P. Sallay

Strict blood-pressure control and progression of renal failure in children.

BACKGROUND Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor. METHODS After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Urinary calcium and oxalate excretion in children

We have established normal values for calcium/creatinine (Ca/Cr) and oxalate/creatinine (Ox/Cr) ratios in 25 infants (aged 1–7 days) and 391 children (aged 1 month to 14.5 years) and compared these with values obtained in 137 children with post-glomerular haematuria and 27 with nephrolithiasis. Oxalate was measured by ion chromatography. Nomograms of Marshall and Robertson were used to calculate urine saturation to calcium oxalate. The Ca/Cr ratio was normally distributed whereas the Ox/Cr ratio had a log-normal distribution. The molar ratio of Ca/Cr was the lowest in the first days of life and the highest between 7 month and 1.5 years (mean±SD=0.39±0.28 mmol/mmol). Following a slight decrease it stabilised by the age of 6 years (0.34±0.19 mmol/mmol). The highest Ox/Cr values were measured during the 1st month of life [geometric mean 133 (range 61–280) μmol/mmol], followed by a gradual decrease until 11 years of age [mean 24 (range 6–82) μmol/mmol]. Thirty-six haematuric children had hypercalciuria (26%), 23 had absorptive hypercalciuria, 13 renal type. Children with absorptive hypercalciuria on a calcium-restricted diet had significantly higher oxalate excretion than those with renal hypercalciuria and the control group [38 (range 28–49) vs. 22 (range 16–29) and 23 (range 22–27) μmol/mol respectively,P<0.01]. Calcium oxalate urine saturation of stone patients was higher than that of patients with haematuria and the normal population (1.18±0.05 vs. 1.06±0.03,P<0.03 and 0.84±0.03,P<0.001 respectively). The measurement of Ca/Cr and Ox/Cr in first-morning urine samples is suitable for screening for hypercalciuria and hyperoxaluria. Interpretation of the values requires age-specific reference values. Both calcium and oxalate determinations should be part of the evaluation of patients with haematuria, hypercalciuria or nephrolithiasis.

24 hour blood pressure monitoring in healthy and hypertensive children.

24 Hour ambulatory blood pressure monitoring (ABPM) was performed to provide data on the normal daily blood pressure of healthy schoolchildren and on patients with hypertension. The subjects studied were 123 healthy schoolchildren with a mean (SD) age of 12.5 (1.6) years (range 9.5-14.5 years), 24 children with borderline or mild hypertension, 17 with renal hypertension and normal renal function, 10 with chronic renal failure, and six with a renal allograft. In eight children with definite renal disease a second measurement was performed after treatment modification. The monitor used for ABPM was validated with a mercury column manometer. The mean (SD) of the signed differences of the blood pressure measured by the two methods was -0.19 (1.75) mmHg for the systolic and -0.21 (2.11) mmHg for the diastolic blood pressure (n = 60). Normal values for daytime and night time blood pressure were determined for those aged 10-14 years. The mean (SD) blood pressure of the 123 children was 109 (7)/66 (8) mmHg (systolic/diastolic) for the daytime and 96 (8)/52 (7) mmHg at night time. Of the 24 children with borderline or mild hypertension 14 had a raised blood pressure on ABPM. The circadian rhythm was disturbed in three children of this group. Even children with normal daytime blood pressure had significantly higher systolic blood pressure in the night when compared with the controls. The incidence of disturbed circadian rhythm was higher in the groups with renal hypertension (4/17 in the subgroup with normal renal function, 5/16 in the group with renal failure and/or transplantation). All children undergoing a second ABPM measurement had a lower average blood pressure after treatment adjustment. ABPM measurements were reproducible and accurate. The method provided new data on the physiological circadian variation of blood pressure in healthy children. It proved to be a helpful tool in the diagnosis of hypertension, particularly in the detection of cases of disturbance of the circadian rhythm of blood pressure pattern and individual adjustment of treatment.

Bone metabolism and mineral density following renal transplantation

AIM To study bone turnover following renal transplantation using a panel of biochemical markers and to correlate the results with both areal and volumetric bone mineral density (BMD). PATIENTS A total of 31 patients aged 18.1 years were transplanted 5.4 years before this study. Control patients (n = 31) were age and gender matched. METHODS In addition to measurement of biochemical markers, BMD was measured by single photon absorptiometry and peripheral quantitative computed tomography on the non-dominant radius. RESULTS Patients had reduced glomerular filtration rate, raised concentrations of serum phosphate, serum procollagene type I carboxy terminal propeptide, osteocalcin, and serum procollagene type I cross linked carboxy terminal telopeptide. The differences were still significant if only patients with normal intact parathyroid hormone were considered. BMD single photon absorptiometry Z score for age was significantly decreased. Following standardisation for height the differences were no longer present. With volumetric techniques patients had normal trabecular but decreased cortical and total BMD compared to age matched controls, but there was no difference from height matched controls. CONCLUSION Markers of bone turnover are increased following renal transplantation. However, the biochemical analysis did not allow conclusions to be drawn on the bone mineral content. BMD single photon absorptiometry Z score corrected for height and BMD measured by quantitative computed tomography compared to height matched controls were normal in paediatric renal transplantation patients. Height matched controls should be used in both areal and volumetric BMD measurements in states of growth failure.

Post‐transplant diabetes mellitus in children following renal transplantation

Abstract:  PTDM plays a role in chronic allograft nephropathy and decreases graft and patient survival. Considering the serious outcome of chronic hyperglycemia, the importance of early recognition and the few data in children, in this retrospective analysis we studied the characteristics and risk factors of PTDM in 45 pediatric renal transplant recipients receiving Tac or CyA‐based immunosuppression. Fasting blood sampling and OGTT were performed. PTDM has been developed in six patients (13%), while seven children (16%) had IGT, with the overall incidence of a glucose metabolic disorder of 29% in pediatric renal transplants. Patients in the PTDM + IGT group were younger and had higher systolic blood pressure and serum triglyceride level than children with normal glucose tolerance. Multivariate analysis identified Tac treatment, Tac trough level, steroid pulse therapy and family history of diabetes to be associated with the onset of PTDM. In pediatric renal transplants, OGTT and frequent assessment of blood glucose levels might be essential not only in the post‐transplant management, but also prior to transplantation, particularly with family history of diabetes. Careful monitoring and modified protocols help to minimize the side effects of Tac and corticosteroids.

Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and vitamin D-fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median eGFR 51 ml/min per 1.73 m(2)), serum 25-hydroxyvitamin D (25(OH)D), FGF-23, and Klotho levels were measured at baseline and after a median 8 months on ACEi. Children with lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum vitamin D-binding protein were not associated, but 25(OH)D ≤50 nmol/L associated with higher diastolic BP (P=0.004). ACEi therapy also associated with increased Klotho levels (P<0.001). The annualized loss of eGFR was inversely associated with baseline 25(OH)D level (P<0.001, r=0.32). Five-year renal survival was 75% in patients with baseline 25(OH)D ≥50 nmol/L and 50% in those with lower 25(OH)D levels (P<0.001). This renoprotective effect remained significant but attenuated with ACEi therapy (P=0.05). Renal survival increased 8.2% per 10 nmol/L increase in 25(OH)D (P=0.03), independent of eGFR; proteinuria, BP, and FGF-23 levels; and underlying renal diagnosis. In children with CKD, 25(OH)D ≥50 nmol/L was associated with greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy.

Sodium transport and bone mineral density in hypercalciuria with thiazide treatment.

Abstract.Erythrocyte sodium-potassium (Na+/K+) -ATPase and sodium-lithium (Na+/Li+) countertransport activities were measured in 18 children (aged 9.6 years, range 6–16 years) with idiopathic hypercalciuria (IHU) to evaluate cellular Na handling. The effect of chronic thiazide administration on these parameters and on bone mineral density was also evaluated. Patients with IHU had significantly lower erythrocyte Na+/K+-ATPase activity than 23 age-matched healthy controls (mean±SEM 2,156±110 μmol P/l erythrocyte per hour vs. 3,165±175, P<0.01). Thiazide treatment significantly lowered urinary calcium excretion; this was followed by a slight suppression of intact parathyroid hormone (iPTH). The urinary calcium/creatinine ratio before and during treatment was 0.90±0.07 mmol/mmol versus 0.51±0.06 respectively, P<0.01. The corresponding iPTH levels were 5.9±0.6 pmol/l and 5.1±0.7, P<0.05. The Na+/K+-ATPase activity increased significantly (2,769±169 μmol P/l erythrocyte per hour vs. 2,156±110 in the control period, P<0.01) and the Na+/Li+ countertransport decreased (268±28 μmol Li/l erythrocyte per hour vs. 328+26 in the control period, P<0.03). The bone mineral density Z score rose from –1.3±0.26 to –0.8±0.22 (P<0.03). We conclude that IHU is accompanied by abnormalities of erythrocyte Na+/K+-ATPase and Na+/Li+ countertransport which are corrected by chronic hydrochlorothiazide administration. These changes could model alterations in renal tubular transport mechanisms still to be elucidated. Chronic thiazide treatment also has a positive effect on bone mineral density.

Cardiac magnetic resonance imaging in children with chronic kidney disease and renal transplantation

Schaefer B, Rusai K, Toth A, Pasti K, Ujszaszi A, Kreko M, Horvath E, Sallay P, Reusz GS, Merkely B, Tulassay T, Szabo AJ. Cardiac magnetic resonance imaging in children with chronic kidney disease and renal transplantation.

Quantitative Histomorphometry of the Healthy Peritoneum

The peritoneum plays an essential role in preventing abdominal frictions and adhesions and can be utilized as a dialysis membrane. Its physiological ultrastructure, however, has not yet been studied systematically. 106 standardized peritoneal and 69 omental specimens were obtained from 107 patients (0.1–60 years) undergoing surgery for disease not affecting the peritoneum for automated quantitative histomorphometry and immunohistochemistry. The mesothelial cell layer morphology and protein expression pattern is similar across all age groups. Infants below one year have a thinner submesothelium; inflammation, profibrotic activity and mesothelial cell translocation is largely absent in all age groups. Peritoneal blood capillaries, lymphatics and nerve fibers locate in three distinct submesothelial layers. Blood vessel density and endothelial surface area follow a U-shaped curve with highest values in infants below one year and lowest values in children aged 7–12 years. Lymphatic vessel density is much lower, and again highest in infants. Omental blood capillary density correlates with parietal peritoneal findings, whereas only few lymphatic vessels are present. The healthy peritoneum exhibits major thus far unknown particularities, pertaining to functionally relevant structures, and subject to substantial changes with age. The reference ranges established here provide a framework for future histomorphometric analyses and peritoneal transport modeling approaches.