twofold to fivefold during dialysis while aldosterone and vasopressin showed a variable response. In contrast to reports in adults, there is no evidence for an insufficiency of vasoactive hormones or of the sympathetic nervous system in children on hemodialysis.

The effect of chronic underfeeding on organ weights of rats. How to interpret organ weight changes in cases of marked growth retardation in toxicity tests?

Growing male rats were kept on a restricted feed intake. After 13 weeks they reached a final body weight of 250 g in comparison with 366 g of their ad lib. fed controls. The relative weights of the heart, kidneys, spleen, pituitary and prostate/seminal vesicle were not altered by underfeeding. The relative weights of the brain, adrenals and tests were increased by 30 to 40% in the feed-restricted groups, the thyroid by about 20%. The relative weight of the liver was decreased by about 30%. When growth is markedly reduced in a toxicity experiment alterations of this kind in the organ weight: body weight ratios have to be expected as a physiological response of the organism to decreased feed intake. They must be differentiated from organ weight changes resulting from primary toxic influences of the drug tested.

Children with chronic renal failure in the Federal Republic of Germany: I. Epidemiology, modes of treatment, survival. Arbeits- gemeinschaft für Pädiatrische Nephrologie.

By a nation-wide retrospective survey in the Federal Republic of Germany, epidemiological data were obtained on children with chronic renal failure (CRF) up to the age of 16.0 years. During a 4-year period (1972-1975), an incidence of 6 new cases per year of CRF occurred when referring to a 1 million population of the same age. The incidence of preterminal CRF (serum creatinine greater than 2 mg/dl to end-stage) was 4.4 and its prevalence 6.4 per million per year. The incidence of terminal CRF, analyzed for a 6-year period from 1972 to 1977 increased only slightly with time (from 4.4 to 5.4 per million of the same age per year). The proportion of children with terminal CRF admitted yearly for renal replacement therapy increased during the observation time from 27% to 79% up to the age of 10 years and from 80% to 96% between 10 and 16 years of age. The number of patients alive with terminal CRF rose significantly from 11.9 in 1972 to 22.0 per 1 million of the same age in 1977. At the end of 1977, 46% of all pediatric patients on renal replacement therapy had a functioning graft, compared to 38% in 1972. The increasing number of renal transplantations was accompanied by shortening of the waiting period from first dialysis to grafting. The patient survival on dialysis and after transplantation rose significantly during two subsequent 4-year periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of low-dose dopamine on kidney function and vasoactive hormones in pediatric patients with advanced renal failure.

Dopamine (DA) was infused in a dose of 2 micrograms/kg/min in 12 children and adolescents with chronic renal failure to test the vasodilatory reserve capacity of the kidney. Mean basal GFR and ERPF were 17.8 and 93.1 ml/min/1.73 m2, respectively. DA infusion had no significant influence on GFR but effective renal plasma flow (ERPF) increased by 14% (p less than 0.05). After DA, GFR did not correlate with ERPF. There was a significant increase in urinary sodium excretion (+22%). Sodium excretion correlated with osmotic clearance and urine flow rate with free water clearance. Plasma prolactin concentration was decreased (p less than 0.01), whereas noradrenaline, adrenaline and free dopamine increased significantly after DA. Plasma renin activity, aldosterone, arginine vasopressin and atrial natriuretic peptide levels remained unchanged. The data indicate that in pediatric patients with advanced renal failure DA fails to increase filtration capacity, whereas effective renal plasma flow and sodium excretion are stimulated. It is speculated that in this situation preglomerular and tubular renal functions regulated by dopamine receptors are better conserved than those affecting glomerular microcirculation.

Plasma inorganic sulfate in children with chronic renal failure.

Plasma sulfate concentration (SO4) was determined in 38 non-dialyzed children with chronic kidney disease and compared to inulin clearance and to other parameters of renal function. SO4 was measured by atomic absorption spectrophotometry. Plasma SO4 was inversely correlated with GFR and effective renal plasma flow. Positive correlations were found between plasma SO4, BUN, serum creatinine and serum phosphate levels. The highest levels of plasma SO4 were observed in 15 children undergoing regular dialysis. It is suggested that sulfate retention might be involved in the pathogenesis of uremic acidosis and bone disease.

Hemolysis and blood loss in children with chronic renal failure.

Erythrocyte life span was determined in 19 children with chronic renal failure on conservative treatment and in 12 children on regular hemodialysis. Erythrocytes were labeled with 111Indium. Blood loss was measured using a special counting chamber. Erythrocyte life span decreased with increasing blood urea nitrogen. Blood loss into the intestine and into the dialysis equipment was found to be a major cause for anemia of children with chronic renal failure. Daily intestinal blood loss amounted to 6 ml/m2 BSA on conservative treatment and 11 ml/m2 on hemodialysis. Mean blood loss in the dialysis equipment was 8 ml/m2 per dialysis, almost half being lost in the connecting tubing systems.

T-lymphocyte populations, cytokines and other growth factors in serum and urine of children with idiopathic nephrotic syndrome.

The T-cell defect present in the idiopathic nephrotic syndrome (INS) was investigated in 29 steroid-sensitive and 14 steroid-resistant children aged 2-19 years. Nine different lymphocyte subpopulations and 15 cytokines, receptors and other growth factors were measured in blood, and some also in urine. In steroid-sensitive patients we found a decreased ratio of helper/inducer cells (CD4+) versus suppressor/cytotoxic cells (CD8+) in relapse and remission, and an increased proportion of natural killer cells (CD16+) during relapse vs long-term remission, as a sign of an elevated cytotoxic potential. Among the serum cytokines mainly produced by monocytes/macrophages interleukin (IL)-8 levels were decreased in steroid-sensitive patients vs controls, with normal levels observed for IL-1 alpha, IL-1 beta, IL-1RA and tumor necrosis factor (TNF-alpha). IL-2 was the only cytokine produced by TH1 cells which was significantly increased during relapse vs long-term remission. We also observed a trend for elevated levels of sIL-2R and IFN-gamma. Serum levels of cytokines derived from TH2 cells were variable. IL-4 was decreased during relapse but increased in patients with long-term remission. SIL-6 receptors were increased during relapse. Finally we observed decreased serum levels of IL-3 and of the adhesion molecule ICAM-1 in active INS. Patients with steroid-resistant INS exhibited similar changes of T-cell populations and cytokines as steroid-sensitive patients; their CD4+/CD8+ ratio was reduced to the same degree and sIL-2R levels were even higher than in steroid-sensitive patients. In conclusion this study indicates that active INS is associated with an increased number of cytotoxic cells in the blood and an elevated TH1 cytokine production. Long-term remission appears to be related to increased TH2 cytokine production downregulating TH1 cytokines and cytotoxic cells. Our data give evidence that different immune mechanisms are involved in the pathogenesis of INS.

Mineralocorticoids in the nephrotic syndrome of children.

Free aldosterone, the aldosterone precursor 18-OH-corticosterone, and 18-OH-deoxycorticosterone as well as the aldosterone metabolites 18-glucuronide and tetrahydroaldosterone were measured by radioimmunoassay in the urine of 24 children with the nephrotic syndrome. In addition renin activity, aldosterone and corticosterone were measured in plasma. All children with manifest edema showed increased values of one or more of the measured aldosterone parameters indicating hyperaldosteronism. In non-edematous patients one or more parameters were increased in 9 of 16 patients. Free aldosterone, tetrahydroaldosterone and 18-OH-corticosterone proved to be the most sensitive urinary parameters for the detection of increased mineralocorticoid function. Free urinary aldosterone was correlated with sodium excretion and with serum albumin. The pathogenesis of hyperaldosteronism in the nephrotic syndrome and its role in the development of edema are discussed.

Increased aggregation with normal surface charge and deformability of red blood cells in children with nephrotic syndrome.

Hemorheological risk factors for thromboembolic disease were evaluated in 25 pediatric patients with idiopathic nephrotic syndrome (NS). In patients with increased proteinuria (greater than 100 mg/m2/24 h) red blood cell (RBC) aggregation and plasma viscosity were significantly increased when compared with patients in remission (less than 100 mg/m2/24 h) and with healthy controls. RBC surface charge was normal during increased proteinuria and remission. RBC aggregation correlated positively with plasma viscosity, fibrinogen, alpha 2-macroglobulin, immunoglobulin M, and the degree of proteinuria, and negatively with plasma albumin levels. RBC aggregation showed no correlation to RBC surface charge. Hematocrit and RBC deformability (rheoscope) were similar in both patient groups and in controls. Increased RBC aggregation and plasma viscosity may contribute to the increased risk of venous thromboembolism in NS.

Spontaneous remissions in frequently relapsing and steroid dependent idiopathic nephrotic syndrome.

We studied retrospectively the clinical course of 32 steroid sensitive nephrotic children with frequent relapses with or without steroid dependency associated with minimal glomerular lesions. Six hundred twenty-seven relapses were traced during a mean observation period of 7 years per patient. The median period between the beginning of significant proteinuria and the start of prednisone therapy was 5 days (range 0-194 days). At least one spontaneous remission occurred in 10 of the 15 frequent relapsers and in 11 of the 17 steroid dependent patients. Twenty-three percent of the relapses in frequent relapsers and 10% of the relapses in steroid dependent patients remitted spontaneously. The disappearance of proteinuria was documented in 79% of these relapses between day 4 and day 14 after onset. A delay of up to 10 days in starting prednisone therapy did not influence the further course of this or the subsequent relapse. Our results suggest that this delay is justified in the absence of progressive clinical signs and may, by the occurrence of spontaneous remissions, contribute to reduce the total amount of steroids needed.

Children with chronic renal failure in the Federal Republic of Germany: II. Primary renal diseases, age and intervals from early renal failure to renal death. Arbeitsgemeinschaft für Pädiatrische Nephrologie.

In a retrospective survey, 623 children with chronic renal failure (CRF) comprising a 7-year period were registered in the Federal Republic of Germany. The primary renal disease could be classified in 91% of the patients. Pyelonephritis was the most frequent diagnosis (31%), followed by glomerulopathies (20%), renal hypoplasia or dysplasia (14%), cystic kidney disease including nephronophthisis (12%), other hereditary nephropathies (7%), and vascular nephropathies (4%). At the time of first presentation, 23% of the children with preterminal chronic renal failure were younger than 5 years, 34% 5 to 10 years and 43% 10 to 16 years old. At the time of renal death, the serum creatinine level was below 10 mg/dl in 84% of the children below 5 years, compared to 5% in the patients older than 10 years. The mean interval from the first presentation of CRF to the terminal stage was 6 months in vascular nephropathies, 19 months in cystic renal disease, 26 months in glomerular disorders, 32 months in pyelonephritis, and 36 months in hereditary nephropathies and in renal hypoplasia or dysplasia. The range of these intervals is so large, even when diagnostic subgroups are considered, that a reliable prediction of the individual course from the underlying kidney disease is not possible.

Idiopathic de Toni-Debré-Fanconi syndrome with absence of proximal tubular brush border.

In a girl with idiopathic de Toni-Debré-Fanconi syndrome associated with psychomotor retardation, severe renal tubular dysfunction was observed from the first day of life. At the age of 21/2 and 4 years the glomerular filtration rate (GFR) was only 60 ml/min/1.73 m2. No tubular transport of glucose, phosphate, paraaminohippurate and amino acids could be demonstrated. The tubular handling of uric acid, potassium and calcium, was also disturbed. Renal net acid excretion was zero at a plasma bicarbonate level of 14 mmol/l. Urinary osmolality ranged between 88 and 680 mosmol/kg. During hypotonic saline diuresis GFR decreased further; a GFR of 19 ml/min/1.73 m2 was accompanied by a fractional distal sodium delivery of 96.5% and a fractional free water clearance of 73%. In a renal biopsy specimen the proximal tubular cells showed variations in height with dedifferentiation and a widespread absence of brush border on electron microscopy. This formerly undescribed tubulopathy offers a unique chance to investigate glomerulo-tubular balance, adaptive mechanisms of distal tubular transport and renal metabolism under conditions where an apparently unchanged ultrafiltrate is offered by the proximal tubule to the loop of Henle and to a primarily intact distal tubule.

Renal function and renotropic effects of secretin in cystic fibrosis.

In ten cystic fibrosis patients and nine age-matched controls, renal function was determined before and after infusion of secretin. Under baseline conditions creatinine excretion and clearance were significantly elevated, exclusively due to those patients who were homozygous for the DF508 mutation (153 vs 132 ml/min*1.73m2), whereas the glomerular filtration rate, measured by inulin clearance showed no difference. Renal plasma flow and the fractional reabsorption rates of electrolytes were similar in patients and controls. During secretin infusion renal plasma flow increased and the fractional reabsorption rates of electrolytes decreased in both groups. The patients had a increased metabolic clearance (2900 vs 1660 ml/min*m2) and endogenous production rate (9,9 vs 2,5 pmol/min*m2) of of secretin. In conclusion global renal function and electrolyte handling, in particular chloride permeability, are unchanged in cystic fibrosis. Individuals expressing the DF508 genotype showed a selective elevation of creatinine excretion and clearance. The secretion and metabolic clearance of secretin are increased in cystic fibrosis.

Evaluation of peritoneal solute transfer by the peritoneal equilibration test in children.

To evaluate the characteristics of peritoneal kinetics in the young, we investigated solute and water transfer rates by a modified Peritoneal Equilibration Test (PET) in 20 pediatric patients aged 1.9 to 19.8 years. 1000 ml/m2 body surface area of a 2.3% glucose PD solution were instilled in the peritoneal cavity. Glucose, creatinine, urea, sodium, potassium and phosphate were measured in the dialysate (D), 7 times during 4 hours and in plasma (P) after 2 hours dwell time. At 4 hours, the mean (+/- SD) D/P ratio was 1.06 +/- 0.16 for urea, 0.79 +/- 0.14 for creatinine, 0.82 +/- 0.21 for potassium, 0.92 +/- 0.04 for sodium and 0.79 +/- 0.30 for phosphate. Mean D/D0 of glucose was 0.36 +/- 0.13. The 4-hour solute equilibration curves were analytically best approximated by logarithmic functions for urea (mean R2 = 0.983), creatinine (R2 = 0.973) and potassium (R2 = 0.979), by a linear function for phosphate (R2 = 0.964), and by an exponential model for glucose (R2 = 0.969). The linear or exponential regression coefficients were used to express the peritoneal solute transfer rates. Although the transfer rates of most solutes were correlated with each other, the individual variation of peritoneal permeability for different solutes was high. Close associations were observed between the glucose and creatinine transfer rates (r = 0.91, p < 0.0001) and between ultrafiltration rate and glucose (r = -0.90, p < 0.0005) and creatinine (r = -0.88, p < 0.005). Peritoneal permeability for all solutes tended to be inversely correlated with body size (urea transfer rate vs. height: r = 0.49, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)