Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation.

The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (-2.1) (p = 0.028) and BMI (-1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.

Urinary chemokines CXCL9 and CXCL10 are noninvasive markers of renal allograft rejection and BK viral infection.

Renal transplant recipients require periodic surveillance for immune-based complications such as rejection and infection. Noninvasive monitoring methods are preferred, particularly for children, for whom invasive testing is problematic. We performed a cross-sectional analysis of adult and pediatric transplant recipients to determine whether a urine-based chemokine assay could noninvasively identify patients with rejection among other common clinical diagnoses. Urine was collected from 110 adults and 46 children with defined clinical conditions: healthy volunteers, stable renal transplant recipients, and recipients with clinical or subclinical acute rejection (AR) or BK infection (BKI), calcineurin inhibitor (CNI) toxicity or interstitial fibrosis (IFTA). Urine was analyzed using a solid-phase bead-array assay for the interferon gamma-induced chemokines CXCL9 and CXCL10. We found that urine CXCL9 and CXCL10 were markedly elevated in adults and children experiencing either AR or BKI (p = 0.0002), but not in stable allograft recipients or recipients with CNI toxicity or IFTA. The sensitivity and specificity of these chemokine assays exceeded that of serum creatinine. Neither chemokine distinguished between AR and BKI. These data show that urine chemokine monitoring identifies patients with renal allograft inflammation. This assay may be useful for noninvasively distinguishing those allograft recipients requiring more intensive surveillance from those with benign clinical courses.

A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation.

In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti-CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n=73) versus continued low-dose steroids (n=59). This study was stopped prior to target enrollment because of the incidence of post-transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p=0.033). There were no differences in acute rejection episodes between treatment groups. The 3-year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p=0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients.

Tacrolimus rescue therapy for children with acute renal transplant rejection.

Seventeen children with renal transplants (11 living-related, age 2-18 years) were converted from cyclosporine to tacrolimus because of acute rejection that failed to respond to high-dose corticosteroids. Resistance to corticosteroids was confirmed by renal biopsy in 14 patients, and assumed in 3 patients because of failure of serum creatinine to improve to baseline values. Four patients were also treated with OKT3, and 15 children had been receiving mycophenolate maintenance therapy prior to conversion to tacrolimus. Rejection occurred at 2-174 weeks post transplant (mean 52 weeks). Actuarial 1- and 2-year graft survival was 87% and 78%. Three children progressed to end-stage renal disease after 4, 12, and 13 months of tacrolimus. The remaining 14 children have functioning allografts after 20-168 weeks of treatment (mean 80 weeks). All 14 children exhibit stable or improved renal function: serum creatinine 1.1+/-0.7 mg/dl versus 2.0+/-0.9 mg/dl prior to tacrolimus. In conclusion, tacrolimus was effective therapy for both early and late acute rejection in children who failed to respond to high-dose corticosteroids. No significant short-term adverse effects were encountered.

Growth preservation after brief growth hormone therapy in chronic renal insufficiency.

A boy of 3 years 8 months with short stature due to chronic renal insufficiency was treated with recombinant human growth hormone (rhGH) for 20 months. Catch-up growth was achieved and the improvement of the height standard deviation score was sustained throughout an additional 4 years of follow-up without further rhGH therapy.

Bacteremia in a pediatric hemodialysis unit secondary to Enterococcus fecalis.

UNLABELLED: Bacteremia is often a serious and recurring problem in children with hemodialysis catheters. We report an outbreak of Enterococcus bacteremia in a pediatric hemodialysis unit occurring from June 1992 to June 1993. During this period, 18 episodes of bacteremia occurred in eight children; 11 infections were polymicrobial. Enterococcus fecalis was associated with 13 infections in five patients (8 polymicrobial). Other pathogens included Enterobacter cloacae (5 infections), Staphylococcus (3), Staphylococcus epidermidis (2), and Klebsiella pneumoniae (2). All Enterococcus infections occurred in patients with dual-lumen subclavian venous catheters. Skin and catheter sites were culture negative, except in one patient. Rectal swabs were positive for Enterococcus in five patients. Enterococcus was not isolated from any source within the unit. Serotypes of all Enterococcus isolates were different, except for 2 isolates in the same patient. Starting in June 1993, catheters were flushed after dialysis with vancomycin or ampicillin. Since initiating this procedure, further episodes of Enterococcus bacteremia have not occurred. A questionnaire sent to other pediatric hemodialysis units failed to identify Enterococcus among 26 cases of bacteremia. IN CONCLUSION: (1) Enterococcus is an unusual pathogen for hemodialysis-related bacteremia in children; (2) patients with dialysis catheters were predisposed to this infection; (3) a common source for Enterococcus could not be identified by either culture or by serotyping; (4) flushing catheters with antibiotics after dialysis was effective prevention.

Evolving strategies in immunosuppressive therapy: the Emory experience.

We have reviewed our experience with various immunosuppression regimens over the past 11 years in 2,065 renal transplant recipients. Patients received triple-drug maintenance therapy with CsA, imuran and prednisone following either no induction therapy or treatment with polyclonal (PCA) or monoclonal (MCA) antibody. The most recent immunosuppressive regimen has included CsA, MMF, and prednisone without induction therapy. We observed that those patients receiving PCA had a better graft survival 5 years after transplantation than recipients with MCA induction or those receiving standard triple drug therapy without induction. Patients receiving MMF experienced superior one-year graft survival compared with those receiving induction with PCA, MCA or standard triple drug therapy. A similar one-year graft survival rate for both Black and White recipients was observed in the MMF group and raises the possibility of achieving improved long-term graft survival in Black recipients with a MMF-based immunosuppression strategy. Our experience indicates that excellent short-term graft survival can be achieved with an immunosuppressive protocol of MMF, CsA and prednisone without induction. Graft survival in MMF-treated recipients was equal to or superior to that which we previously achieved with induction therapy.

Metabolic complications of the use of stomach for urinary reconstruction.

A total of 34 children with normal renal function underwent either gastrocystoplasty or continent urinary reservoirs with stomach at our institutions. Severe hypochloremic hypokalemic metabolic alkalosis developed in 2 patients, manifested by intractable seizure disorder in 1 and altered mental status with respiratory depression in 1. Symptoms developed at 4 and 6 months, respectively. Despite severe alkalosis, urinary pH was less than 5.0 and fractional excretion of chloride remained high in both patients. Resuscitation with sodium chloride, arginine hydrochloride and potassium chloride restored electrolyte balance in less than 48 hours in both patients. Serum gastrin was slightly elevated in 1 patient (137 pg./ml., normal 0 to 125) who responded to long-term histamine-blocker therapy. The other patient had significant hypergastrinemia (624 pg./ml.) with secondary hyperaldosteronism. Maximum doses of histamine blockers, oral replacement of sodium chloride and potassium chloride, and the proton pump inhibitor omeprazole failed to control recurrent bouts of severe hypochloremic metabolic alkalosis. This patient ultimately underwent removal of three-quarters of the gastric augmentation and replacement with ileum. Postoperatively, serum gastrin levels and electrolytes reverted to normal. The pathophysiology of this potentially lethal complication is further discussed.

Evaluation and treatment of the dominant dorsal duct syndrome (pancreas divisum redefined).

The controversial association of pancreatitis and pancreas divisum was studied in 100 patients (77 women, 23 men, median age 35) with episodic acute pancreatitis (49%) or "pancreatic pain" (51%). Seventy-one had classic pancreas divisum (type 1); 23 had only a dorsal duct with an absent Wirsung's duct (type 2); and 6 had a filamentous connection between the two duct systems (type 3). Accessory papilla sphincteroplasty was performed in 88 patients, with a mean follow-up of 53 months. The orifice was stenotic at the mucosal level in 66 patients. Seventy percent of patients have shown improvement: 85% if the accessory papilla was stenotic, compared with 27% if it was not (p less than 0.0001); and 82% with discrete attacks, compared with 56% with chronic pain (p = 0.002). Judged against intraoperative calibration of accessory papilla orifice diameter, ultrasonography with secretin stimulation was 78% sensitive for accessory papilla stenosis, with 3% false-positive results. Ultrasonography with secretin stimulation was the best predictor of surgical success: positive = 92% success (attacks or pain) versus negative = 40% success (64% with attacks; 21% with pain). There have been seven restenoses with six reoperations. We conclude that (1) pancreas divisum is but one variety of pancreatic anatomy characterized by a dominant dorsal duct and dependence on secretion through the accessory papilla; (2) accessory papilla stenosis appears to be a necessary cofactor to produce a morbid state, whether episodic pancreatitis or pancreatic pain; (3) presentation with pancreatitis and a positive result on the ultrasound-secretin test are the best predictors of successful accessory papilla sphincteroplasty.

IgG subclasses in children with nephrotic syndrome.

To determine whether the hypogammaglobulinemia of childhood nephrotic syndrome is characterized by symmetric depression of the IgG subclasses, the authors compared the IgG subclass concentrations in nephrotic patients in relapse versus remission. The authors used a highly sensitive monoclonal antibody-based enzyme immunoassay that allows quantitation with comparable precision of all four subclasses. They analyzed 28 sera obtained from 22 nephrotic patients during relapse (n = 16) and/or remission (n = 12). The mean ages of the two groups were similar. IgG1 and IgG2 were significantly decreased during relapse compared with remission, whereas IgG3 and IgG4 were not significantly different. This pattern of asymmetric depression of IgG subclasses supports a cause other than urinary losses in the pathogenesis of this abnormality.

Daily single-dose and daily reduced-dose prednisone therapy for children with the nephrotic syndrome.

Most current reference sources recommend that initial therapy for minimal lesion nephrotic syndrome consist of prednisone, 60 mg/m2 per 24 hours or 2 mg/kg per 24 hours, given in divided doses, and that this regimen be repeated for each relapse. The need for divided-dose daily-administered prednisone is predicated on anecdotal observations that single-dose daily administration is not effective. Because single-dose daily-administered and reduced-dose daily-administered prednisone has been used to treat this condition for several years, experience with these regimens in nephrotic children was analyzed. Forty-one patients were studied, including 22 treated from the onset of their disease. Of these 22, 17 (77%) responded to single-dose daily-administered prednisone (2 mg/kg); after subsequent biospy, each of the nonresponders proved to have lesions other than minimal change disease. The mean response time with single-dose daily-administered prednisone (9.6 days for treatment of the initial onset of nephrotic syndrome and 11.1 days for treatment of relapses) was comparable to that previously reported with divided-dose regimens. In 14 patients with frequent relapses, a single reduced-dose daily-administered dose of prednisone (0.2 to 1.5 mg/kg/d) successfully induced remissions in 55 of 63 relapse episodes. It is concluded that a single morning dose of prednisone effectively induces remission in children with minimal lesion nephrotic syndrome. Among selected patients with frequent relapses, additional steroid sparing may be achieved by the use of this regimen with reduced doses during treatment of relapses.

Efficacy of OKT3 monoclonal antibody therapy in steroid-resistant, predominantly vascular acute rejection. A report of three cases with morphologic and immunophenotypic evaluation.

We describe three patients who became oliguric and uremic in the early posttransplantation period. Following treatment with pulse methylprednisolone, all had biopsy evidence of severe residual rejection that was predominantly vascular. T cells formed the bulk of the infiltrates. Subsequent treatment with the monoclonal antibody OKT3 was associated with an immediate diuresis and improvement in serum creatinine. Repeat renal biopsy, obtained in clinical remission, in two of the three patients, showed marked improvement in the vascular lesions. All three patients maintain normal renal function 9, 13, and 18 months later. We conclude that OKT3 was effective in reversing steroid-resistant rejection despite a predominantly vascular pattern of cellular infiltration not usually considered amenable to any antirejection therapy.

Thiazide diuretics for the treatment of children with idiopathic hypercalciuria and hematuria.

We describe our experience in 14 children with idiopathic hypercalciuria and hematuria who received a finite course of thiazide diuretics. Thiazides reduced urinary calcium excretion and resolved hematuria in all cases. Serum calcium concentration was not altered with treatment. Serum potassium concentration decreased, and total carbon dioxide content and uric acid concentrations increased in response to therapy but these changes did not necessitate discontinuation of treatment. Thiazides were discontinued electively after 16 +/- 15 months of treatment (range 3 to 40 months). Six children maintained normal urinary calcium excretion, while 8 displayed excessive calcium excretion for 16 +/- 4 months after treatment was stopped. Renal calculi were not detected in any patient during this interval but hematuria recurred in 4 children. These findings suggest that thiazides are safe and effective for resolving hypercalciuria and hematuria. Thiazides may be discontinued safely in some children, while others will require further treatment courses or prolonged continuous therapy.

Families of children with idiopathic hypercalciuria. Evidence for the hormonal basis of familial hypercalciuria.

Six children with idiopathic hypercalciuria and their families were examined with an oral calcium loading test. Family members were divided into two clinical categories: group 1 consisted of the six index children and their parents and siblings with urolithiasis or unexplained hematuria; group 2 comprised the remaining parents and siblings without signs or symptoms associated with hypercalciuria. The results revealed that fasting urinary excretion of calcium was similar in both groups, but group 1 displayed a greater calciuric response to an oral calcium load. Serum concentrations of calcitriol (1,25-dihydroxyvitamin D3) and calcium were higher in group 1 than in group 2, while parathyroid activity was lower in group 1 patients. Urinary excretion of sodium, phosphorus, and magnesium, urine pH, serum levels of calcifediol (25-hydroxyvitamin D3) and phosphorus, and the renal tubular threshold for phosphate were not significantly different in the two groups. These findings suggest that idiopathic hypercalciuria may arise from a disturbance in the regulation of vitamin D metabolism that mediates enhanced intestinal absorption of calcium.

Prognostic features in infants with obstructive uropathy due to posterior urethral valves.

The histories of 22 infants presenting during the first year of life with obstructive uropathy due to posterior urethral valves were analyzed to determine outcome and prognostic features. Mean patient age at the time of the initial surgical intervention was 39 days, and the mean duration of followup inclusive of renal function data was 5.8 years. One patient died (5 per cent) and one had end stage renal disease. The mean preoperative and postoperative serum creatinine concentrations during the initial hospitalization were 3.1 and 1.4 mg. per dl., respectively. Neither value was significantly predictive of the creatinine concentration at final followup. In contrast, the nadir creatinine value during the first year of life correlated significantly with final renal function. Children with nadir creatinine values less than or equal to 0.8 mg. per dl. by 12 months of age maintained creatinine levels less than or equal to 1.1 mg. per dl. at the time of final evaluation, whereas children with higher values during the first year of life were likely to have progressive renal failure. Of 19 final creatinine determinations 6 were normal and 5 exceeded 1.5 mg. per dl. Proteinuria, hypertension, renal biopsy findings, urinary infection, unilateral nephrectomy and type of surgery did not correlate significantly with functional outcome. Followup studies of longer duration are needed to determine the ultimate outcome of these patients, more than half of whom had some degree of renal insufficiency at final evaluation.