Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C
) although it has not ...shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC
and
genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC
formulas and dose requirements.
We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC
and
genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC
normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC
model. We compared the performance of this model with two pediatric LSS-AUC
equations for clinical validation.
Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9 years). When normalizing AUC
by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1 ng*h/mL/mg/kg,
< 0.05). C
had a poor fit with AUC
(
= 0.5011). The model which included C
, C
and C
, showed the best performance to predict LSS-AUC
(
= 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC
, in comparison to other LSS equations.
Estimation of LSS-AUC
with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different
genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits.
Congenital nephrotic syndrome (CNS) is a severe kidney disorder characterized by edema, massive proteinuria, and hypoalbuminemia that manifests
or within three months after birth. CNS affects 1-3 per ...100,000 children, primarily associated with genetic variants and occasionally with infections. Genetic analysis is the first-line method for diagnosis. The most common founder variants have been identified in European populations, often resulting in end-stage kidney disease by 1-2 years of age.
A female full-term neonate, without prenatal signs of kidney disease, was admitted to Rapa Nui (Eastern Island) Hospital at the age of 2 months due to bronchial obstruction. She presented fever, oliguria, edema, urine protein-to-creatinine ratio (UPCR) 433.33, and hypoalbuminemia (0.9 g/dL). She was transferred to a mainland Chilean hospital following CNS diagnosis. Viral screening detected cytomegalovirus (CMV) positivity in both blood and urine. A kidney biopsy revealed interstitial nephritis and diffuse podocyte damage and the tissue PCR resulted negative for CMV. Interviews with the parents revealed consanguinity, suggestive of hereditary CNS. Genetic analysis identified the Maori founder variant,
c.2131C>A (p.R711S), in homozygosis. The patient received albumin infusions and antiviral therapy, being discharged when she was 5 months old, with improved laboratory parameters evidenced by UPCR 28.55, albumin 2.5 g/dL, and cholesterol 190 mg/dL. Subsequent clinical monitoring was conducted through virtual and in-person consultations. At her last follow-up at 4 years 2 months old, she presented UPCR 16.1, albumin 3.3 g/dl and cholesterol 220 mg/dL, maintaining normal kidney function and adequate growth.
To our knowledge, this represents the first case of CNS in Chile carrying a
variant associated with prolonged kidney survival. As described in the Maori population, the patient exhibited a less severe clinical course compared to classical
patients. Genetic testing for the Maori founder variant in CNS patients related to the New Zealand population, could impact management decisions and potentially prevent the need for nephrectomies.
The Potocki-Lupski syndrome (PTLS) is associated with a microduplication of 17p11.2. Clinical features include multiple congenital and neurobehavioral abnormalities and autistic features. We have ...generated a PTLS mouse model, Dp(11)17/+, that recapitulates some of the physical and neurobehavioral phenotypes present in patients. Here, we investigated the social behavior and gene expression pattern of this mouse model in a pure C57BL/6-Tyrc-Brd genetic background. Dp(11)17/+ male mice displayed normal home-cage behavior but increased anxiety and increased dominant behavior in specific tests. A subtle impairment in the preference for a social target versus an inanimate target and abnormal preference for social novelty (the preference to explore an unfamiliar mouse versus a familiar one) was also observed. Our results indicate that these animals could provide a valuable model to identify the specific gene(s) that confer abnormal social behaviors and that map within this delimited genomic deletion interval. In a first attempt to identify candidate genes and for elucidating the mechanisms of regulation of these important phenotypes, we directly assessed the relative transcription of genes within and around this genomic interval. In this mouse model, we found that candidates genes include not only most of the duplicated genes, but also normal-copy genes that flank the engineered interval; both categories of genes showed altered expression levels in the hippocampus of Dp(11)17/+ mice.
A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains ...an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and ...transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on
,
and
genes in Chilean pediatric kidney recipients using TAC and MPA.
A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years Q1-Q3 4.5-11.6 years and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The
polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while
-24G > A,
-275T > A, and
-2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C
), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C
/D), and area under the curve in 12 h normalized by dose requirements (AUC
/D).
The frequencies of the variant alleles
,
,
, and
were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC
/TAC-D were 1.6-fold higher in
patients than in
carriers (
and
). When analyzing patients with steroid withdrawal,
patients had 1.7-fold higher AUC
/TAC-D than the other genotypes. Patients carrying the
genotype had higher TAC-C
, lower TAC-D and higher TAC-C
/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between
and
genotypes were observed in MPA-C
, MPA-D or MPA-C
/D. However, patients carrying the
allele had lower AUC
/MPA-D than those carrying the
ancestral allele.
These results support that
and
genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.
Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to ...the metabolism and transport of these drugs, namely
,
,
and
genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using
® probes, we determined the allelic frequency of seven variants in
,
,
and
in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C
/D and C
/D) at specific time points post-transplant. We found that
carriers required lower doses of TAC. In TAC treated patients, most
carriers presented higher C
/D and a high proportion of patients with C
levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering
genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.
Abstract
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition associated primarily with
PKD1
and
PKD2
genes. However, ADPKD patients in Latin America have ...had limited access to comprehensive care. The ProPKD score predicts the likelihood of kidney failure before the age of 60. This study aimed to describe the clinical and genetic characteristics of Chilean ADPKD patients and assess the ProPKD score.
Methods
We enrolled 40 ADPKD probands and 122 relatives from different centers. Genetic analysis of
PKD1
and
PKD2
genes was performed by combining direct and next-generation sequencing. Pathogenicity was determined using bioinformatic tools. ProPKD scores were calculated based on clinical and genetic data.
Results
ADPKD probands were diagnosed at a median age of 35 years. Pathogenic, likely pathogenic, or uncertain significance variants were identified in 38/40 pedigrees, with 89% involving
PKD1
and 11% involving
PKD2
variants. Among the identified variants, 62% were novel. Patients with
PKD1
truncating variants had a more severe disease course, reaching kidney failure by a median age of 48.5 years. ProPKD scores were assessed in 72 individuals, stratifying them into high-, intermediate-, or low-risk categories and the median ages for kidney failure were 45, 49, and 52 years, respectively (log-rank
p
= 0.001).
Conclusion
This study provides valuable insights into the clinical and genetic profiles of ADPKD patients in Chile. ADPKD poses a significant public health concern, warranting improvements in diagnosis and treatment. The use of the ProPKD score to predict disease progression should be further explored to enhance patient care and management.
Understanding the processes that give rise to genomic variability in extant species is an active area of research within evolutionary biology. With the availability of whole genome sequences, it is ...possible to quantify different forms of variability such as variation in gene copy number, which has been described as an important source of genetic variability and in consequence of phenotypic variability. Most of the research on this topic has been focused on understanding the biological significance of gene duplication, and less attention has been given to the evolutionary role of gene loss. Gremlin 2 is a member of the DAN gene family and plays a significant role in tooth development by blocking the ligand-signaling pathway of BMP2 and BMP4. The goal of this study was to investigate the evolutionary history of gremlin 2 in cetartiodactyl mammals, a group that possesses highly divergent teeth morphology. Results from our analyses indicate that gremlin 2 has experienced a mixture of gene loss, gene duplication, and rate acceleration. Although the last common ancestor of cetartiodactyls possessed a single gene copy, pigs and camels are the only cetartiodactyl groups that have retained gremlin 2. According to the phyletic distribution of this gene and synteny analyses, we propose that gremlin 2 was lost in the common ancestor of ruminants and cetaceans between 56.3 and 63.5 million years ago as a product of a chromosomal rearrangement. Our analyses also indicate that the rate of evolution of gremlin 2 has been accelerated in the two groups that have retained this gene. Additionally, the lack of this gene could explain the high diversity of teeth among cetartiodactyl mammals; specifically, the presence of this gene could act as a biological constraint. Thus, our results support the notions that gene loss is a way to increase phenotypic diversity and that gremlin 2 is a dispensable gene, at least in cetartiodactyl mammals.
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