Ambulatory blood pressure parameters and their association with albuminuria in adolescents with type 1 diabetes mellitus.

BACKGROUND: This study aimed to evaluate the blood pressure (BP) status, including arterial stiffness parameters, hemodynamic indicators, circadian profile, and its association with albuminuria in adolescents with type 1 diabetes mellitus (DM1). METHODS: The analysis included 46 patients, with diabetes duration of 7.38 ± 3.48 years. Ambulatory blood pressure monitoring (ABPM) was conducted using an oscillometric device, the Mobil-O-Graph, which is a Pulse Wave Analysis Monitor. RESULTS: Hypertension (HT) was diagnosed in 31 adolescents (67% of patients), primarily due to isolated nocturnal BP (21 cases, 68% of HT cases). The HT group exhibited significantly increased diastolic load (DL). Pulse wave velocity (PWV, a measure of arterial stiffness) values showed a strong correlation with both peripheral systolic BP (r = 0.954) and central systolic BP (r = 0.838). Additionally, non-dipping status was found in 61% of the HT group. Urinary albumin excretion (UAE) was positively correlated with diastolic BP (particularly nocturnal) peripheral and central BP, DL, heart rate, augmentation index (AIx@75), and nocturnal total vascular resistance (TVR). Diastolic non-dippers exhibited a significant increase in UAE. CONCLUSIONS: Hypertension is a common complication in adolescents with type 1 diabetes mellitus, primarily caused by elevated nocturnal diastolic BP. Albuminuria is mainly associated with diastolic BP, especially during the nocturnal period and in cases of diastolic non-dipping status. The association of UAE with AIx@75 and nocturnal TVR suggests the presence of early-stage vascular disease in diabetic adolescents.

Acute kidney injury and diabetic kidney disease in children with acute complications of diabetes.

BACKGROUND: Diabetic ketoacidosis (DKA) and hyperglycaemia without ketoacidosis are common acute complications of diabetes. Their association with acute kidney injury (AKI) and diabetic kidney disease (DKD) was studied. METHODS: The study group consisted of 197 children with type 1 diabetes with average diabetes duration of 8.08 ± 2.32 years. The medical history of the patients was retrospectively reviewed. The number of children with severe hyperglycaemia, DKA and AKI was assessed. The association with the risk of chronic kidney disease (CKD) was analysed. RESULTS: AKI was found in 14% of cases hospitalised for DKA and 8% of cases hospitalised for hyperglycaemia. Patients with AKI showed a significantly increased corrected sodium (141.23 ± 5.09 mmol/L, p = 0.035). Patients with AKI in DKA showed a significant increase in WBC (20.73 ± 8.71 × 103/µL, p = 0.0009). Follow-up analysis after a minimum of 5 years of diabetes revealed that a single episode of DKA was found in 63 patients and a single episode of AKI in 18 patients. Two or more episodes of DKA were found in 18 patients, and nine cases were complicated by AKI. These patients showed a significant increase in urinary albumin excretion (44.20 ± 64.21 mg/24 h), the highest values of eGFR and the worst glycaemic control. CONCLUSIONS: Diabetic children can develop AKI in the course of DKA and hyperglycaemia without ketoacidosis, which is associated with volume depletion and reflected by corrected sodium concentration. AKI in DKA seems to be complicated by stress and inflammation activation. AKI and poor glycaemic control with repeated DKA episodes can magnify the risk of progression to DKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Limited sampling strategy to predict free mycophenolic acid area under the concentration-time curve in paediatric patients with nephrotic syndrome.

In paediatric patients, there is no data on the recommended area under the concentration-time curve from 0 to 12 h (AUC0-12 ) for free mycophenolic acid (fMPA), which is the active form of the drug, responsible for the pharmacological effect. We decided to establish the limited sampling strategy (LSS) for fMPA for its use in MPA therapeutic monitoring in children with nephrotic syndrome treated with mycophenolate mofetil (MMF). This study included 23 children (aged 11 ± 4 years) from whom eight blood samples were collected within 12 h after MMF administration. The fMPA was determined using the high-performance liquid chromatography with fluorescence detection method. LSSs were estimated with the use of R software and bootstrap procedure. The best model was chosen based on a number of profiles with AUC predicted within ± 20% of AUC0-12 (good guess), r2 , mean prediction error (%MPE) of ±10% and mean absolute error (%MAE) of less than 25%. The fMPA AUC0-12 was 0.1669 ± 0.0697 µg h/mL and the free fraction was within 0.16%-0.81%. In total, there were 92 equations developed of which five fulfilled the acceptance criteria for %MPE, %MAE, good guess >80% and r2 > 0.900. These equations consisted of three time points: model 1 (C1 , C2 , C6 ), model 2 (C1 , C3 , C6 ), model 3 (C1 , C4 , C6 ), model 5 (C0 , C1 , C2 ), and model 6 (C1 , C2 , C9 ). Although blood sampling up to 9 h after MMF dosing is impractical, it is crucial to include C6 or C9 in LSS to assess fMPA AUCpred correctly. The most practical fMPA LSS, which fulfilled the acceptance criteria in the estimation group, was fMPA AUCpred  = 0.040 + 2.220 × C0 + 1.130 × C1 + 1.742 × C2 . Further studies should define the recommended fMPA AUC0-12 value in children with nephrotic syndrome.

Chronic kidney disease predictors in obese adolescents.

BACKGROUND: Glomerular hyperfiltration, initiating development of obesity-related glomerulopathy, results in an enlargement of the glomeruli and unsealing of the filtration barrier. It can be followed by adaptive focal segmental glomerulosclerosis and chronic kidney disease (CKD). The aim of the study was to determine the expression pattern of lipid metabolism and selected kidney damage markers in obese adolescents and to identify potential factors which can predict CKD. METHODS: The study group consisted of 142 adolescents with a BMI z-score > 2. Sixty-two healthy and normal-weight individuals served as controls. The factors associated with the rate of glomerular filtration in obese adolescents were assessed by linear regression methods using univariate and multivariate analyses. The risk of developing CKD was estimated using the Fisher's exact test. RESULTS: The study group was divided into "elevated," "normal," and "decreased" glomerular filtration rate (GFR) patients. Increased urine galectin-3 (Gal-3) concentration was diagnosed in all patients. "Decreased GFR" subjects expressed increased urine concentration of neutrophil gelatinase-associated lipocalin (NGAL) and daily megalin excretion. Thirty-nine study participants developed CKD. Increased uric acid (UA) concentration was associated with CKD development both in "normal" and "decreased GFR" patients. Additionally, in "normal" GFR patients, increased concentrations of cholesterol (Ch), triglycerides (TG), and NGAL were associated with CKD. CONCLUSIONS: Increased serum concentrations of Ch, TG, and UA and increased urine concentration of NGAL might predict CKD development in obese adolescents with normal and decreased GFR. A higher resolution version of the Graphical abstract is available as Supplementary information.

Inosine monophosphate dehydrogenase activity and mycophenolate pharmacokinetics in children with nephrotic syndrome treated with mycophenolate mofetil.

Some studies have shown that the area under the concentration-time curve (AUC) of mycophenolic acid (MPA) should be higher for children with nephrotic syndrome (NS) than after renal transplantation. The pharmacodynamic aspect of MPA, the activity of inosine monophosphate dehydrogenase (IMPDH), has not been studied in children with NS. The study included 21 children (4-16 years old) with NS treated with mycophenolate mofetil. MPA and its glucuronide plasma concentrations were determined using validated high-performance liquid chromatography-ultraviolet (HPLC-UV). The separate HPLC-UV method was applied for IMPDH activity determination. The variability was expressed by the coefficient of variation (CV). IMPDH activity and MPA concentration (Ctrough ) before the morning dose amounted to 29.95 µmol s-1  mol-1 adenosine monophosphate (AMP) (range, 6.71-98.60 µmol s-1  mol-1 AMP) and 1.72 µg/mL (range, 0.39-4.34 µg/mL), respectively, whereas the area under the effect-time curve from 0 to 4 h and MPA AUC0-4 were 130.36 µmol s-1  mol-1 AMP × h (range, 23.58-306.57 µmol s-1  mol-1 AMP × h) and 24.63 µg h/mL (range, 12.21-67.48 µg h/mL), respectively. IMPDH activity decreased concomitantly with MPA concentration increase, however, the variability of the pharmacodynamic parameters was greater than of the pharmacokinetics. The median degree of maximum IMPDH inhibition was 61%. MPA Ctrough and predicted AUC were lower than in our previous study. Only a few MPA pharmacokinetic parameters correlated with the pharmacodynamics. IMPDH activity did not correlate with the children's age and did not differ between boys and girls. MPA clearance was the highest in younger children (median, 10.54 L/m2 /h) and cholesterol correlated negatively with the children's age (r = -0.659, P = 0.003). IMPDH minimum activity and the degree of maximum IMPDH inhibition were similar to those obtained in renal transplant recipients. IMPDH activity does not undergo developmental or gender-specific regulation in children with NS. MPA underexposure might be more frequent in younger children, especially with high cholesterol and triglycerides levels because of high MPA clearance.

Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife.

A study of 269 children enrolled into a National Registry for children with persistent glomerular hematuria identified 131 individuals with genetically confirmed X-linked Alport Syndrome. A single variant c.1871G>A p.Gly624Asp (G624D) in COL4A5 was predominant and accounted for 39% of X-linked Alport Syndrome in unrelated Polish families (44 of 113). To evaluate its origins, the genetic variation in a 2.79 Mb segment encompassing the COL4A5 locus on chromosome X was assessed. All G624D alleles were found on the same rare haplotype background, indicating a founder effect dating back to the 12-13th century. The phenotypic data of 131 children with X-linked Alport Syndrome and their 195 affected adult relatives revealed that the G624D variant was associated with a significantly milder clinical course in comparison to other pathogenic COL4A5 variants. Furthermore the clinical course of this genetically uniform cohort was milder than that observed in individuals with other COL4A5 missense mutations. In spite of the benign clinical manifestation throughout childhood and early adulthood, the G624D variant confers significant risk for both kidney failure and deafness in males, albeit 20-30 years later than that observed in individuals with other COL4A5 pathogenic variants (50% cumulative risk of starting dialysis at 54 years (95% confidence interval: 50-62) v. 26 years (95% confidence interval: 22-30)). Thus, males with G624D are candidates for existing and emerging therapies for Alport Syndrome.

Prediction of steroid resistance and steroid dependence in nephrotic syndrome children.

BACKGROUND: Steroid resistant (SR) nephrotic syndrome (NS) affects up to 30% of children and is responsible for fast progression to end stage renal disease. Currently there is no early prognostic marker of SR and studied candidate variants and parameters differ highly between distinct ethnic cohorts. METHODS: Here, we analyzed 11polymorphic variants, 6 mutations, SOCS3 promoter methylation and biochemical parameters as prognostic markers in a group of 124 Polish NS children (53 steroid resistant, 71 steroid sensitive including 31 steroid dependent) and 55 controls. We used single marker and multiple logistic regression analysis, accompanied by prediction modeling using neural network approach. RESULTS: We achieved 92% (AUC = 0.778) SR prediction for binomial and 63% for multinomial calculations, with the strongest predictors ABCB1 rs1922240, rs1045642 and rs2235048, CD73 rs9444348 and rs4431401, serum creatinine and unmethylated SOCS3 promoter region. Next, we achieved 80% (AUC = 0.720) in binomial and 63% in multinomial prediction of SD, with the strongest predictors ABCB1 rs1045642 and rs2235048. Haplotype analysis revealed CD73_AG to be associated with SR while ABCB1_AGT was associated with SR, SD and membranoproliferative pattern of kidney injury regardless the steroid response. CONCLUSIONS: We achieved prediction of steroid resistance and, as a novelty, steroid dependence, based on early markers in NS children. Such predictions, prior to drug administration, could facilitate decision on a proper treatment and avoid diverse effects of high steroid doses.

Dental caries-related primary hypertension in children and adolescents: Cross-sectional study.

BACKGROUND: Hypertension is a growing clinical problem in pediatric population. Also, the cause of hypertension is usually unknown and it may result from systemic inflammation related to tooth decay. AIM: To estimate the potential association in cross-sectional study between tooth decay and hypertension in children and adolescents. PATIENTS AND METHODS: Study group-65 children diagnosed with primary arterial hypertension; control subjects-44 normotensive children. Blood pressure, dental examination, measurement of salivary cortisol, alpha-amylase, secretory IgA, and lysozyme concentrations were performed in all of the children. RESULTS: Hyper- and normotensive children had similar peripheral blood morphology and serum biochemical parameters, except of uric acid concentration, which was significantly higher in the study group (p = .047). Salivary evening concentrations of cortisol and alpha-amylase were significantly higher in hypertensive children (p = .002 and p = .004, respectively). Although 24-hr systolic blood pressure (SBP), including daytime and nighttime SBP, correlated with "decay," "microalbuminuria," "BMI," and "glomerular filtration rate" (r > .75, r > .7, r < .68, and r < .43, respectively), in multivariate analysis only "decay" was associated with hypertension both in children and in adolescents (p < .0001). CONCLUSION: Tooth decay in children/adolescents might be regarded as a potent trigger factor of hypertension in individuals in whom all other causes of secondary arterial hypertension have been excluded.

The Evaluation of Multiple Linear Regression-Based Limited Sampling Strategies for Mycophenolic Acid in Children with Nephrotic Syndrome.

We evaluated mycophenolic acid (MPA) limited sampling strategies (LSSs) established using multiple linear regression (MLR) in children with nephrotic syndrome treated with mycophenolate mofetil (MMF). MLR-LSS is an easy-to-determine approach of therapeutic drug monitoring (TDM). We assessed the practicability of different LSSs for the estimation of MPA exposure as well as the optimal time points for MPA TDM. The literature search returned 29 studies dated 1998-2020. We applied 53 LSSs (n = 48 for MPA, n = 5 for free MPA [fMPA]) to predict the area under the time-concentration curve (AUCpred) in 24 children with nephrotic syndrome, for whom we previously determined MPA and fMPA concentrations, and compare the results with the determined AUC (AUCtotal). Nine equations met the requirements for bias and precision ±15%. The MPA AUC in children with nephrotic syndrome was predicted the best by four time-point LSSs developed for renal transplant recipients. Out of five LSSs evaluated for fMPA, none fulfilled the ±15% criteria for bias and precision probably due to very high percentage of bound MPA (99.64%). MPA LSS for children with nephrotic syndrome should include blood samples collected 1 h, 2 h and near the second MPA maximum concentration. MPA concentrations determined with the high performance liquid chromatography after multiplying by 1.175 may be used in LSSs based on MPA concentrations determined with the immunoassay technique. MPA LSS may facilitate TDM in the case of MMF, however, more studies on fMPA LSS are required for children with nephrotic syndrome.

Comparison of cuff-based and cuffless continuous blood pressure measurements in children and adolescents.

OBJECTIVE: In recent times, new methods of blood pressure measurements have been introduced, including cuffless blood pressure (BP) measurement device using pulse transit time (PTT) for calculation of BP values. However, it is still unknown how values obtained with a new cuffless device compare with standard ambulatory measurements in children. The main aim of the study was to investigate whether BP values measured by a cuffless PTT device are comparable with measurements by a standard upper arm cuff-based BP device. METHODS: Thirty children were prospectively included. Blood pressure measurements using the cuffless device (Somnotouch-NIBP) and cuff-based standard device (Omron 907) were performed simultaneously on the left and right arm. RESULTS: Mean systolic BP of the standard measurements was 123,47 ± 14,91 mmHg and 127,48 ± 15,98 mmHg (p < .001) measured by cuffless method. Mean diastolic BP of the standard ABPM measurements was 66,88 ± 11,86 mmHg and 68,52 ± 12,36 mmHg (p < .001). There were significant positive correlations between standard and cuffless measurements. CONCLUSION: The results show that the created PWV-BP function produces a significant correlation between BP derived from the PWV and the SBP measured by sphygmomanometry. When applying this device in clinical practice, one may keep in mind that the reported mean values over 24 hours, awake and asleep time are not directly interchangeable with cuff-based standard 24-hour BP values. The measured BP values were higher by the new technique. Although differences in SBP between both methods reached values up to 20 mmHg, we think that the development of a cuffless BP monitoring system will provide novel solutions in various medical situations.

Early kidney damage in diabetic adolescents with increased blood pressure and glomerular hyperfiltration.

BACKGROUND: The early impact of type-1 diabetes mellitus (DM1), increased blood pressure and glomerular hyperfiltration (GHF) on kidney damage in adolescents using two urinary markers of kidney injury - neutrophil gelatinase-associated lipocalin (uNGAL) and transferrin (uTransf) was assessed. METHODS: The study group consisted of 80 adolescents with DM1, of whom 42 were patients with increased blood pressure (IBP), and 38 were patients with normal blood pressure (NBP). Blood pressure was assessed by 24-hour ambulatory bloodpressure monitoring. All patients showed estimated glomerular-filtration rates (eGFRs) above 90 ml/min/1.73m2. The control group consisted of 19 healthy, age and gender-matched adolescents. RESULTS: All diabetic children showed a significant increase in uNGAL (p<0.001). This increase was not related to blood pressure. The uNGAL was elevated in all patients with normal albuminuria, normal eGFR and NBP. The concentration of uTransf was not increased in the entire studied group and was not related to blood pressure. Children with GHF had significantly higher levels of both uTransf (p=0.010) and uNGAL (p<0.001). In patients with GHF, blood pressure was normal. Patients with IBP showed a significantly higher value for triglycerides (r=0.247; p=0.032) and a longer duration of diabetes (r=0.264; p=0.019). CONCLUSIONS: Diabetes is the leading risk factor for early kidney injury. However, increased blood pressure does not lead to kidney damage, at least in the early stage of DM1. The uNGAL is the early indicator of kidney injury and increases in patients with normal albuminuria, normal glomerular filtration and normal blood pressure. Glomerular hyperfiltration seems to be a marker of diabetic-kidney involvement.

Phakomatoses and cutaneous manifestations associated with moyamoya disease and syndrome.

Phakomatoses are a group of neurocutaneous disorders whose origin is derived from the embryonic ectoderm. These disorders affect the central nervous system, the eyes, and the skin. This article presents phakomatoses and cutaneous manifestations associated with moyamoya disease and syndrome. Moyamoya disease is a progressive and occlusive disorder of the cerebral vasculature often presenting with particular phakomatoses. This article aims to reveal why patients with phakomatoses qualify for detailed neuroimaging.

Limited sampling strategy to predict mycophenolic acid area under the curve in pediatric patients with nephrotic syndrome: a retrospective cohort study.

PURPOSE: Limited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches. METHODS: We measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0-12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively. RESULTS: The best three time point equations included C1, C3, C6 (good guess 83%, bias - 2.78%; 95% confidence interval (CI) - 9.85-0.46); C1, C2, C6 (good guess 72%, bias 0.72%; 95% CI - 5.33-7.69); and C1, C2, C4 (good guess 72%, bias 2.05%; 95% CI - 4.92-13.01) for STATISTICA software. For R software, the best equations consisted of C1, C3, C6 (good guess 92%, bias - 2.69%; 95% CI - 27.18-33.75); C0, C1, C3 (good guess 84%, bias - 2.11%; 95% CI - 24.19-22.29); and C0, C1, C2 (good guess 84%, bias - 0.48%; 95% CI - 30.77-54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method. CONCLUSIONS: The most useful equations included C0, C1, C3 and C0, C1, C2 time points; however, the most precise included C1, C3, C6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.

Multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab in children with steroid-resistant nephrotic syndrome.

The aim of the study was a multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab (Rtx) in children with steroid-resistant nephrotic syndrome (SRNS) with particular emphasis on the possibility of permanent discontinuation or dose reduction of other immunosuppressive drugs such as glucocorticoids and cyclosporine A after 6 months of observation. The study group consisted of 30 children with idiopathic nephrotic syndrome, who were unresponsive to standard immunosuppressive treatment, and hospitalized in the years 2010-2017 in eight paediatric nephrology centres in Poland. The children were administered a single initial infusion of rituximab at the dose of 375 mg/m2 of the body surface area. Proteinuria, the daily supply of glucocorticoids, and cyclosporine were assessed at the moment of the start of the treatment and after 6 months since its commencement. Before Rtx therapy, complete remission was found in 13 patients (43%) and partial remission was found in 8 patients (26%). These numbers increased to 16 (53%) and 12 (40%), respectively. At the start of the treatment 23 patients (76.6%) were treated with cyclosporine A. After 6 months, this number decreased to 15 patients (35%). At the start of the treatment, 18 patients (60%) were treated with prednisone. After 6 months, this number decreased to 8 patients (44%). Children with SRNS may potentially benefit from Rtx treatment despite relative risk of side effects. The benefits may include reduction of proteinuria or reduction of other immunosuppressants.

Circulating suPAR as a biomarker of disease severity in children with proteinuric glomerulonephritis.

BACKGROUND: The increase of circulating urokinase plasminogen activator receptor (suPAR) was demonstrated in various diseases showing its prognostic value as well as the link to the inflammatory reaction. In glomerular diseases, suPAR was considered a causative factor of proteinuria. In the present study we aimed to evaluate serum concentration of suPAR in children with primary and secondary glomerulonephritis (GN) and its association with disease severity. METHODS: The study involved 22 children with minimal change disease (MCD), nine with primary focal segmental glomerulosclerosis (FSGS), seven with Henoch-Schönlein nephritis, seven with lupus nephritis (LN) and 16 controls. RESULTS: Serum suPAR was significantly higher in children with FSGS and LN than controls (4.47±1.39 ng/mL vs. 3.23±0.76 ng/mL; P=0.011 and 6.17±1.12 ng/mL vs. 3.23±0.76 ng/mL, respectively; P<0.0001). Further, suPAR was increased in LN when compared to FSGS (P=0.031). In the total group suPAR showed negative correlation with eGFR, serum complement C3 and positive with left ventricular mass index. In children with MCD and FSGS the inverse association of suPAR with eGFR was also shown. CONCLUSIONS: In children with primary and secondary glomerulonephritis suPAR levels are not associated with proteinuria. In primary GN elevated suPAR levels may result from reduced eGFR reflecting renal damage. In LN circulating suPAR can be increased further indicating both multi-organ involvement and systemic inflammation reflecting disease severity.

Atypical thymic carcinoid manifesting with nephrotic-range proteinuria in a 7-year-old boy.

BACKGROUND: Nephrotic-range proteinuria as a paraneoplastic syndrome (PNS) is an exceptional presentation, especially in children. It is usually associated with hematologic malignancies. Solid tumors are very rare causes of proteinuria. CASE-DIAGNOSIS/TREATMENT: We present the case of a 7-year-old boy with an extremely rare atypical thymic carcinoid accompanied by nephrotic-range proteinuria as PNS. The kidney biopsy was consistent with minimal change disease (MCD). Tests for a neuroendocrine tumor were performed due to symptoms of hypercortisolemia and an elevated concentration of chromogranin A in the serum. The chest computed tomography revealed a tumor in the anterior mediastinum, which was diagnosed as an atypical thymic carcinoid. A complete resolution of the nephrotic-range proteinuria was observed within 1 week after the first thoracoscopic surgery, with almost complete reduction of the tumor mass. CONCLUSIONS: This extremely rare case shows that MCD can occur as a PNS even in children. Nephrotic-range proteinuria can be a symptom of malignant solid tumor. This case highlights the possibility of secondary causes of MCD in children.

Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations.

BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder exhibiting a high risk for progressive chronic kidney disease (CKD). METHODS: This is a retrospective multicentre study of 25 paediatric cases with FHHNC in Poland. Median age at diagnosis was 4 years and median follow-up time was 4.8 years. RESULTS: All cases of FHHNC carried recessive mutations in CLDN16. The founder mutation in CLDN16, Leu151Phe, was the most frequent cause of FHHNC in Polish patients, with 13 (52%) cases being homozygous and 5 (20%) carrying Leu151Phe allele in compound heterozygosity. All cases showed nephrocalcinosis, increased urinary fractional excretion of magnesium and hypercalciuria. Other disease features included hypomagnesaemia (76%), hyperparathyroidism (76%), hyperuricaemia (56%) and hypocitraturia (60%). Treatment with thiazides effectively reduced hypercalciuria in most cases. During follow-up, renal function declined in 60% of patients; 12% of patients reached CKD stage 3 or 4 and one patient developed end-stage renal failure. CONCLUSIONS: We report one of the largest cohorts of FHHNC cases caused by CLDN16 mutations. A missense variant of CLDN16, Leu151Phe, is the most common mutation responsible for FHHNC in Poland. Additionally, we found that normomagnesaemia does not exclude FHHNC and the calculation of fractional excretion of Mg can be diagnostic in the setting of normomagnesaemia. We also demonstrate the efficacy of a treatment with thiazides in terms of hypercalciuria in the majority of patients.

Citrate anticoagulation for continuous renal replacement therapy in small children.

BACKGROUND: Regional citrate anticoagulation (RCA) is one of the methods used to prevent clotting in continuous renal replacement therapy (CRRT). The aim of this study was to describe the outcomes and complications of RCA-CRRT in comparison to heparin anticoagulation (HA)-CRRT in critically ill children. METHODS: This study was a retrospective review of 30 critically ill children (16 on RCA- and 14 on HA-CRRT) who underwent at least 24 h of CRRT. The mean body weight of the children was 8.69 ± 5.63 kg. RCA-CRRT was performed with a commercially available pre-dilution citrate solution (Prismocitrate 18/0). RESULTS: The mean time on RCA-CRRT and HA-CRRT was 148.73 ± 131.58 and 110.24 ± 105.38 h, respectively. Circuit lifetime was significantly higher in RCA-CRRT than in HA-CRRT (58.04 ± 51.18 h vs. 37.64 ± 32.51 h, respectively; p = 0.030). Circuit clotting was observed in 11.63 % of children receiving RCA-CRRT and 34.15 % of those receiving HA-CRRT. Episodic electrolyte and metabolic disturbances were more common in children receiving RCA-CRRT. The survival at discharge from the hospital was 37.5 and 14.3 % among children receiving RCA-CRRT and HA-CRRT, respectively. CONCLUSIONS: In critically ill children with a low body weight, RCA appeared to be safe and easy to used. Among our patient cohort, RCA was more effective in preventing circuit clotting and provided a better circuit lifetime than HA.

Urinary angiotensinogen and urinary sodium are associated with blood pressure in normoalbuminuric children with diabetes.

BACKGROUND: The aim of this study was to evaluate the association between blood pressure (BP) and urinary angiotensinogen excretion (uAGT) and renal sodium excretion (uNa) in children with type 1 diabetes mellitus (DM1). METHODS: The study group consisted of 52 children with DM1 (28 males and 24 females) with albumin/creatinine ratio (ACR) below 30 mg/g and glomerular filtration rate (eGFR) above 90 ml/min/1.73 m(2). BP was assessed by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS: The patients showed significantly increased uAGT values with respect to controls (median 0.00 and range 1.76 vs. 0.00 and 0.00 ng/mg, respectively). The significant increase of uAGT was observed even in prehypertensive patients. uAGT concentrations showed positive correlation with systolic and diastolic 24-h BP and with mean arterial pressure (MAP) (r = 0.594). uNa values were negatively correlated with BP parameters, uAGT, ACR and eGFR. CONCLUSIONS: An increase in uAGT precedes hypertension (HTN) in normoalbuminuric children with DM1 and may be considered as a new marker of HTN. Decreased sodium excretion seems to be involved in the development of HTN and early renal injury. Both uAGT and uNa are associated with BP in normoalbuminuric diabetic children.

Liquid chromatography-tandem mass spectrometry method for mycophenolic acid and its glucuronide determination in saliva samples from children with nephrotic syndrome.

BACKGROUND: Saliva sampling is one of the methods of therapeutic drug monitoring for mycophenolic acid (MPA) and its metabolite, mycophenolic acid glucuronide (MPAG). The study describes the liquid chromatography tandem mass spectrometry (LC-MS/MS) method developed for saliva MPA and MPAG determination in children with nephrotic syndrome. METHODS: The mobile phase consisted of methanol and water at gradient flow, both with 0.1% formic acid. Firstly, 100 µL of saliva was evaporated at 45 °C for 2 h to dryness, secondly, it was reconstituted in the mobile phase, and finally 10 µL was injected into the LC-MS/MS system. Saliva from ten children with nephrotic syndrome treated with mycophenolate mofetil was collected with Salivette®. RESULTS: For MPA and MPAG, within the 2-500 ng/mL range, the method was selective, specific, accurate and precise within-run and between-run. No carry-over and matrix effects were observed. Stability tests showed that MPA and MPAG were stable in saliva samples if stored for 2 h at room temperature, 18 h at 4 °C, and at least 5 months at - 80 °C as well as after three freeze-thaw cycles, in a dry extract for 16 h at 4 °C, and for 8 h at 15 °C in the autosampler. The analytes were not adsorbed onto Salivette® cotton swabs. For concentrations above 500 ng/mL, the samples may be diluted twofold. In children, saliva MPA and MPAG were within the ranges of 4.6-531.8 ng/mL and 10.7-183.7 ng/mL, respectively. CONCLUSIONS: The evaluated LC-MS/MS method has met the validation requirements for saliva MPA and MPAG determination in children with nephrotic syndrome. Further studies are needed to explore plasma-saliva correlations and assess their potential contribution to MPA monitoring.