Mouin G. Seikaly

The 12th Annual Report of the North American Pediatric Renal Transplant Cooperative Study : Renal transplantation from 1987 through 1998

Abstract: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) presents an annual report for all transplants registered from January 1987 onwards. In this report we reviewed 6,534 renal transplants recorded for 5,958 patients who had entered the study by January 1999, and attempted to identify changes in practice patterns that had led to improved graft survival. There has been a steady decline in cadaver source transplants nationally and our accrual for 1996 and 1997 reflected this trend. There has also been a decrease in the number of infants and young children receiving a transplant in recent years. From a peak of 23.3% in the 1987–91 cohort, the current report shows that children under 6 yr of age now account for only 20.4% of all transplants. Changing disease patterns and rates of progression of disease have decreased the percentage of Caucasian children in the transplant registry, from 68.5% in the first 5 yr to 62.9% in the most recent cohort. Changing practice patterns have markedly reduced the use of cadaver donor (CD) kidneys (recovered from donors younger than 10 yr of age) from 35% in 1991 to 22% in the current report. Acute rejection patterns are identical for CD and living donor (LD) grafts for the first 2 weeks post‐transplant. The comparative percentages on days 30 and 45 are 36% and 44% for CD, and 26% and 32% for LD recipients respectively. By the end of the first year post‐transplant, 45% of LD and 60% CD recipients have had an acute rejection. There has been a marked improvement in our ability to reverse the initial episode of rejection; in 1987, 52% were completely reversed in LD recipients, and in 1997 61% were reversed. Rejection percentages continued to be lower in patients maintained on cyclosporin A (CsA) doses of > 6.4 mg/kg. One‐, 3‐, and 5‐yr graft survival probabilities were 91%, 85%, and 80%, respectively, for LD recipients, and 83%, 73%, and 65% for CD recipients. Comparative 1‐ and 3‐yr figures from 1987 to 1991 were 88% and 81% for LD and 74% and 63% for CD recipients. When short‐term graft survival (1 yr) results were compared, a significant improvement was demonstrated from 71.7% in 1987/88 to 92.6% in 1998/1999 for CD transplants. Hence, changing practice patterns have gradually brought the short‐term graft survival of CD transplants very close to that of LD transplants. The continuing decrease in the incidence of acute rejections in more recent years should translate into a further delay in the onset of chronic rejection, thus improving graft longevity.

Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement

Growth failure is a clinically important issue in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality. Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH)–insulin-like growth factor-I (IGF-I) axis, malnutrition, acidosis, and renal bone disease. The management of growth failure in children with CKD is complicated by the presence of other disease-related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, some practitioners and families have been reluctant to institute GH therapy, citing an unwillingness to comply with daily injections, reimbursement difficulties, or impending renal transplantation. Suboptimal attention to growth failure management may be further compounded by a lack of clinical guidelines for the appropriate assessment and treatment of growth failure in these children. This review of growth failure in children with CKD concludes with an algorithm developed by members of the consensus committee, outlining their recommendations for appropriate steps to improve growth and overall health outcomes in children with CKD.

Etiology of sustained hypertension in children in the Southwestern United States

We reviewed the records of 132 children with persistent hypertension who were evaluated by our pediatric nephrology services between 1987 and 1991. Eightynine (67%) of these children were found to have renal or renovascular disease, 30 (23%) had primary hypertension and 13 (10%) had a non-renal cause for their hypertension. Glomerulonephritis (n=37) and reflux nephropathy (n=26) were the most frequent renal disorders identified. Renal artery thrombosis was the most common cause of hypertension in the neonatal period (in 6 of 12 neonates, 50%) whereas cystic kidney disease was the most common cause of hypertension in the 1st year of life (in 9 of 30 infants, 30%). The prevalence of primary hypertension increased with age; this diagnosis was made in 16 of 46 (35%) hypertensive patients between 12 and 18 years of age and, more surprisingly, in 8 of 27 (30%) children between 7 and 11 years of age. These data confirm that secondary hypertension is the most common cause of hypertension in children but suggest that primary hypertension is more prevalent than previously recognized in patients between 7 and 18 years of age.

Measuring Health-Related Quality of Life in Children With ESRD: Performance of the Generic and ESRD-Specific Instrument of the Pediatric Quality of Life Inventory (PedsQL)

BACKGROUND Minimal data exist to describe health-related quality of life in children with end-stage renal disease (ESRD). STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 193 children aged 5 to 18 years with ESRD and 190 parents of children aged 2 to 18 years with ESRD at 4 pediatric nephrology centers across the United States. OUTCOMES & MEASUREMENTS Generic and disease-specific health-related quality of life. The Pediatric Quality of Life Inventory version 4.0 (PedsQL 4.0) Generic Core Scales encompass: (1) Physical Functioning (8 items), (2) Emotional Functioning (5 items), (3) Social Functioning (5 items), and (4) School Functioning (5 items). The PedsQL 3.0 ESRD Module encompasses: (1) General Fatigue (4 items), (2) About My Kidney Disease (5 items), (3) Treatment Problems (4 items), (4) Family and Peer Interaction (3 items), (5) Worry (10 items), (6) Perceived Physical Appearance (3 items), and (7) Communication (5 items). RESULTS Internal consistency reliability for the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 ESRD Module was acceptable for both parent-proxy report and child self-report, with the exception of 1 parent-proxy report and 3 child self-report scales on the ESRD Module. The PedsQL Generic Core Scales differentiated between healthy children and children with ESRD, supporting discriminant validity. Intercorrelations between the PedsQL Generic Core Scales and the ESRD Module were in the medium to large range, supporting construct validity. A confirmatory factor analysis further supported construct validity of the ESRD Module. LIMITATIONS Test-retest reliability was not conducted, limited generalizability may exist given the age distribution of the children included, and imperfect agreement between child and parent-proxy reports. CONCLUSIONS Results support the feasibility, reliability, and validity of the PedsQL 4.0 Generic Core Scales in children with ESRD and provide initial support for the PedsQL 3.0 ESRD Module, although additional validation testing is warranted.

Impact of alendronate on quality of life in children with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a debilitating clinical condition characterized by fragile bone and skeletal deformity. Over the past decade frequent reports have suggested that the cyclical administration of intravenous pamidronate has a positive impact on bone density and skeletal fractures; however, the impact of such therapy on the quality of life (QOL) has rarely been reported. Alendronate, an oral bisphosphonate, is widely used to treat osteoporosis. The purpose of this study was to evaluate the impact of daily alendronate on QOL and bone parameters in children with OI. A prospective double-blind crossover study was designed in which placebo was alternated with daily alendronate. Twenty children with types I, III, and IV OI were recruited. Seventeen patients completed the study. Markers of QOL were measured in children with type III and IV OI (n = 15) using total mobility (PEDI), self-care (WeeFIM), well-being, pain, and use of analgesic scores. After 1 year of alendronate therapy, vertebral bone mineral density (BMD) improved from a change in standard deviation score (z-score) of 0.89 ± 0.19 to −0.12 ± 0.14 after 1 year of placebo (P < 0.001). All QOL markers, except for mobility score, improved in response to alendronate therapy. Change in height z-score also improved in response to 1 year of alendronate therapy (0.41 ± 0.21 vs. −0.09 ± 0.11, P < 0.05). Alendronate therapy did not alter serum levels of calcium, osteocalcin, parathyroid hormone (PTH), 1, 5 (OH)2 vitamin D, cholesterol, or urinary hydroxyproline or any other biochemical marker evaluated. Alendronate decreased by 56% urinary cross-linked N-telopeptide of type 1 collagen divided by urinary creatinine (uNTX/uCr). Daily alendronate therapy was well tolerated. Only two patients had mild gastrointestinal discomfort, responding to minor adjustments in alendronate intake. Daily alendronate therapy is safe and effective in improving QOL in children with OI.

Limitations to body length/serum creatinine ratio as an estimate of glomerular filtration in children

Abstract. The ability of the Schwartz formula (CSCH) to estimate glomerular filtration rate (GFR) accurately was investigated in children with renal disease. 125Iodine-iothalamate clearance (CIO) was used as the reference standard for measuring GFR. Data from 176 CIO studies performed on 133 children (aged between 1 and 18 years) were compared with the simultaneous estimation of GFR by CSCH. The overestimation of GFR by CSCH was inversely proportional to the level of renal function. When CIO was >90 ml/min per 1.73 m2, CSCH overestimated GFR by only 0.1%±3%, but when CIO was ≤15 ml/min per 1.73 m2, CSCH overestimated GFR by 164%±42%. When renal function is normal or mildly reduced (GFR >50 ml/min per 1.73 m2), CSCH overestimated CIO by only 10.3±3.0%, compared with 90.3±14.5% when renal function was moderately to severely curtailed (GFR ≤50 ml/min per 1.73 m2). We conclude that CSCH is valid in predicting GFR only in children with normal renal function and mild insufficiency.

Recurrence of focal segmental glomerulosclerosis in renal allograft: An in-depth review

Vinai M, Waber P, Seikaly MG. Recurrence of focal segmental glomerulosclerosis in renal allograft: An in‐depth review.
Pediatr Transplantation 2010: 14: 314–325.

Successful Split Liver-Kidney Transplant for Factor H Associated Hemolytic Uremic Syndrome

BACKGROUND AND OBJECTIVES A male infant with a family history of thrombotic microangiopathy developed atypical hemolytic uremic syndrome (aHUS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Case report. RESULTS Genetic analysis demonstrated a heterozygous mutation (S1191L) of CFH, the gene coding complement factor H (CFH). The child suffered many episodes of HUS, each treated with plasma exchange. In time, despite initiation of a prophylactic regimen of plasma exchange, his renal function declined significantly. At the age of 4 yr he received a (split liver) combined liver-kidney transplant (LKT) with preoperative plasma exchange and enoxaparin anticoagulation. Initial function of both grafts was excellent and is maintained for nearly 2 yr. CONCLUSIONS This report adds to the small but growing number of individuals in whom LKT has provided a favorable outcome for aHUS associated with CFH mutation, expands the technique of using a split liver graft, and describes the unique histologic features of subclinical liver disease in HUS.

Pediatric end stage renal disease health-related quality of life differs by modality: a PedsQL ESRD analysis

We previously validated the 34-item PedsQL 3.0 End Stage Renal Disease (ESRD) Module designed to measure pediatric ESRD-specific health-related quality of life (HRQOL) in children and adolescents receiving maintenance dialysis or with a renal transplant. The study reported here was undertaken to assess for potential HRQOL differences between ESRD modality in children with ESRD and their parents using the PedsQL 3.0 ESRD Module. Parents of patients with a renal transplant reported a significantly higher HRQOL for their children than parents of pediatric patients receiving dialysis on all ESRD Module Scales except the Perceived Physical Appearance Scale, with the majority of the effect sizes in the medium range. Pediatric renal transplant patients self-reported comparable HRQOL to pediatric patients receiving dialysis across the ESRD Module Scales, with the exception of the Family and Peer Interaction Scale, in which pediatric renal transplant patients self-reported significantly higher HRQOL than pediatric patients receiving dialysis. Our cross-sectional data suggest that parents of children with ESRD observe a positive impact from renal transplantation on the majority of HRQOL domains compared to dialysis, whereas children self-report generally non-significant small effect size differences in favor of renal transplantation. These findings suggest that the PedsQL ESRD 3.0 Module may be used to identify ESRD- and modality-specific challenges that impact pediatric patient HRQOL.

Glomerular filtration rate as a putative 'surrogate end-point' for renal transplant clinical trials in children.

Abstract: Only with prospective randomized controlled trials is it possible to evaluate the several immunosuppressive regimens available to renal allograft recipients. Commonly used surrogate markers of clinical outcome, such as patient and graft survival, are constantly improving. Current immunosuppressive protocols have improved 1‐yr graft survival to over 90%. The small differences in graft survival among the various immunosuppressive regimes require large patient cohorts in order to establish statistical significance. Such studies are often difficult to conduct in a timely manner, particularly in children. This necessitates the search for better surrogate markers sensitive enough to detect differences in smaller cohorts and in a shorter period of time. While the degree of fibrosis in transplant biopsies might well predict long‐term graft survival, protocol biopsies are expensive, invasive, and unpopular among clinicians. In native kidneys, glomerular filtration rate (GFR) closely correlates with disease progression and interstitial fibrosis and appears to be well positioned as a less invasive surrogate marker for long‐term outcome. Nonetheless, the ideal marker for GFR remains obscure. Serum creatinine has several major drawbacks, making it a poor predictor of GFR. This review discusses the several methods used to estimate or measure GFR with emphasis on 125I‐iothalamate clearance and serum cystatin C (cys‐C). Of all the serum markers, cys‐C is the most reliable and the most promising. However, cys‐C and other endogenous markers cannot replace the diagnostic sensitivity and reliability of radiolabeled markers of GFR such as 125I‐iothalamate in renal transplant clinical trials. Unfortunately, clearance of most radiolabeled markers of GFR including 125I‐iothalamate remain costly and time consuming.