Long-term patient survival in a pediatric renal transplantation program.

In adult renal transplant recipients, reports have shown continuing mortality beyond 5 years after transplantation with the majority of deaths due to myocardial infarctions, malignancies, and liver failure. Little information is available on the long-term survival of children following renal transplantation. Children with end-stage renal disease have fewer systemic complications than adults and should have better long-term survival. Furthermore, analysis of mortality in the pediatric population should be more informative of the risks of renal transplantation, separate from underlying pretransplant diseases and the inherent complications of aging. We analyzed, therefore, the long-term mortality of renal transplant recipients in a single pediatric center. A total of 299 renal transplants were performed in 251 patients from 1971 through 1990. No patient was excluded from the evaluation. Over all, actuarial survival was 91% at 1 year, 83% at 10 years, and 81% at 15 years. Patient's age at transplantation, donor source, and number of previous allografts were not correlated with patient survival. There were 35 deaths with 51% attributable to infections. The majority of deaths (71%) occurred within the first 6 months after renal transplantation during the period of greatest immunosuppression. Mortality within the first 12 months following renal transplantation was higher during the period 1971-1974 when compared to subsequent years. These data demonstrate that in a pediatric renal transplant center, long-term patient survival is excellent. Most deaths occur within the first 6 months following renal transplantation and are caused by infections. As expected, long-term survival in children is better than reports in adult renal transplant recipients and may more accurately reflect true renal-transplant-related mortality.

Alternate-day steroid dosing improves growth without adversely affecting graft survival or long-term graft function. A report of the North American Pediatric Renal Transplant Cooperative Study.

Data from the North American Pediatric Renal Transplant Cooperative Study were analyzed to determine the effects of alternate-day (QOD) steroid dosing on growth, graft survival, and graft function in children with functioning grafts 12 months after transplantation. At 12 months after transplantation, 16.8% (337/2001) of transplant recipients were receiving QOD dosing. The basis for the selection of a steroid dosing regimen cannot be determined from registry data; however, the frequency of QOD dosing differed by donor source, race, age at transplant, and the occurrence of rejection episodes in the first year. The effect of the steroid dosing pattern on growth was evaluated in children continuously on either QOD or daily (QD) steroid dosing. The mean change in the standardized height scores from 1 month to 24 months after transplantation was significantly greater in those on QOD dosing (+0.5 +/- 0.06) than in those on QD dosing (+0.1 +/- 0.03). Using multiple regression analyses, better growth was associated with QOD dosing, recipient age less than 13 years, lower total steroid dose over 48 hr, and lower serum creatinine (all P < 0.001). Graft survival did not differ on the basis of the steroid dosing pattern. In a proportional hazards model for survival of living donor grafts after 12 months, graft survival was negatively associated with the use of QD dosing, black race, rejection episodes in the first year, and a higher serum creatinine at 12 months. The survival of cadaver grafts was negatively associated with the use of QD steroid dosing, recipient age less than 2 years, rejection episodes in the first year, and a higher serum creatinine at 12 months. In addition, the decline in graft function did not differ between those on QOD steroid therapy and those on QD therapy. We conclude that selected pediatric renal transplant recipients receiving QOD dosing have better growth than those receiving QD dosing without compromising allograft survival or function.

Endocrinologic evaluation of children who grow poorly following renal transplantation.

Some children do not grow well following successful renal transplantation. We reviewed 25 children with renal allografts who receive regular medical care in the renal transplant program at The Children's Hospital, were less than or equal to 18 years of age, and had stable renal function. We compared children who were growing well (n = 14) with those who were growing poorly (n = 11). The children with poor growth more frequently had elevated serum creatinine concentrations (8/11 vs. 3/14). The mean age at transplantation was the same, although the duration of follow-up was shorter for the children growing well (3.3 +/- 0.5 years) than for those growing poorly (6.2 +/- 1.0 years, P less than 0.02). Eight of the children who were growing poorly underwent endocrinologic evaluation. Plasma growth hormone (GH) concentrations were measured during sleep, after arginine and L-DOPA administration, and during a 4-hr oral glucose tolerance test. In 4 patients, the maximum GH concentration was inadequate both following pharmacologic stimulation (4.0 +/- 2.6 ng/ml, n = 4) and during sleep (4.4 +/- 0.2 ng/ml, n = 3). In 2 additional patients, maximal GH concentrations were subnormal during sleep despite adequate responses during pharmacologic stimulation. In the final two patients, GH secretion was adequate both during sleep and after stimulation. All children studied had some degree of renal insufficiency with a mean creatinine clearance of 39 +/- 4 ml/min/1.73 m2. Plasma concentrations of thyroxine, thyrotropin, and IGF-I were normal for age in all eight patients. We conclude that abnormalities in GH secretion occur frequently among patients who grow poorly following successful renal transplantation. Evaluation of GH secretion may be useful in evaluating growth failure in this group of patients, and the usefulness of GH therapy should be investigated.

Interaction between tacrolimus and chloramphenicol in a renal transplant recipient.

BACKGROUND: The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient. METHODS: An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation. RESULTS: Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicol CONCLUSIONS: Chloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

Relationship between birthweight and blood pressure in childhood.

Studies have shown an inverse relationship between birthweight and blood pressure in later life. The objective of this study is to analyze the relationship between birthweight and blood pressure in childhood in a North American-based population. Data on 2,958 births with follow-up at 7 years of age from the Providence, RI, cohort of the Collaborative Perinatal Project of the National Institute of Neurological Diseases and Stroke were retrospectively analyzed using univariate and multivariate analytic methods. Bivariate analysis of the total cohort showed a direct relationship between follow-up weight at age 7 years and birthweight (r = 0.24; P < 0.001) and follow-up weight with systolic (SBP) and diastolic blood pressure (DBP; r = 0.33; P < 0.001 and r = 0.22; P < 0.001, respectively). On multivariate analysis, follow-up weight and height were the strongest predictors of SBP and DBP. There was also a significant inverse relationship between birthweight and SBP. A cohort of term infants (n = 2,561) was subdivided into birthweight-for-gestational-age groupings to further evaluate the effects of birthweight on blood pressure. Small-for-gestational-age (SGA) infants were markedly smaller at age 7 years than those large-for-gestational-age (LGA; 21 +/- 4 kg v 26 +/- 4 kg; P < 0.01). Despite the direct association between follow-up weight and blood pressure, the mean blood pressure did not differ between SGA (103/58 mm Hg) and LGA patients (103/59 mm Hg). To assess whether birthweight was an independent predictor of blood pressure, blood pressures were predicted using linear regression equations. For every 1-kg decrease in birthweight in term infants, SBP at 7 years increased by 1.3 mm Hg and DBP by 0.6 mm Hg. In conclusion, controlling for weight and height in term infants at 7 years of age has an inverse linear effect on blood pressure. This suggests that birthweight in relation to gestation may be a contributor to the multifactorial cause of essential hypertension.

Growth hormone treatment of growth failure among children with renal transplants.

Eight children with growth failure following renal transplant have been selected for recombinant human growth hormone (rhGH) treatment at Children's Hospital using the following criteria: (1) a functioning allograft for at least one year; (2) height < third percentile; (3) growth velocity < 4 cm/year; (4) growth potential; and (5) low-dose alternate-day glucocorticoid dosing. The children were 7.4 to 17.7 years of age; had received transplants 2.6 to 12.3 years before rhGH treatment; and all had decreased allograft function. The growth velocity of these children increased from 1.7 +/- 0.7 to 7.1 +/- 2.1 cm/year during the first year of rhGH treatment (0.05 mg/kg s.c. daily). The mean height SD score improved -3.9 +/- 1.5 to -3.4 +/- 1.3 in the seven children who completed one year of treatment (P < 0.001). There was no change in glucose tolerance during rhGH treatment. The serum creatinine concentration increased in all patients with a concomitant decrease in creatinine clearance. The mean rate of change in the inverse creatinine (1/Cr) increased from -0.005 +/- 0.004 dl/mg/month in the two years prior to rhGH treatment to -0.023 +/- 0.015 dl/mg/month during rhGH treatment (P < 0.01). The relative risks and benefits of rhGH treatment must be carefully considered for each patient.

New hormones in the therapeutic arsenal of chronic renal failure. Growth hormone and erythropoietin.

Although the benefits of rhGH and r-HuEPO therapy in children with CRF and on dialysis are already significant, further study of these new additions to the therapeutic arsenal remains necessary. Data on the final adult height achieved in patients who receive rhGH are extremely important information that is as yet unavailable. The risks and benefits of raising the target hematocrit to a "normal" value in patients receiving r-HuEPO remains under study. Only when these and other issues are soundly evaluated will the full impact of these medications be understood.

[Folie à deux - mental infection or individual psychosis]. / Die Folie à deux - Psychische Ansteckung oder eigenständige Psychoseerkrankungen?

The phenomenon of folie à deux has been a topical issue in psychiatry for more than a century. Mainly, genetic and psychodynamic factors are discussed controversially in terms of their relevance to the etiology of folie à deux. In this paper, effort is taken to reconceive the topic applying the criteria of a differentiated psychopathological classification. Based on the literature and on two own cases, we try to elaborate characteristical psychopathological features of folie à deux patients. We hypothesize that at least a substantial fraction could be classified as "folie simultanée" when Leonhard's criteria of the affect-laden paraphrenia are considered.

The effects of recombinant human erythropoietin on growth and nutritional status.

The availability of recombinant human erythropoietin (rhuEPO) has dramatically improved the care of children with chronic renal failure (CRF). Its use provides the opportunity to determine the relative contribution of anemia to the morbidity of CRF. Growth retardation, one of the most significant complications of CRF in children, is the consequence of several inter-related processes, including decreased protein and energy intake, metabolic bone disease, endocrine abnormalities, and anemia. The literature on the use of rhuEPO in children and data from a United States phase III double-blind, placebo-controlled study of rhuEPO in pediatric dialysis patients are reviewed to determine the effect of rhuEPO treatment on the nutritional status and growth of children with CRF. Despite subjective increases in appetite, there were no consistent improvements in dietary intake or anthropometric measures observed during rhuEPO treatment. Children gained weight during rhuEPO treatment; however, this was not generally associated with increased weight standard deviation scores. There was an improvement in growth velocity in some children; however, improvements in height standard deviation scores were infrequently seen. On review of the available literature, correction of anemia with rhuEPO has not been shown to improve the growth of children with CRF.

Factors affecting growth after renal transplantation.

Renal transplantation has been recognized as the treatment of choice for children with chronic renal failure principally because it can normalize their physiologic status and thus provide them with the potential for normal growth. The results of renal transplantation, however, have been mixed with some reports of excellent posttransplant growth and others with less optimistic results. Some of the differences among these studies may be because of the use of multiple methods to assess the success or failure of posttransplant growth. The usual methods have included assessment of the final adult height, growth velocity, presence of accelerated growth rates, change in height standard deviation scores, and growth survival. All of these methods have advantages and disadvantages in the description of the success or failure of growth after renal transplantation, but no single method stands out as the most appropriate to use in all circumstances. Furthermore, growth is dependent on a large number of complex and interrelated factors. At least four of these factors have been shown to affect the growth rates of children after renal transplantation: age at the time of transplant; allograft function; the type, dose, and schedule of immunosuppressive medication; and other endocrinologic factors. Finally, analysis of long-term growth patterns in children after renal transplantation has shown that growth rates frequently decrease over time. Even children who have grown well immediately after the transplant may develop growth failure after several years. We conclude that the majority of children with renal transplants can experience normal or even accelerated growth rates after the procedure. Unfortunately, growth rates subsequently tend to decline in most children.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human erythropoietin therapy in children on dialysis.

The addition of recombinant human erythropoietin (rHuEPO) to the therapeutic regimen for children with chronic renal failure (CRF) is one of the most important improvements in care in the last 20 years. Anemia had played an important role in the morbidity of chronic dialysis treatment. Before the availability of rHuEPO, repeated erythrocyte transfusions provided incomplete treatment and had significant long-term sequelae. Recombinant erythropoietin treatment resulted in the amelioration of anemia and marked reduction in transfusions. Additional benefits of the correction of anemia with rHuEPO include improvements in exercise tolerance and regression of ventricular hypertrophy. Many rHuEPO-treated patients have had subjective increases in appetite, but there has been no consistent improvement in dietary intake or anthropometric measures. Correction of anemia with rHuEPO has not been shown to improve the growth of children with CRF receiving dialysis. The most significant adverse effects of rHuEPO are the development of iron deficiency and the exacerbation or development de novo of hypertension. RHuEPO treatment has been shown to treat the anemia of CRF in children safely and effectively. In most cases, putative inhibitors of erythropoiesis and blood loss can be overcome. Many of the symptoms previously ascribed to "uremia" have improved with correction of anemia. The full implications of treatment of anemia with rHuEPO will be clearer when the health outcomes for children who never become severely anemic or require transfusions are more completely studied.

The impact of the Dialysis Outcomes Quality Initiative Guidelines on the care of the pediatric end-stage renal disease patient.

The National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Guidelines for hemodialysis and peritoneal dialysis adequacy, management of vascular access, and management of anemia are based primarily on evidence derived from the experience of adult dialysis patients. However, these Guidelines can also be used to improve the care of children with end-stage renal disease (ESRD). Some of the guidelines are directly applicable to pediatric dialysis patients, such as the preferential use of the internal jugular vein for placement of a central venous catheter for dialysis. Other Guidelines, such as targets for adequacy of hemodialysis and peritoneal dialysis, serve as minimal standards of care for children with little supporting data specific to pediatrics. The importance of early referral and proactive care for children and adults with chronic renal failure is emphasized in all of the Guidelines. Optimum care should include early discussion of transplantation and choice of dialysis modality, preservation of sites for future vascular access, and early attention to anemia and nutrition. Clinical algorithms should be developed to implement the current Guidelines while data are generated to support modification of any of the recommendations for children.

Sodium modeling ameliorates intradialytic and interdialytic symptoms in young hemodialysis patients.

Despite advances in the delivery of hemodialysis, significant dialytic morbidity persists. Sodium modeling in older adults has been shown to decrease some dialytic symptoms, but clear benefits in young patients without coexisting diabetes or advanced cardiovascular disease have not been shown. The effects of sodium modeling were evaluated in 16 adolescent and young adult hemodialysis patients (16 to 32 yr of age) treated with conventional hemodialysis for a median of 11.5 months. The 8-wk study was divided into four 2-wk blocks. During each block, one of three sodium programs or a constant (control) dialysate sodium of 138 mEq/L was used. During each sodium program, the initial dialysate sodium of 148 mEq/L was decreased by an exponential, linear, or step program to 138 mEq/L. Treatments with sodium modeling were significantly better than those with constant sodium dialysate. When all sodium programs were grouped and compared with constant dialysate sodium, the odds of improvement in dialytic cramps, headaches, and nausea were 1.8, 2.1, and 3.9, respectively (P < 0.05). Sodium modeling also significantly decreased the frequency of postdialysis hypotension and interdialytic fatigue, dizziness, and muscle cramping (P < 0.05). No differences were seen among the sodium protocols in the incidence of symptomatic hypotension, the amount of normal saline administered, the degree of hemo-concentration during treatments, or the decrease in serum osmolality. There was no increase in pretreatment or posttreatment serum sodium concentrations, interdialytic thirst, weight gain, or hypertension. Sodium modeling dramatically decreases both intradialytic and interdialytic morbidity in young hemodialysis patients. There was no increase in adverse events associated with sodium modeling.

Prostaglandin E2 inhibits Na+-K+-ATPase activity in the inner medullary collecting duct.

Prostaglandin E2 (PGE2) is natriuretic and inhibits collecting duct sodium transport by poorly defined mechanisms. To determine the mechanism of this inhibition, we have studied the effect of PGE2 on ouabain-sensitive (transport-dependent) oxygen consumption (QO2), ouabain-sensitive 86Rb+ uptake and ouabain-sensitive ATPase activity in fresh suspensions of rabbit inner medullary collecting duct cells, as well as Na+-K+-ATPase activity in inner medullary membranes. PGE2 (10(-5) M) reduced total QO2 by 21.6 +/- 2.3% (mean +/- SE) and reduced the ouabain-sensitive component of QO2 in IMCD cells. PGE2 failed to inhibit QO2 in the absence of sodium or in the presence of ouabain and blunted the increase in QO2 in response to amphotericin B. These results suggested that PGE2 inhibited Na+-K+-ATPase activity. Inhibition of pump activity was confirmed by measurements of 86Rb+ uptake: PGE2 (10(-5) M) reduced ouabain-sensitive 86Rb+ uptake by 57% at 10 s without altering equilibrium uptake. Furthermore, PGE2 (10(-6) M) reduced ouabain-sensitive ATPase activity by 46% in permeabilized inner medullary collecting duct cells. PGF2 alpha (10(-5) M) did not significantly alter QO2, 86Rb+ uptake, or Na+-K+-ATPase activity. These results demonstrate that PGE2 inhibits inner medullary collecting duct Na+-K+-ATPase activity and suggest a role for this inhibition in the natriuretic effect of PGE2.

Hemodialysis catheter survival and complications in children and adolescents.

Venous catheters have become an indispensable form of hemodialysis access. We evaluated catheter performance as temporary and long-term access in children with end-stage renal disease (ESRD). We assessed the survival rates and causes of catheter failure in 78 catheters used for hemodialysis access in 23 pediatric patients (aged 10 months to 22 years) with ESRD over a 5-year period. Median survival was 31 days for 56 uncuffed catheters. One- and 2-month actuarial survival was 69% and 48%, respectively. Reasons for removal were: elective (39%), kinking (36%), trauma (11%), infection (7%), and other (5%). Smaller catheters (7 or 9 French) were more likely to be removed for kinking (P = 0.003). One-year actuarial survival for 22 cuffed catheters was 27%. Cuffed catheters were removed due to: infection (36%), kinking (14%), elective (9%), trauma (9%) and other (9%). Twelve catheters were removed for infection. Infection rates leading to removal were 0.58 and 0.71 per patient-year for uncuffed and cuffed catheters, respectively. Staphylococcus species were cultured most commonly. We conclude that uncuffed catheters function well for short-term hemodialysis access of up to 2 months' duration and cuffed catheters are successful for long-term access in children and adolescents with ESRD.

Acute hemodialysis of infants weighing less than five kilograms.

The records of 33 infants weighing 5 kg or less who received acute hemodialysis treatment at Children's Hospital between 1980 and 1991 were reviewed. Dialysis was initiated to treat hyperammonemia (8), primary renal or renovascular disease (7), and acute renal failure (18). The infants weighed 2.2 to 4.0 kg at birth and 27% were born prematurely. The infants were 2 to 120 days of age (median 10 days) and weighed 2.2 to 5.0 kg (median 3.5 kg) at the initiation of hemodialysis. Hemodialysis access was achieved via double-lumen 7 French catheters in 49% of the infants, the ECMO circuit in 24%, and the umbilical vessels in 27%. Thirty-three infants underwent a total of 216 hemodialysis treatments. Only nine treatments were discontinued prematurely: six for intractable hypotension and three for technical problems. Fifty-two percent (17 of 33) of the infants survived through the end of the hemodialysis treatment course. The survival rates for the infants with hyperammonemia (75%) and primary renal disease (71%) were better than those for infants with acute renal failure (33%). The survivors did not differ from those who died with respect to birthweight, weight when hemodialysis was initiated, or the number of hemodialysis treatments administered. We conclude that infants weighing less than 5 kg can be treated successfully with hemodialysis. Patient survival is related to underlying medical problems, not to complications of hemodialysis.

Kinins inhibit conductive Na+ uptake by rabbit inner medullary collecting duct cells.

Kinins promote natriuresis in vivo, at least in part by altering Na+ transport in the collecting duct. Using freshly prepared suspensions of rabbit inner medullary collecting duct (IMCD) cells, we have examined the effects of kinins on Na+ transport using measurements of oxygen consumption (QO2) and isotopic Na+ uptake. Bradykinin (BK) inhibited IMCD cell QO2 by 24.7 +/- 0.9% without significantly reducing QO2 in cells derived from the outer medullary collecting duct. BK and kallidin half-maximally inhibited QO2 at concentrations in the 10(-12)-10-(-11) M range; beta 1-receptor agonists did not alter QO2, and beta 1-receptor antagonism did not reduce the effect of kinins. These observations indicate that the actions of kinins on IMCD cells are mediated by beta 2-receptors or a distinct subclass. Several observations indicate that kinins reduce QO2 by inhibiting Na+ entry: in the absence of Na+, BK did not reduce QO2; BK inhibition of QO2 was not additive with ouabain, amiloride, atrial natriuretic peptide (ANP), or 8-bromoguanosine 3',5'-cyclic monophosphate and was abolished in the presence of the cation ionophore amphotericin B. Measurements of isotopic Na+ uptake demonstrated that BK reduced the initial rate of Na+ entry by 58%; BK inhibited the amiloride-sensitive component of conductive Na+ uptake. Because ANP inhibits conductive Na+ entry in IMCD cells via stimulation of cGMP accumulation, the effect of BK on cGMP levels was determined. Unlike ANP, BK did not increase cGMP levels, indicating that transport effects of kinins in IMCD are not mediated by cGMP. Thus kinins directly inhibit conductive Na+ entry in IMCD cells at concentrations suggestive of a physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune interstitial nephritis and hepatitis in polyglandular autoimmune syndrome.

A 6-year-old female with polyglandular autoimmune syndrome type I, chronic active hepatitis, and renal failure is described. The renal biopsy demonstrated advanced tubulointerstitial disease with antibodies directed against tubular basement membranes. The patient's serum contained circulating antibodies directed against both renal and hepatic parenchyma. Renal disease culminating in renal failure and anti-tubular basement membrane disease have not been previously reported in association with polyglandular autoimmune disease. We describe for the first time a patient with polyglandular autoimmune syndrome, chronic active hepatitis, circulating antibodies directed against both renal and hepatic parenchyma, and primary tubulointerstitial disease culminating in renal failure.

Acyclovir prophylaxis of varicella in children with renal disease receiving steroids.

Varicella, or chickenpox, is very communicable and has been shown to be transmitted to nearly 90% of household contacts. Severe varicella infections with fatal complications have been noted in children receiving corticosteroids despite the administration of varicella-zoster immune globulin (VZIG). The use of post-exposure acyclovir prophylaxis in immunocompetent children exposed to a household contact with varicella has been shown to decrease the transmission rate of varicella significantly. We studied the safety and efficacy of acyclovir prophylaxis as an adjunctive preventive measure in 8 children (10 separate exposures) receiving corticosteroids for renal disease. Four children (6 separate exposures) served as controls. No adverse reactions were reported with the acyclovir prophylaxis. The maximum change between pre- and study serum creatinine levels was 0.1 mg/dl. None of the 8 patients who received acyclovir prophylaxis developed chickenpox. One of these 8 patients developed humoral immunity to varicella despite the absence of clinical infection. One of 4 patients who received VZIG prophylaxis alone developed chickenpox. These data support the use of acyclovir prophylaxis as an adjunctive measure to VZIG for the prevention of potentially serious varicella infection in children receiving steroids.