The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This ...includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.
Until now oligonephropathy to indicate "too few nephrons" has been associated with intrauterine growth restriction and experimentally induced abnormalities of renal development. The purpose of this ...study was to determine whether there is evidence of abnormal postnatal glomerulogenesis in extremely low birth weight preterm infants. Renal autopsy tissue was studied by computer-assisted morphometry from 56 extremely premature infants (birth weight < or = 1000 g) and 10 fullterm infants as controls. Preterm infants were divided into two groups (short survival < or = 40 days vs. long survival > or = 40 days). Each group was subdivided into those with renal failure (RF) and those with normal renal function. Forty-two of 56 preterm infants (75%) were adequate for gestational age. Glomerulogenesis as measured by radial glomerular counts (RGC) was markedly decreased in all preterm infants as compared to term controls and correlated significantly with gestational age (r = 0.87; P < 0.001). Active glomerulogenesis with "basophilic S-shaped bodies" was absent in longer surviving preterm and all term infants. RGC of preterm infants surviving > or =40 days with RF were significantly less than RGC of those with long survival and no RF (P < 0.001). Only this latter group demonstrated increased glomerular size as measured by mesangial tuft area and Bowman's capsule area compared to all other groups (P < 0.001). The kidney continues to form postnatally in preterm neonates, but glomerulogenesis ceases after 40 days. Moreover, it is further inhibited by RF. Compensatory mechanisms in longer surviving preterm infants include glomerular hypertrophy and mesangial proliferation that could lead to hyperfiltration.
Background
Elevated fibroblast growth factor 23 (FGF-23) concentrations associate with left ventricular hypertrophy (LVH) and adverse outcomes in adult patients with chronic kidney disease. We ...hypothesized that similar associations are present in pediatric patients on maintenance hemodialysis.
Methods
In this retrospective study of 26 young patients on chronic hemodialysis, aged 6–21 years, cardiac structure and geometry were measured by echocardiography, and circulating levels of FGF-23 and calciotropic hormones were obtained.
Results
FGF-23 levels were uniformly elevated in all patients from three- to 835-fold above the upper limit of normal. The average LV mass index (LVMI) was 43 ± 13 g/m
2.7
and reflected LVH in 55 % of patients. Log-transformed FGF-23 concentrations correlated with LVMI (
p
= 0.03) and were independently associated with the interventricular septal thickness
Z
-score (
p
< 0.001). Concentric LVH was associated with the highest FGF-23 concentrations and the highest LVMI measurements (
p
< 0.001). Each 1 standard deviation increase in log-transformed FGF-23 levels was associated with a 17 % increase in LVMI.
Conclusions
FGF-23 levels are strongly associated with increased LVMI and with prevalent LVH in pediatric hemodialysis patients. Our cross-sectional findings provide observational evidence supporting the hypothesis linking FGF-23 to cardiac hypertrophy in patients with chronic kidney disease.
Background
As 1,25(OH)
2
D
3
vitamin D3 induces fibroblast growth factor-23 (FGF-23) production and suppresses the renin–angiotensin–aldosterone system (RAAS), its absence in vitamin-D-dependent ...rickets type I (VDDR-I) may have adverse health consequences.
Case description
An infant presented at age 8 months with hypocalcemia and rickets and very low 1,25(OH)
2
D
3
levels. Genetic analysis confirmed VDRR-I, and calcitriol therapy was initiated. During periods of nonadherence to therapy, chemical measurements revealed detectable FGF-23 levels, with undetectable 1,25(OH)
2
D
3
, hypophosphatemia, low tubular reabsorption of phosphate, hypocalcemia, and very elevated parathyroid hormone (PTH) levels. These changes, in addition to elevated RAAS levels, normalized during calcitriol therapy despite elevated FGF-23 levels. At age 12 years, all rachitic manifestations were absent, and bone mineral density (BMD) and the echocardiogram were normal.
Conclusions
Whereas 1,25(OH)
2
D
3
is not indispensable for FGF-23 production, PTH in the absence of vitamin D may maintain FGF-23 secretion despite hypocalcemia. Normalization of urinary phosphate losses despite elevated FGF-23 during calcitriol-mediated suppression of secondary hyperparathyroidism points to a cardinal role of PTH as a cause of the phosphaturia in VDRR-I. Normalization of RAAS by calcitriol may conceivably prevent adverse cardiovascular outcomes.
In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding ...pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children. Regarding pediatric cardiac transplantation, we discuss the mechanisms of cardiac transplant rejection, including the role of endomyocardial biopsy in detecting graft rejection and the role of biomarkers in detecting cardiac graft rejection, including biomarkers of inflammation, cardiomyocyte injury, or stress. We review cardiac allograft vasculopathy. We also address the role of genetic analyses, including genome-wide association studies, gene expression profiling using entities such as AlloMap®, and adenosine triphosphate release as a measure of immune function using the Cylex® ImmuKnow™ cell function assay. Finally, we identify future translational research directions in heart transplantation in children.
Children undergoing chronic hemodialysis are at risk of cardiovascular disease and often develop left ventricular hypertrophy (LVH). Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is ...known to better predict cardiovascular morbidity than casual blood pressure (BP) measurement. Given the BP variability attributed to interdialytic fluid overload, 44-h ABPM should better delineate cardiovascular morbidity in pediatric hemodialysis patients.
In this cross-sectional study, 17 children (16.7 ± 2.9 years) on chronic hemodialysis underwent 44-h interdialytic ABPM and routine echocardiogram. Left ventricular mass index (LVMI) was calculated by height-based equation; LVH was defined as an LVMI in the ≥95th percentile for height-age and gender. Hypertension was defined by the recommendations of the Fourth Report of the National High Blood Pressure Education Program for casual measurements, and by those of the American Heart Association for ABPM.
Twenty-four percentage of patients were hypertensive by casual post-dialytic systolic BP, whereas 59% were hypertensive by ABPM. Eighty-eight percentage of patients had abnormal cardiac geometry: 53% had LVH. Thirty-five percentage (6 of 17) had masked hypertension, including four with abnormal cardiac geometry, of which, three had LVH. LVMI correlated with ABPM, but not with casual measurements. Strongest correlations with an increased LVMI were with 44-h diastolic BP: at night (r = 0.53, P = 0.03) and total load (r = 0.57, P = 0.02). LVH was similarly associated with 44-h nighttime BP: systolic (P = 0.02), diastolic (P = 0.01) and mean arterial (P = 0.01).
Casual BP measurement underestimates hypertension in pediatric hemodialysis patients and does not correlate well with indicators of cardiovascular morbidity. In contrast, 44-h interdialytic ABPM better characterizes hypertension, with nighttime parameters most strongly predicting increased LVMI and LVH.
The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This ...includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.
This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and ...factors associated with complete proteinuria remission (CRever).
We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever.
We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis.
In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.
HIV nephropathy (HIVN) is prevalent in 15%-56% of HIV-infected children and induces mild to severe progressive nephropathy.
A total of 33 renal diuretic scintirenographic studies with ...99mTc-mercaptoacetyltriglycine (MAG3) were reviewed and analyzed from 23 HIV pediatric patients, 21 of whom had HIVN with varying degrees of renal impairment. Results were compared with 10 studies of control patients of matching ages. Visual interpretation of images and renograms as well as semiquantitative analyses were performed. Variables compared were size of kidneys, time of peak and one-half peak activities, residual (or retained) cortical activity at 20 min, ratio of cortical activity at 2.5-20 min, and ratio of kidney activity to kidney plus background activity at 2 min. The results of MAG3 renal studies were also compared with laboratory data pertaining to creatinine clearance in all patients and with sonography in 17 patients.
In most patients with HIVN (18/21), the kidneys were larger than normal, with a diffuse parenchymal dysfunction (decreased uptake, slow processing, and increased retention of activity) and flat renograms, findings similar to those observed in other diffuse parenchymal diseases. In all patients with HIVN, semiquantitative analysis (paired t test) showed statistically significant differences from control patients for all variables. On ANOVA, a statistically significant correlation was found between most scintigraphic parameters and the severity of renal impairment. Of the 17 concurrent sonographic studies in HIVN patients, 7 showed no abnormalities, whereas the results of scintigraphy were abnormal.
Diuretic MAG3 scintirenography shows nonspecific diffuse parenchymal dysfunction in pediatric patients with HIVN. Such dysfunction may provide corroborative evidence of HIVN and should be recognized when the test is performed for standard indications. Further work is necessary to prove that the test has indeed the high sensitivity and good correlation with the seventy of HIVN suggested in this population; the test may be useful to follow up the progression of disease and the effect of treatment.
Angiotensin converting enzyme (ACE) inhibition scintirenography was performed to help establish the diagnosis and plan treatment of renovascular hypertension (RVH) in 57 hypertensive pediatric ...patients, 33 infants and 24 children older than 1 year. In 16 of 33 hypertensive infants, ACE inhibition scintirenography established the diagnosis of RVH from renal ischemia (due to aortic or renal arterial thrombi). Two scintigraphic criteria were used for the diagnosis of RVH: criterion I, ischemic and damaged kidney (a non-functioning kidney on or off ACE inhibition) and criterion II, ischemic but not damaged kidney (ACE inhibition induced deterioration of function of the kidney). When criterion I was present and the contralateral kidney was normal, ACE inhibitors could be used for treatment of hypertension without deterioration of renal function; kidneys satisfying criterion I eventually involuted or manifested growth arrest and frequently caused persistent RVH, even after resolution of the thrombus, requiring nephrectomy. When criterion II was present bilaterally, or it was associated with criterion I contralaterally, the use of antihypertensive drugs other than ACE inhibitors was necessary in order to prevent renal insufficiency or failure from ACE inhibitors. However, kidneys with criterion II showed normal growth and, following retraction or dissolution of the aortic thrombus, hypertension resolved. In 2 of 24 hypertensive children older than 1 year, the test was diagnostic of branch renal artery stenosis; RVH was cured by selective angioplasty. ACE inhibition scintirenography is useful in the evaluation and planning of treatment in children with hypertension and may predict the outcome of therapy and ultimate renal function.
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