Insulin and growth hormone secretion in dialyzed children: influence of dietary manipulation.

The insulin and growth hormone responses to arginine and the growth hormone response to insulin were studied in 10 children undergoing chronic hemodialysis 1) under usual dietary prescription and 2) after 7 days of dietary manipulation (DM) decreasing mean carbohydrate intake from 48 to 36% and increasing lipid intake from 42 to 54% (percent of total energy) with the polyunsaturated/saturated fatty acids ratio being increased from 0.2 to 2. Mean fasting insulin and growth hormone were significantly decreased after DM: 10.3 +/- 3 muunits/ml and 19.9 +/- 3.5 ng/ml before and 4.3 +/- 0.8 muunits/ml and 9.3 +/- 2.4 ng/ml after DM. The mean arginine-induced insulin peak and the growth hormone peaks after arginine and insulin remained very high after DM. There was no decrease of mean plasma triglycerides: 214 +/- 30 mg/dl before and 237 +/- 26 mg/dl after DM. However, two children who had the greatest decrease in carbohydrate intake exhibited a decrease of triglycerides and of arginine-induced insulin secretion. The percent variation of insulin area after DM was significantly correlated with the percent variation of plasma triglycerides.

[Intra-leukocyte cystine in cystinosis treated with cysteamine]. / Cystine intra-leucocytaire dans les cystinoses traitées par la cystéamine.

Data on cystine leukocyte content are analyzed in cystinotic patients receiving cysteamine as a depleting agent of cellular cystine. During 2 years, 63 measurements of cystine leucocyte content were performed in 15 cystinotic patients, aged 20 months to 22 years, taking daily 40 to 65 mg/kg of cysteamine. An original method was used to measure leukocyte cystine: a binding protein assay with a specific cystine-binding protein from E. coli. Results were taken individually because of various clinical situations in patients. In 8 patients taking cysteamine regularly, 6 hours after a dose, cystine leukocyte content was between 1 and 2 nmol 1/2 cystine/mg protein, about 10 times less than basal values without treatment and 5 to 10 times more than control subjects. In less compliant patients, cystine leukocyte content was close to basal values without treatment (3 to 25 nmol/mg). Some variability was observed between individuals receiving cysteamine: pharmacokinetic parameters may need further investigation. This sensitive and specific assay helped in controlling compliance and adjusting dosage regimen in each patient. The aim was to maintain a minimum effective dosage in order to avoid toxic side effects of cysteamine.

[Treatment of cystinosis using cysteamine]. / Traitement de la cystinose par la cystéamine.

Eighteen pediatric patients with cystinosis were treated with cysteamine. Treatment was started at a variable age, between 10 months and 7 years, and was continued for 6 months to eight years. Results were evaluated on renal function changes and growth. Whereas 65% of patients with cystinosis develop terminal renal failure before the age of ten years, three (16%) of our 18 patients given cysteamine started dialysis before the age of ten and all three had first received cysteamine only after 4 1/2 years of age. The plasma creatinine level was also lower in treated patients as compared with a control multicenter group. Growth was also significantly improved by treatment, especially in those children treated before the age of 26 months who were taller by 2 SD at age five and 2.5 SD at age eight than untreated controls. Some children who complied strictly with the treatment regimen had an normal stature (- 1 SD) at ten years of age. In conclusion, the effectiveness of cysteamine seems obvious in this group of patients if rigorous compliance with the drug dosing schedule is achieved.

Late symptoms in infantile cystinosis.

Late symptoms of infantile cystinosis were evaluated in 19 patients aged 15-26 years who had a high graft survival following kidney transplantation. The end-stage cystinotic kidney was responsible for renal hypertension in 5 patients following grafts. Photophobia did not increase in relation to age, but 3 patients became blind and 1 lost the sight in one eye at 25 years of age. Two patients developed clinical symptoms of hypothyroidism, and 15 other patients had a compensated hypothyroidism. Four patients developed permanent insulin-dependent diabetes and 2 developed transient insulin-dependent diabetes after transplantation. The oral glucose tolerance test was abnormal in 11 of 14 patients on low-dose prednisone. Liver enlargement was noted in 10 cases, but only 3 patients developed clinical symptoms of portal hypertension. Symptoms of hypersplenism were observed in 6 cases leading to splenectomy. Repeat gross epistaxis was observed in 7 of the patients when on dialysis and persisted after transplantation in 1 patient, who died from nasal bleeding. A particular encephalopathy developed in 2 patients at the ages of 17 and 24, characterized by speech difficulties, pyramidal symptoms and cranial nerve deficit; one died at the age of 21. The mean adult height of these patients was 136.5 cm in males and 124 cm in females, and their psychosocial adjustment was related to the extra-renal complications of cystinosis rather than to the renal status.

[Urinary lithiasis after kidney transplantation. Experience at a pediatric center]. / Lithiase urinaire après transplantation rénale. Expérience d'un centre pédiatrique.

BACKGROUND: Urologic complications are still a frequent and significant problem in renal transplant recipients. The search for risk factors is therefore mandatory. MATERIAL AND METHODS: 652 renal transplantations were performed in children and adolescents between January 1973 and December 1988. 33 patients (5%) developed urolithiasis; their files were retrospectively analysed at the same time as the files of 28 patients transplanted during the same period and having similar ages, reasons for transplantation and immunosuppressive therapy. RESULTS: The stones contained calcium in 27 patients and uric acid in 6. The first symptoms were hematuria (27 times) with or without dysuria (9 cases), urine retention (2 cases) and anuria (2 cases). Repeated urine infections frequently led to the use of imaging techniques that permitted diagnosis. Urolithiasis was responsible for urinary obstruction in 13 cases; 9 of these required surgery. The course was always good without any modification of renal functions. The main risk factors were local: ureteral reimplantation on intestinal bladder, use of nonresorbable stitches and repeated urinary infections. Metabolic factors were less frequent and included hypercalciuria (18 cases) and hyperparathyroidism (2 cases). CONCLUSIONS: Some of the risk factors such as urinary infections, changes in the metabolism of phosphorus and calcium or insufficient diuresis, can be prevented. Repeated imaging techniques during the follow-up are mandatory.

Cyclosporin in the treatment of idiopathic nephrotic syndrome in children.

Thirty-five children (12 girls, 23 boys), aged from 1 year and 5 months to 14 years at the onset of idiopathic nephrotic syndrome, received cyclosporin A (CyA) because of steroid toxicity or failure to respond to steroids. The initial oral dose was 6 mg/kg per day and this was adjusted to obtain trough plasma levels of 50-150 ng/ml. The duration of treatment was between 2 and 8 months. In patients who responded to CyA treatment, the dosage was tapered off; treatment was stopped if found to be ineffective. Of the 35 children, 20 were frequent-relapsing steroid responders who suffered serious side-effects from steroid therapy. Seventeen of them either went into remission or did not relapse despite the withdrawal of prednisone. Prednisone doses could be lowered but not stopped in 1 patient and the remaining 2 patients relapsed when prednisone was tapered off. At the final examination, 10 of the 12 children in whom CyA was tapered off and who had initially responded to CyA had relapsed. A second course was given to these 10 patients and 3 failed to respond. Five children were partial steroid responders and CyA induced a remission in 1 and a partial remission in another. Among the 10 children who were steroid resistant, only 1 responded to CyA, 2 had a partial response and 7 failed to respond to CyA. A reduction of glomerular filtration rate occurred in 8 patients, 7 of whom had either persistent nephrotic syndrome or were in relapse, which suggests that factors other than CyA nephrotoxicity may have been operative. Complete reversal occurred in only 4 patients. Significant histological changes, likely to be related to CyA, were seen in 2 repeat renal biopsies out of the 11 performed.

Varicella and zoster in children after kidney transplantation: long-term results of vaccination.

OBJECTIVE: To determine the long-term prevalence of varicella infection and herpes zoster after kidney transplantation and to assess the effectiveness of varicella immunization with the Oka attenuated strain. METHODS: This study involved 704 children and adolescents who received a kidney graft in our institution from 1973 to 1994 and had routinely been given varicella vaccine beginning in 1980 in preparation for transplantation. RESULTS: After vaccination 62% of these patients still had varicella/zoster (VZ) antibodies at 1 year and 42% after 10 years. After transplantation the incidence of varicella was significantly lower, 26/212 (12%), in patients who received immunization than in those who did not and had no history of varicella, 22/49 (45%). The disease was also significantly less severe in the vaccinated patients (three deaths among naive patients vs none among vacciness). In the vaccinees, varicella infection was observed only in those who did not develop or lost VZ antibodies; in addition, 21 patients of this subgroup had an asymptomatic seroconversion. Four of the 415 patients with a history of varicella had another episode of benign varicella after grafting. Herpes zoster was observed in 76 of the 704 patients included in the study. The prevalence differed according to VZ status at the time of grafting: 13% in patients with a history of varicella, 7% in the vacciness, and 38% in the naive patients at grafting who developed varicella. Three rejection episodes occurred in association with a varicella episode and four with a zoster episode, but graft function was only transiently impaired, and as a whole varicella or zoster did not significantly affect graft function or survival. CONCLUSION: Naive VZ patients with a kidney graft are at risk to develop severe varicella and this may be effectively prevented by available immunization.

Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine.

Of the 26 cystinotic patients over 19 years of age followed in our institution, 7 developed CNS complications at a mean age of 23 years. Two forms were observed. The first, associating cerebellar and pyramidal signs, mental deterioration and finally pseudo-bulbar palsy, may be called cystinosis encephalopathy. The other form resembled a stroke-like episode with coma and hemiplegia or milder symptoms. Hydrocephalus was rare and not associated with clinical symptoms in this series. Cysteamine was administered for longer than 6 months to 4 of the patients with encephalopathy. Two had an almost complete disappearance of their symptoms including the gross abnormalities of MR imaging in one; one improved partially and remained stable, and one continued to deteriorate but was suspected of non-compliance. These results suggest that cysteamine may be an effective treatment of cystinosis encephalopathy and encourage prescription of this drug in cystinosis in order to prevent this complication.

Plasma lipids in kidney transplanted children and adolescents: influence of pubertal development, dietary intake and steroid therapy.

Plasma triglycerides and/or cholesterol were significantly increased in twenty-four of thirty kidney transplanted children and adolescents with stable renal function, at least one year after the last rejection crisis who received low dose prednisone therapy. The cholesterol increment was related to both low density and high density lipoproteins. However, similar to findings in adult allograft recipients, these increases were very variable: six subjects had normal levels, eight had increased triglycerides, five increased triglycerides and cholesterol, and eleven increased cholesterol. No influence of renal function was found in this series of patients all of whom had plasma creatinine below 160 mumol/l. Subjects who had achieved sexual development had lower cholesterol values. An insignificant difference was observed between patients receiving daily and alternate-day steroid therapy, but a significant negative correlation was found between plasma triglycerides and fractional urinary excretion of 17 OH corticosteroids in the first 6 h after an oral dose of prednisone. Finally, no correlation was found between energy intake and triglycerides; but a significant correlation was observed between protein intake and plasma cholesterol. In conclusion, some patients show a high level of triglycerides and/or cholesterol after renal transplantation, possibly due to a different individual response to steroid therapy.

[Sugar diabetes after renal transplantation in children]. / Diabète sucré après transplantation rénale chez l'enfant.

Posttransplant diabetes mellitus is ascribed to the use of corticosteroids. Because use of cyclosporine has been associated with increased rates of posttransplant diabetes mellitus, risk factors for this condition have been studied in adults and found to include older age, excessive body weight, and a family history for non-insulin-dependent diabetes mellitus. Only about 1% of children develop diabetes mellitus after transplant surgery. A study of pediatric transplant recipients with diabetes mellitus and of pediatric renal transplant recipients suggested that posttransplant diabetes mellitus may be more common in children with risk factors and may reveal types of diabetes which are infrequent in childhood, e.g., non-insulin-dependent diabetes mellitus which would have gone undiagnosed until adulthood in the absence of corticosteroid therapy. In contrast, corticosteroids apparently had little influence on glucose tolerance in subjects free of risk factors. The effect of corticosteroids seemed to be somewhat less marked than that of renal function impairment.

[Pharmacokinetics of prednisone after oral administration in children with renal grafts. Changes induced by phenobarbital and renal insufficiency]. / Pharmacocinétique de la prednisone après dose orale chez l'enfant greffé rénal. Modifications induites par le phénobarbital et l'insuffisance rénale.

A study of blood and urinary clearance of prednisone after ingestion of a 25 mg/m2 body surface test-dose, at 8 AM, was undertaken in 20 children treated for 18 months with prednisone after renal transplant. Results show important variability between patients: the elimination half life was 2.70 +/- 0.78 hr.; Tmax time to reach Cmax was 2.10 +/- 1.08 hr.; Maximal concentration (Cmax) was 474 +/- 153 ng/ml. With respect to the dose of steroid administered, the urinary excretion of corticosteroids: 17-hydroxycorticosteroids was 12.9 +/- 7.4% and that of unchanged prednisolone 2.8 +/- 3.1%. This level was essentially achieved in the 6 first hours: 55.4 +/- 16.2% for 17-OH steroids and 87.2 +/- 14.3% for prednisolone. Two points emerge from this study: (a) Renal failure slows urinary excretion of prednisone and its metabolites, making a reduction in the doses of corticosteroids necessary at certain doses. (b) The association prednisone-phenobarbital changes the blood kinetics (excretion is faster) without a clear change in 17-OH steroid and prednisolone urinary excretion. It is associated with a decrease in graft tolerance. The kinetic changes do not seem to be the only factors implicated in the decreased therapeutic response.

Wolcott-Rallison syndrome: a case with endocrine and exocrine pancreatic deficiency and pancreatic hypotrophy.

Clinical analysis and genetic investigations of new cases of Wolcott-Rallison syndrome are needed to evaluate the role of the gene(s) directly or indirectly implicated in pancreas development and in the aetiology of the syndrome.

Plasma lipids, lipoproteins and apolipoproteins AI, AII, and B in renal transplanted children: what risk for accelerated atherosclerosis?

The aim of the study was to investigate the atherosclerosis risk factors related to hyperlipidemia in renal transplanted children. Plasma cholesterol, triglycerides, apolipoproteins (Apo) AI, AII and B, and the major lipoprotein classes separated by gradient ultracentrifugation were compared in 30 renal transplanted patients and 14 healthy children. Hyperlipidemia was present in 66% of the transplanted children. 'Positive' risk factors for atherosclerosis (high plasma cholesterol and Apo B) were present in hypercholesterolemic and combined hyperlipidemic subgroups. All transplanted children, whether normo- or hyperlipidemic, presented essentially 'negative' risk factors for atherosclerosis, i.e. significantly higher levels of Apo AI and AII in plasma and in high-density lipoprotein HDL2 and higher Apo AI/Apo B and/or Apo AII/B ratios. Repeated evaluations (over a 12-month period) in transplanted children indicated relatively frequent individual changes in the lipid pattern, but not in Apo AI and AII content. These results suggest that the risks for accelerated atherosclerosis related to hyperlipidemia may be considered as moderate in transplanted children.

Diabetes mellitus in patients with infantile cystinosis after renal transplantation.

Diabetes mellitus is a frequent long-term complication of infantile nephropathic cystinosis. We studied 44 cystinotic patients, aged 22.1+/-5.4 years, transplanted at a mean age of 11.3+/-2.5 years; 25% were treated with insulin at 20 years of age or 10 years after transplantation, and over half required insulin at latest follow-up. In comparison, diabetes mellitus occurred in only 1% of non-cystinotic transplanted patients. Sequential oral glucose tolerance tests (OGTTs) in these patients showed the progressive deterioration of glucose metabolism. All but 2 patients had an abnormal response at latest follow-up. The high doses of corticosteroid given after transplantation or during rejection episodes were responsible for transient insulin dependency. However, the development of impaired glucose tolerance and diabetes mellitus depended mainly on the cystinotic process, which developed slowly with time. The deterioration of glucose tolerance was correlated with a decreased early phase of insulin secretion, estimated from the plasma insulin level at 30 min of the OGTT, while there was no evidence of insulin resistance. The occurrence of diabetes mellitus correlated with a worsening of the vital prognosis.