The changing spectrum of hypertension in premature infants.

OBJECTIVE: The objective is to document changes in the etiologic spectrum of hypertension in premature infants. STUDY DESIGN: We reviewed all cases of systemic hypertension (HTN) in premature infants at two centers over 8 years. Infants were sorted into categorical groups as described in 2012 by Flynn. Analyses included frequency of diagnosis, timecourse of HTN, and diagnostics. Phthalate exposure via intravenous fluid and respiratory equipment was compared among groups and centers. RESULTS: One hundred and twenty-nine infants having 130 episodes of HTN met the inclusion criteria. Sixty-five percent of cases were classified as pulmonary and 16% as miscellaneous. Plasma renin activity (PRA) was undetectable or <11 ng/mL/h in almost all hypertensive infants. Cases categorized as Pulmonary, medications/intoxications, and miscellaneous presented near 40 weeks postmenstrual age, with low PRA and large phthalate exposures. CONCLUSIONS: High PRA HTN has been replaced by low PRA in most cases, and may be due to phthalate exposure.

Longitudinal study on the use of dried blood spots for home monitoring in children after kidney transplantation.

The use of DBSs for home monitoring has been limited due to unsatisfactory blood sampling and analytical difficulties. The aim of this longitudinal feasibility trial was to assess the utility of DBS to monitor TAC and Cr at home in transplant recipients. A total of 30 participants (2-21 years, mean±SD, 13.6±5.4 year) were enrolled over 12 months. Eighteen were males. Monthly DBS samples were obtained at home and mailed to the central laboratory for analysis of TAC and Cr. Nineteen patients completed the study, and 216 cards were received in the laboratory from a total of 279 cards expected, with 416/519 (80%) blood spots being suitable for analysis. We found a high correlation between blood TAC and Cr levels by DBS and the clinical laboratory, R2 =.81 and .95, respectively. Fifteen parents and 15 youth completed measures of satisfaction with and preference for DBS testing. All but one parent/caregiver and youth reported satisfaction and preference for this method of testing over laboratory blood draws. We conclude that home DBS monitoring is a feasible method to monitor TAC and Cr in pediatric transplant recipients.

Tacrolimus pharmacokinetics in Hispanic children after kidney transplantation.

Ethnic differences in drug pharmacokinetics are well recognized including that for tacrolimus (TAC) in adult subjects. However, similar knowledge among pediatric populations is missing. Our limited retrospective study compares steady-state pharmacokinetics of TAC in Hispanic versus non-Hispanic children. Serial blood samples were collected and whole blood concentrations of TAC were measured using radioimmunoassay. Compared with non-Hispanic children, Hispanic children had lower measures of drug exposure (maximum drug concentration [Cmax] and area under the drug concentration-time curve [AUC0-∞]), higher volume of distribution, and faster clearance. Interestingly, only in Hispanic children, significant correlations were found between body weight and clearance, age and volume of distribution, and Schwartz estimated glomerular filtration rate and half-life. In conclusion, our study suggests that ethnic differences exist between Hispanic and non-Hispanic children in TAC PK, and based on our preliminary findings, either a higher or more frequent TAC dosing may be required for effective immunosuppression therapy in Hispanic children.

Adolescent Transition to Adult Care in Solid Organ Transplantation: a consensus conference report.

Transition of care from pediatric to adult-oriented health care providers is difficult for children with special health care needs. Children who have received solid organ transplants and their providers experience the same difficulties and frustrations as children with other major illnesses. A consensus conference was organized by several transplant organizations to identify major issues in this area and recommend possible approaches to easing the process of transition for solid organ transplant recipients. This report summarizes the discussions and recommendations.

Posttransplant diabetes mellitus in pediatric renal transplant recipients: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

BACKGROUND: The incidence of renal post transplant diabetes mellitus (PTDM) in adults varies from 3-46%. METHODS: We did a retrospective analysis of 1365 children in The North American Pediatric Renal Transplant Cooperative Study with renal transplant (Tx) reported between January 92 and July 1997. PTDM, defined as >2 weeks of insulin therapy after Tx, developed in 36 patients. A control group of 153/1329 non-PTDM patients was selected and matched for age at Tx and primary diagnosis. RESULTS: African-Americans were overrepresented (36.1 vs. 17.6%, P=0.017) and Hispanics were underrepresented (5.6 vs. 26.1%, P=0.019) among cases. Although prednisone dose 30 days post-Tx was higher among cases (0.89 mg/kg/day) versus controls (0.71 mg/kg/day), P=0.019, cyclosporine dose was similar. No differences in prednisone or cyclosporine doses were observed at 6, 12, or 24 months post-Tx. Tacrolimus use in PTDM group was high (45%). The estimated incidence of first acute rejection at 1, 3, and 12 months was higher among cases, 0.41+/-0.08, 0.52+/-0.08, 0.61+/-0.08, compared to controls, 0.23+/-0.02, 0.37+/-0.02, and 47+/-0.02 (P=0.058). Crude graft failure rates of 13.5% (5/36) and 12.4% (19/153) were similar between the two groups, so was the calculated creatinine clearance at 12 and 24 months and post-Tx hospitalization days. CONCLUSION: PTDM occurs in <3% of children. African-Americans are at higher risk and Hispanics at lower risk for PTDM. Tacrolimus is a significant risk factor for PTDM. Children with PTDM had a higher incidence of acute rejection, but graft survival, kidney function, and hospitalization rates were similar to selected controls.

The clinical efficacy of higher hematocrit levels in children with chronic renal insufficiency and those undergoing dialysis.

The optimal hematocrit target range in children with end-stage renal disease, who are receiving recombinant human erythropoietin, is ambiguous due to the lack of compelling, age-appropriate studies. There are a large number of adult and pediatric studies which show that physical performance as well as morbidity and mortality are positively influenced by partial normalization of the hematocrit to 30 vol% to 36 vol%. Cognition studies performed in adults similarly show improvement with partial correction of hematocrit. Normalization of hematocrit studies show lower mortality rates, incremental further improvement in cognition, and greater resolution of cardiac anomalies when compared with patients with partial correction of anemia. Conversely, cardiac death rates may increase in adult patients receiving hemodialysis with preexisting cardiac disease, and there are concerns about the effect of recombinant human erythropoietin on catheter/shunt/fistula patency and on blood pressure. The high cost of recombinant human erythropoietin and established Medicare and Dialysis Outcomes Quality Initiative target hematocrit ranges have also influenced pediatric nephrologists in their assessment of the risk-benefit ratios, despite new adult data suggesting that maintenance of higher hematocrits may be cost-effective. The rationale of using adult-derived hematocrits in children with end-stage renal disease needs to be re-examined in the context of the unique growth and developmental requirements of children. A prospective, multicenter study which determines the relative benefits and risks of age-adjusted hematocrit normalization in children with renal failure is warranted.

Pulse methylprednisolone treatment of idiopathic steroid-resistant nephrotic syndrome.

Although much of the interest in pulse methylprednisolone therapy (PMT) has centered around its use in children with focal segmental glomerulosclerosis, PMT has also been shown to be effective in the treatment of other proteinuric renal diseases. We hypothesized that a PMT-based treatment protocol, derived from the Tune-Mendoza protocol, would effectively induce a more rapid remission in young children with idiopathic steroid-resistant nephrotic syndrome (SRNS). A retrospective analysis was conducted of 11 consecutive SRNS patients (mean age 3.6 +/- 1.5 years) that received PMT between 1 August 1992 and 1 May 1998. The initial mean urinary protein/urinary creatinine ratio (UP/UC, mg/mg) was 8.3 +/- 9.7 and mean estimated creatinine clearance (CCr) 137.7 +/- 47.0 ml/min per 1.73 m2. An average of 24.8 +/- 10.5 PMT doses were given. The mean duration of PMT therapy until remission was 23.4 +/- 29.9 days (median 12 days). Cyclosporine and cyclophosphamide were used to maintain and extend remissions in 5 and 4 patients, respectively. At the conclusion of the study, the mean UP/UC was 0.12 +/- 0.22 and mean CCr 151.8 +/- 39.8 ml/min per 1.73 m2 (no CCr < or = 100 ml/min per 1.73 m2). Of the 11 patients, 9 attained complete remission. Adverse effects were mild and infrequent. This PMT protocol appears to safely and effectively induce remission in young children with SRNS. A future prospective trial that evaluates the efficacy of PMT in young children with SRNS is warranted.

Coccidioidomycosis in adolescents with lupus nephritis.

Coccidioidomycosis, a fungal infection endemic in the southwestern United States, can cause life-threatening infections in immunosuppressed patients. We report the contrasting cases of two adolescents with lupus nephritis, treated with intravenous pulse cyclophosphamide and daily oral corticosteroids, who developed pulmonary coccidioidomycosis. One patient developed a fatal form of fulminant disseminated coccidioidomycosis, while the other patient developed a solitary pulmonary Coccidioides immitis abscess which was responsive to intravenous liposomal amphotericin and fluconazole therapy. Because serologies and initial X-ray studies can be negative, definitive diagnostic studies including bronchoaveolar lavage and needle aspiration should be performed when there is clinical suspicion of coccidioidomycosis in an immunocompromised patient. Immunosuppressed patients with coccidioidomycosis should receive early intravenous amphotericin therapy and may benefit from long-term suppressive antifungal therapy to prevent relapse.

Long-term plasmapheresis and protein A column treatment of recurrent FSGS.

Transient or intermittent plasmapheresis with concurrent immunosuppressive therapy is thought to be beneficial in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the early post-transplant period. The results of long-term (6-year) plasmapheresis therapy, in a 9-year-old female with an immediate recurrence of FSGS [urinary protein/urinary creatinine (UP/UC)=17.7] after cadaveric renal transplant, are presented. A 4-week plasmapheresis course induced a decline in the proteinuria, but a relapse occurred after cessation of plasmapheresis. Addition of protein A column therapy led to a further decrease in the proteinuria, to a non-nephrotic range. Long-term control of the nephrotic syndrome was established using a chronic treatment regimen consisting of a single-volume plasmapheresis, followed by a protein A column treatment, performed on sequential days every 3-4 weeks. Mean UP/UC values decreased to 1.15+/-0.9. A course of cyclophosphamide was successfully used to control a worsening of proteinuria 4 years post transplant. Although sequential renal biopsies demonstrated progressive glomerular sclerosis, the patient's mean calculated creatinine clearance only modestly declined from 78.3 ml/min per 1.73 m2, at the time of transplantation, to 62.7 ml/min per 1.73 m2, 6 years later. This patient demonstrated dependence on plasmapheresis/protein A column therapy to maintain a clinical remission of her FSGS recurrence. While long-term plasmapheresis and protein A column therapy in combination with immunosuppressive therapy reversed the effects of uncontrolled nephrosis and possibly facilitated long-term renal allograft survival, the glomerular sclerosis continued to progress.

Concurrent centrifugation plasmapheresis and continuous venovenous hemodiafiltration.

Continuous venovenous hemofiltration/hemodiafiltration (CVVH/D) is commonly used to provide renal replacement therapy for critically ill patients who are hemodynamically unstable. Occasionally, the addition of plasmapheresis therapy is necessary for some conditions, including immune-mediated acute renal failure, sepsis, fulminant hepatic failure, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Most tertiary care facilities provide centrifugation plasmapheresis instead of membrane plasmapheresis, because of the requirement for both therapeutic plasma exchange and pheresis of cellular blood products. We report a new technique where centrifugation plasmapheresis and CVVHD (P-CVVHD) are combined and used concurrently. Blood from the patient was concurrently filtered utilizing a Hospal BSM 22 machine with a Multiflow 60 hemofilter and a Cobe Spectra continuous cell separator in a parallel configuration. P-CVVHD is technically possible and can be used for long periods of time with limited risks. There may be advantages to P-CVVHD compared with discontinuous combined CVVH/D and plasmapheresis therapy.

A new, unique and simple method for ureteral implantation in kidney recipients with small, defunctionalized bladders.

BACKGROUND: Major, almost insurmountable, deterrents exist to the use of the small capacity, defunctionalized, nonneurogenic urinary bladder in renal transplantation, namely, the technical difficulty in performing a satisfactory ureteral implantation with conventional methods and the potential secondary problems with high grade ureteral reflux and obstruction. Alternatives are less than ideal and include transplantation into a bowel-augmented urinary bladder with intermittent self-catheterization, ileal conduit urinary diversion, or avoidance of transplantation and relegating the patient to life-long dialysis. METHODS: Eight consecutive patients (ages 13 months to 29 years) with small, defunctionalized urinary bladders underwent a new method of intravesical implantation of the transplant ureter. The mean capacity of these bladders was 18.5+/-13.1 ml (range 6 to 45 ml), with the bladders defunctionalized for a mean 81.6+/-24.3% of the patients' total lifetime. The technique involved placement of the transplant ureter into a shallow, mucosa-denuded, rectangular trough extending from a superiorly placed ureteral hiatus distally to the trigone. We hypothesized that the mucosal margins on the two lateral aspects of the rectangular trough would grow over the anterior surface of the ureter until they met the advancing mucosal edges from the contralateral side to form a natural neosubmucosal tunnel. RESULTS: Posttransplantation cystoscopic examination demonstrated bladder mucosal regeneration and growth over the ureter, confirming the spontaneous development of a good length neosubmucosal tunnel. All patients demonstrated no evidence of ureteral reflux or ureteral obstruction, whereas an immediate prior cohort of four consecutive patients with bladder capacities < or =30 ml showed that three of four had ureteral reflux (P=0.02) and four of four developed hydronephrosis (P=0.002). All urinary bladders in the present cohort enlarged to expected normal or nearnormal capacities. Serum creatinines were stable throughout the entire follow-up period, with the exception of one patient who had rejection episodes. Two patients had urinary tract infections posttransplantation, but there were no episodes of acute pyelonephritis. CONCLUSIONS: This novel technique for ureteral implantation successfully capitalizes on the regenerative potential of the bladder mucosa, resulting in a physiological, anatomically natural, and very effective neosubmucosal tunnel. It appears to guarantee success against both ureteral reflux and obstruction, no matter how small the urinary bladder, and offers no hindrance to enlarging the bladder to near normal capacity posttransplantation. The implantation technique is simple and safe, and its use should eliminate the reluctance to use these bladders. Moreover, this procedure offers a major incentive for the successful rehabilitation of small, defunctionalized, nonneurogenic bladders after kidney transplantation.

Prenatally diagnosed autosomal recessive polycystic kidney disease: initial postnatal management.

We report a case of autosomal recessive polycystic kidney disease (ARPKD). A presumptive diagnosis was made after a late-term prenatal ultrasound revealed hypoplastic lungs, massive polycystic kidneys, and oligohydramnios. A full-term baby girl was delivered vaginally. Respiratory distress required intubation. Twelve hours after birth, she underwent bilateral nephrectomy and peritoneal dialysis catheter placement. The average kidney size was 150 g and 9.25 cm. Pathologic examination confirmed ARPKD. Peritoneal dialysis was started on the third day of life. The baby had no gross neurologic deficit. At 6 months of age, she was growing well, and the mother was a candidate to be a living-related kidney donor.

Living-unrelated renal transplantation in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

The shortage of cadaver kidneys available for organ donation compared to growing demand has led to an increase in the use of living-unrelated donors (LURD) for renal transplantation (Tx). Results from trials in adults show that 1-year graft survival rates in LURD are similar to living-related donor (LRD) rates and superior to those of cadaver renal donor (CAD) transplants. We report our experience with 38 LURD transplants for children enrolled in NAPRTCS that were performed between 1987 and 1997. Ages of recipients at Tx were 0-5 years (n=8), 6-12 (n=10), and >12 years (n=20). Twenty nine were primary Tx, seven were second Tx, and two were third Tx. HLA antigen data showed that the number of 2-antigen mismatches for each locus was 44.7% for HLA-A, 71.1% for HLA-B, and 55.3% for HLA-DR. There were 7 donor/recipient pairs with a 6-antigen mismatch, 12 pairs with a 5-antigen mismatch, while there were 6 pairs with a 3-antigen match of which 3 pairs had at least one match at each of the A, B, and DR loci. A total of 38 acute rejection episodes occurred in 25 LURD recipients. Among primary grafts the incidence of first acute rejection at 30 d post-Tx was 46% in LURD vs. 29% in LRD and 37% in CAD recipients; at 1 year post-Tx it was 76% in LURD vs. 48% in LRD and 62% in CAD recipients. Acute tubular necrosis (ATN) was reported in four or 10.5% of LURD transplants compared with 5.4% in LRD and 19.0% in CAD recipients. There were 12 LURD graft failures, due to vascular thrombosis (3), acute rejection (2), recurrence of original disease (1), infection (3), and patient death (3). Estimated primary graft survival probabilities (+/- SE) at 12 months post-Tx are 0.825 +/- 0.071 for LURD, compared to 0.911 +/- 0.006 for LRD, and 0.815 +/- 0.009 for CAD. We conclude that data from this study show that LURD Tx in children have a low rate of ATN that is similar to that of LRD Tx. However, LURD Tx have a high incidence of acute rejection, and the graft survival at 12 and 24 months post-Tx is inferior to LRD Tx. There is a high frequency of graft loss due to causes other than rejection, and these may be related to adverse recipient selection criteria.

Quantitative specificity of the Mnt repressor.

The Mnt protein of Salmonella phage P22 binds site-specifically to its operator. To better understand this binding we used dideoxy DNA sequencing in a quantitative manner to determine the relative binding constants, and hence the relative free energies, of wild-type Mnt protein to a substantial number of variants of its operator. These measurements were supported by experiments which used the SELEX procedure to generate a set of operators from an initially randomized population. In the Discussion we show that the present model of Mnt protein/operator binding, due to Sauer and co-workers, along with the assumption of an independent contribution of each position in the operator to the total binding, provides a reasonably accurate description of the system. We also discuss the use of information content as a measure of DNA-protein binding specificity with the Mnt protein/operator system serving as an example and show again that the assumption of independence supports the current view of this case of site-specific binding.

Propylene glycol-induced proximal renal tubular cell injury.

Propylene glycol is a solvent that is used in many oral, injectable, and topical medications. Although uncommon, acute renal failure has been attributed to propylene glycol. The mechanism of propylene glycol-mediated renal injury is unknown. We report a case of acute renal failure in a 16-year-old boy given large doses of pentobarbital and phenobarbital, both of which are solubilized with propylene glycol. A renal biopsy showed proximal renal tubular cell swelling and vacuole formation. The data from this case suggest that the reversible acute renal failure caused by propylene glycol is attributable to proximal renal tubular cell injury.

Pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor: the effects of zidovudine.

Recombinant human granulocyte-macrophage colony-stimulating factor (rHu GM-CSF) enhances bone marrow production of and stimulates granulocytes, macrophages, and eosinophils. Granulocyte-macrophage colony-stimulating factor may be used concomitantly with zidovudine in human immunodeficiency virus (HIV)-positive patients to minimize zidovudine-associated neutropenia. This open-label, randomized, placebo-controlled study was performed to evaluate the pharmacokinetic disposition of rHu GM-CSF in HIV-positive, asymptomatic patients in the absence and presence of concomitant zidovudine administration. Eight participants received rHu GM-CSF (5 micrograms/kg subcutaneously) daily for 4 days in combination with placebo or zidovudine (200 mg orally every 8 hours) in a randomized, crossover fashion, with each study period separated by a 3-day washout phase. Pharmacokinetic blood sampling was performed over 16 hours on days 1 and 4 of both treatment periods, and subsequent analysis of serum was performed using an enzyme-linked immunosorbent assay. Pharmacokinetic results of rHu GM-CSF at steady state (days 4 of periods I and II) in the absence (placebo) and presence of zidovudine included apparent total body clearance, half-life, and apparent volume of distribution, all of which were not significantly altered with concomitant administration of zidovudine. Mean pharmacokinetic results of rHu GM-CSF after the first dose (days 1 of periods I and II) were similar to steady-state values; however, total body clearance was significantly increased at steady state compared with the results of the first dose. Concurrent administration of zidovudine does not influence the pharmacokinetic disposition of rHu GM-CSF after single or multiple doses.

Continuous venovenous hemofiltration with dialysis in combination with total hepatectomy and portocaval shunting. Bridge to liver transplantation.

Children who experience acute liver failure following liver transplantation will have multiple organ failure and a high rate of mortality unless emergency retransplantation can be performed. Transplant hepatectomy with portocaval shunting has been described as a bridge to transplantation in the most severe cases, as well as in patients with fulminant hepatic failure at high risk for mortality who have not undergone liver transplantation. Patients with multiple organ failure who have undergone hepatectomy require renal replacement therapy. Continuous hemofiltration may be used in patients with fulminant hepatic failure to facilitate fluid removal and circulatory and metabolic balance. We used continuous venovenous hemofiltration with dialysis following hepatectomy with portocaval shunting in a patient who remained anhepatic for 66 hr in order to achieve circulatory and metabolic homeostasis as well as stable neurologic function prior to successful retransplantation.

Oral and intravenous zidovudine pharmacokinetics: the effect of granulocyte-macrophage colony stimulating factor.

Combination therapy with zidovudine and recombinant human granulocyte-macrophage colony stimulating factor (rHu GM-CSF) may be warranted, owing to the bone marrow suppressive effects of zidovudine. A study of 16 patients, 8 of whom had acquired immune deficiency syndrome (AIDS) and 8 of whom were infected with human immunodeficiency virus (HIV) but were asymptomatic, was conducted. The effect of 4 days of rHU GM-CSF versus placebo on intermittent zidovudine therapy (200 mg every 8 hours) was evaluated using a randomized, cross-over study design. Pharmacokinetics of oral and intravenous zidovudine were determined on days 1 (oral), 3 (oral), and 4 (intravenous) of rHu-GM-CSF (placebo) administration. After intravenous dosing, zidovudine plasma clearance for placebo and rHu GM-CSF averaged 1.4 +/- 0.2 and 1.3 +/- 0.2 L/hr/kg, respectively (P = 0.017), mean residence time averaged 1.5 +/- 0.5 and 1.9 +/- 0.6 hours, respectively (P = 0.012), and the steady-state volume of distribution was 2.0 +/- 0.7 and 2.3 +/- 0.7 L/kg, respectively (P = 0.027) for the two treatment arms. Stratified data for patients with AIDS and those with asymptomatic HIV infection revealed no significant difference in plasma clearance or mean residence time between the two patient groups. These pharmacokinetic results indicate that dosage adjustments for zidovudine are not warranted when administered with rHu GM-CSF owing to the small changes observed. However, the statistically significant increase in Vss suggests the possibility of enhanced zidovudine cellular uptake in the presence of rHu GM-CSF.

Prevention of rejection and graft loss with an aggressive quadruple immunosuppressive therapy regimen in children and adolescents.

During the two-year period May 1991 to April 1993, 36 kidney transplants were performed in children less than 18 years of age at California Pacific Medical Center using an aggressive quadruple-therapy regimen of immunosuppression. The regimen consisted of induction with an antilymphocyte preparation (MALG in 21, OKT3 in 2, ATGAM in 12, none in 1), initial moderate-dose steroid therapy, early intravenous cyclosporine therapy, and azathioprine. Twenty living-related graft recipients were pretreated with donor-specific transfusions. Long-term cyclosporine was dosed by levels to keep through whole-blood levels (RIA) at 200-300 ng/ml. Twenty-five grafts were from living-related donors, two from living unrelated donors, and nine from cadaveric donors. Eleven (30%) recipients were five years old or under at the time of transplantation. Of these recipients 44% had complex congenital urologic disease and required urologic surgery prior to or at the time of transplantation. Patients have been followed for a mean of one year, with actual patient and graft survivals of 100% and 97%, respectively. Only one graft has been lost, to severe, early recurrent focal segmental glomerulosclerosis. Four of the 36 patients have had one rejection episode each, all reversed completely. Graft function is stable, with serum creatinine proportionate to age--mean serum creatinine in the children under two years old being 0.4 mg/dl, and in the adolescents 1.3 mg/dl, with two adolescent boys having the highest creatinine levels at 1.8 mg/dl. We conclude that an aggressive approach to immunosuppressive therapy in the early posttransplant period with MALG/OKT3/ATGAM induction and rapid achievement of therapeutic cyclosporine levels prevents rejection and results in excellent patient and graft survival with subsequent stable good graft function.