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The hemodynamic profile of the Fontan circulation presents challenges that raise questions about candidacy for organ transplantation. We report a case of a 24-year-old male with double-inlet right ventricle and aortic atresia, who suffered bilateral renal cortical necrosis due to neonatal cardiovascular shock, received a live-donor kidney transplant from his mother at age 17, and has diminished yet stable renal function seven years posttransplant.

Background. Optimal immunosuppression after organ transplant should balance the risks of rejection, infection, and malignancy while minimizing barriers to adherence including frequent or time-sensitive dosing. There is currently no reliable immune function assay to directly measure the degree of immunosuppression after transplantation. Methods. We developed an immune function assay to mea//sure T-cell proliferation after exposure to immunosuppression in vivo. We tested the assay in mice, and then piloted the approach using single time point samples, 11 pediatric kidney transplant recipients prescribed tacrolimus, mycophenolate, and prednisone 6 months to 5 years posttransplant, with no history of rejection, opportunistic infection, or cancer. Twelve healthy adults were controls. Results. We demonstrated that our assay can quantify suppression of murine T-cell proliferation after tacrolimus treatment in vivo. In humans, we found a mean 25% reduction in CD4 and CD8 T-cell proliferation in pediatric renal transplant recipients on triple immunosuppression compared with adult healthy controls, but the pilot results were not statistically significant nor correlated with serum tacrolimus levels. We observed that cell processing and washing reduced the effects of tacrolimus on T-cell proliferation, as did discontinuation of tacrolimus treatment shortly before sampling. Conclusions. T-cell proliferation is currently not suitable to measure immunosuppression because sample processing diminishes observable effects. Future immune function testing should focus on fresh samples with minimal washing steps. Our results also emphasize the importance of adherence to immunosuppressive treatment, because T-cell proliferation recovered substantially after even brief discontinuation of tacrolimus.

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P

Folate and vitamin B12 metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.

Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for one's own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.

LaR Pediatric solid-organ transplantation is an increasingly successful treatment for organ failure. Five- and 10-yr patient survival rates have dramatically improved over the last couple of decades, and currently, over 80% of pediatric patients survive into adolescence and young adulthood. Waiting list mortality has been a concern for liver, heart, and intestinal transplantation, illustrating the importance of transplant as a life-saving therapy. Unfortunately, the success of pediatric transplantation comes at the cost of long-term or late complications that arise as a result of allograft rejection or injury, immunosuppression-related morbidity, or both. As transplant recipients enter adolescence treatment, non-adherence becomes a significant issue, and the medical and psychosocial impacts transition to adulthood not only with regard to healthcare but also in terms of functional outcomes, economic potential, and overall QoL. This review addresses the clinical and psychosocial challenges encountered by pediatric transplant recipients in the current era. A better understanding of pediatric transplant outcomes and adult morbidity and mortality requires further ongoing assessment.

Obesity and hypertension frequently complicate renal transplantation (RTxp). The objective was to assess relations among obesity, hypertension, and glucocorticoids in pediatric RTxp recipients. A retrospective cohort study was carried out in 141 RTxp recipients, 2–21 years of age, with ≥12 months of follow-up. Body mass index Z-score (BMI-Z), systolic and diastolic blood pressure Z-scores (SBP-Z and DBP-Z), and medications at 1, 3, 6, and 12 months and annually thereafter were recorded. Quasi-least squares regression analysis was used. The prevalence of obesity (BMI ≥ 95th percentile) increased from 13% at baseline to >30% from 3 months onward. Greater glucocorticoid exposure (mg/kg/day) was associated with greater increases in BMI-Z (p < 0.001). This association was greater in males, younger recipients, and those with lower baseline BMI-Z (all interactions p < 0.02). The prevalence of systolic hypertension (SBP ≥ 95th percentile) was 73% at 1 month and ≥ 40% at all follow-up visits. Greater glucocorticoid exposure (p < 0.001) and increases in BMI-Z (p = 0.005) were independent determinants of SBP-Z over time. Cyclosporine (versus tacrolimus) was independently associated with greater SBP-Z and DBP-Z (p = 0.001). Sustained obesity and hypertension frequently complicated pediatric RTxp. Obesity was an independent determinant of systolic hypertension. Strategies are needed to prevent obesity and its impact on hypertension, cardiovascular disease, and allograft survival.

The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia, variable degrees of rickets/osteomalacia, and hypercalciuria secondary to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. HHRH is caused by mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc. A 6 ½-year-old female presented with a history of nephrolithiasis. Her metabolic evaluation revealed increased 24- hour urine calcium excretion with high serum calcium, low intact parathyroid hormone (PTH) levels, and elevated 1,25(OH)2D level. In addition, the patient had low to low-normal serum phosphorus with high urine phosphorus. The patient had normal stature; without rachitic or boney deformities or a history of fractures. Genetic analysis of SLC34A3 revealed the patient to be a compound heterozygote for a novel single base pair deletion in exon 12 (c.1304delG) and 30-base pair deletion in intron 6 (g.1440–1469del). The single-base pair mutation causes a frameshift, which results in premature stop codon. The intronic deletion is likely caused by misalignment of the 4-basepair homologous repeats and results in the truncation of an already small intron to 63 bp, which would impair proper RNA splicing of the intron. This is the fourth unique intronic deletion identified in patients with HHRH, suggesting the frequent occurrence of sequence misalignments in SLC34A3 and the importance of screening introns in patients with HHRH.

Evidence-based practice is a shift in the health care culture from basing decisions on consensus opinion, past practice, and precedent toward the use of rigorous analysis of scientific evidence using outcomes research and clinical evidence to guide clinical decision making. The development of evidence-based clinical practice guidelines (CPG) is critical to guide the assessment and management of children with diabetes. This article provides an overview of the infrastructure and processes that are crucial to providing evidence-based care in a large urban pediatric diabetes center. Development of a CPG to identify microalbuminuria in children with type 1 diabetes is discussed.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

Historically surgeons caring for children with urinary diversion for bladder outlet obstruction have routinely performed undiversion before renal transplantation. We hypothesized that patients undergoing transplantation into a diverted system would have outcomes similar to those undergoing transplantation into a normal bladder. We review the outcomes of patients with and without diversion undergoing kidney transplantation at our institution.We retrospectively studied a cohort of children undergoing renal transplant between 1993 and 2006. Patients whose etiology of end-stage renal disease was either obstructive uropathy or renal dysplasia were included. Patients with less than 5 years of followup were excluded from the analysis. Four groups were assembled, ie controls with renal dysplasia and no history of obstructive uropathy undergoing transplant (group 1), patients with obstructive uropathy not diverted at transplant (group 2), patients with obstructive uropathy diverted at transplant (group 3) and patients with obstructive uropathy augmented before transplant (group 4). The groups were compared for outcomes of frequency of urinary tract infection, renal graft function and graft loss.Of the 80 subjects eligible based on diagnostic criteria 43 had completed 5 years of followup. There was no significant difference between groups based on age (p = 0.508), renal function as measured by glomerular filtration rate (p = 0.526) or creatinine (p = 0.612), or frequency of urinary tract infections (p = 0.083). Only 1 patient in the cohort suffered graft loss.Based on frequency of urinary tract infection, renal function and graft loss 5 years after transplant, there appears to be no added risk to transplanting a kidney into a diverted system.

To measure the impact of the Share-35 policy on the allocation of ideal deceased donor kidneys and to examine the impact of age on outcomes after kidney transplantation using ideal donor kidneys.In the United States, through Share-35, transplant candidates aged 18 years or younger receive priority for the highest-quality deceased donor kidneys. Adolescent (15-18 years) kidney transplant recipients (KTRs), however, may be more susceptible to allograft loss due to elevated rates of acute rejection and a possible increased risk of primary renal disease recurrence.We used registry data to perform a retrospective cohort study of 39,136 KTRs from January 1, 1994, to December 31, 2008. Ideal donors were defined as 2 to 34 years old with creatinine1.5 mg/dL and absence of hypertension, diabetes, and hepatitis C.After Share-35, the percentage of ideal donor kidneys allocated to pediatric recipients increased from 7% to 16%. In multivariable Cox regression, compared with adolescent KTRs, all age strata except recipients older than 70 years had a lower risk of allograft failure (P0.01 for each comparison); results were similar after excluding KTRs with diseases at high risk of recurrence. Adolescent recipients had higher mortality rates than KTRs younger than 14 years, similar mortality compared with that of KTRs older than 18 and younger than 40 years, and lower mortality than KTRs older than 40 years.The allocation of "ideal donors" to adolescent recipients may not maximize graft utility. Reevaluation of pediatric allocation priority may offer opportunities to optimize ideal renal allograft survival.

During the 1980s all children with growth potential and stable/adequate renal function at 6–9 months after kidney transplantation underwent conversion to alternate-day corticosteroids in an attempt to maximize growth. Conversion was attempted in 79 of 160 children who received allografts during this decade and was considered successful if they remained on alternate-day prednisone for more than 1 year, with a calculated creatinine clearance of at least 75% of the pre-conversion baseline value. Conversion succeeded in 55 children but failed in 24. Growth was markedly improved among those successfully converted when compared with the failure group, as measured by standard deviation score for growth velocity based on chronological age (+0.94±1.58 vs. −0.86±1.53,P

One hundred twenty-seven children (83 males, 44 females, 86 white, 41 nonwhite; mean age 12.1 years) who received 160 renal transplants between 1980 and 1989 were retrospectively studied. Variables such as age, sex, primary diagnosis, type, HLA-DR mismatching, and repeated transplants were compared between races and found not to be significant. However, HLA-A and -B cadaveric-graft mismatching, which was equivalent between whites and nonwhites prior to 1985 (pre-cyclosporine A era), has significantly favored whites (49% with 0 to 2 HLA-A and -B mismatch vs 16% in nonwhites) since 1985 (P < .05), and a significantly higher proportion of nonwhite patients (59%) were receiving medical assistance (P < .0001). Graft survival was evaluated with significantly poorer results in nonwhites as compared to whites (P < .05). Although no difference was found between white and nonwhite cadaveric-graft survival before 1985, nonwhites had significantly worse graft survival since 1985 (72% vs 59% for 1 year and 61% vs 24% for 3 years in whites and nonwhites, respectively; P < .05). Subpopulations such as nonwhite adolescents, nonwhite females, nonwhites with repeated transplants, and all low socioeconomic patients were identified as high-risk children with poor long-term survival. It is concluded that secondary to poorer matching since 1985 there has been decreased graft survival in nonwhites despite cyclosporine A. Attempts to improve matching and attention to high-risk groups are needed for equivalent survival.

Recurrence of focal segmental glomerulosclerosis (FSGS) in an allograft is a challenging clinical situation because it frequently results in graft loss. We report our experience with early use of plasmapheresis in recurrent FSGS. Of the 18 (33%) children with biopsy-proven FSGS (in their native kidneys) transplanted at our institution, 6 had recurrence (elevated urine protein/creatinine ratios) post transplant and were treated with plasmapheresis. Patients who received treatment within 1 day of the recurrence (4/6) went into remission after 5-13 plasmapheresis treatments, within 5-27 days of starting treatment. Patients who did not respond to plasmapheresis (2/6) were treated 7 and 17 days after onset of proteinuria; 1 of these had acute tubular necrosis and acute rejection leading to graft loss and the other developed acute rejections, ongoing proteinuria, and subsequent graft loss. All 4 patients who went into remission have maintained good graft function, 22-53 months post transplant. In our experience early institution of plasmapheresis for recurrent post-transplant proteinuria in FSGS is effective.

The records of 14 boys with posterior urethral valves who had renal failure and subsequently underwent renal transplantation were reviewed to determine the postoperative incidence of urinary tract infection relative to that of 29 male transplant children without valves, who served as controls. There were no significant differences between the posterior urethral valve patients and controls with regard to age, donor source, immunosuppression, followup after transplantation or mean calculated creatinine clearance. Vesicoureteral reflux was found in 1 child with posterior urethral valves and 3 of the children in the control group (p not significant). A total of 15 urinary tract infections occurred in 5 children (36%) with posterior urethral valves, for a rate of 1 per 30 patient-months of followup, and 6 urinary tract infections occurred in 2 controls (7%), for a rate of 1 per 216 patient-months of followup (p0.05). However, only 1 of 26 controls (4%) without vesicoureteral reflux had urinary tract infection, for a rate 1 per 1,144 patient-months (p0.01). Conversely, the rate of urinary tract infections in controls with vesicoureteral reflux was similar to that of children with posterior urethral valves. Of the 5 children with posterior urethral valves 4 had the initial urinary tract infection within 2 months of transplantation and 10 of 15 episodes occurred within the first 4 months. Antimicrobial prophylaxis did not appear to decrease the rate of infection in children with posterior urethral valves. A history of posterior urethral valves increases the frequency of urinary tract infection after renal transplantation but the usefulness of antimicrobial prophylaxis and the relationship to long-term graft function remain to be determined. Urinary tract infection rarely develops in other transplanted boys without vesicoureteral reflux.

During the control period of the Growth Failure in Children With Renal Diseases Study, investigators at 23 centers were able to observe and characterize growth and to make anthropometric and nutritional measurements in 82 children with mild to moderate renal insufficiency. As a multicenter, controlled clinical trial designed to study the relative efficacy of 1,25-dihydroxyvitamin D 3 and dihyderotachysterol in the treatment of renal osteodystrophy, no prior vitamin D exposure and a creatinine clearance of 25 to 75 ml/min/1.73 m 2 were criteria for entrance into the clinical trial. Ages ranged from 18 months to 11 years (mean 5.6±3.1 years), and distribution by age category was as follows: 38%, 1 to 3 years; 28%, 4 to 6 years; and 34%, 7 to 10 years. There was a 3:1 male/female ratio; 72% of the patients had congenital disease by the international Classification of Diseases (ninth revision). Mean creatinine clearance was 49.5±20 ml/min/1.73 m 2 . The C-terminal parathyroid hormone values (1121±1562 pg/ml) were well above 2 SD of the mean of a normal growing population of similar age. Parathyroid hormone values correlated with degree of renal insufficiency ( r =−0.57) and with height by bone age but not with chronologic height or growth velocity. The bone age/height age ratio, a predictor of growth potential in normal children, was low for the entire series of patients (0.88±0.35) but failed to correlate with growth velocity and was negatively correlated with rising parathyroid hormone levels. Average values for height, weight, triceps skin fold, mid-arm muscle circumference, and body mass index were within 2 SD of the mean of the normal population, although measurements for the 1- to 3-year age group were significantly less than those of the older patients. Total energy intake averaged less than 86% of the recommended dietary allowances; total protein intake was more than 161% of the allowance. Nitrogen balance in 23 patients was positive and correlated most significantly with increasing energy intake ( r =0.6). Growth velocity, calculated from the interval gain during the 6-month control period, averaged +0.3 SD, with the highest growth velocity z scores recorded for those with acquired disease. A growth velocity index, expressed as the slope of the regression between change in height SD and growth velocity z score, was used to describe the growth accomplished in the control period by age category. Each of these regressions was significant ( r >0.5; p

Function of the parathyroid gland was evaluated in children with renal insufficiency prior to and after initiation of hemodialysis, and again following renal transplantation. Serum levels of immunoreactive parathyroid hormone responded appropriately to increases or decreases of serum calcium concentrations in the three groups. Functional and histologic studies in the children with renal insufficiency demonstrated the cause of their elevated circulating levels of iPTH to be diffuse parathyroid hyperplasia. During hemodialysis, the serum concentration of calcium rose and that of iPTH decreased, when the calcium gradient between the dialysate and the blood favored movement of calcium into the body. During treatment with prednisolone (20 mg/kg intravenously) for reversal of renal transplant rejection, the serum concentration of calcium decreased and that of iPTH increased. These observations suggest that autonomy of the parathyroid gland rarely occurs in children with renal insufficiency, and that hemodialysis using a dialysate with a high concentration of calcium might assist in retarding the progression of renal osteodystrophy. Furthermore, if hyperparathyroidism contributes in part to growth failure in children with chronic renal disease, steroid-induced changes in cirulating iPTH following renal transplantation may inhibit growth.

The convective aspects of pediatric peritoneal dialysis (PD) -fluid transfer with its attendant solvent drag -were evaluated in vivo in 8 children on maintenance PD. The evaluation was performed according to the mass transport model of pyle. Reflection coefficients were calculated for urea, creatinine, uric acid, glucose and idealized total protein. These values were compared to adult means. There were no differences in reflection coefficients, except for total protein, which had a lower value. Maximum ultrafiltration rates were also calculated for the three commercially avail able dialysate glucose concentrations (1.5%, 2.5%, 4.25%). These values were scaled for body surface area to allow comparison with adult means. All values were lower than the adult means, but were not outside two standard deviations. Convective transport in PD in children over 1 Vl years of age, does not appear to be significantly different than that in adults. There are two components to solute removal in peritoneal dialysis: diffusion and convection. Convective transport, the passive movement of solute in a solvent stream across a semipernleable membrane, is directly related to the rate of ultrafiltration. The convective component of solute removal in peritoneal dialysis may be responsible for a significant per cent of transport of larger molecular weight solutes (I). Little infornlation is currently available concerning this aspect of pediatric peritoneal dialysis. Kohaut and Alexander have reported that it is more difficult to achieve ultrafiltration in infants than in older children, adolescents, and adults (2). The convective component of peritoneal dialysis in infants may therefore contribute less to overall solute removal than in older children and adults.

Thirteen infants, 2 to 10 months of age, developed hypochloremic alkalosis (serum chloride 59 to 92 mEq/l) while taking Neo-Mull-Soy (Syntex), a soy-based formula low in chloride (measured to be 0 to 2 mEq/l) but with considerable potassium citrate. Range of symptoms included lethargy, anorexia, mild spitting up, diarrhea, hematuria, and growth failure. Urine chloride excretion was less than 3 mEq/l. Plasma renin activity or aldosterone, measured in six infants, was elevated. All responded promptly to supplemental salt. One infant receiving Neo-Mull-Soy redeveloped alkalosis when supplemental salt was discontinued. Two of nine apparently normal infants receiving Neo-Mull-Soy also had hypochloremia (85, 86 mEq/l). Three of four receiving Prosobee (Mead Johnson; Cl content 7 mEq/l) had urine chloride concentration less than 20 mEq/l. The chloride content of some infant formulas is insufficient to offset salt losses following mild stress.

Vascular access for chronic hemodialysis in children is difficult because of problems that include obtaining vessels of sufficient size, the limited life-span of external shunts, and the multiple painful punctures associated with internal fistulae. Twenty-five expanded polytetraflouroethylene (PTFE) grafts of 6-mm diameter were inserted for dialysis access over a 2-yr period in 23 children. Grafts were placed either in the upper arm or thigh. Each patient was successfully dialyzed from 60 to 370 times. Longterm patency of the PTFE grafts was 88%, with a complication rate of 36%, mostly minor. The same ease of insertion and high flow characteristics were noted in a series of 22 bovine carotid heterograft (BCH) fistulae inserted in the two years immediately preceeding this study. However, the patency rate was only 36% and the complication rate was 69%, mostly major. We consider the PTFE graft fistula to be the preferred method for long-term hemodialysis access in children.

Bacteremia caused by Bacteroides fragilis occurred in four of 75 children after renal transplantation, and B. fragilis was the most common cause of postoperative bacteremia. Bacteroides bacteremia was significantly associated with performance of elective appendectomy at the time of transplantation (P less than 0.01) and with profound lymphocytopenia (P = 0.01). No patient received antibiotics at the time of surgery or prior to the first positive blood culture, yet B. fragilis was the single organism isolated from blood and abscesses in these patients. A role for lymphocytes in containment of B. fragilis has not been suggested previously, although unexplained occurrence of bacteroides bacteremia in immunocompromised patients has occasionally been reported. Lymphocytes themselves may be important in this host-bacterium interaction, or lymphocytopenia may be the marker for a more generalized deficiency in host defenses.

Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.

A controlled clinical trial was performed using two dosage regimens of chlorambucil to treat childrenwith frequently relapsing nephrotic syndrome. All children concurrently received prednisone (60 mg/m 2 on alternate days). Ten children (Group I) were given chlorambucil as a stable dose (0.2 mg/kg/day) for 56 to 60 days, and 11 children (Group II) received increasing doses (0.2 to 0.63 mg/kg/day) for 42 to 77 days. Two children in each group subsequently relapsed. Follow-up averaged 28.6 and 27.2 months in Groups I and II, respectively. Three children in Group II developed infectious complications. The data indicate that a stable dosage regimen for chlorambucil is as effective as an increasing dose regimen in achieving long-term remission of frequently relapsing nephrotic syndrome.

Serum uric acid concentrations and the fractional excretion of uric acid were determined in 31 children from 3 1/2 to 18 years of age with essential hypertension. While on an unrestricted sodium intake, elevated serum values of uric acid were found in 13 of 31 (42%) of the children. After ingesting a low-sodium diet (200 mg/day) for three days, mean serum uric acid values increased by 0.7 mg/dl (P less than 0.001). There was a significant inverse correlation between the serum uric acid concentrations and fractional excretion of uric acid during the normal and low-sodium diet. This study indicates that the major factor leading to hyperuricemia in our hypertensive patients was a decrease in urate clearance. Insofar as hyperuricemia may represent a cardiovascular risk factor, this abnormality already exists in a significant fraction of hypertensive children and adolescents.

Hypertension in adults is recognized as being a significant precursor of stroke, myocardial infarction, congestive heart failure and renal insufficiency. Many feel that the origins of adult hypertension occur during the childhood years and that a further understanding of normal and abnormal blood pressure regulation in children can lead to better control of abnormal (elevated) blood pressures during childhood and adulthood and perhaps prevent the long term consequences of uncontrolled hypertension.

To determine the utility of steroid response in classifying childhood nephrotic syndrome, we reviewed 119 biopsies in 92 children aged 1 to 16 years who had been followed for a mean of 7.2 years. Steroid responses were classified as steroid resistant, steroid dependent, and frequent relapser as defined by the International Study of Kidney Disease in Children. Biopsy specimens were classified as showing focal glomerulosclerosis (FSGS) in 39 children, as showing lipoid nephrosis in 28, and as questionable in another 25 with either focal global sclerosis, IgM nephropathy, or mesangial prominence and tubular changes. A strong agreement (p less than 0.01) was found between children whose FSGS was steroid resistant and children whose lipoid nephrosis resulted in frequent relapses. The length of the remission after therapy with chlorambucil or cyclophosphamide was determined in 84 children. A significantly shorter length of remission after cytotoxic drug therapy (p less than 0.05) was identified for patients with FSGS versus those with lipoid nephrosis; this difference became more significant for steroid-resistant patients in comparison with those who were steroid dependent or were frequent relapsers (p less than 0.005). Among all steroid-resistant patients, those with FSGS had shorter remissions than patients with other histologic changes (p less than 0.001). The data suggest that patterns of response to corticosteroid therapy correlate with the histologic abnormality. Thus steroid-sensitive patients need not undergo renal biopsy before receiving cytotoxic drugs. Steroid-resistant patients would benefit from a biopsy, because the findings tend to predict the outcome.

Although hyperuricemia has been found in a large number of disorders, (1) its occurrence in the hemolytic uremic syndrome (HUS) is not generally appreciated. (2,3) In 1969, while performing studies of the transperitoneal movement of solute (4) (including uric acid) in children undergoing their initial dialysis, we observed marked hyperuricemia disproportionate to the degree of renal failure in two infants with HUS. We have subsequently confirmed these observations in a series of 26 children with HUS and have performed studies in rabbits in an effort to identify the mechanism(s) leading to hyperuricemia. This report has four objectives: 1) to review our experience with and interpretation of uric acid metabolism in patients with HUS, 2) to present data which provide information on possible mechanisms for the hyperuricemia, 3) to consider uric acid metabolism in experimental models of hemolysis and acute and chronic renal failure, and 4) to review available literature on the subject of uric acid metabolism in renal failure.

Metabolic alkalosis is a subject which tends to be under-emphasized in pediatric medicine because it occurs less frequently than other acid-base disturbances. Consequently, its presence is often overlooked and its pathophysiology inadequately understood. The purpose of this presentation will be to consider 1) definitions involved with the evaluation of patients with metabolic alkalosis; 2) factors which enable metabolic alkalosis to be generated/as well as those factors which permit metabolic alkalosis to persist and 3) a discussion of the pathophysiology of diseases associated with metabolic alkalosis,stressing disorders which occur during infancy. Therapy will not be considered.

Gout has plagued man for centuries with evidence of gouty arthritis dating back to the ancient Egyptians. Over the years, numerous disease states have been described in children and adults which result from abnormalities in uric acid metabolism. This review will consider three aspects of urate metabolism: First, a brief description of disorders associated with altered uric acid homeostasis; secondly, the current understanding of uric acid metabolism occurring in healthy man; thirdly, an in depth consideration of the hyperuricemia found in hypertensive adults and children.

Although the technique of peritoneal dialysis is being used with increased frequency in children, relatively few studies dealing with dialysis kinetics, i.e. the movement of solute and water across the peritoneal membrane, have been performed in children and/or the developing animal. The purpose of this presentation is three-fold. Firstly, a few general principles of transperitoneal solute and water movement will be reviewed. Secondly, the available data describing peritoneal dialysis kinetics in children will be reviewed. Thirdly, certain aspects of studies which we have performed in order to increase our knowledge of peritoneal dialysis kinetics in the experimental animal as well as in children will be reviewed.

A 9 1/2-year-old female developed pneumatosis cystoides intestinalis (PCI) which was detected radiographically 4 1/2 months after transperitoneal cadaveric renal transplantation, during a period characterized by recurrent episodes of acute rejection. Radiographic evaluation was prompted by the development of cramping abdominal pain, distention, and tenderness localized to the region of the allograft, which occurred during one such episode. Pneumatosis was localized primarily to an area of colon that lay in direct contact with the allograft. Evaluation of the available clinical and roentgenographic evidence suggested that pneumatosis may have resulted from the development of a sympathetic inflammatory reaction within the bowel wall adjacent to the acutely inflamed allograft. Subsequent stabilization of renal function was associated with resolution of the pneumatosis over the ensuing 8 months without surgical intervention or additional medical therapy.

Acute renal failure (ARF) may be defined as a symptom complex that occurs when body fluid homeostasis is impaired by the rapid loss of kidney function. The diagnosis and pathophysiology of ARF are considered elsewhere in this volume. The past few decades have brought about major advances in the treatment of the biochemical derangements, hypertension, and fluid imbalance associated with acute renal failure. With widespread availability of dialysis, mortality has markedly decreased; those deaths that do occur are related more to the primary disorder and its complications than to renal failure. Therapy for acute renal failure depends upon the nature or the degree of renal impairment.

The control of infection remains an important aspect of treatment in patients with renal insufficiency. A large fraction of deaths associated with acute renal failure as well as the three phases of end stage renal disease, the period of chronic uremia, dialysis and transplantation, are due to infection. A large fraction of patients with renal disease need antibiotics for treating bacterial infections exclusive of urinary tract infection. Little data is available in children with renal failure on the incidence of infection or its treatment with anti-infectious agents. In a recent survey of our transplantation experience involving 107 transplants at St. Christopher’s Hospital for Children, positive blood cultures were obtained in 10 patients in the initial 21 days following the transplant (1). Moreover, antibiotics have been administered for a variety of infectious problems to virtually all of our patients with end stage renal disease. In one report of 497 children undergoing maintenance dialysis, infection was responsible for death in 13 percent (2). Thus, the need to understand how best to administer antibiotics to uremic children is obvious.

Hyponatremia is amongst the more common disorders of electrolyte imbalance observed in children. Failure to recognize its presence may lead to catastrophic problems. Moreover, appropriate therapy which in certain cases may be life saving, depends initially upon the proper diagnosis being made. Nine combinations define the relationship between serum sodium concentration and total body water, one normal and eight abnormal (Figure 1).

The purpose of this presentation is threefold: 1) to review the normal renal handling of uric acid in man; 2) to present our data on the subject of hyperuricemia in hypertensive pediatric patients and 3) to discuss several mechanisms which may be responsible for the production of hyperuricemia in our hypertensive children.