Cystinosis is an autosomal recessive lysosomal storage disorder caused by
CTNS
gene mutations. The
CTNS
gene encodes the protein cystinosin, which transports free cystine from lysosomes to cytoplasm. ...In cases of cystinosin deficiency, free cystine accumulates in lysosomes and forms toxic crystals that lead to tissue and organ damage. Since
CTNS
gene mutations were first described, many variations have been identified that vary according to geographic region, although the phenotype remains the same. Cystinosis is a hereditary disease that can be treated with the cystine-depleting agent cysteamine. Cysteamine slows organ deterioration, but cannot treat renal Fanconi syndrome or prevent eventual kidney failure; therefore, novel treatment modalities for cystinosis are of great interest to researchers. The present review aims to highlight the geographic differences in cystinosis—specifically in terms of its genetic aspects, clinical features, management, and long-term complications.
Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN ...(FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.
Cystinosis is a rare autosomal recessive disease with an incidence 1 per 100,000–200,000 live births. It is caused by pathogenic variants of the
cystinosin
(
CTNS
) gene that lead to impaired cystine ...transport from lysosomes to cystosol, resulting in cystine accumulation in lysosomes and subsequent cellular dysfunction. The initial manifestation, cystine accumulation in proximal tubular cells (PTCs), causes renal Fanconi syndrome, which presents with proximal renal tubular acidosis and generalized dysfunction of the proximal tubule, including the presence of polyuria, glycosuria, phosphaturia, aminoaciduria, tubular proteinuria, growth retardation, and rickets. Eventually, glomerular involvement, glomerular proteinuria, focal segmental glomerulosclerosis (FSGS), and progression to kidney failure occur. Although the kidneys are the first organs affected, and play a key role in morbidity and mortality, extrarenal multiorgan involvement can occur in patients with cystinosis, which is seen not only in adults but in early ages in untreated patients, patients with insufficient treatment, and in those that don’t comply with treatment. The treatment of cystinosis consists of supportive treatment for Fanconi syndrome, and specific lifelong cystine-depleting therapy using oral cysteamine. There is strong evidence that as early as possible, initiation and ongoing appropriate therapy with cysteamine are essential for delaying the progression to kidney failure, end-organ damage, and extrarenal involvement. The present review aimed to evaluate the extra renal complications of cystinosis.
Abstract
Distal renal tubular acidosis (dRTA) is characterized by an impaired ability of the distal tubule to excrete acid, leading to metabolic acidosis. Associated complications include bone ...disease, growth failure, urolithiasis and hypokalaemia. Due to its rarity, there is limited evidence to guide diagnosis and management; however, available data strongly suggest that metabolic control of the acidosis by alkali supplementation can halt or revert almost all complications. Despite this, cohort studies show that adequate metabolic control is present in only about half of patients, highlighting problems with treatment provision or adherence. With these clinical practice points the authors, part of the working groups tubulopathies in the European Rare Kidney Disease Reference network and inherited kidney diseases of the European Society for Paediatric Nephrology, aim to provide guidance for the management of patients with dRTA to facilitate adequate treatment and establish an initial best practice standard against which treatment of patients can be audited.
Background
The rising number of infections due to Severe Acute Respiratory Syndrome Coronavirus-2 (popularly known as COVID-19) has brought to the fore new antiviral drugs as possible treatments, ...including favipiravir. However, there is currently no data regarding the safety of this drug in patients with kidney impairment. The aim of this paper, therefore, is to share our experience of the use of favipiravir in pediatric patients affected by COVID-19 with any degree of kidney impairment.
Methods
The study enrolled pediatric patients aged under 18 years and confirmed as suffering from COVID-19 and multisystem inflammatory syndrome in children (MIS-C) with any degree of kidney injury, who were treated with favipiravir at the time of admission.
Results
Out of a total of 11 patients, 7 were diagnosed with MIS-C and 4 with severe COVID-19. The median age of the cases was 15.45 (9–17.8) years and the male/female ratio was 7/4. At the time of admission, the median serum creatinine level was 1.1 mg/dl. Nine patients were treated with favipiravir for 5 days, and 2 patients for 5 days followed by remdesivir for 5–10 days despite kidney injury at the time of admission. Seven patients underwent plasma exchange for MIS-C while 2 severely affected cases underwent continuous kidney replacement therapy (CKRT) as well. One severe COVID-19 patient received plasma exchange as well as CKRT. Serum creatinine values returned to normal in mean 3.07 days.
Conclusions
Favipiravir seems a suitable therapeutic option in patients affected by COVID-19 with kidney injury without a need for dose adjustment.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Cystinosis is a rare, devastating hereditary disease secondary to recessive
gene mutations. The most commonly used diagnostic method is confirmation of an elevated leukocyte cystine level; however, ...this method is expensive and difficult to perform. This study aimed to identify candidate biomarkers for the diagnosis and follow-up of cystinosis based on multiomics studies. The study included three groups: newly-diagnosed cystinosis patients (patient group, n = 14); cystinosis patients under treatment (treatment group, n = 19); and healthy controls (control group, n = 30). Plasma metabolomics analysis identified 10 metabolites as candidate biomarkers that differed between the patient and control groups L-serine, taurine, lyxose, 4-trimethylammoniobutanoic acid, orotic acid, glutathione, PE(O-18:1(9Z)/0:0), 2-hydroxyphenyl acetic acid, acetyl-N-formil-5-metoxikinuramine, 3-indoxyl sulphate. As compared to the healthy control group, in the treatment group, hypotaurine, phosphatidylethanolamine, N-acetyl-d-mannosamine, 3-indolacetic acid, p-cresol, phenylethylamine, 5-aminovaleric acid, glycine, creatinine, and saccharic acid levels were significantly higher, and the metabolites quinic acid, capric acid, lenticin, xanthotoxin, glucose-6-phosphate, taurine, uric acid, glyceric acid, alpha-D-glucosamine phosphate, and serine levels were significantly lower. Urinary metabolomic analysis clearly differentiated the patient group from the control group by means of higher allo-inositol, talose, glucose, 2-hydroxybutiric acid, cystine, pyruvic acid, valine, and phenylalanine levels, and lower metabolite (N-acetyl-L-glutamic acid, 3-aminopropionitrile, ribitol, hydroquinone, glucuronic acid, 3-phosphoglycerate, xanthine, creatinine, and 5-aminovaleric acid) levels in the patient group. Urine metabolites were also found to be significantly different in the treatment group than in the control group. Thus, this study identified candidate biomarkers that could be used for the diagnosis and follow-up of cystinosis.
Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data ...after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry.
A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS.
Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children <6 years were shortest at KT and showed the greatest increase in height, whereas there was no catch-up growth in children transplanted >12.
Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.
SLE is a disease of the adaptive immune system where T lymphocyte dysfunction has an important role as well. We assessed the plasma levels of checkpoint receptors expressed on T cells, along with ...Galectin-9 to reflect type-1 IFN activity and IL-2Rα in childhood SLE patients. Forty-nine children with SLE and15 healthy controls were included. SLEDAI scores were evaluated at the time of sampling. CD25 (IL-2Rα), 4-1BB, B7.2 (CD86), TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG- 3, Galectin-9 levels were studied by cytometric bead-based multiplex assay panel. Galectin-9 and PD-L1 were significantly higher in SLE patients. Other checkpoint proteins and IL-2Rα were also higher but did not reach statistical significance. There were significant correlations between SLEDAI and IL-2Rα, Galectin-9 and PDL1. There were three clinical clusters: Cluster 1 included patients with no major organ involvement, cluster 2 had predominantly haematological involvement(n=16) and cluster 3 (n=11) had predominantly renal involvement. Checkpoint proteins were not different among these three clusters. Our data supports that Galectin 9 and IL-2Rα are good markers for disease activity in childhood SLE. We need larger series to evaluate differences between disease clusters in SLE. We failed to show a significant correlation with checkpoint proteins and SLEDAI except for PDL1.
Complementary and alternative medicine are treatments administered alone or in combination with conventional medical treatments. Data on complementary and alternative medicine use in children with ...kidney and urinary tract diseases are limited. In this cross-sectional study, the frequency and preferred methods of complementary and alternative medicine use and factors associated with their use were evaluated in 201 patients (48% female; median age, 11 years; median disease duration, 5.1 years) with kidney and urinary tract diseases and 260 healthy (without chronic disease) controls. Data were collected through a questionnaire-based interview and patients’ medical records. Herbal and dietary supplements, including fish oil, were the most commonly used complementary and alternative medicine agents in both groups. There was no difference in herbal and dietary supplement use between the groups when fish oil was excluded (29% vs. 28%;
p
= 0.88). Herbal and dietary supplements were mainly used to improve/mitigate renal disease (52%). Logistic regression analysis revealed that disease duration > 7 years (odds ratio (OR), 3.70; 95% confidence interval (CI), 1.48–9.20), current use of six or more drugs (OR, 5.6; 95% CI, 1.28–24.41), and recurrent urinary tract infection or nephrolithiasis (OR, 3.92; 95% CI, 1.02–15.09) were the independent risk factors for herbal and dietary supplement use, except fish oil. Middle socioeconomic status was associated with decreased herbal and dietary supplement use, except fish oil, compared with low socioeconomic status (OR, 0.30; 95% CI, 0.11–0.81). Herbal and dietary supplements were used by 78% patients, despite knowing that these products could have side effects; only 42% of the patients shared the information about herbal and dietary supplement use with their doctors.
Conclusion
: Herbal and dietary supplement use is frequent in children with kidney and urinary tract diseases. Educating health professionals regarding such use is mandatory for developing strategies to prevent critical consequences.
What is Known:
• Complementary and alternative medicine (CAM) practices are therapeutic approaches that do not have sufficient efficacy and safety evidence.
• CAM is widely used in healthy children and in certain chronic diseases.
What is New:
• Herbal and dietary supplements (HDSs) were the most commonly used method in kidney and urinary tract diseases.
• Duration of disease, number of drugs, and socioeconomic status are determinants of HDS use except fish oil.
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