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Contains fulltext : 69717.pdf (Publisher’s version ) (Closed access) BACKGROUND: Low birth weight (LBW) has been shown to lead to a low nephron endowment with subsequent glomerular hyperfiltration. Additional renal disease can therefore be expected to have a more severe course. Minimal change nephrotic syndrome (MCNS) is a common chronic illness in childhood. As it is important to be able to predict prognosis in MCNS, we set out to study the effect of LBW on MCNS in a cohort of patients from our University Medical Center, and performed a meta-analysis. METHODS: A retrospective chart review of children with MCNS treated at the VU University Medical Center was performed, identifying 55 patients of whom 4 had LBW. The meta-analysis was performed using Review Manager (The Cochrane Collaboration). RESULTS: The meta-analysis consisted of 201 patients (25 LBW, 176 normal birth weight). More LBW patients were classified as steroid resistant [odds ratio (OR) 6.97 (95% confidence interval [CI] 2.02-24.04), P = 0.002]. The number of relapses per year of follow-up was significantly higher in the LBW patients with MCNS [weighted mean difference 0.93 (95% CI 0.71-1.15) relapse per year, P < 0.0001]. MCNS patients with LBW were significantly more likely to be treated with cyclosporine [OR 4.4 (95% CI 1.7-11.8), P = 0.003] or cytotoxic agents [OR 4.2 (95% CI 1.8-10.2), P = 0.001] during the course of their disease, and they had a higher chance of developing several complications during the follow-up period, including hypertension. CONCLUSIONS: This meta-analysis provides support for an adverse effect of LBW on the course and prognosis of MCNS in children, which can aid clinicians and parents in assessing the expected clinical course.

To the Editor: We read with great interest the article by He and MacGregor1 concerning the effect of salt intake on blood pressure in children. Their meta-analysis shows that salt reduction in children causes a fall in blood pressure, which may have serious implications. The authors …

Background: Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-5. A recent study showed that defects in OCRL1 , encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease). Methods: We investigated 20 CLCN5 -negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1 . Results: In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70R fs X88 and T121N fs X122, detected twice) or missense mutations (I257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5 -positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. Conclusion: Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.

Acute renal failure (ARF) requiring renal replacement therapy (RRT) has been associated with an excess risk of mortality in adult patients with septic shock, but it is unknown whether this is also applicable to pediatric patients. We therefore conducted a retrospective pilot study. All children presenting with septic shock between 1st January 1998 and 1st April 2004 were analyzed. Patients with fluid refractory-dopamine resistant shock, necessitating the use of noradrenaline, were included. ARF was defined as the deterioration of renal function to the extent that renal replacement therapy was required (ARF group). This ARF group was compared with patients without ARF (non-ARF group). Out of the 22 children with severe septic shock, seven developed ARF. PIM2 and PRISM scores upon admission were comparable between both groups. Mortality rates were significantly higher in patients with ARF (57.1% vs 6.7%; p=0.02). Pediatric patients with severe septic shock developing ARF have excess mortality compared to pediatric patients who do not develop ARF, although on diagnosis, severity of underlying disease and calculated risk of mortality were comparable. A multicenter trial is necessary to confirm these findings and to determine the contribution of ARF to pediatric sepsis mortality.

A link exists between low birth weight and diseases in adulthood, such as hypertension, cardiovascular disease, and insulin resistance. Intrauterine growth restriction (IUGR) has been used to explain this association and has been shown to lead to a nephron endowment in humans. A reduction in glomerular number has been described in animal models with induced low birth weight as well but not in animals with spontaneous low birth weight. It therefore is debatable whether the models are suitable. The effect on glomerular number and size was studied in rats with naturally occurring IUGR and experimental IUGR, induced by bilateral uterine artery ligation. Design-based stereologic methods were used. Urinary protein excretion was determined as a measure of renal damage. Results showed a decrease of approximately 20% in glomerular number in both groups of IUGR (control 35,400, naturally occurring IUGR 30,900, and experimental IUGR 28,000 glomeruli per kidney). Mean glomerular volume was increased in both IUGR groups, which was associated with an increased proteinuria. It is concluded that IUGR leads to a nephron endowment with a compensatory glomerular enlargement. This compensation is associated with more proteinuria in the long run. Uterine artery ligation in the pregnant rat is a suitable model to study the effects of IUGR on the kidney.

OBJECTIVE: The hyperfiltration hypothesis implies that children with a solitary functioning kidney are at risk to develop hypertension, proteinuria, and chronic kidney disease. We sought to determine the presenting age of renal injury and identify risk factors for children with a solitary functioning kidney. METHODS: We evaluated 407 patients for signs of renal injury, defined as hypertension, proteinuria, an impaired glomerular filtration rate, and/or the use of renoprotective medication. Patients were subdivided on the basis of type of solitary functioning kidney and the presence of ipsilateral congenital anomalies of the kidney and urinary tract (CAKUT). The development of renal injury was analyzed with Kaplan-Meier analysis. Risk factors were identified by using logistic regression models. RESULTS: Renal injury was found in 37% of all children. Development of renal injury increased by presence of ipsilateral CAKUT (odds ratio [OR] 1.66; P = .04) and age (OR 1.09; P < .001). Renal length was inversely associated with the risk to develop renal injury (OR 0.91; P = .04). In all patients, the median time to renal injury was 14.8 years (95% confidence interval 13.7–16.0 years). This was significantly shortened for patients with ipsilateral CAKUT (12.8 years, 95% confidence interval 10.6–15.1 years). CONCLUSIONS: Our study determines independent risk factors for renal injury in children with a solitary functioning kidney. Because many children develop renal injury, we emphasize the need for clinical follow-up in these patients starting at birth.

A 3-year old girl with a body weight of 15 kg was admitted to our pediatric intensive care unit with acute renal failure. She was the first of a twin pregnancy, born at a gestational age of 28 weeks with a birth weight of 1140 g. There had been no significant neonatal complications. The present history began 5 days before admission with diarrhea and vomiting. She was admitted to a local hospital with signs of severe dehydration and progressive renal failure, which persisted after aggressive fluid therapy. Hemolytic uremic syndrome (HUS) was suspected and she was referred to our hospital. On admission, hemoglobin level was 5.5 mmol/L (9.2 g/dL), serum LDH 4459 U/l and platelets 55×10/L with schistocytes on blood smear. While faeces culture was negative for E. coli 0157, there was a positive PCR for E. coli 0157 on peripheral white blood cells. Complement studies showed no evidence for atypical HUS/thrombotic microangiopathy. Serum creatinine was 458 μmol/L (5.2 mg/dL) and urea 33.1 mmol/L (92.7 mg/dL) in the anuric child. Under the diagnosis of a diarrhea-associated HUS, a Tenckhoff catheter was placed and peritoneal dialysis (PD) begun with a dwell volume of 15 mL/kg of Gambro-Trio (Gambro BCT Europe NV/SA, Zaventem, Belgium) containing 1.9% glucose. Ultrafiltration was 20 mL per hour on day 1. Despite this therapy, the patient remained ventilator-dependent and needed increasing amounts of supplemental oxygen. In order to increase ultrafiltration, the glucose concentration was increased to 2.5% with good effect (ultrafiltration rate 41 mL per hour). A large pleural effusion was noted on the right side (Fig. 1) and about 200 mL of a clear transudate (RBC 5–10/field, WBC 5–10/field, protein concentration 0.594 g/L) was aspirated. Despite this intervention, her respiratory situation deteriorated rapidly and she developed a severe acute respiratory distress syndrome (ARDS). This required highlevel ventilatory support with mean airway pressure values of up to 30 cmH2O. Mechanical ventilation was complicated by subcutaneous and mediastinal emphysema and recurrent pneumothoraces (Fig. 2). During this period, peritoneal dialysis was continued with dwell volumes between 8 and 20 mL/kg and transiently combined with continuous veno-venous hemodiafiltration. When her respiratory situation improved and the ventilator settings could be reduced, leakage of clear fluid of around 150 mL per day was noted from an incision site of a previous thorax-drain on the right side.

Answers1. Leakage of peritoneal dialysis (PD) fluid into thepleural cavity.2. Measurement of the glucose concentration in thepleural effusion.3. Very high intrathoracic pressure during mechanicalventilation for acute respiratory distress syndrome(ARDS) transiently prevented leakage of PD fluid intothe pleural cavity. Reduction of ventilator settingsunmasked the pleuro-peritoneal connection with PDfluid leaking through the incision site.4. To decrease PD dwell volume or temporarily discontinuePD and switch to hemodialysis / hemofiltration.CommentaryHydrothorax - mostly on the right side - is a well-knowncomplication of PD, which is observed in approximately2% of all PD patients [1]. In our patient, the glucoseconcentration in the pleural fluid obtained in the firstpuncture was 24.9 mmol/L (452.7 mg/dL), in the fluiddraining from the insertion site four weeks later this was20.5 mmol/L (372.7 mg/dL). Her blood glucose levels werearound 10 mmol/L (180 mg/dL) during the time of the firstpuncture and around 7 mmol/L (126 mg/dL) on the secondoccasion. Thus, the intrapleural glucose concentrationgreatly exceeded the serum values. This finding can onlybe explained by leakage of PD fluid into the pleural cavity,which ceased transiently during high-pressure ventilation.With these ventilator settings, the intrathoracic pressureexceeded the intraaabdomial pressure thereby preventingperitoneal-pleural shunting.Usually, demonstration of high glucose concentrations inthe pleural fluid is sufficient to confirm a peritoneal-pleuralleak [2]. In ambiguous cases - or if no pleural puncture isdone - peritoneal-pleural shunting can be demonstrated byadding a radioactive tracer to the dialysate [3, 4]. Although2 - 4 times higher than the serum concentrations, theintrapleural glucose concentration was still significantlylower than the glucose concentration in the PD fluid, whichwas 137.5 mmol/L (2475 mg/dL). This reflects incompleteequilibration between the fluid collections in both compart-ments due to inconstant shunting or a small communicationbetween both cavities.Leakage of PD fluid into the pleural cavity has to bedifferentiated from other causes of transudative pleuraleffusionsuchascongestivecardiacfailure,hypoalbuminemia,or fluid overload. In the latter conditions, ultrafiltration ispreserved and can typically be increased by using higherPD fluid glucose concentrations. Pleural effusions from aperitoneal-pleural leak typically do not improve with thisintervention. In this respect the present case is atypical asultrafiltration was preserved and could be increased afterswitch to a higher PD fluid glucose concentration.

A 5-year-old boy underwent total plasma exchange to remove anti-neuronal anti-Hu autoantibodies as a complication of neuroblastoma, leading to autonomic bowel dysfunction. Total plasma exchange (TPE) resulted eventually in a reduction of autoantibody levels, but, more importantly, led to improvement of bowel function. TPE proved to be a safe and effective treatment option in neuroblastoma-related anti-Hu syndrome in a child.

INTRODUCTION The current practice for estimating glomerular fi ltration rate in children uses the Schwartz-equation (eGFR-Schwartz), which requires patient height and serum creatinine concentration. Unfortunately, height data are not routinely available in most laboratories so that eGFR-Schwartz cannot be reported automatically. Recently, Pottel et al. established a method (eGFR-Pottel) to estimate GFR from serum creatinine and age-related creatinine reference values. In their hands, performance was similar to eGFR-Schwartz. If reliable, eGFR-Pottel allows direct reporting of GFR in children by the laboratory leading to improved patient care. We validated eGFR-Pottel in a well-characterized patient population.

To the Editor: To determine which aspect of blood pressure is associated the most with end-organ damage, several parameters are used like average blood pressure, pulse pressure, and blood pressure variability. In a recent article, Tatasciore et al1 showed that blood pressure variability is more closely associated with cardiovascular damage than mean blood pressure levels. An increased blood pressure and a higher incidence of cardiovascular diseases are frequently described after intrauterine growth restriction (IUGR).2 It has also been shown that blood pressure variability is highest in …

Objective To compare the diagnostic performance of 2 height-independent equations used to calculate estimated glomerular filtration rate (eGFR), those of Pottel (eGFR-Pottel) and the British Columbia Children's Hospital (BCCH) (eGFR-BCCH), with the commonly used Schwartz equation (eGFR-Schwartz). Study design We externally validated eGFR-Pottel and eGFR-BCCH in a well-characterized pediatric patient population (n = 152) and compared their diagnostic performance with that of eGFR-Schwartz using Bland-Altman analysis. All patients underwent glomerular filtration rate measurement using the gold standard single-injection inulin clearance method (GFR-inulin). Results Median GFR-inulin was 92.0 mL/min/1.73 m² (IQR, 76.1-107.4 mL/min/1.73 m²). Compared with GFR-inulin, the mean bias for eGFR-Schwartz was −10.1 mL/min/1.73 m 2 (95% limits of agreement [LOA], −77.5 to 57.2 mL/min/1.73 m 2 ), compared with −12.3 mL/min/1.73 m² (95% LOA, −72.6 to 47.9 mL/min/1.73 m 2 ) for eGFR-Pottel and −22.1 mL/min/1.73 m² (95% LOA, −105.0 to 60.8 mL/min/1.73 m 2 ) for eGFR-BCCH. eGFR-Pottel showed comparable accuracy to eGFR-Schwartz, with 77% and 76% of estimates within 30% of GFR-inulin, respectively. eGFR-BCCH was less accurate than eGFR-Schwartz (66% of estimates within 30% of GFR-inulin; P Conclusion The performance of eGFR-Pottel is superior to that of eGFR-BCCH and comparable with that of eGFR-Schwartz. eGFR-Pottel is a valid alternative to eGFR-Schwartz in children and could be reported by the laboratory if height data are not available.

Background The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. Methods Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. Results Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. Conclusions In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well. Electronic supplementary material The online version of this article (doi:10.1007/s00467-016-3496-0) contains supplementary material, which is available to authorized users.

Background: Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review. Design: PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein–creatinine ratio > Albustix) was used for NP classification. Results: Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRLmutation. TPE was not significantly different between both forms (p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP (p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria. Conclusion: More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.