Abstract
Background and Aims
Chronic kidney disease (CKD) is associated with significant morbidity and mortality among patients with sickle cell anemia (SCA). Glomerular hyperfiltration (GHF) and ...albuminuria are known as early manifestations of kidney disease occurring in early childhood and can predict the progression to CKD in these patients. Studies reported the prevalence of these kidney abnormalities in SCA children using a single measure and their association with genetic risk factors, especially the co-inheritance of APOL1 risk variants (RVs). However, data on the prevalence of persistent kidney abnormalities (based on the KDIGO CKD definition) and their association with APOL1 RVs are limited in SCA children, particularly those living in sub-Saharan Africa. This study aimed: (i) to determine the prevalence of persistent kidney abnormalities (albuminuria and/or GHF) in SCA children living in the Democratic Republic of Congo (DRC); and (ii) to assess the association between persistent kidney abnormalities with clinical and genetic risk factors.
Method
From March 2021 to December 2022, we prospectively enrolled 585 steady state SCA children aged 2 to 18 years (male gender 278/585; 47.5%). The SCA status was confirmed through the molecular sequencing of beta-globin gene. Clinical and biological parameters were obtained. All participants were genotyped for apolipoprotein-L1 (APOL1) G1 (rs73885319, rs60910145) and G2 (rs71785313) variants. APOL1 high-risk genotype (HRG) was defined by the presence of 2 risk variants (G1/G1, G2/G2, and G1/G2), and low-risk genotype (LRG) by the presence of 0 or 1 risk variant. Albuminuria was defined as urinary albumin-to-creatinine ratio (ACR) ≥ 30mg/g. The estimated glomerular filtration rate (eGFRcr) was calculated using the original Schwartz formula and GHF was defined as eGFRcr ≥ 180 ml/min/1.73 m2 for children between 2-10 years of age and > 140 ml/min/1.73 m2 for children more than 10 years of age. All measurements were repeated at least three months later in participants who presented with kidney abnormalities at the first screening. The main outcome parameter was persistent albuminuria or persistent GHF for more than three months.
Results
At enrollment, 234/585 (40.0%) participants presented with kidney abnormalities, among which 80/585 (13.7%) with albuminuria and 171/585 (29.2%) with hyperfiltration. From participants found with kidney abnormalities at the first screening, 176/234 (75.2%) were available for repeated screening: 56/176 (31.8%) presented with persistent kidney abnormalities and 120/176 (68.2%) had a regression of kidney abnormalities without any treatment. Out of 176 participants who benefited from repeated screening, 57 had baseline albuminuria and 130 had baseline GHF. Persistent albuminuria and persistent GHF were found in 38.6% (22/57) and 28.5% (37/130), respectively. Multivariate logistic regression revealed that APOL1 HRG was significantly associated with persistent albuminuria (OR 3.4, 95CI 1.1-10.7, p = 0.037), while male gender was significantly associated with persistent GHF (OR 2.1, 95CI 1.0-4.2, p = 0.042).
Conclusion
A significant proportion (almost 70.0%) of SCA children who had kidney abnormalities at the first measure, presented regression of these abnormalities without any reno-protective drugs. This result emphasizes the importance of repeating screening at least three months later to confirm CKD, as recommended by the KDIGO Guidelines. This strategy will reduce the need for unnecessary treatment, which represents a high financial burden in a resource-limited area.
Objective To analyze the fertility status in adult, male cystinosis patients treated with cysteamine. Cystinosis is an autosomal recessive disease leading to intralysosomal cystine accumulation. ...Worldwide, a few female cystinosis patients have given birth. However, no male cystinosis patients are known to have induced pregnancy. Adequate cysteamine treatment might improve male fertility. Patient(s) Seven male cystinosis patients (19–43 years) were submitted. Intervention(s) Glomerular filtration rate was estimated using the Cockcroft formula. Serum LH, FSH, testosterone, and inhibin B were determined. Semen analysis was performed in five patients. Testicular biopsy was performed in one patient. Results Glomerular filtration rate ranged between 10 and 110 (normal >90) mL/min/1.73 m2 , LH and FSH levels ranged between 7.4 and 235.0 (normal 1.4–8.5) E/L and 6.8–298.0 (normal 1.5–11) E/L, respectively. Plasma testosterone level ranged between 8.7 and 31.3 (normal 11–45) nmol/L; plasma inhibin B level ranged between 10 and 210 (normal 150–400) ng/L. All of the collected sperm samples showed azoospermia. The testicular biopsy showed a Johnson score of 8 to 9. Conclusion(s) We demonstrate azoospermia in male cystinosis patients, even if adequately treated with cysteamine starting from an early age. The finding of spermatogenesis in the testis biopsy of one patient may provide opportunities to male cystinosis patients to produce their own offspring by in vitro fertilization after testicular sperm extraction.
Recent evidence implies that impaired metabolism of glutathione has a role in the pathogenesis of nephropathic cystinosis. This recessive inherited disorder is characterized by lysosomal cystine ...accumulation and results in renal Fanconi syndrome progressing to end stage renal disease in the majority of patients. The most common treatment involves intracellular cystine depletion by cysteamine, delaying the development of end stage renal disease by a yet elusive mechanism. However, cystine depletion does not arrest the disease nor cures Fanconi syndrome in patients, indicating involvement of other yet unknown pathologic pathways. Using a newly developed proximal tubular epithelial cell model from cystinotic patients, we investigate the effect of cystine accumulation and cysteamine on both glutathione and ATP metabolism. In addition to the expected increase in cystine and defective sodium-dependent phosphate reabsorption, we observed less negative glutathione redox status and decreased intracellular ATP levels. No differences between control and cystinosis cell lines were observed with respect to protein turnover, albumin uptake, cytosolic and mitochondrial ATP production, total glutathione levels, protein oxidation and lipid peroxidation. Cysteamine treatment increased total glutathione in both control and cystinotic cells and normalized cystine levels and glutathione redox status in cystinotic cells. However, cysteamine did not improve decreased sodium-dependent phosphate uptake. Our data implicate that cysteamine increases total glutathione and restores glutathione redox status in cystinosis, which is a positive side-effect of this agent next to cystine depletion. This beneficial effect points to a potential role of cysteamine as anti-oxidant for other renal disorders associated with enhanced oxidative stress.
► Presentation of a new human cystinosis renal proximal tubular cell model. ► Altered GSSG/2GSH redox status in cystinosis cells. ► Energy generating capacity is normal in cystinosis cells, but decreased ATP levels are found. ► Treatment with cysteamine restores redox status in vitro via increased GSH levels. ► Restoration of redox status by cysteamine might be beneficial in other renal disorders.
ABSTRACT
Background
Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is ...unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background.
Methods
PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients.
Results
PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus M1} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype.
Conclusions
Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.
Graphical Abstract
Graphical Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is an inhibitor of megakaryopoiesis and platelet function. Recently, PACAP deficiency was observed in children with nephrotic syndrome (NS), ...associated with increased platelet count and aggregability and increased risk of thrombosis. To further study PACAP deficiency in NS, we used transgenic Tg(cd41:EGFP) zebrafish with GFP-labeled thrombocytes. We generated two models for congenital NS, a morpholino injected model targeting nphs1 (nephrin), which is mutated in the Finnish-type congenital NS. The second model was induced by exposure to the nephrotoxic compound adriamycin. Nephrin RNA expression was quantified and zebrafish embryos were live-screened for proteinuria and pericardial edema as evidence of renal impairment. Protein levels of PACAP and its binding-protein ceruloplasmin were measured and GFP-labeled thrombocytes were quantified. We also evaluated the effects of PACAP morpholino injection and the rescue effects of PACAP-38 peptide in both congenital NS models. Nephrin downregulation and pericardial edema were observed in both nephrin morpholino injected and adriamycin exposed congenital NS models. However, PACAP deficiency was demonstrated only in the adriamycin exposed condition. Ceruloplasmin levels and the number of GFP-labeled thrombocytes remained unchanged in both models. PACAP morpholino injections worsened survival rates and the edema phenotype in both congenital NS models while injection with human PACAP-38 could only rescue the adriamycin exposed model. We hereby report, for the first time, PACAP deficiency in a NS zebrafish model as a consequence of adriamycin exposure. However, distinct from the human congenital NS, both zebrafish models retained normal levels of ceruloplasmin and thrombocytes. We further extend the renoprotective effects of the PACAP-38 peptide against adriamycin toxicity in zebrafish.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autophagy is the cell biology process in which cytoplasmic components are degraded in lysosomes to maintain cellular homeostasis and energy production. In the healthy kidney, autophagy plays an ...important role in the homeostasis and viability of renal cells such as podocytes and tubular epithelial cells and of immune cells. Recently, evidence is mounting that (dys)regulation of autophagy is implicated in the pathogenesis of various renal diseases, and might be an attractive target for new renoprotective therapies. In this review, we provide an overview of the role of autophagy in kidney physiology and kidney diseases.
Improving the prognosis of nephropathic cystinosis Besouw, Martine Tp; Levtchenko, Elena N
International journal of nephrology and renovascular disease,
01/2014, Letnik:
7, Številka:
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Journal Article
Recenzirano
Odprti dostop
Cystinosis is an autosomal recessive inherited lysosomal storage disease. It is characterized by generalized proximal tubular dysfunction known as renal Fanconi syndrome and causes end-stage renal ...disease by the age of about 10 years if left untreated. Extrarenal organs are also affected, including the thyroid gland, gonads, pancreas, liver, muscle, and brain. Treatment consists of administration of cysteamine, resulting in depletion of cystine that is trapped inside the lysosomes. Since cysteamine has a short half-life, it should be administered every 6 hours. Recently, a new delayed-release formulation was marketed, that should be administered every 12 hours. The first studies comparing both cysteamine formulations show comparable results regarding white blood cell cystine depletion (which serves as a measure for cystine accumulation in the body), while a slightly lower daily dose of cysteamine can be used.
The Schwartz equation is the most widely used serum creatinine (SCr)-based formula to estimate the glomerular filtration rate (GFR) in children of European descent, but whether this applies to ...African children is unclear.
In a cross-sectional study, 513 apparently healthy African children aged 6 to 16 years were randomly recruited in school area of Kinshasa, the Democratic Republic of Congo (DRC). SCr was measured using calibrated enzymatic method. SCr was normalized using Q-values designed for European descent children, due to the absence of Q-values for African children. Commonly used eGFR equations were applied in this population.
Normalization of SCr using Q-values for European descent children was effective in this cohort. The majority of African children (93.4%) have normalized SCr (SCr/Q) values within the reference interval (0.67-1.33) of children of European descent. The bedside-Schwartz equation was associated with significant age and sex dependency. However, the FAS-Age formula showed no sex and age dependency. The new CKiDU25 equation did not show a significant sex dependency. The recently introduced EKFC and LMR18 equations also showed no age and sex dependency, although the distribution of eGFR-values was not symmetrical. On the other hand, the FAS-Height and the Schwartz-Lyon equations showed significant sex dependency but no age dependency.
The reference interval for SCr designed for European descent children can be applied to African children. Of all the equations studied, FAS-Age performed best and is most suitable because no height measurements are required. Establishment of specific Q-values for the widespread Jaffe-measured creatinine in Africa can further broaden applicability.
Glomerular hyperfiltration (GHF) is a phenomenon that can occur in various clinical conditions affecting the kidneys such as sickle cell disease, diabetes mellitus, autosomal dominant polycystic ...kidney disease, and solitary functioning kidney. Yet, the pathophysiological mechanisms vary from one disease to another and are not well understood. More so, it has been demonstrated that GHF may occur at the single-nephron in some clinical conditions while in others at the whole-kidney level. In this review, we explore the pathophysiological mechanisms of GHF in relation to various clinical conditions in the pediatric population. In addition, we discuss the role and mechanism of action of important factors such as gender, low birth weight, and race in the pathogenesis of GHF. Finally, in this current review, we further highlight the consequences of GHF in the progression of kidney disease.
Background: Calcineurin inhibitors (CNIs) are the primary immunosuppressive drugs used in solid organ transplantation but are associated with the development of histological lesions leading to kidney ...failure. CNIs are metabolized by CYP3A and excreted by not only P-glycoprotein (P-gp) (ABCB1) in the gut and liver, but also by proximal tubule cells (PTCs) in the kidney. Multiple studies have demonstrated the importance of genetic variation in CYP3A5 and ABCB1 for CNI disposition and nephrotoxicity. The present study was designed to study the functional implication of variation in these two genes in human PTCs. Methods: A technique was developed to culture cells from renal tissue obtained from renal graft recipients by routine kidney biopsy. Primary cells were immortalized, subcloned, and then characterized for specific PTC markers (AQP1, CD13, brush border morphology) and donor CYP3A5(rs776746)/ABCB1(rs1045642) genotype. We then selected specific sets of confirmed conditionally immortalized PTCs (ciPTC) according to different combinations of the aforementioned genetic variants. Quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry were performed for studying CYP3A5 and ABCB1 expression. CYP3A5 activity was assessed by differential midazolam (MDZ) hydroxylation and P-gp (ABCB1 product) activity by a calcein efflux assay. Differential drug metabolism between cell lines was assessed by tacrolimus disappearance over 24 h. Results: Cell lines were generated from 27 out of 38 tissue samples. On the basis of genotype and PTC biomarkers, 11 subclones were selected. In vitro PTC morphology with brush border microvilli was confirmed. CYP3A5*1 carriers had increased 1-OH/4-OH MDZ formation versus homozygous *3 carriers (mean: 2.36 (95% CI:1.11–3.40) vs 0.88 (95% CI:0.48–1.27); p < 0.05). P-gp activity was confirmed by calcein accumulation (mean 38.6%; 95% CI:32.8–44.4%), which was higher in cell lines with the ABCB1 3435TT than the 3435CC/CT genotype (46.2% vs 35.5%; 95% CI:28.7–42.2%). Tacrolimus disappearance was about two-fold higher in cell lines with the combined CYP3A5*1/ABCB1 3435TT genotype versus other genotype combinations. Conclusion: Biopsy-derived and immortalized human PTC cell lines demonstrate functional expression of genes involved in CNI metabolism. Differences in functional expression were detected according to common genetic variants in CYP3A5 and ABCB1. The studied genetic variants had a significant impact on in vitro tacrolimus metabolism. In particular, ciPTC with the combined CYP3A5*1/ABCB1 3435TT genotype demonstrated higher tacrolimus disappearance versus ciPTCs with a different pharmacogenetic profile. This in vitro model stresses the importance of the incorporation of pharmacogenetic variation in studies involved in (renal) drug disposition.
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