[A case of crizotinib-associated renal cysts].

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

A review of preclinical evidence of Cryptolepis nigrescens (Wennberg) L. Joubert. and Bruyns., Prosopsis africana (Guill. and Perr.) Taub. and Pterygota macrocarpa K. Schum. traditionally used to manage tumours in Ghana.

ETHNOPHARMACOLOGICAL RELEVANCE: Cancer stands as one of the leading causes of death worldwide according to the World Health Organization (WHO), and it has led to approximately 10 million fatalities in 2020. Medicinal plants are still widely used and accepted form of treatment for most diseases including cancer in Ghana. This review presented Cryptolepis nigrescens (Wennberg) L. Joubert. and Bruyns., Prosopsis africana (Guill. and Perr.) Taub. and Pterygota macrocarpa K. Schum. as medicinal plants that are traditionally used to treat tumour growth, amongst other diseases, in the Ashanti region of Ghana. AIM OF REVIEW: This paper aims to present a comprehensive review on the botanical description, ecological distribution, ethnomedicinal uses, phytochemical composition and ethnopharmacological relevance of C. nigrescens, P. africana and P. macrocarpa. MATERIALS AND METHODS: The review covers works published between 1962 and 2023 from various countries. Published books, thesis, scientific and medical articles on C. nigrescens, P. africana and P. macrocarpa were collected from the following databases: 'Scopus', 'Science Direct', 'Medline', 'PubMed', 'Research Gate' 'Google Scholar, and 'Springer link' using the keywords. RESULTS: Phytochemical analysis of C. nigrescens, P. africana and P. macrocarpa revealed the presence of some prominent bioactive compounds such as convallatoxin, 7,3,4-trihydroxy-3-methoxyflavanone and dioxane, respectively. Plant extracts and isolated compounds of these medicinal plants exhibited a wide range of ethnopharmacological activities including antimicrobial, anti-inflammatory, antioxidant, analgesic, cytotoxic, antimalarial, antipyretic, haematinic, hepato-protective, aphrodisiac and antihypertensive properties. CONCLUSION: The present review on C. nigrescens , P.africana and P. macrocarpa provided a credible summary of the ethnopharmacological research conducted on these medicinal plants till date. The data also highligted the potential therapeutic profiles of these plants in Ghana that could serve as foundation for future studies. Additionally, the information significantly supported the traditional and commercial use of these plants among the people.

Repurposing small molecules for nephronophthisis and related renal ciliopathies.

Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It is the most common genetic cause of kidney failure in children and young adults. Clinically and genetically heterogeneous, it is caused by variants in ciliary genes, resulting in either an isolated kidney disease or syndromic forms in association with other manifestations of ciliopathy disorders. No curative treatment is currently available. Over the past 2 decades, advances in understanding disease mechanisms have identified several dysregulated signaling pathways, some shared with other cystic kidney diseases. Notably, molecules previously developed to target these pathways have shown promising beneficial effects in orthologous mouse models. In addition to these knowledge-based repurposing approaches, unbiased "in cellulo" phenotypic screens of "repurposing" libraries identified small molecules able to rescue the ciliogenesis defects observed in nephronophthisis conditions. Those compounds appeared to act on relevant pathways and, when tested, showed beneficial nephronophthisis-associated kidney and/or extrarenal defects in mice. In this review, we have summarized those studies that highlight the drug repurposing strategies in the context of a rare disorders, such as nephronophthisis-related ciliopathies, with broad genetic heterogeneity and systemic manifestations but with shared disease mechanisms.

Efficacy of single-session 99.5% ethanol sclerotherapy for incidentally found simple renal cysts.

Simple renal cysts are the most common masses in the kidney. Most are asymptomatic and are incidentally detected on imaging examinations performed for other reasons. This study aimed to compare the results of 40 and 120 minutes ethanol sclerotherapies that were performed in a single session to treat incidentally found simple renal cysts. We retrospectively reviewed 63 renal cysts in 62 patients treated by single session percutaneous ethanol sclerotherapy. Thirty-one patients with 32 cysts underwent a 40 minutes sclerotherapy (group A), and 31 patients with 31 cysts underwent a 120 minutes retention technique (group B). Under ultrasonographic and fluoroscopic guidance, cystic fluid was completely aspirated, and 50% of the aspirated volume was replaced with 99.5% ethanol (a maximum of 100 mL). Imaging follow-up of the patients was performed 3 months after sclerotherapy. The technical success rates were 100% in both groups. Eighteen patients (29.0%) were symptomatic (flank pain or discomfort). Indications of the other patients were large cysts (>5 cm; 46%) and an increment in the diameter on serial studies (25.4%). A significant difference between the 2 groups in terms of age, cyst diameter, volume of aspirated fluid, volume of injected ethanol, and percentage of reduction in cyst diameter (P > .05) was not found. After treatment, flank pain or discomfort resolved in 17 of 18 (94.4%) symptomatic patients. One patient complained of persistent flank pain; however, no significant abnormality was detected on post-procedural computed tomography images. There were no other complications after therapy in the 2 groups. Single session ethanol sclerotherapy with a 40 minutes retention technique is an effective, safe, and cost-effective method for the treatment of incidentally found simple renal cysts. Although the procedural time was reduced, there was no significant difference in therapeutic efficacy between the 40 and 120 minutes therapies.

Proton pump inhibitors and increased reporting odds of renal neoplasms: FAERS-based adverse event data mining and analysis.

BACKGROUND: Long-term use of proton pump inhibitors (PPIs) is associated with some safety issues. In this study, data mining was carried out to discover the potential association between renal neoplasms and PPIs. RESEARCH DESIGN AND METHODS: Neoplasms signals of PPIs were detected in the Food and Drug Administration Adverse Event Reporting System from 2014 to 2020 by examining the reporting odds ratio. Adjusted odds ratios were analyzed using logistic regression. RESULTS: Signals were detected with respect to renal hemangioma, acquired or unspecified cystic kidney disease, and papillary and unspecified renal cell carcinoma, of which intervals between adverse effects onset and medication were 7.00 (3.33, 15.67) years, 5.00 (1.70, 10.25) years, and 7.00 (4.72, 12.25) years, respectively. The lansoprazole had the strongest signal. Adjusted odds ratios for PPIs associated with renal cell carcinoma in cases with or without acquired cystic kidney disease or chronic kidney disease were 1.67 [95% confidence interval (CI) 1.46-1.91] and 1.62 (95% CI 1.41-1.87). CONCLUSIONS: Exposure to PPIs was related to the raised risk of renal neoplasms. Careful consideration should be given to the possibility of an increased risk when PPIs are administered.

[Sclerotherapy of a simple, solitary kidney cyst using intraluminal ethanol instillation in a Swiss Fleckvieh cow]. / Sklerotherapie einer einfachen, solitären Nierenzyste mittels intraluminaler Ethanolinstillation bei einer Swiss Fleckvieh-Kuh.

INTRODUCTION: Renal cysts are fluid-filled cavities with an epithelial lining that, depending on their size, can cause clinical symptoms and thus require conservative or surgical therapy. Nephrectomy is primarily used in cattle for simple kidney cysts while sclerotherapy is well established in humans and individual case reports have been published in small animal medicine. This case report describes the first successful treatment of a solitary, perirenal cyst using a right-sided laparotomy and intraluminal instillation of 96% ethanol solution in a Swiss Fleckvieh cow. Diagnostics, surgical procedures and aftercare are descripted and risks are compared to other methods. Sclerotherapy is an organ-preserving alternative to nephrectomy that is suitable for buiatric practice, the methodology should be confirmed in subsequent intervention studies.

INTRODUCTION: Les kystes rénaux sont des cavités remplies de liquide avec une muqueuse épithéliale qui, en fonction de leur taille, peuvent provoquer des symptômes cliniques et nécessitent donc un traitement conservateur ou chirurgical. Alors que la sclérothérapie pour le traitement des kystes rénaux simples est bien établie chez l'homme et que des rapports de cas individuels ont également été décrits en médecine des petits animaux, la néphrectomie est principalement utilisée chez les bovins. Ce rapport de cas décrit pour la première fois le traitement réussi d'un kyste périrénal solitaire par instillation intraluminale d'une solution d'éthanol à 96% après une laparotomie droite chez une vache de race Swiss Fleckvieh. Les aspects du diagnostic, des procédures chirurgicales et des soins de suivi sont expliqués et les risques par rapport aux autres méthodes sont discutés. La sclérothérapie est une alternative de préservation des organes à la néphrectomie qui convient à la pratique buiatrique et dont la méthodologie doit être confirmée dans des études d'interventions ultérieures.

Maturity-Onset diabetes of the young type 5 treated with the glucagon-like peptide-1 receptor agonist: A case report.

RATIONALE: Maturity-onset diabetes of the young type 5 (MODY 5) is a form of monogenic diabetes that is often accompanied by pancreatic dysfunction. To date, no cases of MODY 5 treated with glucagon-like peptide-1 receptor agonist (GLP-1RA) have been reported. We present the first case of MODY 5 treated with GLP-1RA. PATIENT CONCERNS: A 17-year-old woman, with a history of being operated for congenital ileal atresia at birth, was admitted to our hospital due to hyperglycemia. She had been clinically diagnosed with type 1 diabetes 1 month prior, and administered 14 units of insulin glargine 300 U/mL per day. DIAGNOSIS: She had hypopotassemia, hypomagnesaemia, pancreatic body, and tail defects, multiple renal cysts, and a family history of diabetes, and urogenital anomaly. Genetic testing revealed heterozygous deletion of hepatocyte nuclear transcription factor-1 beta, leading to the diagnosis of MODY 5. INTERVENTIONS: The patient was treated with multiple daily insulin injections for 9 days (22 units/d) before administration of GLP-1RA, and then liraglutide was initiated. OUTCOMES: Liraglutide treatment (0.6 mg/d) alone maintained the patient's glycated hemoglobin level below 7.0% for at least 12 months after discharge. A higher dose, 0.9 mg/d, of liraglutide was not tolerated by the patient due to nausea. Serum levels of C-peptide immunoreactivity were 1.15 ng/mL and 1.91 ng/mL, respectively, after 6 and 12 months of liraglutide therapy. LESSONS: GLP-1RA might be effective at regulating glucose metabolism by utilizing residual pancreatic endocrine function in patients with MODY 5. Imaging and genetic screening were helpful in the diagnosis of MODY 5.

A novel HNF1B mutation p.R177Q in autosomal dominant tubulointerstitial kidney disease and maturity-onset diabetes of the young type 5: A pedigree-based case report.

RATIONALE: Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene result in a very variable presentation, including maturity onset diabetes of the young (MODY), renal cysts, renal dysplasia, and autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterized by tubular damage, renal fibrosis, and progressive renal dysfunction. PATIENT CONCERNS: A 22-year-old man came to the hospital presenting with hyperglycemia, hyperuricemia and elevated serum creatinine. His urine protein was within the normal range. The ultrasound examination revealed shrunken kidneys with renal cysts. The patient's mother was diagnosed with diabetes mellitus when she was 25 years old. Her laboratory results showed elevated serum creatinine. Her ultrasonography revealed shrunken kidneys with renal cysts and hydronephrosis without kidney stones. The next-generation sequencing revealed that the proband and his mother held the same heterozygous missense mutation (c.530G>A, NM_000458, p.R177Q) in the HNF1B gene. Bioinformatic analyses predicted that the mutation was likely pathogenic. DIAGNOSIS: The patient and his mother were diagnosed as ADTKD and MODY5 due to HNF1B mutation. INTERVENTION: The proband was administered metformin at a dose of 500 mg/day. OUTCOMES: The patient had well-controlled blood glucose levels and a stable renal function at his 12-month follow-up. LESSONS: We should take into account the diagnoses of ADTKD and MODY5 if patients present with early onset diabetes and multiple renal cysts or evidence of renal tubulointerstitial dysplasia, especially those with negative proteinuria results. Genetic testing helps detect the HNF1B gene mutations.

Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex-associated cystic kidney disease.

Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex (TSC) disease. The mechanisms underlying TSC cystic kidney disease remain unclear, with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1-null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1-null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1-null kidneys. Dexamethasone administration during pregnancy decreased cyst formation by not only inhibiting the inflammatory response, but also interfering with the mTORC1 pathway. These results reveal mechanisms of cystogenesis in TSC disease and suggest interventions before birth to ameliorate cystic disease in offspring.

Targeting glycolysis in proliferative kidney diseases.

Glycolytic activity is increased in proliferating cells, leading to the concept that glycolysis could be a therapeutic target in cystic diseases and kidney cancer. Preclinical studies using the glucose analog 2-deoxy-d-glucose have shown promise; however, inhibiting glycolysis in humans is unlikely to be without risks. While proximal tubules are predominantly aerobic, later segments are more glycolytic. Understanding exactly where and why glycolysis is important in the physiology of the distal nephron is thus crucial in predicting potential adverse effects of glycolysis inhibitors. Live imaging techniques could play an important role in the process of characterizing cellular metabolism in the functioning kidney. The goal of this review is to briefly summarize recent findings on targeting glycolysis in proliferative kidney diseases and to highlight the necessity for future research focusing on glycolysis in the healthy kidney.

Chemical Strike against a Dominant-Inherited MUC1-Frameshifted Protein Associated with Progressive Kidney Disease.

In a recent paper by Dvela-Levitt et al., chemical screening using an immunofluorescent assay identified a compound that caused removal of a dominant-inherited misfolded secretory protein, mucin1-frameshifted, from an intracellular location in immortalized renal epithelial cells of a patient affected with progressive medullary cystic kidney disease. This illustrates the power of chemical screening at the cellular level to address specific proteinopathies and the utility of such compounds to illuminate novel cellular pathways that can clear toxic proteins.

Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys.

Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.

Joubert syndrome with multiple pituitary hormone deficiency.

Joubert syndrome (JS) and JS-related disorders are a group of developmental delay, multiple congenital anomalies and complex midbrain-hindbrain malformations. A few cases of JS with multiple pituitary hormone deficiency (MPHD) have been reported in literature. Here, we presented an unusual presentation of JS in a newborn with MPHD. This case is intended to draw attention to the rare association of JS and MDPH by increasing the awareness of this syndrome.

[The pathway of vasopressin as a pharmacological target in nephrology: a narrative review].

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use. Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression. Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome. Due to the activity of ADH in coagulation and haemostasis, ADH's activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.

Renal disease in tuberous sclerosis complex: pathogenesis and therapy.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartomatous tumours of the brain, heart, skin, lung and kidney. Patients with TSC show a diverse range of neurological features (including seizures, cognitive disability and autism) and renal manifestations (including angiomyolipomas, epithelial cysts and renal cell carcinoma (RCC)). TSC is caused by inactivating mutations in TSC1 and TSC2, which encode hamartin and tuberin, respectively. These two proteins form a complex that negatively regulates mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular growth and metabolism. In clinical trials, allosteric inhibitors of mTORC1 decrease angiomyolipoma size, but the tumours regrow after treatment cessation. Therefore, the development of strategies to eliminate rather than suppress angiomyolipomas remains a high priority. This Review describes important advances in the TSC field and highlights several remaining critical knowledge gaps: the factors that promote aggressive behaviour by a subset of TSC-associated RCCs; the molecular mechanisms underlying early-onset cystogenesis in TSC2-PKD1 contiguous gene deletion syndrome; the effect of early, long-term mTORC1 inhibition on the development of TSC renal disease; and the identification of the cell or cells of origin of angiomyolipomas.

Isosorbide dinitrate in nephronophthisis treatment.

Nephronophthisis is a progressive disease that affects development of the renal tubules and leads to end stage renal disease. Many affected children have isolated renal disease; however, there can be additional manifestations including heart defects, liver fibrosis, brain malformations, and situs inversus. There is no way to slow or modify the disease. We describe a patient who presented at birth with cholestatic jaundice and decreased kidney function, found by exome sequencing to have two NPHP3 variants. Her clinical status deteriorated rapidly, and two disease-modifying agents were given in hopes of slowing disease progression, the arginine vasopressin type II receptor antagonist tolvaptan to stabilize her renal function and isosorbide dinitrate to manage her poorly controlled hypertension. Tolvaptan therapy initiated at 82 days of life had limited effect on the rate of decline in renal function and was insufficient to abrogate the need for dialysis; however, isosorbide dinitrate therapy led to a dramatic improvement in blood pressure control and allowed for the discontinuation of multiple anti-hypertensive agents. This is the first report of the use of tolvaptan and isosorbide dinitrate for nephronophthisis management. We suggest that isosorbide dinitrate may represent a disease-modifying agent in nephronophthisis treatment.

A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies.

Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganized primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinase inhibition (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognized convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.