Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial.

Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.

Association of histologic variants in FSGS clinical trial with presenting features and outcomes.

BACKGROUND AND OBJECTIVES: FSGS histologic variants have correlated with outcomes in retrospective studies. The FSGS Clinical Trial provided a unique opportunity to study the clinical impact of histologic variants in a well defined prospective cohort with steroid-resistant primary FSGS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal biopsies of 138 FSGS Clinical Trial participants aged 2-38 years enrolled from 2004 to 2008 were analyzed using the Columbia classification by core pathologists. This study assessed the distribution of histologic variants and examined their clinical and biopsy characteristics and relationships to patient outcomes. RESULTS: The distribution of histologic variants was 68% (n=94) FSGS not otherwise specified, 12% (n=16) collapsing, 10% (n=14) tip, 7% (n=10) perihilar, and 3% (n=4) cellular. Individuals with not otherwise specified FSGS were more likely to have subnephrotic proteinuria (P=0.01); 33% of teenagers and adults had tip or collapsing variants compared with 10% of children, and subjects with these variants had greater proteinuria and hypoalbuminemia than not otherwise specified patients. Tip variant had the strongest association with white race (86%) and the lowest pathologic injury scores, baseline creatinine, and rate of progression. Collapsing variant had the strongest association with black race (63%, P=0.03) and the highest pathologic injury scores (P=0.003), baseline serum creatinine (P=0.003), and rate of progression. At 3 years, 47% of collapsing, 20% of not otherwise specified, and 7% of tip variant patients reached ESRD (P=0.005). CONCLUSIONS: This is the first prospective study with protocol-defined immunomodulating therapies confirming poor renal survival in collapsing variant and showing better renal survival in tip variant among steroid-resistant patients.

Circulating suPAR in two cohorts of primary FSGS.

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

Galloway-Mowat syndrome: neurologic features in two sibling pairs.

Galloway-Mowat syndrome is an autosomal recessive disorder presenting as early-onset nephrotic syndrome and central nervous system abnormalities, including microcephaly and developmental delays. Neurologic findings are universal in children with this disorder, and often precede renal abnormalities. However, relatively few descriptions of associated neurologic features are available. We describe two pairs of siblings with Galloway-Mowat syndrome who illustrate the spectrum of neurologic findings, to increase awareness of this syndrome among pediatric neurologists.

Clinical trial of focal segmental glomerulosclerosis in children and young adults.

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Clinical trials treating focal segmental glomerulosclerosis should measure patient quality of life.

Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2-40 years, with an estimated glomerular filtration rate > 40 ml/min per 1.73 m², a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m², and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials.

Report of colloquium I: the future of pediatric health care delivery and education--pondering imponderables to create an ideal residency in a world of critical uncertainties.

Participants of the first colloquium of the Residency Review and Redesign in Pediatrics (R(3)P) Project considered possible scenarios affecting pediatric practice over the next 15 to 20 years and speculated about the knowledge and skills that pediatricians would need to care for children, adolescents, and young adults in the future. They concluded that the imponderables and complexity of that undertaking fell into the category of a "wicked problem" with no unique solutions. The specifics of the future cannot be predicted, but the themes important to thinking about the future are clear and must be incorporated into thinking about pediatric residency education.

Maintenance fluid therapy: what it is and what it is not.

Fifty years after the publication of a prescription for maintenance fluid therapy, concerns have been raised about the use of hypotonic fluids in hospitalized children. We discuss what maintenance fluid therapy is or what it is not; where maintenance fluid therapy has been misused. We also discuss concerns with the immediate adoption of isotonic fluid as maintenance fluid without careful consideration and testing.

Enhancing the diversity of the pediatrician workforce.

This policy statement describes the key issues related to diversity within the pediatrician and health care workforce to identify barriers to enhancing diversity and offer policy recommendations to overcome these barriers in the future. The statement addresses topics such as health disparities, affirmative action, recent policy developments and reports on workforce diversity, and research on patient and provider diversity. It also broadens the discussion of diversity beyond the traditional realms of race and ethnicity to include cultural attributes that may have an effect on the quality of health care. Although workforce diversity is related to the provision of culturally effective pediatric care, it is a discrete issue that merits separate discussion and policy formulation. At the heart of this policy-driven action are multiorganizational and multispecialty collaborations designed to address substantive educational, financial, organizational, and other barriers to improved workforce diversity.

Fluid therapy for children: facts, fashions and questions.

Fluid therapy restores circulation by expanding extracellular fluid. However, a dispute has arisen regarding the nature of intravenous therapy for acutely ill children following the development of acute hyponatraemia from overuse of hypotonic saline. The foundation on which correct maintenance fluid therapy is built is examined and the difference between maintenance fluid therapy and restoration or replenishment fluid therapy for reduction in extracellular fluid volume is delineated. Changing practices and the basic physiology of extracellular fluid are discussed. Some propose changing the definition of "maintenance therapy" and recommend isotonic saline be used as maintenance and restoration therapy in undefined amounts leading to excess intravenous sodium chloride intake. Intravenous fluid therapy for children with volume depletion should first restore extracellular volume with measured infusions of isotonic saline followed by defined, appropriate maintenance therapy to replace physiological losses according to principles established 50 years ago.

Impact of specialization of primary nephrologist on the care of pediatric hemodialysis patients.

BACKGROUND: Children with end-stage renal disease (ESRD) receiving hemodialysis may have their care overseen primarily by a pediatric nephrologist or internal medicine (IM) nephrologist. METHODS: To examine specific clinical outcomes by nephrologist specialization, a cross-sectional analysis of demographic and clinical data collected in the 2002 ESRD Clinical Performance Measures Project was performed. RESULTS: Of 653 pediatric patients meeting inclusion criteria, 27% were cared for by IM nephrologists, and 73%, by pediatric nephrologists. Pediatric nephrologists were significantly more likely than IM nephrologists to care for patients who were younger and of Hispanic ethnicity. Patients of pediatric compared with IM nephrologists also were more likely to have a congenital cause of ESRD, smaller body mass index, and longer time on dialysis therapy. No significant differences in achieving a mean Kt/V of 1.2 or greater or mean hemoglobin level of 11 g/dL or greater (> or =110 g/L) according to nephrologist specialization were observed. After adjustment for patient clinical characteristics, no significant difference in use of arteriovenous fistulae was observed. Patients cared for by pediatric nephrologists were less likely to achieve a mean serum albumin level of 4.0/3.7 g/dL (40/37 g/L; bromcresol green laboratory method/bromcresol purple laboratory method; adjusted odds ratio, 0.60; 95% confidence interval, 0.42 to 0.86). Patients cared for by pediatric nephrologists had significantly greater serum calcium levels, lower serum phosphate levels, and lower intact parathyroid hormone levels. CONCLUSION: Using adult-focused clinical care targets, care provided by pediatric and IM nephrologists to pediatric patients receiving hemodialysis in the United States is similar. However, differences exist, and the significance of these differences requires further study.

Growth in adolescent hemodialysis patients: data from the Centers for Medicare & Medicaid Services ESRD Clinical Performance Measures Project.

The Centers for Medicare & Medicaid Services' (CMS) end-stage renal disease (ESRD) Clinical Performance Measures (CPM) Project has collected data on all adolescent hemodialysis patients since 2000. Thus, by 2002 data were available on all adolescents on hemodialysis in the USA for 3 consecutive years. Possible associations between clinical parameters and linear growth in this cohort were evaluated. Ninety-four adolescents were on hemodialysis for the 3 study years. The mean height standard deviation score (ht SDS) fell from -1.97 to -2.36 over the 3 study years. Compared with patients with ht SDS > or =-1.88, patients with ht SDS <-1.88 in the 2002 study year (n =53) were more likely to be male (66% vs 44%, p <0.05), on dialysis longer (6.9+/-4.5 years vs 4.1+/-2.3 years, p <0.001), and had lower height SDS in the 2000 study year (-2.90+/-1.31 vs -0.772+/-1.10, p <0.001). Patients with a ht SDS <-1.88 had a lower mean hemoglobin (11.4+/-1.6 g/dl vs 12.0+/-1.1 g/dl, p <0.05), but there were no differences in other clinical parameters. Among patients with ht SDS <-1.88, 38.8% (n =20) were prescribed recombinant human growth hormone (rhGH) in the 2002 study year. There were no differences in demographic or clinical parameters between rhGH treated and untreated patients. Many adolescents who remain on hemodialysis have poor linear growth. Further evaluation is needed to delineate contributory factors and the possible underutilization of rhGH.

Longitudinal analysis of intermediate outcomes in adolescent hemodialysis patients.

In 2000 and 2001, The Centers for Medicare & Medicaid Services (CMS) End-Stage Renal Disease (ESRD) Clinical Performance Measures (CPM) project collected data on all in-center hemodialysis (HD) patients in the United States aged >or=12 and <18 years. There were 433 of 486 (89%) patients and 435 of 516 (84%) patients who had the minimum required data submitted and were included in the 2000 and 2001 study years, respectively. There were 188 patients (43%) who had data submitted in both study years, providing longitudinal data on this cohort. A comparison of clinical parameters on these 188 patients in the 2000 and 2001 study years reveals significant improvement in mean calculated spKt/V (1.50+/-0.36 vs. 1.58+/-0.30, P<0.01), mean hemoglobin (11.0+/-1.6 g/dl vs. 11.5+/-1.3 g/dl, P<0.001), mean ferritin (286+/-278 ng/ml vs. 460+/-353 ng/ml, P<0.001), mean transferrin saturation (27.8+/-15.1% vs. 31.3+/-15.0%, P<0.05), mean serum albumin as measured by the bromocresol green method (3.83+/-0.54 g/dl vs. 3.95+/-0.42 g/dl, P<0.01), and mean height standard deviation score (-1.814+/-1.756 vs. -1.699+/-1.657, P<0.05). In addition, 20 of 29 (69%) patients who had a spKt/V <1.2 in the 2000 study year had a spKt/V >1.2 in the 2001 study year. Of 68 (44%) patients who had a catheter as their HD access in the 2000 study year, 30 had an arteriovenous fistula or graft in the 2001 study year and 49 of 80 (61%) patients who had a mean hemoglobin <11 g/dl in the 2000 study year had a hemoglobin >11 g/dl in the 2001 study year. In summary, these longitudinal data demonstrate significant improvements in nearly all clinical parameters studied in these adolescent HD patients.

Renin-angiotensin gene polymorphism in children with uremia and essential hypertension.

The M235T polymorphism of the angiotensinogen (ANG) gene, the I/D polymorphism of the angiotensin converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene were identified in 70 patients with end-stage renal disease [20 pediatric ESRD, aged 14.9+/-3.1, years blood pressure (BP) 139+/-14/91+/-13 mmHg, 50 adult ESRD, aged 48.7+/-18.7 years, BP 149.1+/-24/96.9+/-12 mmHg], 35 with juvenile essential hypertension (JEHT, aged 14.4+/-2.7 years, 24-h mean BP 135.37+/-7.37/72.4+/-7.68 mmHg), 130 adult healthy normotensive controls (aged 34.9+/-8.1 years, BP 117.8+/-8.7/78.7+/-8.5 mmHg), and 20 pediatric controls (aged 13.2+/-1.2 years, BP 109+/-6.5/71+/-5.9 mmHg). The ACE gene polymorphism was determined by polymerase chain reaction and the ANG and AT1R gene polymorphisms by single-step LightCycler technology. The ACE gene distribution of the Hungarian controls did not differ from the results of the other Caucasian populations. In JEHT and pediatric ESRD patients, the MT genotype of ANG was more frequent than in controls (JEHT 80%, pediatric ESRD 74% versus controls 50%, P<0.02). The DD genotype of ACE was over-represented in pediatric ESRD compared with controls (ESRD 45% versus controls 22%, P<0.05). There was a non-significant increase in the CC genotype frequency of AT1R in adult patients with ESRD compared with controls. In conclusion, there was an increased frequency of the ACE DD genotype in pediatric ESRD, which could be a genetic risk factor for the development of ESRD. Furthermore, there was a significant increase in MT genotype frequency of ANG M235T polymorphism in pediatric ESRD and JEHT. The role of AT1R gene polymorphism needs further investigation.

ACE gene polymorphism and renal scarring in primary vesicoureteric reflux.

The objective of this study was to investigate whether mutations of the renin-angiotensin system genes are involved in primary vesicoureteric reflux (VUR) and VUR-associated renal scarring. The M235T polymorphism of the angiotensinogen ( ATG) gene, the I/D polymorphism of the angiotensin converting enzyme ( ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor ( AT1) gene were identified in 77 patients with primary VUR (aged 6.9+/-3.2 years, mean+/-SD) and 80 healthy controls (aged 33+/-7 years). Thirty-eight of the 77 VUR patients had low-grade VUR (grade I-III) and 39 had high-grade VUR (grade IV and V). Renal scarring was found in 43 VUR patients, while 34 patients had normal kidneys on dimercaptosuccinic acid scan. The ACE gene polymorphism was determined by polymerase chain reaction and the ATG and AT1 gene polymorphisms were determined by single-step LightCycler technology. We found significant over-representation of the DD genotype in patients with renal scarring (44 %) compared with normal controls (23%, P<0.05) and patients with no scar formation (21%, P<0.05). Significantly higher D and significantly lower I allele frequencies were present in VUR patients with scarred kidneys (D allele 0.64 and I allele 0.36) compared with controls (D allele 0.53 and I allele 0.47, P<0.05) and patients with unscarred kidneys (D allele 0.4 and I allele 0.6, P<0.05). No differences in the ATG and AT1 genotype distributions and allele frequencies were observed in VUR patients compared with the normal population. The DD genotype and D allele of ACE may be a genetic susceptibility factor contributing to scar formation in VUR. We detected no linkage of genetic polymorphisms of ATG and AT1 to VUR and VUR-associated renal scarring.