Search Results (48)

Background and Clinical Significance: Polycystic kidney disease (PKD) is the most common inherited kidney condition, affecting approximately 500,000 individuals in the US. It causes fluid-filled cysts to develop throughout the kidneys, leading to decreased kidney function. Autosomal dominant polycystic kidney disease (ADPKD) is the more prevalent form, subdivided into the PKD1 and PKD2 variants. PKD1 variants typically result in more severe symptoms and an earlier need for dialysis compared to PKD2. A prenatal diagnosis of ADPKD is rare due to its late-onset manifestations, but early detection can be crucial for management and family counseling. Case Presentation: A 24-year-old woman, during her first pregnancy, presented for her first prenatal ultrasound at 22 + 2 weeks gestation. The ultrasound revealed an increased echogenicity of the renal parenchyma in the left kidney, with pelvic dystopia, while the right kidney appeared normal. Follow-up scans showed significant progression, with both kidneys exhibiting thinning parenchyma and cyst formation. The baby was delivered via an elective cesarean section at 38 weeks, and a postnatal ultrasound confirmed ADPKD. Genetic testing identified a heterozygous variant of the PKD1 gene, NM_001009944.3 (PKD1):c.9157G>A p.(Ala3053Thr), classified as likely pathogenic. The baby displayed electrolyte abnormalities but improved after a week of hospitalization. Conclusions: This case highlights an unusual early presentation of ADPKD in a fetus with no family history of the disease. A prenatal diagnosis through ultrasounds and genetic testing can aid in early detection and management, providing valuable information for family counseling. Regular monitoring and genetic identification are essential for managing ADPKD and improving patient outcomes. Full article

Background/Objectives: Uric acid is a key metabolic byproduct of purine degradation and plays a dual role in human health. At physiological levels, it acts as an antioxidant, protecting against oxidative stress. However, excessive uric acid can lead to hyperuricemia, contributing to conditions like gout, kidney stones, and cardiovascular diseases. Emerging evidence also links elevated uric acid levels with metabolic disorders, including hypertension and insulin resistance. Understanding its regulation is crucial for preventing associated health complications. Methods: This study, part of the Tlalpan 2020 project, aimed to predict uric acid levels using advanced machine learning algorithms. The dataset included clinical, anthropometric, lifestyle, and nutritional characteristics from a cohort in Mexico City. We applied Boosted Decision Trees (Boosted DTR), eXtreme Gradient Boosting (XGBoost), Categorical Boosting (CatBoost), and Shapley Additive Explanations (SHAP) to identify the most relevant variables associated with hyperuricemia. Feature engineering techniques improved model performance, evaluated using Mean Squared Error (MSE), Root-Mean-Square Error (RMSE), and the coefficient of determination (R²). Results: Our study showed that XGBoost had the highest accuracy for anthropometric and clinical predictors, while CatBoost was the most effective at identifying nutritional risk factors. Distinct predictive profiles were observed between men and women. In men, uric acid levels were primarily influenced by renal function markers, lipid profiles, and hereditary predisposition to hyperuricemia, particularly paternal gout and diabetes. Diets rich in processed meats, high-fructose foods, and sugary drinks showed stronger associations with elevated uric acid levels. In women, metabolic and cardiovascular markers, family history of metabolic disorders, and lifestyle factors such as passive smoking and sleep quality were the main contributors. Additionally, while carbohydrate intake was more strongly associated with uric acid levels in women, fructose and sugary beverages had a greater impact in men. To enhance model robustness, a cross-feature selection approach was applied, integrating top features from multiple models, which further improved predictive accuracy, particularly in gender-specific analyses. Conclusions: These findings provide insights into the metabolic, nutritional characteristics, and lifestyle determinants of uric acid levels, supporting targeted public health strategies for hyperuricemia prevention. Full article

Background: Alport syndrome (AS) is one of the most common monogenic kidney disorders. Recent studies have highlighted the modifier effect of variants involving podocyte and non-collagenous extracellular matrix (ECM) proteins in AS. Methods: We report a case series of eight patients with genetically proven AS and simultaneous variants involving podocyte and non-collagenous ECM proteins. Our aim is to describe the influence of such variants on the phenotype of patients with AS. Results: We identified 10 different type IV collagen variants. Patients were diagnosed with autosomal dominant (3/8), autosomal recessive (2/8), digenic (2/8) and X-linked AS (1/8). There were eight different variants involving podocyte and non-collagenous ECM proteins. The genes involved were CRB2, LAMA5, LAMB2, NUP107, MYO1E and PLCE1. Four patients (LAMB2, LAMA5 and PLCE1 variants) presented with nephrotic syndrome or nephrotic range proteinuria. Two patients had hearing loss. Most patients (7/8) had a family history of kidney disease. Two patients (LAMB2 and LAMA5 variants) were diagnosed with focal segmental glomerulosclerosis. Two patients developed end-stage kidney disease (LAMA5, MYO1E and NUP107 variants). Conclusions: Although mutations of podocyte and ECM proteins do not have phenotypic expression in monoallelic form, the presence of such variants could explain the phenotypic variability of AS. Full article

Background and Clinical Significance: Ciliopathies are a heterogeneous group of diseases caused by damage to the primary cilium. Disorders of ciliary motility can lead to a wide range of clinical manifestations, including infertility, lateralization defects, lung infections, and more. Some ciliopathies associated with kidney disease include nephronophthisis, polycystic disease, and renal cell carcinoma. Since they are clinically and genetically diverse, their diagnosis may require a longer time and one or more genetic assays. Case presentation: We present the case of a 43-year-old man with a wide anamnesis, including unexplained nephrolithiasis, bronchiectasis, recurrent otitis media since infancy, appendicular lithiasis, and infertility. After a long history of various clinical examinations and consultations with diverse specialists, he was referred to genetic counseling. Whole exome sequencing (WES) revealed a homozygous pathogenic variant in the RSPH3 gene—NM_031924.8:c.205-2A>G—which was later confirmed through Sanger sequencing. It is classified as pathogenic in widely used databases and is associated with primary ciliary dyskinesia. This condition can present nontypically, and the patients might suffer from an extensive diagnostic odyssey. Being mindful of its clinical and genetic heterogeneity can shorten the period until diagnosis. Conclusions: It is essential to have this condition included in differential diagnosis and involve specialists from the medical/clinical genetic department in a multidisciplinary team. Genetic confirmation through WES or another molecular genetic method is crucial for the therapeutic approach and to adequately perform genetic counseling for patients and their families. Full article

Background: Nephrogenic diabetes insipidus (NDI) is defined as the inability of the kidney to concentrate urine owing to the insensitivity of the distal nephron to the antidiuretic hormone, arginine vasopressin. NDI is a heterogeneous rare autosomal dominant or X-linked disease. Objective: We present a family with nephrogenic diabetes affecting three males in two generations. Methods: We report two boys with NDI: a 4-month-old infant who was treated for fever, vomiting, and failure to thrive, and his 10-year-old uncle (the mother’s brother), who was admitted concurrently for consuming 11 L of fluid per day. According to family history, the mother’s sibling passed away at the age of two from severe hypernatremic dehydration. Results: The infant’s clinical and laboratory evaluation revealed a 7.8 mL/kg/h urine output, hypernatremic hyperchloremic alkalosis, extremely low urine density (1002), and elevated copeptin level. In contrast, the uncle’s clinical and laboratory evaluation revealed marked polyuria, low urine density, and elevated copeptin, all of which were suggestive of diabetes insipidus. After starting hydrochlorothiazide treatment (2 mg/kg/body), the infant’s urine production reduced (2.85 mL/kg/h); however, severe hypokalemia and alkalosis followed. Spironolactone, an aldosterone antagonist, were added, with good therapeutic response. Hydrochlorothiazide was administered to the uncle, and his daily fluid intake decreased to 3–4 L. Given the family history, Sanger sequencing for the AVPR2 variant was performed on the boys and the infant’s mother. Analysis showed hemizygous likely pathogenic variant c.335G>A p. (Cys112Tyr) in the 2 boys and heterozygous (carrier) status of the mother. Within the same family, we observed phenotypic heterogeneity: one child died at the age of two, another lived well into ten years without therapy, and a four month-old baby could have had a poor outcome without specific treatment. Conclusions: NDI is a rare and possibly fatal genetic disorder with heterogeneous manifestations. In families with a history of NDI, molecular genetic testing is crucial for family planning. Full article

Background and Objectives: Familial Mediterranean fever (FMF) is a lifelong autoinflammatory disease characterized by episodes of fever and aseptic polyserositis. Commonly associated with vasculitis, FMF’s impact on microcirculation was investigated by examining nailfold capillaries using capillaroscopy. Materials and Methods: This study included 32 female and 28 male FMF patients diagnosed according to the Tel Hashomer and Yalçınkaya criteria and a control group of 20 female and 10 male age-matched cases. Demographic characteristics, medical history (abdominal pain, fever, chest pain, and joint pain), and physical examination findings of the cases were assessed. FMF gene mutations, acute-phase reactants, urine analysis, and spot urine protein/creatinine ratios were evaluated. Nailfold capillaries were examined via capillaroscopy by the same dermatology specialist. Results: There was no significant age or gender difference between groups. The most common symptoms in the case group were abdominal pain (81.7%) and joint pain (65%). Pathological findings in capillaroscopy, such as microhemorrhages and avascular areas, were significantly more frequent in the FMF case group (p < 0.001; p < 0.001). Physiological findings, including hairpin-shaped capillaries and shortened loops, were significantly more common in the control group (p = 0.001; p = 0.034). No significant relationships were found between kidney involvement, subclinical inflammation, presence of microhemorrhages and avascular areas in capillaroscopy, and disease duration. Additionally, no significant differences were observed in capillaroscopic findings between those with exon-10 mutations in the MEFV gene and those with non-exon-10 mutations. Conclusions: In conclusion, our study demonstrated secondary microvascular findings due to inflammation in FMF patients using capillaroscopy, a cost-effective and safe tool. Full article

Background: Alport syndrome (AS) is a clinically and genetically heterogeneous glomerulopathy resulting from pathogenic variants in COL4A3, COL4A4, and COL4A5. Genetic diagnosis is increasingly being conducted using next-generation sequencing (NGS). Methods: Within eight years, we examined a group of 247 Polish individuals and found in total 138 unrelated probands suspected with AS based on clinical course, laboratory findings, and/or family history, as well as the total of 109 family members. We applied a targeted NGS panel to identify the genetic spectrum of AS. Known and novel variants were revealed, and detailed evaluation was performed according to ACMG/AMP guidelines to classify them as pathogenic/likely pathogenic/VUS changes. Identified genotypes were compared with clinical manifestations: hematuria, proteinuria, chronic kidney disease, sensorineural hearing impairment, ocular abnormalities, and hypertension. Results: The molecular background was established in 109/138 probands. Overall, 79 different COL4A3-COL4A5 changes (56 known and 23 novel) were revealed. About 97% were SNVs, and only two COL4A5 CNVs were identified. In total, 11 recurrent COL4A3-COL4A5 variants were observed, including the most frequent COL4A5:p.Gly624Asp, accounting for 31% of X-linked AS. Conclusions: The use of NGS panel has shown considerable promise in the field of AS, increasing diagnostic rate to 79% and reducing time to diagnosis. The phenotype-driven gene panel, specific for genetic diseases in the pediatric population, is an affordable alternative to WGS and WES, offering comparable diagnostic efficacy and supporting its implementation as a first-line genetic test in rare diseases, including AS. Based on the obtained genotype–phenotype correlation, we assessed that NGS allows us to avoid invasive renal biopsy in AS diagnosis. It provides AS confirmation/exclusion, atypical AS identification, symptomatic/asymptomatic monoallelic COL4A3-COL4A5 carrier (especially COL4A5 females) determination, and inheritance pattern establishment. AS diagnosis confirmation enables clinical course prediction and is crucial for the early introduction of renoprotective treatment with renin–angiotensin–aldosterone system blockade, aimed at slowing the disease progression and estimating the risk in family members, which is important for genetic counselling. Full article

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 (FN1) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice. Full article

Gout is a common inflammatory joint disease in China. In recent years, the prevalence of gout in China has been increasing and the onset age of gout has been trending younger. The common risk factors for gout in China include hyperuricemia, age, sex, obesity, hypertension, metabolic syndrome, use of drugs (e.g., diuretics), dietary factors, chronic kidney disease (CKD), ethnicity, and income. Chinese clinical guidelines recommend the diagnosis of subclinical gout, refractory gout, and clinical classification of hyperuricemia in gout patients with early-onset or family history. Maintaining a consistently low level of serum urate is crucial for the effective long-term treatment of gout. However, the Chinese guidelines recommend paying special attention to allopurinol hypersensitivity when considering urate-lowering drugs. The adherence rate to urate-lowering therapy (ULT) in Chinese patients with gout ranges from 9.6% to 40.7%. Patient education and reducing drug side effects are effective approaches to improve the adherence to ULT and the rate of achieving the target urate level. The development of new treatment principles based on clinical trials, such as ULT based on the classification of hyperuricemia and urine alkalization, is recommended to improve patient outcomes and reduce potential side effects. The study of genetics, metabolites, and intestinal microbiota has yielded new findings that may aid in the diagnosis, classification, and pathogenesis of gout in China. Full article

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is mainly characterized by renal involvement with progressive bilateral development of renal cysts and volumetric increase in the kidneys, causing a loss of renal function, chronic kidney disease (CKD), and kidney failure. The occurrence of mosaicism may modulate the clinical course of the disease. Mosaicism is characterized by a few cell populations with different genomes. In these special cases, a genetic diagnosis could be challenging. Methods: Herein, we describe the case of a 47-year-old woman presenting with typical ultrasound and computed tomography features of ADPKD. She had stage 3b CKD and hypertension. There was no family history of ADPKD, prompting an investigation with a genetic test. Target next-generation sequencing (NGS) did not detect the presence of any genomic variants. Therefore, we carried out second-level genetic analysis to investigate the presence of a large rearrangement through a multiple ligation-dependent probe amplification (MLPA) analysis of PKD1 and PKD2 genes. Results: MLPA showed a large deletion (portion including exons 2–34 of PKD1) present in the heterozygosis with a percentage of cells close to the resolution limits of the technique used (<25–30%). We concluded that the large deletion identified was mosaicism. This variant is not reported in major ADPKD databases, but due to the type of mutation and the patient’s clinical picture, it should be considered as likely pathogenic. Conclusions: A stepwise genetic approach might be useful in those cases where standard methods do not allow one to reach a definitive diagnosis. Full article

Background and Objectives: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic renal disease with a complex physiopathology. More and more studies sustain that inflammation plays a crucial role in ADPKD pathogenesis and progression. We evaluated IL-12 involvement in ADPKD pathophysiology by assessing the serum levels of its monomers and heterodimers. Materials and Methods: A prospective case-control study was developed and included 66 ADPKD subjects and a control group of 40 healthy subjects. The diagnosis of ADPKD was based on familial history clinical and imagistic exams. The study included subjects with eGFR > 60 mL/min/1.73 mp, with no history of hematuria or other renal disorders, with stable blood pressure in the last 6 months. We tested serum levels of monomers IL-12 p40 and IL-12 p35 and heterodimers IL-12 p70, IL-23, IL 35, assessed by ELISA method. Results: IL-12 family programming was abnormal in ADPKD patients. IL-12p70, IL-12p40, and IL-23 secretion increased, while IL-12p35 and IL-35 secretion decreased compared to control. IL-12p70, IL-12p40, and IL-23 had a progressive increase correlated with immune response amplification, a decrease of eGFR, an increase in TKV, and in albuminuria. On the other hand, IL-35 and IL-12p35 were correlated negatively with CRP and albuminuria and positively with eGFR in advanced ADPKD. Conclusions: The present study investigated IL-12 cytokine family members’ involvement in ADPKD pathogenesis, enriching our understanding of inflammation in the most common renal genetic disorder. Full article

Background: Kidney stone disease (KSD) is characterized by an increasing prevalence worldwide, representing an important clinical issue and a financial burden for healthcare systems. A KSD-causing monogenic variant is traditionally expected in up to 30% of children and 1–5% of adults forming stones, confirmed by a strong connection between a positive family history and KSD. The insufficient use of genetic testing in these patients is associated with a lack of perceived benefit and a scarce awareness of inherited kidney diseases. Genetic testing has important practical implications, such as the possibility of earlier diagnoses, familial counseling, and tailored therapy, based on the evaluation of fine-mapped pathogenic variants. Our aim is to analyze the current evidence on genetic testing in KSD patients to whom genetic tests were applied without strict a priori selection criteria, to provide an overview of its diagnostic yield and factors potentially affecting it (such as the age of KSD onset, a familial history of KSD, consanguinity, and extrarenal features). Methods: A literature review was performed, selecting original articles published in the last 10 years concerning genetic investigations in patients affected by nephrolithiasis or nephrocalcinosis. Available data were subsequently extracted and analyzed. Results: In total, 13 studies on 1675 patients (77% pediatric populations) were included; 333 patients were determined to be affected by a monogenic disorder, with an overall yield of about 20%. The likelihood of a positive genetic finding was much higher in pediatric (26%) than adult populations (8%). Cystinuria was the most common diagnosis in both populations. After the removal of conditions that could be identified with a stone composition analysis or urinary chemistry investigation, the diagnostic yield dropped to 19% among pediatric patients and below 5% for adults. Conclusions: Genetic testing should be considered in KSD pediatric patients and in selected subgroups of adults with suggestive features when a diagnosis is not established after stone examination and blood as well as urine metabolic profiling. Full article

Background: Traditional cardiovascular disease risk prediction models generate a combined risk assessment for myocardial infarction (MI) and ischemic stroke (IS), which may inadequately reflect the distinct etiologies and disparate risk factors of MI and IS. We aim to develop prediction models that separately estimate the risks of MI and IS. Methods: Our analysis included 6,242,404 individuals over 40 years old who participated in a cardiovascular health screening examination in 2009. Potential predictors were selected based on a literature review and the available data. Cox proportional hazards models were used to construct 5-year risk prediction models for MI, and IS. Model performance was assessed through discrimination and calibration. Results: During a follow-up of 39,322,434.39 person-years, 89,140 individuals were diagnosed with MI and 116,259 with IS. Both models included age, sex, body mass index, smoking, alcohol consumption, physical activity, diabetes, hypertension, dyslipidemia, chronic kidney disease, and family history. Statin use was factored into the classification of dyslipidemia. The c-indices for the prediction models were 0.709 (0.707–0.712) for MI, and 0.770 (0.768–0.772) for IS. Age and hypertension exhibited a more pronounced effect on IS risk prediction than MI, whereas smoking, body mass index, dyslipidemia, and chronic kidney disease showed the opposite effect. The models calibrated well for low-risk individuals. Conclusions: Our findings underscore the necessity of tailored risk assessments for MI and IS to facilitate the early detection and accurate identification of heterogeneous at-risk populations for atherosclerotic cardiovascular disease. Full article

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent heritable disorders, characterized by the progressive development of kidney cysts leading to renal failure. It is primarily caused by mutations in the PKD1 and PKD2 genes, which account for approximately 85% and 15% of cases, respectively. This case report describes a previously unreported mutation in the PKD1 gene, identified in a family involving an aunt and her niece with ADPKD. Case Presentation: The index case, a 56-year-old female with chronic kidney disease stage 3b secondary to ADPKD and hypertension, exhibited a strong family history of polycystic kidney disease (PKD). Initial genetic evaluations did not identify any recognized pathogenic mutations, leading to a more detailed investigation which revealed a novel mutation in the PKD1 gene. This mutation was also found in her niece, who presented with early-onset disease. Conclusions: The identification of a heterozygous six-nucleotide deletion, c.2084_2089del, resulting in the in-frame deletion of two amino acids, p.Pro695_Ala696del, in the PKD1 gene, has been linked with ADPKD in these patients. This report emphasizes the need for continuous updates to genetic data for a deeper understanding of the diagnosis and prognosis of ADPKD that could potentially aid in targeted therapy. Full article

Background and Objectives: Hypertensive disorders, particularly pre-eclampsia, pose significant risks during pregnancy, affecting both maternal and neonatal health. The study aims to analyze short- and long-term health implications for mothers and their children, comparing those with pre-eclampsia to those without, to improve understanding of risk factors, diagnostic markers, and outcomes. Materials and Methods: This retrospective observational study involved 235 patients, 98 with pre-eclampsia and 137 without, monitored from 2015 to 2018 at the Obstetrics and Gynecology Department of the “Pius Brînzeu” Emergency County Clinical Hospital in Timișoara, Romania. Results: Women with pre-eclampsia were older, had higher BMIs, and more frequently had a family history of pre-eclampsia, hypertension, and diabetes. They also had lower educational and socioeconomic levels and fewer prenatal visits. Biochemical markers such as higher proteinuria, elevated sFlt-1, and lower PlGF were significant in diagnosing pre-eclampsia. Short-term maternal complications like eclampsia, HELLP syndrome, and acute kidney injury were more prevalent in the pre-eclampsia group. Neonatal outcomes included higher rates of preterm birth, low birth weight, and NICU admissions. Long-term mothers with a history of pre-eclampsia had higher incidences of chronic hypertension, cardiovascular disease, kidney problems, diabetes, and mental health disorders. Their children faced increased risks of neuropsychological delays, chronic respiratory issues, behavioral disorders, learning difficulties, and frequent infections. Conclusions: The study highlights the significant short- and long-term health impacts of pre-eclampsia on both mothers and their children. Early monitoring, intervention, and comprehensive management are crucial in mitigating these risks. These findings underscore the need for personalized care strategies to improve health outcomes for affected individuals. Full article