Background
Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1–20 % risk of progressing to end-stage renal disease during their ...lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1–4) with/without nephroprotective therapy.
Methods
This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan–Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed.
Results
The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2–18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0–52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of <60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy.
Conclusions
Treatment with blockers of the renin–angiotensin–aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most—if not all—AS patients with heterozygous mutations in the causal genes.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
► We present a method to simultaneously quantify MPA and MPAG in saliva and plasma. ► A collection device allowed standardized saliva collection and processing. ► The method appears easy to utilize ...for pharmacokinetic studies in pediatric patients. ► A non-invasive approach to monitor MPA exposure can be derived from this study.
A liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for simultaneous quantification of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in saliva and plasma. Saliva was collected and processed using a standardized commercially available collection device. Sample preparation comprised of protein precipitation with acetonitrile and subsequent centrifugation, followed by evaporation and reconstitution with mobile phase. A labeled isotope of MPA was used as internal standard, and chromatographic separation was achieved on a C18 column with an isocratic flow. LC–MS/MS detection was performed using a triple-stage quadrupole mass spectrometer working in selected reaction monitoring mode with positive electrospray ionization (ESI). The analytes were quantified in a single run within 2min. For saliva, linearity was demonstrated over the concentration range of 5.0 to 400.0ng/ml for both MPA and MPAG, and from 0.08 to 20.00μg/ml for MPA and 0.4 to 100.0μg/ml for MPAG in plasma. The lower limits of quantification for MPA and MPAG were 0.07 and 0.80ng/ml in saliva, and 0.002 and 0.009μg/ml in plasma, respectively. Inter- and intra-day precisions expressed as relative standard deviation (RSD) and accuracies were less than 15%. The recoveries for MPA and MPAG from the collection device's swab were higher than 90%. Sample stability was confirmed for bench times up to 24h at room temperature. The method was validated according to International Conference on Harmonization (ICH) guidelines Q2 (R1) Validation of Analytical Procedures. The applicability of the method was tested in a renal pediatric patient. Based on a limited sampling strategy, MPA saliva and plasma concentrations were found in good agreement with each other. We suggest that the described method is suitable to analyze saliva and plasma samples of small volumes for therapeutic drug monitoring (TDM) and pharmacokinetic studies in pediatric patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE)-inhibitors delays end stage renal failure by years. ...The efficiency of ACE inhibition depends on the onset of therapy—the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required.
Methods
Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays.
Results
The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies.
Conclusions
These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Objective
Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise ...training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT).
Methods
Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter.
Results
We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14–13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 0.33 vs. 1.79 0.55) at V0 and (1.70 0.36 vs. 1.71 0.51) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions.
Conclusions
Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated.
Trial registration
The trial was registered in
ClinicalTrials.Gov
(
Clinicaltrials.gov
identifier: NCT01561118) on March 22, 2012.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Cystic renal diseases are characterized by intrarenal cysts of different size and number. Further important diagnostic criteria include, e.g., liver fibrosis. The latter represents a significant ...cause of morbidity and mortality in autosomal-recessive polycystic kidney disease (ARPKD), whereas patients with autosomal-dominant polycystic kidney disease (ADPKD) can develop hepatic cysts without fibrosis. We report the use of transient elastography FibroScan®, (FS) for early and noninvasive detection of increased liver stiffness as marker of liver fibrosis. Compared with matched healthy controls, ADPKD patients (
n
= 7) showed no significant difference in liver stiffness (5.3 kPa vs. 4.5 kPa; ns). ARPKD patients (
n
= 7) had significantly increased median liver stiffness compared with controls (12.0 kPa vs. 4.5 kPa,
p
= 0.002) and ADPKD patients (12.0 kPa vs. 5.3 kPa,
p
= 0.002). Conventional ultrasound revealed evidence of liver fibrosis in only four of seven ARPKD patients (57%) compared with 100% detection by FS. Additional laboratory examinations showed no pathologic liver parameters. In conclusion, our data found FS to be a valuable, sensitive, and noninvasive new tool for early evaluation of liver fibrosis in cystic kidney diseases. This could facilitate diagnosis, monitoring, and management of liver involvement in ARPKD or any other cystic kidney disease.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Background
There are currently three distinct autosomal recessive inherited types of primary hyperoxaluria (PH: PHI, PHII, and PHIII), all characterized by the endogenous overproduction of oxalate. ...The PH type is difficult to differentiate by clinical features alone. In addition to universal general characteristics to all hyperoxaluria subtypes, specific urinary metabolites can be detected: glycolate in PHI,
L
-glyceric acid in PHII, and hydroxy-oxo-glutarate (HOG) in PHIII. PHIII is considered to be the most benign form and is characterized by severe recurrent urolithiasis in early life, followed by clinical remission in many, but not all patients. We examined urinary HOG (U
HOG
) excretion as a diagnostic marker and its correlation to progression of the clinical course of PHIII.
Methods
U
HOG
was analyzed by combined ion chromatography/mass spectrometry (IC/MS) in urine samples from 30 PHIII and 68 PHI/II patients and 79 non-PH hyperoxaluria patients.
Results
Mean U
HOG
excretion was significantly higher in patients with PHIII than in those with PHI/II and in non-PH patients(51.6 vs. 6.61 vs. 8.36 μmol/1.73 m
2
/24 h, respectively;
p
<0.01).
Conclusions
Significantly elevated U
HOG
excretion was exclusively seen in PHIII patients and showed a 100 % consensus with the results of hydroxy-oxo-glutarate aldolase (
HOGA1
) mutational analysis in newly diagnosed patients. However, U
HOG
excretion did not correlate with clinical course on follow-up and could not be used to discriminate between active stone formers and patients with a clinically uneventful follow-up.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Calcification of renal allografts has been reported in adult kidney transplant (KTx) recipients with a widely differing prevalence (2-60%). Persistent hyperparathyroidism, hypercalcemia and ...concomitant hypercalciuria were identified as major risk factors. We aimed to determine the prevalence and risk factors for such calcifications in children.
We investigated histological stains of routine graft biopsies from pediatric KTx patients for renal calcifications and determined the urinary excretion of lithogenic (oxalate, calcium) and stone-inhibitory substances (citrate).
In our series of transplant patients, tubular calcification was found in 16 of the 36 (44.4%) KTx biopsies by an additional Kossa stain. This transplant calcification was not associated with any singular risk factor and was not correlated to a worse transplant outcome.
Although our pediatric findings confirm the reported incidence rates of KTx calcification in adults, we could neither identify hypercalciuria as a risk factor nor confirm any negative influence on graft function. However, long-term studies are clearly needed to prove or disprove a negative impact of calcifications on graft function.
The unit of the HOG-creatinine ratio presented in this article is calculated in μmol/mg creatinine instead of the demonstrated unit of μmol/μmol. This applies to the parameter in the text of the ...article and the labeling of Figs. 1, 2b and 3c.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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