Background
Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease ...(CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk.
Methods
Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1–5 and 97 age-matched patients with CKD of other etiology between the ages of 2–17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models.
Results
Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio
z
-scores (> 1.0), while those of patients with CKD were only mildly affected (
z
-score within ± 1.0). Ratio
z
-scores differed significantly between both patient groups from 2–6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2–6, 7–12, and 13–17 years).
Conclusion
Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function.
Graphical abstract
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Supplementary information
In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the ...analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.
Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of ...monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTP-bound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.
Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, ...double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.
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Gingivitis is a common intraoral disease in patients with chronic kidney disease (CKD), which poses a particular interdisciplinary challenge. We aimed to determine the influence of an intensive oral ...prophylaxis program (OPP) compared to standard prevention measures on the tongue microbiome of young patients with CKD.IntroductionGingivitis is a common intraoral disease in patients with chronic kidney disease (CKD), which poses a particular interdisciplinary challenge. We aimed to determine the influence of an intensive oral prophylaxis program (OPP) compared to standard prevention measures on the tongue microbiome of young patients with CKD.Thirty patients with CKD (mean age 14.2 ± 5.2 years) and generalized gingivitis were included. The effects of the intensive OPP were compared with standard prophylaxis according to statutory health insurance (treatment as usual, TAU) as a control. Tongue swabs were taken from the patients at baseline (t1) and after 3 (t2) and 6 (t3) months. Next-generation sequencing of 16S rDNA genes was used to quantitatively characterize microbial communities.MethodsThirty patients with CKD (mean age 14.2 ± 5.2 years) and generalized gingivitis were included. The effects of the intensive OPP were compared with standard prophylaxis according to statutory health insurance (treatment as usual, TAU) as a control. Tongue swabs were taken from the patients at baseline (t1) and after 3 (t2) and 6 (t3) months. Next-generation sequencing of 16S rDNA genes was used to quantitatively characterize microbial communities.There were no differences in the abundance, richness, or diversity of the observed genera and species between the two study groups at baseline or after 3 or 6 months. Furthermore, no change in predefined gingivitis and oral health bacterial clusters were found. At the phylum level, Firmicutes were decreased after intervention in the TAU group (t2TAU 42.9 ± 7.1 to t3TAU 34.8 ± 4.7 (npairs=14), p=0.003; false discovery rate 0.02). The decrease of Firmicutes was not significant in the OPP group.ResultsThere were no differences in the abundance, richness, or diversity of the observed genera and species between the two study groups at baseline or after 3 or 6 months. Furthermore, no change in predefined gingivitis and oral health bacterial clusters were found. At the phylum level, Firmicutes were decreased after intervention in the TAU group (t2TAU 42.9 ± 7.1 to t3TAU 34.8 ± 4.7 (npairs=14), p=0.003; false discovery rate 0.02). The decrease of Firmicutes was not significant in the OPP group.Despite the intensity of dental prophylaxis and decreasing clinical signs of inflammation and decreasing plaque amount, no clinically relevant changes in the tongue microbiome were observed. Our results confirm the conserved and stable nature of the tongue microbiome, even in children with CKD.ConclusionsDespite the intensity of dental prophylaxis and decreasing clinical signs of inflammation and decreasing plaque amount, no clinically relevant changes in the tongue microbiome were observed. Our results confirm the conserved and stable nature of the tongue microbiome, even in children with CKD.
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 0.5–1/100 newborns and as a group they represent the most frequent cause for chronic kidney failure in children. CAKUT comprise ...clinically heterogeneous conditions, ranging from mild vesicoureteral reflux to kidney aplasia. Most forms of CAKUT share the pathophysiology of an impaired developmental interaction of the ureteric bud (UB) and the metanephric mesenchyme (MM). In most cases, CAKUT present as an isolated condition. They also may occur as a component in rare multi-organ syndromes. Many CAKUT probably have a multifactorial etiology. However, up to 20% of human patients and > 200 transgenic mouse models have a monogenic form of CAKUT, which has fueled our efforts to unravel molecular kidney (mal-)development. To date, genetic variants in more than 50 genes have been associated with (isolated) CAKUT in humans. In this short review, we will summarize typical imaging findings in patients with CAKUT and highlight recent mechanistic insight in the molecular pathogenesis of monogenic forms of CAKUT.
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