José A. Ramirez

A Randomized, Double-Blind, Placebo-Controlled Trial of the Effects of Prophylactic Theophylline on Renal Function in Term Neonates With Perinatal Asphyxia

Background. The kidney is the most damaged organ in asphyxiated full-term infants. Experiments in rabbits and rats have shown that renal adenosine acts as a vasoconstrictive metabolite in the kidney after hypoxemia and/or ischemia, contributing to the fall in glomerular filtration rate (GFR) and filtration fraction. Vasoconstriction produced by adenosine can be inhibited by the nonspecific adenosine receptor antagonist, theophylline. Gouyon and Guignard performed studies in newborn and adult rabbits subjected to normocapnic hypoxemia. Their results clearly showed that the hypoxemia-induced drop in GFR could be avoided by the administration of low doses of theophylline. Objective. This study was designed to determine whether theophylline could prevent and/or ameliorate renal dysfunction in term neonates with perinatal asphyxia. Setting. Buenos Aires, Argentina. Study Design. We randomized 51 severe asphyxiated term infants to receive intravenously a single dose of either theophylline (8 mg/kg; study group: n = 24) or placebo (control group: n = 27) during the first 60 minutes of life. The 24-hour fluid intake and the urine volumes formed were recorded during the first 5 days of life. Daily volume balances (water output/input ratio and weights) were determined. Severe renal dysfunction was defined as serum creatinine elevated above 1.50 mg/dL, for at least 2 consecutive days after a fluid challenge, or rising levels of serum creatinine (.3 mg/dL/day). The GFR was estimated during the second to third days of life by endogenous creatinine clearance (mL/minute/1.73 m2) and using Schwartzs formula: GFR (mL/minute/1.73 m2) = .45 × length (cm)/plasma creatinine (mg/100 mL) during the first 5 days of life. Tubular performance was assessed as the concentration of β2-microglobulin (β2M) determined by enzyme immunoassay, on the first voided urine 12 hours after theophylline administration. The statistical analysis for the evaluation of the differences between the groups was performed with Studentst and χ2 tests as appropriate. Results. During the first day of life, the 24-hour fluid balance was significantly more positive in the infants receiving placebo compared with the infants receiving theophyline. Over the next few days, the change in fluid balance favored the theophyline group. Significantly higher mean plasma values were recorded in the placebo group from the second to the fifth days of life. Severe renal dysfunction was present in 4 of 24 (17%) infants of the theophylline group and in 15 of 27 (55%) infants of the control group (relative risk: .30; 95% confidence interval: .12–.78). Mean endogenous creatinine clearance of the theophylline group was significantly increased compared with the creatinine clearance in infants receiving placebo (21.84 ± 7.96 vs 6.42 ± 4.16). The GFR (estimated by Schwartzs formula) was markedly decreased in the placebo group. Urinary β2M concentrations were significantly reduced in the theophylline group (5.01 ± 2.3 mg/L vs 11.5 ± 7.1 mg/L). Moreover, 9 (33%) patients of the theophylline group versus 20 (63%) infants of the control group had urinary β2M above the normal limit (<.018). There was no difference in the severity of the asphyxia between infants belonging to the theophylline and control groups in regards of Portmans score. Except for renal involvement, a similar frequency of multiorganic dysfunction, including neurologic impairment, was observed in both groups. The theophylline group achieved an average serum level of 12.7 μg/mL (range: 7.5–18.9 μg/mL) at 36 to 48 hours of live versus traces (an average serum level of .87 μg/mg) in the placebo group. Conclusions. Our data suggest that prophylactic theophylline, given early after birth, has beneficial effects on reducing the renal dysfunction in asphyxiated full-term infants. A single dose of 8 mg/kg of theophylline within the first postnatal hour in term neonates with severe perinatal asphyxia results in a significant decrease in serum creatine and urinary β2M, together with a significant increase in the creatine clearance. The potential clinical relevance of the data would be the avoidance of the contributory role of hypoxemia in the development of acute renal failure. Additional studies will be necessary before the use of theophylline in asphyxiated newborns can be considered for clinical practice.

Renal transplantation in patients with classical haemolytic-uraemic syndrome

Eighteen records from children with renal transplants (RT) and classical haemolytic-uraemic syndrome (HUS) were reviewed. The mean oliguric period was 17.9±7.5 days; the interval between acute phase and endstage renal disease (ESRD) was 9.3±5.2 years. HUS was the most frequent cause of renal transplantation (23.4%). There were no significant differences between patients with HUS and controls (children with RT but without HUS), regarding renal function, frequency of rejections, renal survival (HUS 65%, controls 57%) or patient survival (94.4% and 96.6%, respectively) after 9 years. None had clinical or histopathological evidence of HUS recurrence in the allograft. Of all children with living-related donors (LRD), renal survival after 3 years was longer for those who received cyclosporin A (CSA) (HUS and controls 86%) than for those who did not receive it (HUS 50%, controls 53%). Classical HUS is a frequent cause of ESRD in Argentina. The duration of the acute oliguric period is a good predictor of the likelihood of progression to chronicity. In the classical form of HUS there is no recurrence in the allograft. CSA and LRD can be used without risk in renal transplantation of children with classical HUS.

Effect of therapy with a new glucocorticoid, deflazacort, on linear growth and growth hormone secretion after renal transplantation

Deflazacort is an oxazoline compound derived from prednisolone with similar antiinflammatory effects but fewer side effects. We studied changes in kidney function, growth velocity, weight/height ratio, and growth hormone secretion before and a year after substitution of deflazacort for methylprednisone in nine patients aged 9 to 15 years, 4 years after renal transplantation; all were in Tanner pubertal stage 1. Methylprednisone (mean +/- SEM: 0.2 +/- 0.02 mg/kg per day) was replaced by deflazacort (0.3 +/- 0.03 mg/kg per day) for a mean period of 15 months. Serum creatinine and calculated creatinine clearance did not change significantly during deflazacort treatment. Growth velocity increased from 1.5 +/- 0.3 to 3.2 +/- 0.5 cm/yr (p < 0.005) in the nine patients. Weight/height ratio decreased from 28.4% +/- 8.5% to 16% +/- 6.7% (p < 0.005). Cushingoid appearance decreased in all patients. Mean spontaneous growth hormone secretion increased from 2.5 +/- 0.4 to 4.4 +/- 1.2 ng/ml (p < 0.05). Our findings indicate that immunosuppressive treatment with deflazacort is as effective as methylprednisone and is associated with fewer side effects.

QUALITY OF LIFE AFTER KIDNEY TRANSPLANTATION IN CHILDREN

We assessed the long-term rehabilitation and quality of life after kidney transplantation in 17 recipients of transplants during their childhood who had reached 10 years or more after grafting. We found that all recipients considered themselves to be in good to excellent health, and 59% were completely satisfied with their life. Ninety-four percent of the recipients did not report any interference of their health with their family life. Only one recipient was unemployed, and five recipients have to miss work (n=2) and school (n=3) a few days a year due to their health status. Health seldom or never interfered with social life in 11 recipients, and in 6 of 9 sexually active recipients, their health status was not an obstacle in their sexual relationships. Two recipients expressed concerns about their short stature, and three were concerned with their body appearance. In conclusion, we describe a group of young adult recipients who presented a highly satisfactory rehabilitation and quality of life after their successful transplantation.

Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease*

Patients with end-stage renal disease may have abnormalities of growth and of gonadal and thyroid hormones, so we attempted to determine the mechanisms that may be involved in the altered thyroid function. We evaluated serum thyroid hormone levels, their changes immediately after hemodialysis, the serum thyrotropin (thyroid-stimulating hormone (TSH) response to thyrotropin releasing hormone, and the circadian pattern of serum TSH in nine children with end-stage renal disease who were between 7 1/2 years and 17 years 1 month of age. Seven patients had been receiving hemodialysis for a median of 3.3 years; the other two were receiving continuous ambulatory peritoneal dialysis. Four patients had low serum total thyroxine (T4) values, and all nine had low free T4 values. Mean concentrations of total T4, free T4, and total triiodothyronine (T3), which were significantly less than normal before hemodialysis, returned to normal levels immediately after dialysis. Postdialysis thyroid hormone increases did not correlate with the decrease in weight or the increase in hematocrit observed immediately after dialysis. All but one patient had basal TSH levels within the normal range. Three patients had a deficient TSH response to thyrotropin releasing hormone, and the TSH response was prolonged in all of them. The mean (+/- SD) nocturnal TSH surge was 50 +/- 68%. Five of the eight patients studied had a nocturnal TSH surge below the normal range (95% confidence limits 47% to 300%). Serum free T4 values correlated with the TSH nocturnal surge (r, 0.73; p less than 0.05). Our findings support the hypothesis that some patients with end-stage renal disease have central hypothyroidism.

Hyperhomocysteinemia In Stable Pediatric, Adolescents, And Young Adult Renal Transplant Recipients

Background. High total plasma homocysteine (tHcy) levels are accompanied by an increased risk for premature development of atherosclerosis and atherothrombosis. Adult renal transplant recipients have elevated tHcy levels. Corresponding data in pediatric, adolescent, and young adult renal transplant recipients are scarce. We investigated whether tHcy levels were elevated in stable renal transplant recipients who received kidney grafts before age 18. Methods. This cross-sectional study was conducted during routine posttransplantation follow-up. Fasting tHcy levels, serum creatinine, and lipoprotein profile were measured in 38 clinically stable renal transplant recipients with different degrees of renal function. No patient was receiving B vitamin or folic acid supplementation. Estimated glomerular filtration rate (GFR) was assessed according to Schwartz’s formula. All patients followed a triple-drug immunosuppressive regimen, with the exception of three patients (deflazacort and azathioprine). Forty-one apparently healthy subjects constituted the control group. tHcy levels were determined by fluorescence polarization immunoassay in an IMx analyzer. Results. Mean tHcy levels in transplant recipients were significantly higher than in controls (16.8±8.7 &mgr;mol/L and 9.5±2.3 &mgr;mol/L, respectively;P <0.01). A significant positive correlation between tHcy and serum creatinine levels was observed for both transplant recipients (rS=0.70, P <0.01) and controls (rS=0.54, P <0.01). In transplant recipients, tHcy correlated negatively with estimated GFR (rS=[minus]0.47, P <0.05). Fasting tHcy levels in excess of 14.6 &mgr;mol/L (>95th percentile in controls) were present in 19 (50%) patients; 14 of these patients had an estimated GFR<60 ml/min per 1.73 m2. When the renal transplant recipients were analyzed by renal function, mean tHcy was significantly higher in patients with an estimated GFR<60 ml/min per 1.73 m2 compared with patients with an estimated GFR≥60 ml/min per 1.73 m2 (20.5±9.9 vs. 13.2±5.8 &mgr;mol/L, P <0.01). Both groups were significantly different from controls (P <0.01). No relationship was found between tHcy level and either cumulative cyclosporine or cumula-tive methylprednisone doses. No differences were observed in tHcy levels or lipoprotein profile between patients who were receiving deflazacort and those on methylprednisone. Conclusions. Hyperhomocysteinemia in renal transplant recipients is a common condition. Testing for fasting tHcy level might be a useful tool to identify patients at increased risk for development of vascular disease.

Ambulatory blood pressure monitoring after recovery from hemolytic uremic syndrome.

Abstract. The outcome of acute renal failure due to diarrhea-associated hemolytic uremic syndrome (D+ HUS) is generally predicted to be good. However, there are only a few long-term observations with detailed reports on long-term sequelae. Specifically, adequate long- term blood pressure (BP) evaluations are scarce. The present study evaluated BP in pediatric patients after childhood D+ HUS. The study group comprised 28 patients (20 males) aged 6–23.5 years (median 10.1 years). All patients had a history of D+ HUS at a median age of 1.1 years (range 0.5–6 years). Based on the duration of oliguria and/or anuria, the primary disease was classified as mild (n=6), moderate (n=6), or severe (n=16). The BP in these patients was studied at a median time of 8.4 years (range 2.3–22.9 years) after manifestation of D+ HUS by means of office BP measurements and 24-h ambulatory BP monitoring (ABPM) using a Spacelabs 90207 oscillometric monitor. Measurements were compared with normal values of published standards for healthy children and adolescents. Conventional office BP measurements were above the 95th percentile in 1 patient. By ABPM, 2 patients were diagnosed to have mean systolic daytime and nighttime values in the hypertensive range, and systolic and diastolic hypertension was confirmed in the first patient. All these patients had a severe form of D+ HUS in the past. By applying ABPM, BP anomalies were detected in 5 additional patients. Elevated systolic BP loads were found in 4 patients, and daytime systolic and diastolic hypertension in the other 1. At the time of the study, 2 of them were classified as ”recovered.” The late outcome of D+ HUS may be worse than anticipated. BP anomalies as long-term sequelae of D+ HUS could be identified by ABPM but not by office BP measurements. These findings may repre- sent an isolated sign of residual renal disturbance.

Syndrome of inappropriate secretion of antidiuretic hormone in nasopharynx carcinoma

Abstract. The syndrome of inappropriate secretion of antidiuretic hormone (ADH) or SIADH has been reported in various disorders. We report a pediatric patient with nasopharynx carcinoma who may have developed a clinical SIADH with severe hyponatremia and generalized seizure during the administration of intravenous hydration. We propose that the inappropriately high plasma level of ADH led to the inability to excrete sufficient amounts of free water during a hyperhydration protocol with a relatively hypotonic fluid, which resulted in acute hyponatremia and central nervous system involvement. To avoid this complication, intravenous hydration before chemotherapy in children with nasopharynx carcinoma should be performed at a slower infusion rate and with a sodium chloride concentration of more than half isotonic.

Growth Hormone-Insulin-Like Growth Factor-I (IGF-I) Axis in Prepubertal Children with Chronic Renal Failure

UNLABELLED The hypothalamic-pituitary insulin-like growth factor I (IGF-I) axis was evaluated in 12 children with chronic renal failure (CRF) aged 3.2 to 16.5 yr (mean 9.5) on chronic dialysis, and in 13 renal transplantation patients aged 7.5 to 15.0 yr (mean 11.1). Height standard deviation score (SDS) was -2.8 +/- 0.5 (mean +/- SE) and -3.0 +/- 0.3 SDS (p = NS), and growth velocity was 3.7 +/- 0.4 and 1.5 +/- 0.3 cm/year (p < 0.01), respectively. Mean nocturnal growth hormone (mean GH) and number of pulses > 5 ng/ml in CRF and transplantation children were 4.2 +/- 0.8 vs 2.4 +/- 0.3 ng/ml, p = 0.08 and 1.7 +/- 0.2 vs 1.0 +/- 0.2, p < 0.05, respectively. In transplant children there was a positive correlation between mean GH and growth velocity (p < 0.02). GH peak response and the area under the curve post GH releasing hormone test were significantly higher in CRF and transplant children treated with deflazacort (new steroid derived from prednisolone) vs transplant children treated with methylprednisone. Mean serum IGF-I levels were -0.5 +/- 0.2 SDS for chronological age (CA) in CRF patients and +0.8 +/- 0.2 SDS(CA) in transplant patients, p = NS. In the latter, serum IGF-I values were positively correlated with growth velocity (p < 0.02) and negatively correlated with methylprednisone dose (p < 0.05). CONCLUSIONS Patients with CRF and growth retardation have a higher number of GH peaks and slightly elevated mean GH levels compared to transplant patients. After renal transplantation GH secretion may be influenced by glucocorticoids as shown by the lower GH response to GHRH which improved with deflazacort and the inverse correlation between methylprednisone dose and IGF-I levels.

Soluble HLA class I antigens in pediatric patients with renal transplants from related living donors without acute rejection and treated with triple therapy.

All HLA class I Ag-expressing cells may be the source of serum Ag sHLA I. T and B lymphocytes secrete considerable amounts of Ag sHLA I in a variety of in vitro and in vivo activation systems. The purpose of this study was to evaluate the level of Ag sHLA I in serum of children with kidney transplants from related living donors without acute rejection and with triple therapy. We studied 25 patients (2-21 years) with first kidney transplant, 19 individuals (10-20 years) undergoing hemodialysis without transplant, and 25 normal children (4-21 years). The levels of Ag sHLA in transplant patients was 0.2-3.2 micrograms/ml (mean = 1.04). The hemodialyzed patients was 0.48-4.5 micrograms/ml (mean = 2.09), and the normal control was 0.30-4.38 micrograms/ml (mean = 2.04). A statistically significant reduction was observed in transplant patients compared to normal control and hemodialyzed patients (p < 0.05 in both cases), whereas between normal and hemodialyzed patients no significant difference was seen (p > 0.05). The reduced levels of Ag sHLA I in blood could be an expression of adequate immunosuppressive treatment.