We report the case of a 72-year-old man referred to cardiothoracic services with a right-sided spontaneous pneumothorax. High-resolution computed tomography (HRCT) revealed extensive bilateral lung cysts and recurrence of the pneumothorax. Further clinical assessment led to a diagnosis of Birt-Hogg-Dubé (BHD) syndrome-a rare genetic condition marked by cystic lung disease, spontaneous pneumothoraces, skin fibrofolliculomas, and an elevated risk of renal tumors. We discuss the thoracic implications of BHD and the utility of uniportal video-assisted thoracoscopic surgery (UVATS) with pleurodesis in recurrent cases. The report underlines the importance of genetic evaluation and long-term surveillance for patients and at-risk relatives. Genetic testing for the FLCN (Folliculin) gene was initiated and results were consistent with Birt-Hogg-Dubé syndrome.

Unexpected nephrotoxicity during clinical stages of drug development, due to undetected toxicity in in vitro and in vivo settings, can lead to drug attrition and jeopardize drug development. The latter highlights the importance of in vitro renal toxicity testing that can safely be translated to humans. Two factors commonly overlooked in the latter are the continuous cell proliferation that occurs in regeneration processes after renal insult and the physiological O2 tension in the kidney. Autosomal Dominant Polycystic Kidney Disease is a genetic disorder characterized by the development of renal cysts and cellular changes, i.e. abnormal proliferation in conjunction with the Warburg effect. There is only one drug approved for the disease, tolvaptan, which, however, presents with liver toxicity and polyuria. In a quest for potential alternatives to tolvaptan, we compared the nephrotoxic and metabolic effects of four repurposed drugs, salicylic acid (up to 10 mM), birinapant (up to 100 µM), bardoxolone methyl (up to 1000 nM), and rapamycin (up to 160 nM) to tolvaptan (up to 100 µM) on human differentiated and proliferating (RPTEC/TERT1) and mouse proliferating (mProx24) renal proximal tubular epithelial cells at atmospheric (21%) and physiological (10%) O2 tensions. The focus was on improved interpretation of in vitro test results for the detection of potential adverse effects. We found that cell proliferation and O2 tension are major factors that determine the susceptibility of cells to compounds, while the drug effects on the metabolism and mitochondrial function provided further insight into the mechanisms underlying the observed in vitro toxicity.

Coagulation factor VII (FVII) is a vitamin K-dependent glycoprotein and serves as a key initiator of the extrinsic coagulation pathway. Hereditary FVII deficiency is an autosomal recessive genetic disorder with a highly heterogeneous bleeding phenotype. It is the most prevalent among rare hereditary bleeding disorders. Among the various genotypes, complex heterozygous variants are of particular importance in hereditary coagulation factor deficiency. This study reports a case of a patient with hereditary FVII deficiency. The patient presented for planned surgery for renal cysts. Preoperative evaluation revealed abnormal coagulation indicators; therefore, the surgery was temporarily postponed. Further investigations to clarify the cause revealed markedly prolonged prothrombin time (PT), significantly reduced FVII activity (FVII:C), and mildly decreased FVII antigen (FVII:Ag). Complex heterozygous variants (p.Ile303Thr and p.Cys389Gly) were identified, confirming the diagnosis of hereditary FVII deficiency. Thrombin generation assay (TGA) and thromboelastography (TEG) suggested that the patient's global coagulation capacity was not substantially impaired. No specific treatment was administered, and regular follow-up was conducted. In this compound heterozygous patient with markedly reduced FVII:C without bleeding, TGA and TEG may offer a better assessment of bleeding risk than FVII:C alone, and family screening facilitates identification and management of at-risk individuals.

Type IV collagen related nephropathy caused by heterozygous variants in the COL4A3 or COL4A4 genes shows a wide phenotypic variability, with asymptomatic individuals being relatively common. A cystic phenotype in these cases is uncommon and rarely presents with nephromegaly mimicking autosomal dominant polycystic kidney disease (ADPKD). We report a family with hereditary kidney disease showing an autosomal dominant inheritance pattern and marked phenotypic variability. Some family members were diagnosed with urate nephropathy, others met the Ravine-Pei criteria for ADPKD, and others were labeled as having chronic kidney disease of unknown etiology; five progressed to renal replacement therapy. The proband, who presented with bilateral renal cysts fulfilling ADPKD criteria, along with microhematuria and non-nephrotic proteinuria, tested negative for PKD1 and PKD2 variants after sequential genetic analysis. Meanwhile, another family member studied for persistent microhematuria and non-nephrotic proteinuria underwent a renal biopsy that revealed thinning of the glomerular basement membrane on electron microscopy, suggesting Alport syndrome. Genetic testing in both individuals identified the c.735+2T>C (p?) variant in the COL4A4 gene, classified as likely pathogenic due to its disruption of a splicing site. This case illustrates the phenotypic heterogeneity of heterozygous COL4A4-related Alport syndrome and highlights the importance of implementing genetic testing in the differential diagnosis of hereditary kidney disorders to prevent diagnostic delays with potential clinical consequences.

Nephronophthisis (NPH), a rare but serious ciliopathy, is the predominant genetic cause of end-stage kidney disease (ESKD) in children and adolescents. Renal tubular dilatation and cyst formation are key pathological features of NPH. The mechanisms underlying renal cystogenesis remain poorly understood. This study employed sex-balanced Nphp1 deletion gene knockout (Nphp1[KO]) mice at 8, 12, and 24 weeks of age to investigate the spatiotemporal dynamics of renal tubules and cyst development, aiming to identify the origins of renal cysts. Quantitative evaluation of cyst progression revealed a significant increase in cyst number from 8 to 12 weeks of age, but no substantial change from 12 to 24 weeks. Additionally, cyst size remained stable throughout the study period. Serial section tracing and segment-specific tubular marker analysis confirmed that these cysts originated from the distal convoluted tubule (DCT), which displayed segmental dilation while preserving anatomical connections with adjacent, morphologically normal DCT. 3D reconstruction revealed that renal cysts appeared either as a single or in a bead-like arrangement. We demonstrated that human renal cyst epithelial cells from patients with NPH1 also originate primarily from the DCT. This study provides critical experimental evidence of the histopathological features of renal cysts in NPH1, advancing our understanding of the pathogenesis of NPHP-associated tubular dilation and cystogenesis.

Tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) is a rare systemic disorder characterized by smooth muscle-like cell proliferation, leading to cystic lung destruction, predominantly affecting women of reproductive age. We report a female patient in her mid-30s who presented with recurrent spontaneous pneumothoraces temporally associated with menstruation, diffuse bilateral pulmonary cysts on high-resolution computed tomography, bilateral renal angiomyolipomas, and facial angiofibromas. Genetic testing confirmed TSC-LAM. The patient was initiated on sirolimus (1 mg/day) with therapeutic drug monitoring to maintain trough levels within the target range. Regular follow-up included pulmonary function tests, serial imaging, and genetic counseling with cascade screening for offspring. After treatment, the disease remained clinically stable without significant adverse effects; imaging demonstrated no progression of pulmonary cysts and a reduction in renal angiomyolipoma volume. This case underscores the importance of early recognition, individualized sirolimus dosing to balance efficacy and toxicity, and systematic family screening for early detection and prevention of disease transmission in this heritable condition.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by progressive kidney enlargement and cyst growth leading to progressive loss of kidney function. The two main genes implicated are PKD1 and PKD2; however, pathogenic variants in other less frequent genes can also cause the disease. Diagnosis may be established in various clinical settings, including family screening, the investigation of arterial hypertension, urological events such as hematuria or flank pain, or incidental imaging findings. Diagnostic confirmation relies on targeted imaging studies and/or genetic testing. Extrarenal manifestations include hepatic cysts and an increased risk of intracranial aneurysms (ICA). The disease course varies considerably among individuals: while the median age at kidney failure is around 60years, some patients reach kidney failure before the age of 40 while others never require renal replacement therapy. Nephroprotective measures are central to the management of ADPKD and include blood pressure control with renin-angiotensin-aldosterone system (RAAS) blockade, sodium intake reduction, smoking cessation, maintenance of a healthy body weight, and regular physical activity. Tolvaptan is currently the only approved pharmacological therapy shown to slow disease progression. Several other promising therapies are under investigation to expand therapeutic options for patients with ADPKD.

Polycystic ovary syndrome is a prevalent, heterogeneous endocrine and metabolic disorder affecting approximately 10% of women of reproductive age, often characterized by hyperandrogenism, anovulation, and insulin resistance. Metformin, a first-line treatment for type 2 diabetes, is also widely prescribed for PCOS to reduce insulin resistance and induce ovulation. However, therapeutic response varies significantly across individuals, partly due to genetic variations in solute carrier (SLC) transporters. The organic cation transporter family, encoded by SLC22A1 (O15245), SLC22A2 (O15244), and SLC22A3 (O75751), facilitates metformin uptake into hepatocytes and renal excretion. Using an in silico pipeline, Align GVGD, PolyPhen-2, PROVEAN, PANTHER, PhD-SNP, and the ensemble predictor Meta-SNP, we screened 14 deleterious nonsynonymous SNPs. Solvent accessibility values were derived using NetSurfP, indicating that L42R (RSA: 0.54, ASA: 96.2 Å2) and F422S (RSA: 0.49, ASA: 85.7 Å2) are surface-exposed and likely to influence protein interaction. In contrast, R175L (RSA: 0.07, ASA: 18.4 Å2) and T275M (RSA: 0.06, ASA: 21.1 Å2) were buried and may impact local folding. ΔΔG predictions using MuPro ranged from -0.01745 to -1.99395, consistently indicating decreased protein stability. Structural models were built in SWISS-MODEL and validated via MolProbity scores (<1.5), ERRAT (>85%), and PROSA Z-scores (-6.8 to -8.2). Functional enrichment of the PPI network (STRING-DB) highlighted significant roles in drug transmembrane transport (GO:0006857, p = 2·3e-06), organic cation transport (GO:0015695, p = 4·7e-05), and xenobiotic metabolism pathways. These mutations may impair metformin pharmacokinetics and contribute to inter-individual therapeutic variability. While this study is limited by its computational design, the findings identify high-priority SNPs for future experimental validation, offering a foundation for precision pharmacogenomics in PCOS management.

Autosomal recessive polycystic kidney disease (ARPKD) is a pediatric genetic nephropathy caused by mutations in PKHD1, which encodes fibrocystin. The cellular basis and epithelial dynamics of cyst formation remain incompletely understood. We used lineage-tracing systems in rat and mouse to define epithelial behavior during cystogenesis. Clonal labeling revealed that renal and biliary epithelial cells undergo marked expansion as cysts form. Genetic mosaic analysis showed that individual Pkhd1-deficient cholangiocytes can generate millimeter-scale cysts within one year. Mathematical modeling demonstrated that biliary epithelial proliferation alone can account for cyst growth to millimeter size within weeks to months, depending on initial cell number and doubling time. Transcriptomic profiling of early cystic liver identified upregulated cell-cycle regulators, including CDK1. Pharmacological CDK1 inhibition attenuated fibrocystic liver disease in vivo. These findings show that epithelial cell expansion is the primary driver of cystogenesis and loss of fibrocystin activates a pro-proliferative program that can be therapeutically targeted.