Genetic Kidney Disease Research Articles

Clinical implementation of Nephrologist-led Genomic Testing for Glomerular Diseases in Singapore: Rationale and Protocol.

Introduction The early diagnosis and appropriate treatment of monogenic glomerular diseases can reduce kidney failure, avoid unnecessary investigations such as kidney biopsies and ineffective treatment with immunosuppressants, guide transplant decisions, and inform the genetic risks of their family members. Yet, genetic testing for kidney disease is under-utilized in Singapore. We aimed to implement a nephrologist-led genetic service and evaluate the acceptance, adoption, utility and cost-effectiveness of genetic testing for monogenic glomerular disease in Singapore. Methods We will perform a prospective, multi-center, Type II hybrid effectiveness-implementation study with a post design to evaluate both implementation and clinical outcomes of nephrologist-led genetic testing for suspected genetic glomerular kidney diseases. The multi-disciplinary implementation team will train "genetic nephrologists" to provide pre- and post-test counselling, order targeted exome panel sequencing for suspected glomerular kidney diseases (persistent microscopic haematuria and/or albuminuria or proteinuria in the absence of known causes; steroid-resistant primary nephrotic syndrome; apparent familial IgA nephropathy; or chronic kidney disease with no apparent cause) and interpret genetic test results; create workflows for patient referral, evaluation and management, and discuss genetic results at regular genomic board meetings. The outcomes are acceptance, appropriateness and adoption among patients and nephrologists, utility (proportion of patients who received genetic testing and have a confirmed diagnosis of genetic glomerular disease) and cost-effectiveness. Conclusion This study will create and evaluate a nephrologist-led genetic service, develop an efficient variant curation process and inform future recommendations on the optimal referral and genetic testing strategy for monogenic glomerular disease in Singapore. This will facilitate the future mainstreaming of genetic testing that will enable precision medicine in kidney care.

Risk of chronic kidney disease in individuals on lithium therapy in Iceland: a nationwide retrospective cohort study

The association between lithium use and chronic kidney disease, and the effect of comorbidities on this association are poorly understood. Our aim was to examine the risk of developing stage 3 or higher chronic kidney disease among people receiving lithium therapy. This was a retrospective, population-based cohort study of all adults (aged ≥18 years) in Iceland treated with lithium for a mood disorder who had two or more serum creatinine measurements available in the years 2008-17, irrespective of duration of lithium therapy, identified from the Prescription Medicines Register of the Directorate of Health, or through blood lithium measurements. The control group comprised all eligible outpatients with mood disorders (ICD-10 codes F30-F39) who had not been prescribed lithium and who had attended the national tertiary referral centre in 2014-16. Individuals with chronic kidney disease (identified by ICD codes or an estimated glomerular filtration rate [eGFR] <60 mL/min per 1·73 m2) before Jan 1, 2008, or those with glomerular disease, genetic or congenital kidney disease, or small kidneys diagnosed before or after 2008 were excluded. Chronic kidney disease stages 3 and higher were defined according to the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, and the eGFR was calculated from serum creatinine; all ICD-10 and ICD-9 diagnosis codes, serum creatinine and blood lithium concentrations, and urine albumin-to-creatinine ratios were obtained from health-care institutions and laboratories. Risk of developing stage 3 or higher chronic kidney disease between Jan 1, 2008, and Dec 31, 2017, was assessed using time-to-event regression analysis, accounting for competing risk of death. People with lived experience were not involved in the design or conduct of this study. We identified 4310 individuals (2695 who had received lithium and 1615 control participants), of whom 3198 were included in the study. 2025 (75·1%) individuals in the lithium group (1165 [57·5%] female and 860 [42·5%] male) and 1173 (72·6%) in the control group (737 [62·8%] female and 436 [37·2%] male) were included in the study at end of follow-up. The mean age of the study sample at the end of follow-up was 46·6 years (SD 16·4; range 18·5-98·9). Ethnicity data were not available. In the lithium group, 211 (10·4%) of 2025 individuals developed stage 3 or higher chronic kidney disease, compared with 35 (3·0%) of 1173 individuals in the control group (hazard ratio [HR] 1·90, 95% CI 1·32-2·75 after adjusting for sex, age, and comorbid conditions). Compared with control participants, the risk of stage 3 or higher chronic kidney disease was significantly increased for subgroups with a mean blood lithium concentration of 0·60-0·79 mmol/L (HR 2·93, 95% CI 1·97-4·36) or 0·80-0·99 mmol/L (4·31, 2·66-6·99), but not for the subgroup with a mean blood lithium concentration of 0·30-0·59 mmol/L (1·22, 0·78-1·90). Analyses also showed that age, initial eGFR, diabetes, and history of acute kidney injury were significant risk factors for developing stage 3 or higher chronic kidney disease. Individuals with mood disorders receiving lithium treatment had an increased risk of developing stage 3 or higher chronic kidney disease in a blood concentration-dependent manner. We also found that other factors, including age, initial eGFR, and comorbidities were associated with increased risk of for developing stage 3 or higher chronic kidney disease. Overall, our findings suggest that in addition to considering other risk factors (eg, age or clinical comorbidities), careful monitoring of blood lithium concentrations and use of the lowest effective lithium dose for adequate mood stabilisation is recommended for helping to mitigate the risk of chronic kidney disease. Akureyri Hospital Research Fund and Landspitali University Hospital Science Fund.

MUC1-associated autosomal dominant tubulointerstitial kidney disease: prevalence in kidney failure of undetermined aetiology and clinical insights from Danish families

Abstract Background Frameshift variants in the variable number tandem repeat region of MUC1 cause autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1) but are challenging to detect. We investigated the prevalence in patients with kidney failure of undetermined aetiology and compared Danish families with ADTKD-MUC1. Methods We recruited patients with suspected kidney failure of undetermined aetiology at ≤ 50 years and excluded those with a clear-cut clinical or histopathological kidney diagnoses or established genetic kidney diseases identified thorough medical record review. MUC1 genotyping was performed by SNaPshot analysis, detecting the most common pathogenic cytosine duplication, followed by bioinformatics pipeline VNtyper analysis of short-read sequencing data.. Results Of 172 recruited patients, 123 underwent SNaPshot analyses, which were abnormal in 5/123 patients (4%). Next, VNtyper genotyping was performed in all patients, including the five with abnormal SNaPshot analysis. VNtyper re-identified the common cytosine duplication in all five patients and revealed novel frameshift variants in two additional patients, while the analyses were normal in the remaining 116 patients. All patients carrying frameshift variants in MUC1 full-filled ADTKD criteria and had a family history of kidney failure . A considerable inter- and intra-familial variability of chronic kidney disease stage relative to age was observed in families with ADTKD-MUC1. Conclusions ADTKD-MUC1 was identified in 7/123 patients (6%) in a selected cohort of kidney failure of undetermined aetiology ≤ 50 years, and VNtyper effectively identified all pathogenic MUC1 variants.

Mechanisms of podocyte injury in genetic kidney disease.

Glomerular diseases are a leading cause of chronic kidney disease worldwide. Both acquired and hereditary glomerulopathies frequently share a common final disease mechanism: disruption of the glomerular filtration barrier, podocyte injury, and ultimately podocyte death and detachment. Over 70 monogenic causes of proteinuric kidney disease have been identified, and most of these genes are highly expressed in podocytes, regulating key processes such as maintenance of the slit diaphragm, regulation of actin cytoskeleton remodeling, and modulation of downstream transcriptional pathways. Collectively, these are increasingly being referred to as hereditary "podocytopathies," in which podocyte injury is the central feature driving proteinuria and kidney dysfunction. In this review, we provide an overview of the monogenic podocytopathies and discuss the molecular mechanisms by which single-gene defects lead to podocyte injury and ultimately glomerulosclerosis. We review how advances in genomic technology and a better understanding of the cell biological basis of disease have led to the development of more targeted and personalized therapeutic strategies, including an overview of small molecule and gene therapy approaches.

Analysis of a Familial IgAN Accompanied by COL4A3 Mutation.

IgA nephropathy (IgAN) is the prevailing primary glomerulonephritis globally and is the key factor contributing to the onset of chronic kidney disease and eventual progression to end-stage renal disease. This study aims to explore the mutated gene in a familial case of IgAN, especially COL4A3. Family lineages diagnosed with familial IgAN at the Longyan First Hospital of Fujian Medical University were selected for this study, followed by comprehensive whole exome sequencing. After obtaining the sequencing data, bioinformatics analyses were conducted to discern potential mutated genes. These findings within the familial lineages were validated using Sanger sequencing to identify IgAN-associated mutated genes, based on literature references and in accordance with the genetic variation classification criteria determined by the American College of Medical Genetics and Genomics. Whole exome sequencing analysis of familial IgAN family lineages led to the identification of a total of 212,187 single nucleotide variant/insertion-deletion mutation sites, annotated using ANNOVAR. These sites were screened targeting four mutated genes, revealing three mutations of undetermined significance along with a single disease-causing mutation: a heterozygous disease-causing mutation within COL4A3 (p.G1167R). This mutation manifested across seven family members within the group, encompassing both family members diagnosed with kidney disease and those serving as normal carriers. Notably, one additional family member with IgAN within the familial lineage exhibited an absence of the pathogenic mutation. This study identified four mutated genes that may be involved in the onset and progression of IgAN, further revealing the complex multigenic inheritance characteristics of IgAN. The underlying mechanisms of the disease require further investigation. Additionally, we discovered potential mutations associated with known genetic kidney diseases, such as COL4A3 mutations. Therefore, we recommend comprehensive genetic screening in familial cases of IgAN to improve disease diagnosis and facilitate genetic counseling.

Implementation of a Kidney Genetic Service Into the Diagnostic Pathway for Patients With CKD in Canada

BACKGROUNDGenetic kidney disease (GKD) accounts for 10-20% of chronic kidney disease (CKD). Genetic testing using gene-panel or targeted exome sequencing (ES) can confirm genetic kidney disease, however integration into clinical practice has been hampered by small studies, selective populations, and data predominately derived from research settings. Using pre-specified clinical referral criteria and a diagnostic pipeline, we performed a prospective cohort study describing diagnostic efficacy and clinical utility of genetic assessment in patients with CKD. METHODSWe analyzed a prospective cohort of 300 participants (256 families) referred to a kidney genetics clinic, between March 2020 and March 2024. Testing strategies included gene-panels, and if negative or unsuitable, targeted ES analysis. Testing was performed for the detection of variants in genes known to cause CKD. RESULTSWe identified a causative variant in 33% of families (85/256). Diagnostic yield increased from 23% (n=70/300) following gene panel alone to 34% (n=103/300) with comprehensive testing. The median time from first diagnosis of CKD to genetic assessment was long at 10.4 years. Following genetic assessment, the median time to receive a positive genetic result was 2.9 months. Multiple levels of clinical utility were recorded in patients receiving a genetic diagnosis, varying across CKD subtype. CONCLUSIONInstituting referral guidelines and a standardized testing algorithm established a genetic diagnosis in a third of participants, providing insight into the viability of integrating genetic assessment in the CKD diagnostic pathway. Considering the potential for clinical utility, strategies to reduce the time from CKD diagnosis to genetics assessment are needed.

A guide to gene-disease relationships in nephrology.

The use of next-generation sequencing technologies such as exome and genome sequencing in research and clinical care has transformed our understanding of the molecular architecture of genetic kidney diseases. Although the capability to identify and rigorously assess genetic variants and their relationship to disease has advanced considerably in the past decade, the curation of clinically relevant relationships between genes and specific phenotypes has received less attention, despite it underpinning accurate interpretation of genomic tests. Here, we discuss the need to accurately define gene-disease relationships in nephrology and provide a framework for appraising genetic and experimental evidence critically. We describe existing international programmes that provide expert curation of gene-disease relationships and discuss sources of discrepancy as well as efforts at harmonization. Further, we highlight the need for alignment of disease and phenotype terminology to ensure robust and reproducible curation of knowledge. These collective efforts to support evidence-based translation of genomic sequencing into practice across clinical, diagnostic and research settings are crucial for delivering the promise of precision medicine in nephrology, providing more patients with timely diagnoses, accurate prognostic information and access to targeted treatments.

Genetics in nephrology - any news?

While genetic kidney diseases were long regarded as a rare cause of kidney failure, it has been shown in recent years that they account for a relevant proportion of cases. In cohorts of kidney transplant recipients, a monogenic cause is found in up to 30% of cases. Identifying the genetic cause of kidney disease has become much easier thanks to technological advances in DNA sequencing. The focus has now shifted to understanding the significance of the findings and identifying diagnostic gaps. It is still not possible to clarify all CKD cases of unclear aetiology. Besides very effective generic treatments for monogenic kidney disease (e.g., ACE-inhibitor use in Alport Syndrome), increasing knowledge of the pathophysiology of genetic kidney diseases has led to a growing number of targeted therapies. These include the treatment of ADPKD with Tolvaptan, which has now been in use for 10 years. Recently, exciting, and completely new approaches have been added, such as the first siRNA therapies in nephrology for primary hyperoxaluria type 1, the targeted treatment of hyperphagia in Bardet-Biedl syndrome, the therapy of APOL1-associated kidney disease or the use of the HIF-2 antagonist Belzutifan for renal cell carcinoma associated with Von-Hippel-Lindau syndrome. The new possibilities in the treatment of patients with genetic kidney diseases have also clearly revealed deficits in current patient care. Centers of excellence with extensive experience in this area therefore play an important role in improving care. This also applies to the further training of colleagues in the field. In Germany, the National Action Alliance for People with Rare Diseases (NAMSE) and the nationwide establishment of - to date - 36 centers for rare diseases play an important role in this regard.

Slowly progressive autosomal dominant Alport Syndrome due to COL4A3 splicing variant.

Alport syndrome is a rare genetic kidney disease caused by variants in the COL4A3/A4/A5 genes. It's characterised by progressive kidney failure, though therapies targeting Renin-Angiotensin System can delay its progression. Additionally, extrarenal manifestations may sometimes coexist. Recent advances in genetic analysis and the necessity to better clarify genotype-phenotype correlations in affected patients raises the importance of detecting even cryptic splicing variants, lying in both canonical and non-canonical splice sites variants such as last exonic nucleotide variants. These variants, often, do not cause an amino acid change but alter the snRNP proteins binding. We studied a big Italian family with Alport syndrome showing a clear dominant pattern of transmission with younger family members having only haematuria and older individuals presenting with End-Stage Kidney Failure (ESKF). Kidney biopsy showed the typical disease hallmarks. We deeply mined the data for SNV and CNV through exome sequencing on DNA from both peripheral blood samples and patients' podocytes-lineage cells. We identified an already reported synonymous variant, c.765G>A (p.(Thr255Thr)), in the last exonic nucleotide of exon 13 of the COL4A3 gene. Employing the patient's podocytes we demonstrated that this variant results in exon skipping leading to an in-frame deletion of 28 amino acids without leaky effect. According to the pattern of transmission, to the kidney biopsy and to the exome data analysis we provided further evidence that autosomal dominant Alport syndrome is a well-defined clinical entity. We also confirmed the pathogenicity of the synonymous COL4A3 variant for the first time demonstrating its role in a dominant pattern of transmission.

The Impact of Primary Renal Diagnosis on Prognosis and the Varying Predictive Power of Albuminuria in the NURTuRE-CKD Study

Plain Language SummaryChronic kidney disease (CKD) is a broad term that describes a reduction in kidney function. However, there are several underlying causes of CKD. Using the NURTuRE-CKD study, we explore how the individual causes of CKD affect the risk of disease progression and how some of the tests we do are more accurate in predicting kidney failure (KF) in some causes of CKD rather than others. We found that a person’s type of kidney disease can significantly impact their risk of KF and death. For example, people with DKD or certain genetic conditions had a higher risk of KF, while those with other types, like tubulointerstitial disease, had a lower risk. Albuminuria, which measures the amount of a protein called albumin in the urine, is commonly used to predict kidney disease progression. However, we found that its effectiveness varies depending on the type of kidney disease. It was most helpful in predicting outcomes for people with vasculitis and DKD but added little value for those with genetic kidney diseases. In conclusion, recognizing the specific type of kidney disease is crucial for accurate risk assessment and effective treatment planning in CKD. This study highlights the importance of a tailored approach to managing kidney disease based on the primary diagnosis.

Detection of Alport gene variants in children and young people with persistent haematuria.

Genetic kidney disease is an important cause of persistent microscopic haematuria in children and young people. We aimed to determine the frequency of variants in the Alport syndrome genes (COL4A3, COL4A4 or COL4A5) in individuals under 18 years of age presenting with persistent microscopic haematuria to a single specialist centre in the UK over a 10-year period. We conducted a retrospective longitudinal study of individuals referred to a tertiary paediatric nephrology service with persistent microscopic haematuria between April 2012 to 2022. A total of 224 individuals (female 51.8%) were evaluated with persistent microscopic haematuria of greater than 6 months duration. The age at presentation was 7.5 ± 4.3 years (mean ± SD) with a duration of follow-up of 6.8 ± 4.6 years (mean ± SD). Targeted exome sequencing was performed in 134 individuals and 91 (68%) had a pathogenic or likely pathogenic variant in COL4A3, COL4A4 or COL4A5. Only 49.5% of individuals with identified variants had a family history of microscopic haematuria documented and 37.4% (34/91) had additional proteinuria at presentation. COL4A5 was the most common gene affected and missense variants affecting glycine residues were the most common variant type. Over two-thirds of children and young people who underwent genetic testing had an identifiable genetic basis for their microscopic haematuria and over half did not have a documented family history. Genetic testing should be part of the evaluation of persistent microscopic haematuria despite a negative family history.

Prenatal and preimplantation genetic testing for monogenic kidney disorders

In recent years, advances in genetic sequencing techniques and the analysis of sequencing data have significantly improved our ability to diagnose genetic kidney diseases. Identification of the disease-causing genetic variant(s) is crucial not only for prognostication and personalized management, but also for providing genetic counseling and guiding family planning decisions. It is particularly important that patients desiring children receive advice on their reproductive choices early, ideally before conception. This concise review focuses on the options available for prenatal and preimplantation genetic testing in the context of monogenic kidney diseases, including the latest progress and the legal and ethical issues associated with these reproductive technologies. Although these tests could be performed for all monogenic disorders where the disease-causing variant(s) has been identified in the index patient, invasive prenatal testing is currently primarily performed for severe childhood-onset monogenic kidney disorders. Non-invasive prenatal diagnosis for monogenic disorders is a rapidly developing field that promises to provide an accurate and acceptable alternative to invasive procedures once several technical challenges have been addressed.Preimplantation genetic testing allows for the selection and implantation of embryos free from the disease-causing genetic variants, significantly lowering the risk of affected pregnancies. This option is becoming more popular among individuals with monogenic kidney diseases, particularly those with disorders that manifest later in life, such as autosomal dominant polycystic kidney disease. This review covers the procedure, its outcomes, and the technical, ethical and legal challenges of preimplantation genetic testing for monogenic kidney diseases.

Diagnostic Yield and Clinical Utility of Genomic Testing in Patients with Suspected Genetic Kidney Disease: Singapore's First-Year Experience

Diagnostic Yield and Clinical Utility of Genomic Testing in Patients with Suspected Genetic Kidney Disease: Singapore's First-Year Experience

Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases.

Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases.

Risk of kidney failure among patients with genetic kidney diseases.

Risk of kidney failure among patients with genetic kidney diseases.

Nephrologists’ Views on a Workflow for Returning Genetic Results to Research Participants

IntroductionReturning research-based genetic results (gRoR) to participants in nephrology research can improve care but the practice raises implementational questions and no established guidelines for this process currently exists. Nephrologists' views on this issue can inform the process but are understudied. MethodsWe developed a conceptual workflow for gRoR from literature and experience, covering aspects such as which results to return, how, and by whom. We surveyed U.S. nephrologists to gauge their views on the workflow and anticipated barriers and collected participants' demographics including professional backgrounds. ResultsA total of 201 adult and pediatric nephrologists completed the survey. Most agreed that all diagnostic kidney-related results (93%), secondary findings (80%), and kidney-related risk variants (83%) should be returned. No significant differences were found between adult and pediatric nephrologists’ responses, except that 48% of adult nephrologists vs. 26% of pediatric nephrologists supported returning polygenic risk scores (p<0.01). Seventy-nine percent wanted to know about research results before clinical confirmation. Most (63%) believed a genetic counselor should return clinically confirmed results. Key barriers included the cost of clinical validation (77%) and unavailability of genetic counseling services (63%). Facilitators included educational resources on genetic kidney diseases (91%), a referral list of experts (89%), and clear clinical care guidelines (89%). We discuss findings’ implications and provide “points-to-consider”. ConclusionThere is significant interest in gRoR among nephrologists, but logistical and economic concerns need addressing. Identified facilitators can help large nephrology studies planning to return genetic results to participants.

Autosomal Dominant Tubulointerstitial Kidney Disease–UMOD: A Monogenic Renal Disease that Cannot Be Ignored

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of monogenic renal diseases characterized by autosomal dominant inheritance and progressive tubulointerstitial damage with bland urinary sediment. With the discovery of pathogenic variants, ADTKD was recognized as the most frequent non-polycystic genetic kidney disease. ADTKD–UMOD is caused by pathogenic variants of UMOD (coding gene of uromodulin) and is the most common subtype of ADTKD. With the improved awareness of the disease and the advance of genetic testing technology, cohort studies on affected families have gradually increased and deepened our understanding of the clinical and genetic spectrum of ADTKD–UMOD. In addition, extensive research has been conducted on the pathogenetic mechanism. This review highlights recent research progress in the genetic and clinical spectrum, as well as the underlying mechanisms of ADTKD–UMOD.

Rare heterozygous variants in paediatric steroid resistant nephrotic syndrome – a population-based analysis of their significance

Genetic testing in nephrotic syndrome may identify heterozygous predicted-pathogenic variants (HPPVs) in autosomal recessive (AR) genes that are known to cause disease in the homozygous or compound heterozygous state. In such cases, it can be difficult to define the variant’s true significance and questions remain about whether a second pathogenic variant has been missed during analysis or whether the variant is an incidental finding. There are now known to be over 70 genes associated with nephrotic syndrome, the majority inherited as an AR trait. Knowledge of whether such HPPVs occur with equal frequency in patients compared to the general population would assist interpretation of their significance. Exome sequencing was performed on 187 Steroid-Resistant Nephrotic Syndrome (SRNS) paediatric patients recruited to a UK rare disease registry plus originating from clinics at Evelina, London. 59 AR podocytopathy linked genes were analysed in each patient and a list of HPPVs created. We compared the frequency of detected HPPVs with a ‘control’ population from the gnomAD database containing exome data from approximately 50,000 individuals. A bespoke filtering process was used for both patients and controls to predict ‘likely pathogenicity’ of variants. In total 130 Caucasian SRNS patients were screened across 59 AR genes and 201 rare heterozygous variants were identified. 17/201 (8.5%) were assigned as ‘likely pathogenic’ (HPPV) using our bespoke filtering method. Comparing each gene in turn, for SRNS patients with a confirmed genetic diagnosis, in 57 of the 59 genes we found no statistically significant difference in the frequency of these HPPVs between patients and controls (In genes ARHGDIA and TP53RK, we identified a significantly higher number of HPPVs in the control population compared with the patients when filtering was performed with ‘high stringency’ settings only). In the SRNS patients without a genetics diagnosis confirmed, there was no statistically significant difference identified in any gene between patient and control. In children with SRNS, we propose that identification of HPPV in AR podocytopathy linked genes is not necessarily representative of pathogenicity, given that the frequency is similar to that seen in controls for the majority. Whilst this may not exclude the presence of genetic kidney disease, this type of heterozygous variant is unlikely to be causal and each result must be interpreted in its clinical context.

Targeted gene therapy for rare genetic kidney diseases

Chronic kidney disease is one of the leading causes of mortality worldwide because of kidney failure and the associated challenges of its treatment including dialysis and kidney transplantation. About one-third of chronic kidney disease cases are linked to inherited monogenic factors, making them suitable for potential gene therapy interventions. However, the intricate anatomical structure of the kidney poses a challenge, limiting the effectiveness of targeted gene delivery to the renal system. In this review, we explore the progress made in the field of targeted gene therapy approaches and their implications for rare genetic kidney disorders, examining preclinical studies and prospects for clinical application. Invivo gene therapy is most commonly used for kidney-targeted gene delivery and involves administering viral and nonviral vectors through various routes such as systemic, renal vein, and renal arterial injections. Small nucleic acids have also been used in preclinical and clinical studies for treating certain kidney disorders. Unexpectedly, hematopoietic stem and progenitor cells have been used as an exvivo gene therapy vehicle for kidney gene delivery, highlighting their ability to differentiate into macrophages within the kidney, forming tunneling nanotubes that can deliver genetic material and organelles to adjacent kidney cells, even across the basement membrane to target the proximal tubular cells. As gene therapy technologies continue to advance and our understanding of kidney biology deepens, there is hope for patients with genetic kidney disorders to eventually avoid kidney transplantation.

Advancements in Research on Genetic Kidney Diseases Using Human-Induced Pluripotent Stem Cell-Derived Kidney Organoids.

Genetic or hereditary kidney disease stands as a pivotal cause of chronic kidney disease (CKD). The proliferation and widespread utilization of DNA testing in clinical settings have notably eased the diagnosis of genetic kidney diseases, which were once elusive but are now increasingly identified in cases previously deemed CKD of unknown etiology. However, despite these diagnostic strides, research into disease pathogenesis and novel drug development faces significant hurdles, chiefly due to the dearth of appropriate animal models and the challenges posed by limited patient cohorts in clinical studies. Conversely, the advent and utilization of human-induced pluripotent stem cells (hiPSCs) offer a promising avenue for genetic kidney disease research. Particularly, the development of hiPSC-derived kidney organoid systems presents a novel platform for investigating various forms of genetic kidney diseases. Moreover, the integration of the CRISPR/Cas9 technique into this system holds immense potential for efficient research on genetic kidney diseases. This review aims to explore the applications of in vitro kidney organoids generated from hiPSCs in the study of diverse genetic kidney diseases. Additionally, it will delve into the limitations of this research platform and outline future perspectives for advancing research in this crucial area.