Validation of PD Adequest 2.0 for pediatric dialysis patients.

Kinetic modeling has proven to be a valuable tool for peritoneal dialysis (PD) prescription in adult PD patients. The clinical application of this procedure has rarely been studied in children. We therefore evaluated the PD Adequest 2.0 for Windows program (Baxter Healthcare Co., Deerfield, IL) as a prescription aid for the management of pediatric PD patients by comparing the measured and predicted PD clearances, total drain volumes, and net ultrafiltration in 34 children (15 males) (mean age 10.9 +/- 6.0 years) receiving long-term PD. In each case, a 4-h peritoneal equilibration test was conducted with a standardized test exchange volume of 1,100 ml/m2 BSA. A total of 43 24-h dialysate (plus urine in 12) collections were analyzed. The levels of agreement between measured and predicted values for weekly peritoneal and total urea Kt/V, weekly peritoneal and total creatinine clearance, daily drain volume, net ultrafiltration and daily peritoneal urea and creatinine mass removal were assessed with correlation coefficients (re) and Bland-Altman limits of agreement. The study revealed that there is a basic level of agreement between measured and modeled values for solute removal and total drain volume, with correlation coefficients ranging from 0.75 to 0.98. In contrast, the rc for net ultrafiltration was only 0.34. The majority (75%) of patients had modeled urea and creatinine clearances that were within 20% of their measured values. These data suggest that the PD Adequest 2.0 for Windows program can predict urea and creatinine clearances with reasonable accuracy in pediatric PD patients, making it a valuable resource in prescription management.

Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

We define delayed graft function (DGF) as the need for dialysis during the first post-transplant week. We analyzed 5272 transplants, of which 2486 were of living donor (LD) and 2786 were of cadaver donor (CD) origin. Twelve per cent (620/5272) of all patients developed DGF. Donor specific rates were 5.6% for LD and 19.1% for CD patients. Factors predictive of DGF in CD patients were: African-American race (25%), prolonged cold ischemia (24%), absence of T-cell induction antibody therapy and absence of HLA-DR matching. The relative risk (RR) for graft failure due to DGF was 6.02 (p < 0.001) in LD patients and 2.58 (p < 0.001) for CD recipients. Two-year graft survival (GS) in LD patients without DGF was 89.6%, compared to 41.6% for those with DGF (p < 0.001); in CD patients it was 80.2% and 49.5%, respectively (p < 0.001). Censoring for primary non-function, GS for LD patients with a functioning graft at 30 d post-transplant and no DGF was 91.5%, compared to 70.1% for those with DGF (p < 0.001); GS for CD patients was 83.8% and 68.7%, respectively (p < 0.001). However, when patients whose grafts had failed during the first year were censored no differences in GS were noted between patients with and without DGF for either LD or CD recipients. To determine whether DGF acts as an independent risk factor for graft failure, patients were segregated into four groups: rejection with DGF; rejection without DGF; DGF without rejection; and no DGF, no rejection. When these groups were compared DGF emerged as an independent risk factor for graft failure. This large study reviewing pediatric renal transplantation over 10 yr clearly delineates the role of DGF as a major risk factor for graft failure.

Therapy of focal and segmental glomerulosclerosis with methylprednisolone, cyclosporine A, and prednisone.

Patients with steroid-resistant focal and segmental glomerulosclerosis (FSGS) have a poor prognosis but may benefit from high-dose methylprednisolone or cyclosporine A therapy. Ten patients were treated with a protocol of methylprednisolone infusions for 8 weeks followed by a combination of cyclosporine A and alternate-day prednisone for maintenance of remission for 2 weeks. Eight of ten patients remitted the nephrotic syndrome within 8 weeks of beginning treatment. One patient remitted edema but remained proteinuric, and one did not respond. After observation for 12-24 months, seven patients maintained remission with normal glomerular filtration rate. One non-responder had renal insufficiency and one patient had secondary non-response and end-stage renal disease. No patients developed hypertension. One patient had the diagnosis of Hodgkin disease made after 10 months of therapy. Follow-up renal biopsy in four patients showed no evidence of progressive interstitial disease. There were no other major side effects. Steroid-resistant FSGS may be successfully treated with the described protocol. Additional studies will be needed to determine if this approach prevents progression of renal disease.

The impact of donor source, recipient age, pre-operative immunotherapy and induction therapy on early and late acute rejections in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Acute rejection is a frequent event in pediatric transplantation. In addition to graft loss, acute rejection episodes stimulate the development of chronic rejection and inhibit growth in children post-transplantation. In this study, we analyzed our data from 1987 through 1996 to identify acute rejection episodes in children. In 2,520 living donor (LD) transplants there were 2,540 rejection episodes (rejection ratio: 1.1), and in 2,579 cadaver donor (CD) transplants 3,653 episodes were observed (rejection ratio: 1.32). For LD recipients the first rejection occurred sooner when there was at least one HLA-DR mismatch (RR=1.6, p<0.001) and prophylactic T-cell antibody was not used (RR=1.4, p<0.001). For CD transplants absence of prophylactic T-cell antibody (RR=1.2, p<0.001) and donor age below five years were risk factors (RR=1.5, p<0.001). Late initial acute rejections were seen in 327 of 1,471 patients (22.2%) who were rejection free at one year. At risk for the development of late rejections were children over the age of six years at transplantation (RR=1.7, p<0.001) and children of non-white origin (RR=1.5, p <0.002). For LD transplant recipients in the age range of 0-5 years, irreversible rejection was observed in 8.7% compared to 4.1% for older children (RR=1.46, p<0.001). Similar results for CD transplants were 12.6% versus 6.6% (RR=1.5, p<0.00). The high frequency of rejection episodes in children and the greater irreversibility in younger children suggest pediatric patients may have a more robust immune response. Current ongoing studies in the molecular mechanisms of the pathogenesis of rejection in surveillance biopsies of children may help determine if this hypothesis is valid.

The effect of rhGH in vitro on donor-specific hyporesponsiveness in pediatric transplantation.

Recombinant human growth hormone (rhGH) improves growth in children after renal transplantation, but may be associated with augmented immune responses. To understand the effect of rhGH in transplantation, we evaluated the role of rhGH in a mixed leukocyte culture (MLC) in vitro. We demonstrated that PBMC isolated from normal adult volunteers cultured in an MLC in the presence of rhGH develop an augmented proliferative (25-400%) and cytotoxic (50-600%) response. Using in situ hybridization (ISH), we demonstrated that the frequency of cells expressing mRNA for IFNgamma increased in the presence of rhGH (100-800%). In vitro responses of PBMC from adults in an MLC may only loosely reflect responses in vivo during pediatric transplantation. After transplantation, adults develop decreased responses to donor-specific antigens in an MLC (donor-specific hyporesponsiveness - DSH). We evaluated the donor-specific responses of 20 pediatric patients who had each received a renal allograft from one parent. Pediatric patients developed DSH similarly to adults; however, no correlation was seen between the amount of DSH and graft function. We also evaluated the expression/production of IFNgamma and IL4 in response to donor-specific alloantigens. Patients exhibit marked DSH of IFNgamma expression and production. However, IL4 production was seen in 8 out of 10 patients with normal renal function, but only 1 out of 7 patients with biopsy proven chronic rejection. Finally, we evaluated the effect of rhGH in vitro on DSH. Only 3 out of 20 patients developed augmented donor-specific responses in the presence of rhGH in vitro. rhGH augments proliferation, cytotoxicity and IFNgamma expression during an MLC. After renal transplantation, rhGH augments donor-specific responses during an MLC in some pediatric patients.

Growth hormone is safe in children after renal transplantation.

With the availability of an easily produced and safely administered form of recombinant human growth hormone (GH), the clinical indications for its use have increased. Recent studies have shown that GH therapy is both safe and effective in the treatment of growth failure in children with chronic renal insufficiency. Similarly, GH has been used to treat growth failure in children after renal transplantation. GH therapy increases growth in these patients, but in some of them increased organ rejection or worsening of kidney function occurs. GH is a neuroendocrine peptide that is important to somatic growth, but it has also been shown to have pleiotropic effects on many cells and organ systems including the immune system. We have shown that GH in vitro augments the responses during a mixed leukocyte culture in normal adult volunteers. GH also augments the responses to donor-specific alloantigens in some patients. We conclude that if in vitro assays such as these can successfully identify those patients who are at risk for organ rejection and worsening kidney function, then GH therapy is safe in children with growth failure after renal transplantation.

Peritoneal membrane transport function in children receiving long-term dialysis.

Accurate characterization of peritoneal solute transport capacity in children has been hampered by a lack of standardized test mechanics and small patient numbers. A standardized peritoneal equilibration test was used to study 95 pediatric patients (mean age, 9.9 +/- 5.6 yr) receiving chronic peritoneal dialysis at 14 centers. Patients were divided into four age groups (< 1, 1 to 3, 4 to 11, 12 to 19 yr) for analysis. Each patient received a 4-h peritoneal equilibration test with an exchange volume of 1100 mL/m2 per body surface area. Dialysate to plasma (D/P) ratios for creatinine (C) and urea (U) and the ratio of dialysate glucose (G) to initial dialysate glucose concentration (D/D0) were determined. Mass transfer area coefficients (MTAC) were calculated for the three solutes and potassium (P). The mean (+/- SD) 4-h D/P ratios for C and U were 0.64 +/- 0.13 and 0.82 +/- 0.09, respectively. The mean 4-h D/D0 for G was 0.33 +/- 0.10. D/P and D/D0 ratio results were similar across age groups. Normalized (for body surface area) mean MTAC (+/- SD) values were as follows: C, 10.66 +/- 3.74; G, 12.93 +/- 5.02; U, 18.43 +/- 4.02; and P, 14.02 +/- 3.94. Whereas a comparison of the normalized MTAC values across age groups with an analysis of variance showed significant age group differences only for glucose (P = 0.001) and potassium (P = 0.036), analysis by quadratic regression demonstrated a nonlinear decrease with age for C (P = 0.016), G (P < 0.001), and P (P = 0.034). In summary, evaluation of D/P and D/D0 ratios obtained from a large group of children in a standardized manner reveals values that are similar across the pediatric age range and not unlike the results obtained in adults. In contrast, normalized MTAC values of young children are greater than the values of older children, possibly as a result of maturational changes in the peritoneal membrane or differences in the effective peritoneal membrane surface area.

The 1994 annual report of the North American Pediatric Renal Transplant Cooperative Study.

The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) is a research effort that was organized and initiated in 1987. The following manuscript is the 1994 NAPRTCS annual report which has summarized data that has been voluntarily contributed by 83 centers. The report includes data on 3,183 patients who have undergone a total of 3,445 renal transplants between 1 January 1987 and 18 February 1994 when the data set was closed. The report also contains data on 1,611 independent courses of dialysis which were initiated between 1 January 1992 and 18 February 1994. This report is meant to update the previous NAPRTCS annual reports as well as demonstrate how the NAPRTCS database has changed clinical practice since its inception. There have been 855 graft failures among the 3,438 transplants. Due to the maturing of the database, chronic rejection now accounts for 34% of graft failures which have occurred over the last year. Graft failure was increased in recipients if the recipients were < 2 years of age, of the black race, or had received five or more prior transfusions. Early treatment with antithymocyte globulin/antilymphocyte globulin/OKT3 was associated with increased graft survival. Catch-up growth post transplant was only seen in the youngest patients (< 6 years of age). Those patients > 6 years did not have catch-up growth post transplant. Overall graft survival has improved markedly since the inception of this study. The dialysis database is just maturing and the data confirm that growth on dialysis continues to be very poor. The 1994 annual report of NAPRTCS extends previous findings of this valuable database. It is gratifying to know that early findings of NAPRTCS have led to changes in therapy which have led to improvement in the care of these very special children.

The effect of recombinant human growth hormone on responses to alloantigens in the pediatric transplant patient.

Recombinant human growth hormone (rhGH) improves growth in children after renal transplantation, but may be associated with augmented immune responses. We previously demonstrated that rhGH augments proliferative and cytotoxic responses and interferon-gamma (IFN-gamma) mRNA expression during a mixed leukocyte culture (MLC). In this study, we evaluated 12 pediatric patients after receiving a renal allograft from one of their parents. Peripheral blood mononuclear cells (PBMC) were isolated from patients and cultured with either donor or unrelated third-party PBMC in an MLC. Patients developed significant donor-specific hyporesponsiveness (DSH), however, no correlation was seen between the amount of DSH and graft function. Of the 12 patients, 2 developed augmented responses in the presence of rhGH. rhGH augments proliferation, cytotoxicity, and IFN-gamma expression during an MLC. Some patients develop increased responses to donor-specific alloantigens after renal transplantation. Further study is needed to better determine the significance of this finding.

Prevention of tumor lysis syndrome using continuous veno-venous hemofiltration.

Tumor lysis syndrome (TLS) and renal failure remain significant causes of morbidity and mortality in children with newly diagnosed Burkitt's lymphoma and high white blood cell count acute lymphocytic leukemia (ALL) despite conventional management with aggressive hydration, alkalinization, allopurinol, and the slow introduction of chemotherapy. A subgroup of patients at very high risk for TLS and renal failure can be identified based on the level of serum lactate dehydrogenase (LDH) and urine output. We evaluated the prospective use of continuous veno-venous hemofiltration (CVVH), in addition to conventional management to prevent renal failure from tumor lysis, in three children with advanced abdominal Burkitt's lymphoma and in two children with high white blood cell count T-cell ALL who were at very high risk based on LDH and urine output. In this cohort of very high-risk patients, the LDH ratio (value at diagnosis/upper limit of normal) ranged from 0.88 to 10.3 and urine output from 0.13 to 4.7 ml/kg per hour. CVVH was begun at a mean time of 10.5 h before chemotherapy was initiated. Full-dose induction chemotherapy was begun within 24 h of diagnosis. After beginning CVVH, the uric acid levels decreased 46% prior to beginning chemotherapy and decreased to a mean of 4.2 mg/dl 24 h after chemotherapy was initiated. Four of the five patients had either no change or a drop in the serum creatinine. In patient one, blood urea nitrogen peaked at 58 mg/dl, and the creatinine at 4.7 mg/dl 6 days after beginning chemotherapy with a subsequent return to normal. Asymptomatic hypokalemia developed in all patients. After beginning chemotherapy, CVVH was continued for a mean of 85 h (range 70-91 h). No patient had complications secondary to CVVH. In summary, CVVH prevented renal failure secondary to TLS in 80% of these very high-risk patients. In the fifth patient, CVVH allowed full-dose chemotherapy to continue. The prospective use of CVVH could potentially decrease the morbidity and mortality associated with induction chemotherapy in very high-risk patients with a large tumor burden.

Recombinant human growth hormone in infants and young children with chronic renal insufficiency. Genentech Collaborative Study Group.

Children with chronic renal insufficiency (CRI) secondary to congenital structural abnormalities frequently have significant growth retardation by 2 years of age. In a multicenter placebo-controlled study of the use of recombinant human growth hormone (rhGH), 30 of 125 (24%) participants were < 2.5 years of age at enrollment. Since the treatment arms of the study were balanced for age at randomization, data for these patients were examined for efficacy and safety. During the first 2 years of the study, approximately two-thirds of the patients (n = 19) received rhGH 0.05 mg/kg per day subcutaneously and one-third (n = 11) received placebo injections. At entry into the study, the mean (+/- SD) calculated creatinine clearance was 29.2 +/- 14.3 (range 12.0-63.7) ml/min per 1.73 m2 in the rhGH-treated group and 23.3 +/- 15.1 (range 8.0-59.4) ml/min per 1.73 m2 in the placebo-treated group. The 1st year growth rate was 14.1 +/- 2.6 cm/year for the rhGH-treated group and 9.3 +/- 1.5 cm/year in the placebo-treated group (P < 0.00005). During the 2nd year of the study, the growth rate was 8.6 +/- 1.2 cm/year in the rhGH-treated group compared with 6.9 +/- 1.0 in the placebo group (P = 0.025). The delta height standard deviation score was +2.0 +/- 0.7 for the rhGH-treated group compared with -0.2 +/- 1.1 in the placebo-treated group (P < 0.00005) during the 2 years of the study. Minor adverse events occurred with similar frequency in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dialytic management of childhood acute renal failure: a survey of North American pediatric nephrologists.

A 35-question survey was mailed to 19 pediatric nephrologists regarding dialytic management of acute renal failure (ARF). Fifteen surveys were returned (79%). The purpose of the survey was to determine which renal replacement therapies (RRT) are most frequently used in the management of children with ARF in North America. Nephrologists were also questioned about clinical factors that influence the decisions to initiate RRT and choice of a particular modality. Survey results showed that hemofiltration was the initial choice for RRT among nephrologists (median value 40%, range 0%-100%) more often in their patients in the past 12 months than peritoneal dialysis (median value 30%, range 0%-85%) or hemodialysis (median value 20%, range 0%-50%). Factors considered most important in the decision to initiate dialysis include abnormalities in serum potassium, fluid balance, blood pressure and nutritional needs. Patient size and dialysis access were additional factors considered important in the choice of RRT modality.

Chronic renal disease and growth in childhood.

Growth failure, sometimes of a severe nature, has been recognized for many years as a consequence of chronic renal insufficiency (CRI) in childhood. The factors associated with growth failure, including renal osteodystrophy, anorexia and malnutrition, acidosis, salt wasting, and anemia, have also been recognized for many years. Despite vigorous treatment of these factors, patients with CRI continue to grow poorly. It was hoped that, with modern dialysis and transplantation, these patients would have normal growth or even catch-up growth and therefore overcome the height deficit that accrued during the time they had CRI. Unfortunately, this has not been the case. Although normal growth may be seen after transplantation, catch-up growth is rare. In the past year, studies have been reported demonstrating that supraphysiologic doses of growth hormone will produce catch-up growth in children with CRI. These reports are encouraging and are reviewed here.

Current approach to peritoneal access in North American children: a report of the Pediatric Peritoneal Dialysis Study Consortium.

To determine standard peritoneal access practices in North American children, a questionnaire was distributed to the 18 participating centers of the Pediatric Peritoneal Dialysis Study Consortium. The survey covered areas including catheter placement, postoperative catheter break-in, chronic catheter care, and treatment of exit-site and tunnel infection.

Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized double-blind placebo-controlled study. Genentech Cooperative Study Group.

OBJECTIVE: To determine whether treatment with recombinant human growth hormone (rhGH) enhances growth rate in growth-retarded children with chronic renal failure. DESIGN: One hundred twenty-five prepubertal growth-retarded children with chronic renal failure were randomly assigned to receive either rhGH (n = 82) or placebo (n = 43) for 2 years. SETTING: The study was undertaken at 17 pediatric nephrology centers in the United States. MEASUREMENTS: Growth rate, standardized height, bone age, fasting and 2-hour postprandial glucose and insulin levels, biochemical values, and insulin-like growth factor I and anti-growth hormone antibody levels were evaluated serially during the 2-year study period. RESULTS: Standardized height increased from -2.94 to -1.55 in the rhGH group after 24 months of treatment, and decreased from -2.82 to -2.91 in the placebo group (p < 0.00005). Patients in the rhGH group who completed 24 months of study (n = 55) had a greater growth rate during the first year (10.7 +/- 3.1 cm/yr) than during the second year (7.8 +/- 2.1 cm/yr) of treatment. These growth rates were significantly greater than those in the placebo group (n = 27) in the first (6.5 +/- 2.6 cm/yr) and second (5.5 +/- 1.9 cm/yr) years (p < 0.00005 for both years). The mean delta height age minus the delta bone age was positive in the rhGH group, suggesting improved final height potential. There was no significant difference in the change in calculated creatinine clearance over baseline values in the rhGH group from that in the placebo group after 24 months of study (p = 0.63). Mean fasting and postprandial insulin values were elevated at 12 months but not at 24 months in the rhGH-treated patients. Mean fasting and 2-hour postprandial glucose values at 24 months were not significantly elevated over baseline values in either group. CONCLUSIONS: Growth rate and standardized height were significantly increased in growth-retarded prepubertal children with chronic renal failure when rhGH was used. The acceleration in growth was not associated with undue advancement of bone age. No clinically significant side effects were associated with rhGH treatment. The use of rhGH in growth-retarded children with chronic renal failure may facilitate the achievement of the inherent growth potential of such children.

The effect of changes in dialysate volume on glucose and urea equilibration.

OBJECTIVES: To determine the effect of changing dialysate volume on urea and glucose equilibration curves and to determine, if dialysate volume is prescribed on the basis of body surface area, whether equilibrium curves will be consistent in patients of different sizes and ages. DESIGN: A prospective study wherein children with acute or chronic renal failure had peritoneal equilibrium studies done with dwell volumes of 30 mL/kg, 40 mL/kg, and 1200 mL/m2. PATIENT POPULATION: Twenty-two children: 7 under 3 years of age; 8 between 3 and 10 years of age; 7 older than 10 years of age. STATISTICS: Student's t-test. RESULTS: Urea and glucose equilibrated rapidly at dwell volumes of 30 mL/kg, slower at dwell volumes of 40 mL/kg, and slowest at dwell volumes of 1200 mL/m2. Equilibration curves were similar in children of different ages when dialysate volumes of 1200 mL/m2 were infused. CONCLUSION: Dialysate volumes of 1200 mL/m2 should be used when equilibration studies are being done to compare individuals of different ages and sizes.

Treatment of IgA nephropathy in children: efficacy of alternate-day oral prednisone.

We have previously reported our experience with the use of alternate-day prednisone in the treatment of 6 patients with IgA nephropathy who have clinical or pathological risk factors for disease progression. We have now treated a total of 13 patients and followed them from 4 to 10 years. Patients received an alternate-morning dose of prednisone for 2-4 years. Dosage began at 60 mg/m2 for 3 month, was reduced to 30 mg/m2 by 1 year and 15 mg/m2 by 2 years. At last observation, urinary protein excretion was normal in 12 patients and no patient had hematuria. Twelve patients had normal estimated glomerular filtration rate (GFR) and one had renal insufficiency (GFR = 38 ml/min per 1.73 m2). A renal biopsy was performed in 11 patients after 2 years of treatment. Activity score decreased from 5.2 to 4.3 (P = 0.03) and chronicity score increased from 2.2 to 2.8 (P = 0.12). There were no complications of treatment. When compared with a historical group, the treated patients had a significant improvement in urinalysis (P < 0.00001) and preservation of normal GFR (P = 0.03). We conclude that alternate-day prednisone therapy may benefit patients with IgA nephropathy. A large prospective controlled trial is needed.

Growth hormone in the treatment of growth failure in children after renal transplantation.

Growth failure continues to be a problem in the management of children with renal failure. Children have improved growth after successful renal transplantation, but seldom have "catch-up" growth, or achieve normal adult height. Several investigators have reported the use of rhGH in children after renal transplantation and demonstrated improved height, growth velocity, and standard deviation score (SDS). We review the existing literature, present additional data from our center, and offer possible explanations.