Inferior Outcomes on the Waiting List in Low-Volume Pediatric Heart Transplant Centers.

Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low-volume centers (fewer than three annual transplantations). Of these listed candidates in low-volume centers, only 36% received a transplant versus 89% in high-volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low-volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5-5.7 in multivariate Cox regression and HR 5.6, CI 4.4-7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0-1.6 in multivariate Cox regression). During the study period, one-fourth of pediatric transplant candidates were listed in low-volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist.

Kidney and pancreas transplantation in the United States, 1999-2008: the changing face of living donation.

The waiting list for kidney transplantation continued to grow between 1999 and 2008, from 41 177 to 76 089 candidates. However, active candidates represented the minority of this increase (36 951-50 624, a 37% change), while inactive candidates increased over 500% (4226-25 465). There were 5966 living donor (LD) and 10 551 deceased donor (DD) kidney transplants performed in 2008. The total number of pancreas transplants peaked at 1484 in 2004 and has declined to 1273. Although the number of LD transplants increased by 26% from 1999 to 2008, the total number peaked in 2004 at 6647 before declining 10% by 2008. The rate of LD transplantation continues to vary significantly as a function of demographic and geographic factors, including waiting time for DD transplant. Posttransplant survival remains excellent, and there appears to be greater use of induction agents and reduced use of corticosteroids in LD recipients. Significant changes occurred in the pediatric population, with a dramatic reduction in the use of LD organs after passage of the Share 35 rule. Many strategies have been adopted to reverse the decline in LD transplant rates for all age groups, including expansion of kidney paired donation, adoption of laparoscopic donor nephrectomy and use of incompatible LD.

Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) have high serum levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), -2, and -6. The excess IGFBP-2 and -1 may play a role in the growth failure of CRF children by sequestering IGF peptides. In contrast, IGFBP-3 levels rise with GH treatment of CRF children, suggesting a role for IGFBP-3 in their accelerated growth. The present studies used sensitive and specific antisera to characterize levels and forms of IGFBP-4 and -5 in serum from CRF children. By RIA, the mean baseline serum level of IGFBP-4 was high in CRF children compared to that in normal children, but the IGFBP-4 level in CRF serum did not correlate with height SD score; by immunoblot, high CRF levels were associated with increases in both intact and fragmented IGFBP-4. Mean RIA levels of IGFBP-5 were comparable in sera from CRF and normal children. Treating CRF children with GH for 12 months increased serum IGFBP-4 levels by 26% and IGFBP-5 levels by 49%, as determined by RIA; levels of IGFBP-5, but not IGFBP-4, correlated significantly with serum levels of IGF-I, IGF-II, IGFBP-3, and acid-labile subunit and with growth rate in these GH-treated children. In summary, IGFBP-4 levels are high in serum of CRF children, and GH increases serum levels of IGFBP-4 and IGFBP-5 in these children. The data suggest a role for IGFBP-5 in the accelerated growth of GH-treated CRF children, perhaps as part of a ternary complex with acid-labile subunit and IGFs. Additional studies on the relationship between intact IGFBP-4 levels and growth are needed to determine what role IGFBP-4 plays in the linear growth process in vivo.

The insulin-like growth factor axis and growth in children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) are often growth recarded despite normal serum levels of GH and insulin-like growth factors (IGFs). Recent studies suggest that excess IGF-binding proteins (IGFBPs) in the 35-kDa fractions of CRF serum contribute to CRF growth failure. This report characterizes the relationship between IGFBP-3 and IGF peptides in the serum of growth-retarded CRF children. Size-exclusion chromatography at pH 7.4 found IGFBP-3 and IGFs almost exclusively in the 150-kDa fractions of normal serum, where their molar stoichiometry was approximately 1:1. However, similar chromatography of CRF serum found a molar excess of IGFBP-3 over total IGFs in the 150-kDa fractions and large amounts of IGFs in the 35-kDa fractions. In the 150-kDa fractions of CRF serum, IGFBP-3 was present in normal amounts, but a greater than normal amount was in the form of a 29-kDa IGFBP-3 fragment. Treatment of these CRF children with recombinant human GH increased the molar excess of IGFBP-3 over total IGFs in the 150-kDa fractions, the amount of IGFBP-3 and total IGFs in the 150-kDa fractions, and the amount of IGFs, but not IGFBPs, in the 35-kDa fractions. These data suggest that in untreated CRF children, proteolysis of IGFBP-3 in the 150-kDa fractions releases IGFs to the excess IGFBPs in the 35-kDa fractions, but insufficient IGF is released to overcome the growth-inhibiting effects of these excess IGFBPs. Treatment with recombinant human GH increases levels of IGFs and IGFBP-3 in the 150-kDa fractions, and subsequent IGFBP-3 proteolysis releases sufficient IGF to overcome the growth inhibitory effects of excess IGFBPs in the 35-kDa fractions of CRF serum.

Insulin-like growth factor-binding protein-6 levels are elevated in serum of children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.

Previous studies suggest that growth retardation in children with chronic renal failure (CRF) results in part from inhibition of insulin-like growth factor (IGF) action by excess serum IGF-binding proteins (IGFBPs). Excess IGFBPs in CRF serum include IGFBP-1, -2, and -3 and a diffuse approximately 24- to 28-kDa IGFBP band identified by [125I]IGF ligand blot. The present studies characterized this diffuse approximately 24- to 28-kDa band. Initial studies identified this band as IGFBP-6, because it was immunoprecipitated by antiserum raised against a synthetic peptide of human IGFBP-6 (hIGFBP-6). Additional [125I]IGF ligand blots found that the immunoprecipitated band was 1) recognized by [125I]IGF-II but not [125I]IGF-1, 2) more abundant in CRF than in normal serum, and 3) more abundant in serum from dialyzed than nondialyzed prepubertal CRF children. Using the hIGFBP-6 antiserum in a specific and sensitive RIA, we found that serum IGFBP-6 levels were 4.7 +/- 1.7 nmol/L in 10 normal prepubertal children, 21.4 +/- 6.1 nmol/L in 44 nondialyzed prepubertal CRF children, 73.5 +/- 14.4 nmol/L in 7 dialyzed prepubertal CRF children, and 94.6 +/- 26.2 nmol/L in 14 dialyzed pubertal CRF children. IGFBP-6 levels were also elevated in 71 nondialyzed European children with CRF. In nondialyzed CRF children, serum IGFBP-6 levels 1) correlated inversely with the glomerular filtration rate, 2) did not correlate with height SD score, and 3) were not altered by 12 months of daily recombinant hGH treatment. In summary, a specific antiserum and RIA were used to demonstrate elevated levels of intact IGF-II-binding IGFBP-6 in serum of CRF children. We postulate that the excess IGFBP-6 may modulate the action of IGF-II on target tissues.

Relationship of human milk pH during course of lactation to concentrations of citrate and fatty acids.

Human milk pH was measured in 309 samples obtained from 52 women who had delivered at term and lactated for as long as 10 months thereafter. The mean pH decreased from 7.45 for colostrum to a nadir of 7.04 during the second week of lactation. Thereafter, the pH of milk remained between 7.0 and 7.1 until 3 months postpartum and then increased gradually to 7.4 by 10 months. The change in hydrogen ion concentration in milk was associated with corresponding changes throughout lactation in the concentration of citrate but not with the concentration of lactose. Lactose concentration increased gradually for 3 weeks; the concentration of saturated medium-chain fatty acids increased more rapidly. One interpretation of these findings is that the hydrogen ions and citrate generated by mammary secretory cell metabolism are used after the second week of lactation for de novo synthesis of fatty acids more rapidly than they are synthesized. Milk samples from ruminants were found to have concentrations of hydrogen ions and citrate that are greater than and pH that is less than the respective measurements in human milk. The significance for the recipient infant of the predictable changes in human milk pH during lactation and of the higher pH of human milk throughout lactation relative to bovine milk is unknown. However, drug excretion into milk, milk enzyme activity, milk leukocyte function, and neonatal gastrointestinal function are affected by ambient pH and may be influenced by the pH of milk.

Pediatric experience with intradialytic parenteral nutrition and supplemental tube feeding.

Good nutrition is necessary to maximize the potential for growth and development in the pediatric age-group, but children, like adults with chronic renal failure and end-stage renal disease, may be anorectic and eat poorly. Infants and adolescents are at special risk because of the intense demands of growth during the first 2 years of life and again during puberty. Neurodevelopment is also adversely affected by poor nutrition, especially in infants. Approximately two-thirds of pediatric dialysis patients are treated with chronic peritoneal dialysis, which results in significant protein losses in the dialysis effluent that can contribute to protein-calorie malnutrition. Meeting the nutritional needs of pediatric patients usually requires supplemental sources, such as intradialytic parenteral nutrition (IDPN) or tube feeding. Little is known about the effectiveness or desirability of IDPN in pediatric patients. More studies, especially of amino acid-based dialysis fluids for chronic peritoneal dialysis, need to be done before making IDPN a standard for pediatrics. Supplemental nasogastric or gastrostomy tube feedings have been very successful in maintaining and improving growth in infants, but no studies are available to evaluate their success in older children and adolescents. Recombinant growth hormone therapy, in addition to good nutrition and control of other growth factors such as acidosis, renal osteodystrophy, and chronic volume depletion, may be necessary for most growth-retarded children with chronic renal failure to achieve normal adult height.

Logarithmic extrapolation of a 15-minute postdialysis BUN to predict equilibrated BUN and calculate double-pool Kt/V in the pediatric hemodialysis population.

Blood urea nitrogen (BUN) concentration rebounds logarithmically for 1 hour after a hemodialysis treatment. We have previously devised and evaluated an equilibrated Kt/V (eqKt/V) estimation method using logarithmic extrapolation of the BUN increase from 30 seconds to 15 minutes postdialysis in six pediatric hemodialysis patients. The current study evaluates logarithmic extrapolation in 15 additional pediatric patients. Mean measured equilibrated BUN (eqBUN) and estimated BUN at equilibrium (estBUN) using logarithmic extrapolation were 23.1 +/- 9.2 and 23.0 +/- 9.4 mg/dL, respectively. The mean absolute difference between estBUN and eqBUN was 0.7 +/- 0. 4 mg/dL (range, 0.1 to 1.55 mg/dL). All treatments had an absolute difference less than the SD of the laboratory measurement itself. The mean absolute percentage of difference between eqKt/V using eqBUN and estimated double-pool equilibrated Kt/V (estKt/V) using estBUN from logarithmic extrapolation was 3.4% +/- 2.3% and did not vary as a function of patient size, urea generation rate, dialyzer urea clearance, Kd/V, or ultrafiltration fraction. Mean absolute percentages of difference between eqKt/V and Kt/V estimated by the Tattersall, Daugirdas, or Maduell formulas were 4.5% +/- 3.9%, 4.4% +/- 3.7%, and 6.7% +/- 8.3%, respectively. Total percentages of error (absolute mean percentage of error + 2 SD) between eqKt/V and estKt/V by logarithmic extrapolation or the Tattersall, Daugirdas, or Maduell formulas were 8.0%, 12.3%, 11.8%, and 22.3%, respectively. The greater accuracy of logarithmic extrapolation compared with other methods of double-pool Kt/V estimation held true for patients weighing less than 35 kg. We have validated the use of an easy and accurate method requiring only an additional 15-minute posttreatment BUN level to estimate double-pool Kt/V in children.

Evaluation and prediction of urea rebound and equilibrated Kt/V in the pediatric hemodialysis population.

The posthemodialysis blood urea nitrogen (BUN) concentration rebounds for 30 to 60 minutes after hemodialysis in adults. Timing of the posttreatment BUN sample has a significant impact on the calculation of Kt/V. Urea rebound and its effect on Kt/V have not been extensively studied in children and adolescents. We evaluated posthemodialysis urea rebound after 46 treatments in 18 pediatric patients with end-stage renal disease. BUN levels were drawn at 30 seconds and 5 and 15 minutes posttreatment. From these values, a logarithmic regression curve was derived that defined percentage of urea rebound (%UR) = -0.254 + 10.9*log(t), (r = 0.79). Using this equation, we estimated BUN, %UR, and Kt/V at equilibration (50 minutes) for each treatment. Estimated mean %UR was 18.7%. Single-pool Kt/V (spKt/V) and estimated double-pool Kt/V (estKt/V) values were significantly different (P < 0.0001). %UR and percentage of difference between spKt/V and estKt/V did not vary as a function of dry weight, body surface area, or K/V. To test the validity of logarithmic extrapolation, additional BUN levels were drawn at 30 seconds and every 10 minutes for 1 hour postdialysis in six patients. Percentage of difference between estKt/V and measured equilibrated Kt/V was 3.6% +/- 1.7%. Our results show %UR has a significant impact on the calculation of Kt/V in children, does not vary with patient size, and is similar to that seen in adults. We have devised an easy and accurate method to predict equilibrated BUN and calculate double-pool Kt/V in children, which requires only an additional 15-minute posttreatment BUN sample.

Ambulatory blood pressure monitoring and interdialytic weight gain in children receiving chronic hemodialysis.

Volume overload appears to induce hypertension in hemodialysis patients, yet studies of the effect of hydration status on interdialytic blood pressure (BP) have yielded contradictory results. We measured interdialytic BP by ambulatory BP monitoring (ABPM) during inpatient fluid restriction in 12 children receiving chronic hemodialysis to describe the overall BP pattern and to determine the effect of weight gain on BP change. Weight was measured on admission and four times each day. For each weight, casual BP was measured and compared with the mean of 3 hours of ABPM surrounding the weight measurement. Sleep BP decreased from daytime BP by 6% for systolic BP (SBP) and 11% for diastolic BP (DBP). Sleep loads were greater than daytime loads (P < 0.01) for SBP (53% v 28%) and DBP (57% v 27%). Overall, 58% (7 of 12) of the patients had sleep SBP load greater than 50%, and 67% (8 of 12) of the patients had sleep DBP load greater than 50%. Casual and ABPM measurements of BP showed moderate correlations for SBP (r = 0.51) and DBP (r = 0.46) and mean differences between methods of 6.3 +/- 13.2 mm Hg and -1.4 +/- 12.6 mm Hg, respectively. Increases in interdialytic weight were positively associated with increases in SBP (r = 0.41; P < 0.001), and interdialytic BP changes varied closely with corresponding weight changes. We conclude that in children receiving chronic hemodialysis: (1) sleep BP decreases are attenuated and sleep BP loads are elevated, (2) casual BP correlates poorly with ABPM, and (3) interdialytic weight and BP are related.

Long-term treatment of focal segmental glomerulosclerosis in children with cyclosporine given as a single daily dose.

Cyclosporine (CsA) has been successfully used for treatment of children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) for the last decade. Response rates of 50% to 100% have been reported using twice-daily dosing of 5 to 32 mg/kg/d, achieving trough blood levels of 70 to 500 ng/mL. Treatment has been associated with a high incidence of side effects, including nephrotoxicity, hypertension, gingival hyperplasia, and hirsutism. To determine whether once-daily low-dose CsA could minimize side effects and still induce remission, 21 children with biopsy-proven FSGS and NS, each treated with CsA, 4.6 +/- 0.8 mg/kg/d, with no predetermined target trough blood levels, were studied. Eleven of 21 children (52%) attained complete remission and 5 of 21 children (24%) attained partial remission, for a total response rate of 76%. Mean time to response was 2.8 +/- 0.8 months, and mean duration of therapy was 20.6 +/- 13.7 months. CsA dosage was tapered or stopped in 9 responders; 3 of these patients maintained remission at last follow-up 6 to 13 months later, and 6 patients relapsed at 1.5 to 18.7 months (mean, 8.7 months). Five of these 6 patients responded again when CsA therapy was restarted or the dosage was increased. Twelve of 16 responders were still being administered CsA at last follow-up 11 to 60 months (mean, 24.6 months) later. Five of 21 patients (24%) had no response to CsA during 2 to 27 months of therapy; 4 of these 5 patients developed end-stage renal disease after CsA therapy was stopped. Side effects of CsA therapy were minimal: 1 patient each developed new-onset hypertension or gingival hyperplasia, and no patient had hirsutism or nephrotoxicity. Single daily low-dose CsA appears to be effective for long-term treatment of children with FSGS and NS, with fewer side effects than twice-daily dosing.

Successful use of Tesio catheters in pediatric patients receiving chronic hemodialysis.

Semipermanent venous catheters remain the most commonly used access for chronic hemodialysis (HD) in pediatric patients. The recent availability of Tesio catheters in 7 and 10 F has expanded available HD catheter options for children and adolescents. We report our experience with Tesio catheter survival, complications, and effect on dialysis adequacy in comparison to standard dual-lumen (DL) catheters in our pediatric HD patients. Demographic data were similar between the two groups. Overall actuarial survival was significantly longer for Tesio versus DL catheters (46% versus 0% at 1 year; P = 0.003). A comparison of smaller catheters (7 F Tesio catheter, 8 or 10 F DL catheter) showed that smaller Tesio catheters had a significantly longer survival (median survival, 244 versus 13 catheter-days; P < 0.01). Tesio 10 F catheters also survived significantly longer than the larger 11.5 and 12 F DL catheters (P < 0.02). Catheter sepsis occurred less frequently with Tesio catheters (one episode/20 catheter-months) than DL catheters (one episode/5 catheter-months) despite the longer duration of Tesio catheters. Adequate dialysis (single-pool Kt/V > 1.2) was delivered with the same frequency, but for a longer duration with Tesio catheters (76% +/- 32% over 100 monthly measurements versus DL catheter, 57% +/- 45% over 54 monthly measurements). Our clinical practice was to replace cuffed catheters when adequate dialysis could not be delivered. We conclude that Tesio catheters provide superior performance compared with DL catheters in terms of catheter survival, infection rates, and duration of adequate performance.

New syndrome involving the visual, auditory, respiratory, gastrointestinal, and renal systems.

A previously undescribed fatal multisystem syndrome involving the eyes, ears, lungs, intestines, and kidneys occurred in sibs. They both presented during early childhood with cataracts, otitis media, intestinal malabsorption, chronic respiratory infection, and failure to thrive. Later, they developed recurrent pneumonia (one was shown to have immotile bronchial cilia) and progressive azotemia leading to end-stage renal disease (ESRD) by late childhood. Both died of overwhelming infection (sepsis, meningitis). An autosomal recessive mode of inheritance is proposed since the normal parents were distant cousins, and 4 other sibs were normal.

Disorders of acid-base balance.

Acid-base disorders are common in sick children. This article is a practical guide to the differential diagnosis and treatment of simple and mixed acid-base disorders of children. Special attention is given to fundamentals of acid-base physiology, to clinical use of the Henderson equation, and to interpretation of readily available laboratory tests.

Growth of small children managed with chronic peritoneal dialysis and nasogastric tube feedings: 203-month experience in 14 patients.

This 203-month experience with CPD and NG feedings in 14 small children weighing less than or equal to 10 kg at initiation of CPD for ESRD, provides evidence that CPD and vigorous nutritional therapy is effective in maintaining and improving growth until a successful renal transplant can be performed. Nutritional therapy should be initiated early, if possible when growth begins to decline even before the onset of ESRD and the need for CPD. Infants who are less than or equal to 4 months old at initiation of CPD are more likely to have a complicated clinical course and poor growth, despite the provision of CPD and vigorous nutritional support. More experience with this group of patients is needed to determine appropriate therapy.

A survey of pediatric nephrologists on adolescent sexual health.

Chronic renal disease often has an adverse effect on adolescent physiologic and psychosocial development. The severity of the disease may necessitate that the pediatric nephrologist be the adolescent's main medical provider and the most available physician to screen for adolescent health risk behaviors. The purpose of this study was to determine pediatric nephrologists' practices of sexual history taking and diagnosis and treatment of sexually transmitted infections in their adolescent patients. A survey was performed on a convenience sample of 66 pediatric nephrologists attending an educational seminar on adolescent care at the 1997 national meeting of the American Society of Pediatric Nephrology. The outcome measures included physicians' reports of interviewing adolescents alone and screening for sexually transmitted infections. Fifty-six percent reported interviewing adolescents alone, 55% routinely ask female adolescents about sexual intercourse (53% ask males) and 10% routinely perform pelvic exams. Current practice in this selected sample of pediatric nephrologists, who by their attendance at the seminar may represent those most motivated to do screening, still leaves adolescents with chronic renal disease potentially at risk for sexually transmitted infections and pregnancy. Educational efforts should be directed at increasing routine confidential sexual history taking for adolescents with chronic renal disease.

Natural logarithmic estimates of Kt/V in the pediatric hemodialysis population.

The natural logarithm formula for Kt/V proposed by Daugirdas is recognized as a valid and simple alternative to formal urea kinetic modeling (UKM) in adults receiving hemodialysis. No data have been published to validate the use of this formula in infants, children, and adolescents. We compared Kt/V derived by formal UKM with the natural logarithmic formula for 103 treatments in 21 pediatric end-stage renal disease patients receiving chronic hemodialysis. Values for Kt/V derived by formal UKM ranged from 0.65 to 2.06. Patients ranged in age from 1.8 to 22.5 years and in dry weight from 10.2 to 82.5 kg. The largest percent error between the two methods for any data point was less than 6%. The total error (absolute value percent error + 2 SD) was less than 6% across the entire range of dry weights. Our data show excellent agreement between formal UKM and the natural logarithm formula for Kt/V in pediatric hemodialysis patients, even those weighing less than 30 kg. These results support the use of the natural logarithm formula as a valid alternative to formal UKM in children. The simplicity of this formula should allow for the use of Kt/V as the best measure to study the relationship between delivered dialysis dose and outcomes in children.

Platelet activation and prostacyclin supporting capacity in the loin pain hematuria syndrome.

The loin pain hematuria syndrome has been characterized as a constellation of severe recurrent flank pain and hematuria, occurring predominantly in young women. We studied a 17-year-old woman who had recurrent right flank pain, gross hematuria, and fever, without evidence of urinary tract infection. Her physical exam was remarkable for right costovertebral angle tenderness and a normal BP. Her urinalysis showed blood and protein but her creatinine clearance and 24-hour urinary calcium excretion were normal. A kidney biopsy was remarkable for arteriolar subintimal fibrous thickening and fibrin deposition, but no glomerulonephritis. Her peripheral hemostasis evaluation was normal except for circulating platelet aggregates and elevated fibrinopeptide A levels. On two occasions, her serum was unable to normally support prostacyclin (PGI2) production by cultured human umbilical endothelial cells, as measured by radioimmunoassay (RIA) of its stable metabolite 6-keto-PGF alpha. Blood samples from the right renal vein and inferior vena cava revealed a selective elevation of fibrinopeptide A in the right renal venous effluent. The presence of circulating platelet aggregates and elevated levels of fibrinopeptide A (a cleavage product of fibrin) suggests that platelet activation and fibrin deposition may play a role in the pathogenesis of this disorder. The inability of her serum to normally support the production of the potent antiplatelet and antithrombotic substance, PGI2, could represent a primary renovascular endothelial cell defect.