Family History Of Kidney Disease Research Articles

Prevalence and assessment of risk factors of chronic kidney disease in the ASIR region of Saudi Arabia

Introduction: Chronic kidney disease (CKD) is a major health concern in Saudi Arabia. The prevalence of CKD and associated risk factors in Saudi Arabia’s general population are not efficiently studied. The goal of this research is to determine the prevalence rate of CKD in the ASIR region and its associated epidemiological risk factors. Methodology: This is a cross-sectional study that used a comprehensive direct questionnaire to collect data on CKD prevalence and risk factors in the ASIR region of Saudi Arabia. The study was carried out in different age groups. Demographic characteristics, presence of CKD, and associated factors such as a history of acute kidney disease, obstructive sleep apnea, family history, history of non-steroid anti-inflammatory drugs (NSAID), smoking status, comorbidities, and history of periodontal diseases were asked. The survey tool was validated through a pilot study, and a statistical p-value of 0.05 was considered significant. Results: A total of 967 participants were included in the study, with a CKD prevalence rate of 1.9%. Gender, history of acute kidney disease, obstructive sleep apnea, family history of kidney disease, smoking, diabetes, peptic ulcer disease, hypertension and hyperlipidemia were commonly found to be associated with CKD. A binary logistic regression model was carried out to assess the risk factors for CKD. Gender, history of acute kidney disease, family history of kidney disease, obstructive sleep apnea, smoking status, peptic ulcer, diabetes, hypertension, hyperlipidemia, hypertension and diabetes, two or more comorbidities and NSAID use had an increased risk of CKD. Conclusion: Gender, history of acute kidney disease, obstructive sleep apnea, family history, smoking, diabetes, hypertension, peptic ulcer, hyperlipidemia, multi-comorbidity, and use of NSAIDs are all associated with an increased risk of CKD. The prevalence of CKD in this study is comparatively lower when compared to other regions in Saudi Arabia.

A pragmatic approach to selective genetic testing in kidney transplant candidates

IntroductionAdvances in the field of genetic testing have spurred its use in transplantation. Potential benefits of genetic testing in transplant nephrology include diagnosis, treatment, risk stratification of recurrent disease, and risk stratification in potential donors. However, it is unclear how to best apply genetic testing in this population to maximize its yield. We describe our transplant center's approach to selective genetic testing as part of kidney transplant candidate and donor evaluation.MethodsTransplant recipient candidates were tested if they had a history of ESRD at age <50, primary FSGS, complement-mediated or unknown etiology of kidney disease, or had a family history of kidney disease. Donors were tested if age <35, were related to their potential recipients with known genetic susceptibility or had a first-degree relative with a history of kidney disease of unknown etiology. A targeted NGS gene panel of 385 genes was used. Clinical implications and downstream effects were monitored.ResultsOver 30% of recipients tested within the established criteria were positive for a pathogenic variant. The most common pathogenic variants were APOL1 high-risk genotypes as well as collagen 4-alpha-3, -4 and -5. Donor testing done according to our inclusion criteria resulted in about 12% yield. Positive test results in recipients helped with stratification of the risk of recurrent disease. Positive test results in potential donors guided informed decisions on when not to move forward with a donation.DiscussionIntegrating targeted panel genetic testing into a kidney transplant clinic in conjunction with a selective criteria for testing donors and recipients ensured a reasonable diagnostic yield. The results had implications on clinical management, risk stratification and in some cases were instrumental in directing downstream changes including when to stop the evaluation process. Given the impact on management and transplant decisions, we advocate for the widespread use of genetic testing in selected individuals undergoing transplant evaluation and donation who meet pre-defined criteria.

Prevalence of multimorbidity and its associated risk factors among population of Mechinagar municipality of Nepal.

Multimorbidity is a group of conditions, it has significant impact on the population as a whole, resulting in lower quality of life, higher mortality, frequent use of medical services, and consequently higher healthcare costs. The objective of this study is to document the prevalence of common multimorbidity and its associated risk factors among population of Mechinagar Municipality. Community-based cross-sectional study was conducted where selected multimorbidity were assessed in selected areas of Mechinagar municipality of Jhapa District . Systematic random sampling technique was used to select 590 adult participants from three pre-defined pocket areas. Pre-designed semi-structured multimorbidity assessment questionnaire for primary care (MAQ-PC)was used to assess prevalence of multimorbidity. Multiple logistic regression was conducted to identify the strongest determinants of multimorbidity. The prevalence of multimorbidity was 22.4%.Hypertension, Diabetes mellitus and COPD was seen in 39.2%, 7.8.% and 4.4% of the participants respectively . Participants with advancing age i. e. 40-49yrs were 12.62 times (AOR) more likely to have multimorbidity compared to their counterparts who were 20-29yrs old( p=<0.01,CI3.01-15.28) after adjusting for occupation, physical activity and family history of kidney disease. Working individuals, Physical inactivity and positive family history of kidney disease were the strongest determinates of multimorbidity. The study revealed that participants with increasing age, working individuals, physical inactivity and family history of kidney disease were more vulnerable of having multimorbidity. The findings of our study indicate need of intervention strategies and community-based health promotion programs in reducing burden of chronic disease among adult population.

Chronic kidney disease and its predictors among highly active antiretroviral therapy naïve and experienced HIV-infected individuals at the selected hospitals, Southwest Ethiopia: a comparative cross-sectional study

ObjectiveThis study aimed to determine the prevalence of chronic kidney disease (CKD) and its predictors among highly active antiretroviral therapy (HAART) naïve and experienced HIV-infected individuals.Method and analysisHospital-based comparative cross-sectional...

Awareness of chronic kidney disease and its risk factors in the former Soviet Union countries

&lt;b&gt;Purpose:&lt;/b&gt; Assessment of public knowledge of chronic kidney disease (CKD) is an essential step in&lt;b&gt; &lt;/b&gt;development of CKD prevention and screening programs. Our aim was to estimate the level of public CKD knowledge and its predictors in the former Soviet Union countries using a validated questionnaire.&lt;br /&gt; &lt;b&gt;Materials and methods: &lt;/b&gt;This cross-sectional survey was conducted in 10 countries using an adapted validated online questionnaire. Descriptive statistics were used to describe participants’ characteristics and assess public CKD knowledge level. A multiple linear regression analysis was performed to identify predictors of CKD knowledge.&lt;br /&gt; &lt;b&gt;Results: &lt;/b&gt;2,715 participants satisfied the inclusion criteria. Respondents having higher level of education, living in countries belonging to the lower middle-income countries, having a personal history of diabetes and hypertension, and having a family history of kidney disease showed significantly better CKD knowledge.&lt;br /&gt; &lt;b&gt;Conclusions:&lt;/b&gt; The level of CKD knowledge among the population of post-Soviet states was found to be low, although some personal characteristics were associated with better CKD knowledge.

Diagnosis of Kidney Diseases of Unknown Etiology Through Biopsy-Genetic Analysis

Previous studies have suggested that genetic kidney diseases in adults are often overlooked, representing up to 10% of all cases of chronic kidney disease (CKD). We present data obtained from exome sequencing (ES) analysis of patients with biopsy-proven undetermined kidney disease (UKD). ES was proposed during routine clinical care in patients with UKD from January 2020 to December 2021. We used in silico custom kidney genes panel analysis to detect pathological variations using American College of Medical Genetics guidelines in 52 patients with biopsy-proven UKD with histological finding reassessment. We detected 12 monogenic renal disorders in 21 (40.4%) patients. The most common diagnoses were collagenopathies (8/21,38.1%), COL4A3 and COL4A4 accounting for 80% of these diagnoses, and ciliopathies (5/21, 23.8%). The diagnostic yield of ES was higher in female patients and patients with a family history of kidney disease (57.1% and 71%, respectively). Clinical nephropathy categories matched with the final genetic diagnoses in 72.7% of cases, whereas histological renal lesions matched with the final diagnoses in 92.3% of cases. The genetics diagnoses and histopathological findings were in complete agreement for both glomerular and tubulointerstitial cases. Interstitial inflammation without tubulitis was only observed in tubulopathies or ciliopathies. Isolated CKD, CKD with proteinuria or hematuria, and isolated proteinuria or hematuria yielded the highest diagnostic yields (54.6%, 52.6%, and 42.9%, respectively). ES done in patients with biopsy-proven UKD should be considered as a first-line tool for CKD patients with a family history of kidney disease. Combination of ES and kidney biopsy may have major impacts on kidney disease ontology.

#5940 CLINICAL UTILITY OF GENETIC TESTING IN A KIDNEY TRANSPLANT CLINIC

Abstract Background and Aims Inherited kidney disease (IKD) is one of the leading causes of end-stage of kidney disease. Genetic diagnosis plays an important role in the counseling and management of kidney transplant patients or those on the waiting list, as it makes it possible to identify the cause of CKD, help in the selection of living donors, carry out genetic counseling and find out the prognosis around the graft survival and the risk of recurrence of the primary disease. The objective of the following study is to analyze the prevalence of IKD in our kidney transplant population and those on the waiting list, the phenotypic characteristics, genetic findings, and the diagnostic reclassification performed after the genetic study. Method This retrospective study has incluyed all genetic test (by next-generation sequencing (NGS) until 529 genes associated with kidney disease) performance between January 2018 and January 2023 in kidney transplant patients or on the waiting list for kidney transplant at Doctor Peset Hospital, using a multidisciplinary team approach. The patients were considered for genomic evaluation if they met one of the inclusion criteria: CKD of unknown etiology, family history of CKD, glomerular disease or chronic tubulo–interstitial disease with no recognized cause, suspicion of aHUS, CKD and other extrarenal syndromic signs or with renal malformations or nephrocalcinosis. Demographic data, family burden and screening, CKD phenotype, urinary anormalities, hypertension, diabetes, results of genetic test, were analyzed. Results We performed genetic testing in 76 patients (43,4% women; 88% Caucasian). Median age at time of kidney failure was 37 years (range: 17–77), 62% of patients had a positive family history of CKD and 29% presented extrarenal manifestations. The majority were male patients (56.6%) and Caucasian patients (88.2%). Most patients presented with an original clinical diagnosis glomerular disease 52,6% (FSGS lesion on biopsy (8/27) and non-diagnostic histology (10/27)), followed by ciliopathy (13%), aHUS (10.5%), and chronic kidney disease of unknown cause (6.6%), tubulointerstitial nephritis (6.6%), and with congenital anomalies (6.6%). In 46 patients had a genetic diagnosis defined as finding a pathogenic or likely pathogenic gene variant that explained the patient's kidney disease. With majority being COL4 variants (26.3%), followed by autosomal dominant polycystic kidney disease (ADPKD) (10.5%), podocytopathy and autosomal dominant tubulointerstitial kidney diseases. There were confirmed within a clinical diagnostic in 28% (above all ADPKD) and resulted in reclassification of the clinical diagnosis in 33% (above all COL4-related nephropathy) and there are more frequently a negative result if clinical diagnosis was unknown etiology, congenital anomalies o aHUS until 60%. With this data, 78% of the patients could have avoided a biopsy and 50% a immunossuppresive treatment with the diagnosis by genetic test. A genetic cause was identified by family screening in 16 families comprising 19 patients. A genetic diagnosis were more likely to have a family history of kidney disease (47,4% versus 14,5%, P &amp;lt; 0.001). There was otherwise no statistically significant difference in any other clinical characteristic (age at onset of kidney disease, age at kidney failure, race, hypertension, diabetes, hematuria, renal cyst or stone). Conclusion Our study demonstrates the clinical utility of genetic study in kidney transplants with unknown etiology or glomerulonephritis or chronic tubule-interstitial disease with no recognized cause or with positive family history of kidney disease, getting a genetic diagnosis until 60%, with a reclassification of the clinical diagnosis in a one-third. A genetic diagnosis is necessary to evaluate to kidney transplant recipients, to identify the etiology of CKD, to perform a genetic counseling and to improve patient management and prognosis.

#2907 ASYMPTOMATIC NEPHROTIC SYNDROME: AN INTERESTING PRESENTATION OF ADULT ONSET MINIMAL CHANGE DISEASE

Abstract Background and Aims Minimal change disease (MCD), a predominantly pediatric disease, is less common in adults. Patients often present with florid hypervolemia, manifested by significant lower extremity edema, anasarca, pericardial effusion or pleural effusion. Herein, we present a case of newly diagnosed MCD in an elderly gentleman with an atypical presentation. Method A 69 year old male with hypertension and benign prostate hypertrophy presented to the emergency department (ED). He was noted to have abnormal labs at an outside clinic on routine testing and was directed to the ED. In the ED, he was found to have a serum creatinine (SCr) of 10.89 mg/dL. Initial urine studies also revealed proteinuria of 11g/g with 6.5 g/g of albuminuria. Other initial labs were significant for a potassium of 4.5 mEq/L, BUN 126 mg/dL and albumin 2.2 g/dL with normal liver enzymes. Renal ultrasound was unremarkable. Upon further discussion with the patient, he endorsed long term daily use of diclofenac for many months. He stated that he stopped diclofenac three weeks prior to presentation. He denied any proton pump inhibitor or recent antibiotic use. He denied any fevers, nights sweats or weight loss to suggest Type B symptoms. There was no personal kidney disease history nor family history of kidney disease. He was a non-alcoholic and non-smoker. We continued to hold further non-steroidal anti-inflammatory medications as well as other nephrotoxic medications. Although patient had elevated SCr and azotemia, he did not meet any acute indications for dialysis and we continued to manage the patient conservatively. Serologies were negative for ANA, ANCA, Anti-GBM, HIV, hepatitis B and C, as well as antiPLA2R. Serum protein electrophoresis, kappa to lambda ratio, complements 3 and 4 were all within normal values. A kidney biopsy was revealing for patchy interstitial inflammatory infiltrate containing mononuclear cells admixed with few eosinophils on light microscopy as well as diffuse foot process effacement on electron microscopy (Figure 2). The patient had a one-week hospital stay with improvement of SCr to 2.29 mg/dL without any prednisone or treatment for MCD. Spot urine protein improved to 7.4 g/g by time of discharge. At clinic follow up 2 weeks later his creatinine had improved to 1.1 mg/dL with UPCR of 0.4 g/g. Results MCD is a podocytopathy that can occur in up to 10% of adults with nephrotic syndrome [1]. Secondary MCD has been reported with NSAIDs. Steroids are the first line therapy for MCD and can lead to remission in the majority of the cases. In patients who do not respond to steroids, calcineurin inhibitors or mycophenolate can be used. Conclusion Our patient presented with biopsy proven-MCD that was presumed to be secondary to diclofenac. His clinical presentation was not characteristic of nephrotic syndrome with no edema. Few reports exist of spontaneous remission in these patients with most of the patient requiring steroids. While it is uncommon for patients with MCD to spontaneously resolve, not all patients with NSAID-induced MCD require treatment and these patients could be monitored conservatively.

#2850 EFFICIENCY OF THE GENETIC STUDY IN THE DIAGNOSIS OF AUTOSOMAL DOMINANT TUBULOINTERSTITIAL NEPHROPATHY

Abstract Background and Aims Autosomal dominant tubulointerstitial nephropathy (ADTKD) is a rare underdiagnosed cause of chronic kidney disease (CKD). ADTKD is a renal disease with a non-specific phenotypic expression that cause a slow progression over time. Given the great variability in its inter-familial presentation and among the same family members carrying the same mutation, its diagnosis is a challenge. Five genes have been identified to date such as Uromodulin (UMOD), Renin (REN), Hepatocyte Nuclear Factor 1b (HNF1β), Mucin-1 (MUC1) and, more recently, new genes, SEC61A1(encoding protein transport protein Sec61 subunit α and atypical (DNAJB11). Our main objective is to analyze the diagnostic yield of the genetic study in cases of clinical suspicion of ADTKD in patients with CKD of unknown etiology. We present a case series of patients from our center with CKD of unknown etiology and clinical suspicion of ADTKD. Genetic analysis of the gene SEC61A1 and DNAJB11 was not available at that time. Method This is a descriptive observational retrospective study from 2016 to 2021 at the Virgen del Rocio University Hospital in Seville, Spain. A total of 26 cases had phenotypic presentation of ADTKD. We collected clinical, laboratory, radiologic, and pathologic data. We performed in all the cases genetic testing for UMOD, MUC1, REN and HNF1β mutations. We collected data in a database, including age of presentation of kidney disease, sex, family history of kidney disease, the presence of hypertension at early age (defined as under 40 years of age), hyperuricemia (defined as uric acid &amp;gt;7.5 mg/dl) at early age (&amp;lt;40 years), hemoglobin at the time of diagnosis, age at last follow up with renal function and estimated glomerular filtration rate (eGFR) using the CKD-EPI (CKD Epidemiology Collaboration), urine elemental, renal ultrasound and renal biopsy if it had been performed. Descriptive results of quantitative variables are expressed as median. For categorical data, frequency and percentage are reported. Results Of the 26 cases with suspected ADTKD, 4 cases presented a genetic study that confirmed the diagnosis, that is, 15% of the cases. The median age at the time of the diagnosis was 41 years (IQR 32.7–48). 84% of the cases were male; 34% of cases had a family history of CKD of unknown etiology. 65% percent of the cases had a history of hyperuricemia at early age (&amp;lt;40 years), with a personal history of hypertension &amp;lt;40 years in 30% of the cases; 44% of the cases had renal lithiasis. The median glomerular filtration rate (CKD-EPI) at the time of diagnosis was 70 ml/min/1.73 m2 (46.4–70.7). In most of the patients, the urine elemental was normal. Renal cysts were found on ultrasound in 46% of patients. In 5 of the twenty-six patients a renal biopsy was performed, in which 60% presented data compatible with ADTKD with interstitial fibrosis and tubular atrophy. 4 of the patients with clinical suspicion of ADTKD obtained a genetic study that confirmed the diagnosis. The most frequently identified gene was HNF1β, being present in two of the four patients. The other genes identified were UMOD and MUC. The results are summarized in Table 1. Conclusion Adequate selection of patients based on clinical suspicion is essential to give greater profitability to the genetic study of this entity. The negativity of the study cannot exclude the diagnosis, since at the moment not all the causative genes of this pathology have been identified and it is necessary to use massive sequencing techniques or even the analysis of the complete exome to see the possibility of other variants of the disease.

#6213 RISK FACTORS FOR END-STAGE RENAL DISEASE IN IGA NEPHROPATHY

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular nephropathy worldwide and one of the principal causes of chronic kidney disease. The presentation of this nephropathy is different between ethnic groups. The aim of our work is to describe the clinical, biological, and pathological symptoms of maghrebian patients diagnosed with IgAN. Method We conducted a retrospective descriptive study over 46 years from 1975 and 2021. This study included 213 patients with renal biopsy-proven IgAN whose clinical, biological, and pathological data were assessed and classified according to the Oxford classification. Results The mean age of the patients was 34.48 [15-80] with male predominance (sex ratio=1.77). Thirty-nine patients had a family history of kidney disease. 109 patients (51%) had hypertension. The median proteinuria was 2.6 g/24 h [0-46.17 g/24 h]. Nephrotic proteinuria(&amp;gt;3 g/24h) was found in 98 patients (46%). The initial median glomerular filtration rate was 33.9 ml/min/1,73 m²SC. At the end of the follow-up, it was 23.7 ml/min/1.73 m²SC. Renal biopsy was performed in all the cases. The lesions observed in optical microscopy were mesangial proliferation M1 (63.8%), endocapillary proliferation E1(8.5%), glomerulosclerosis S1 (71.4%), interstitial fibrosis or tubular atrophy T1-T2 (72.8%) and crescents C1 (16.9%). Fifty-two percent of the patients were treated with ACE inhibitors or ARAII.47.9% of our population reached end-stage kidney disease and required dialysis. Only 23 patients (10.8%) had a kidney transplant. Conclusion The treatment of IgA nephropathy is based on early diagnosis, hence the need for a screening strategy to prevent the discovery of this nephropathy in an advanced stage.

#4440 PREVALENCE OF GENES INVOLVED IN HEREDITARY KIDNEY DISEASE AS A TOOL FOR THE DEVELOPMENT OF A GENE PANEL

Abstract Background and Aims Genetic study is the fundamental tool for the diagnosis of Hereditary Kidney Diseases (HKD). The proliferation of its use has led to an increase in diagnostic complexity due to phenotypic overlap and genotypic heterogeneity. The aim of this study is to evaluate the prevalence of genes in our series of adult patients with suspected monogenic kidney disease in order to develop the basis for the elaboration of a gene panel that will make its usefulness in our routine clinical practice profitable. Method A retrospective descriptive observational study was performed with the collection of all genetic studies that were positive in the period between October 2014 and December 2020 in our center. With a description of the causative genes involved, as well as the clinical data of the proband patients who turned out to be carriers of these variants. Descriptive results of continuous variables are expressed as mean and standard deviation (SD) or median and interquartile range (IQR) according to their distribution. For categorical data, frequency and percentage are reported. Results The results of a total of 77 genetic studies on probands were collected, of whom 51% were women with a mean age at diagnosis of 46 years (SD ± 13.4) and 64.9% had a family history of kidney disease. Renal function measured by mean estimated glomerular filtration rate (eGFR) using the CKD-EPI (CKD Epidemiology Collaboration) was 90.1 ml/min/1,73 m2 (SD ± 29.64) with a mean proteinuria quantified in 24-hour urine of 627.9 mg (SD ±43.7) and 7.7% were on renal replacement therapy. (Table 1) 40.25% of probands were carriers of a mutation for Alport syndrome, in this group the most frequent gene was COL4A3 in 50% of cases. The second most frequent entity was autosomal dominant polycystic kidney disease (ADPKD) with 37% of the studies and among these the great majority were carriers of a variant in the PKD1 gene with 96.5%. The remaining diagnostic entities in order of frequency were Fabry disease, autosomal dominant tubulointerstitial nephropathy (ADTKD), congenital anomalies of the kidney and urinary tract (CAKUT), nephrotic syndrome, hereditary angiopathy with nephropathy, aneurysm and cramps syndrome (HANAC) and tuberous sclerosis (Figure 1). Conclusion Alport syndrome was the most frequently identified entity in patients with suspected monogenic renal disease in whom the genetic study was performed. Based on the results of our series, a proposal has been made for the genes to be included in a panel for hereditary renal diseases in our center. The development of these panels increases the efficiency and increases the cost-effectiveness of genetic studies in the diagnosis of these patients.

COL4A gene variants are common in children with hematuria and a family history of kidney disease.

Inherited kidney diseases are a common cause of chronic kidney disease (CKD) in children. Identification of a monogenic cause of CKD is more common in children than in adults. This study evaluated the diagnostic yield and phenotypic spectrum of children who received genetic testing through the KIDNEYCODE sponsored genetic testing program. Unrelated children < 18years of age who received panel testing through the KIDNEYCODE sponsored genetic testing program from September 2019 through August 2021 were included (N = 832). Eligible children met at least one of the following clinician-reported criteria: estimated GFR ≤ 90ml/min/1.73 m2, hematuria, a family history of kidney disease, or suspected or biopsy confirmed Alport syndrome or focal segmental glomerulosclerosis (FSGS) in the tested individual or family member. A positive genetic diagnosis was observed in 234 children (28.1%, 95% CI [25.2-31.4%]) in genes associated with Alport syndrome (N = 213), FSGS (N = 9), or other disorders (N = 12). Among children with a family history of kidney disease, 30.8% had a positive genetic diagnosis. Among those with hematuria and a family history of CKD, the genetic diagnostic rate increased to 40.4%. Children with hematuria and a family history of CKD have a high likelihood of being diagnosed with a monogenic cause of kidney disease, identified through KIDNEYCODE panel testing, particularly COL4A variants. Early genetic diagnosis can be valuable in targeting appropriate therapy and identification of other at-risk family members. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical Course of Adult FSGS and Minimal Change Disease in North American and Japanese Cohorts.

Regional differences in presentation and clinical course of nephrotic syndrome (NS) have not been studied well because few studies directly compared the data from different intercontinental regions. We included adult nephrotic patients with Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD) who received immunosuppressive therapy (IST) in a North American (NEPTUNE, n=89) or Japanese (N-KDR, n=288) cohort. Baseline characteristics and rates of complete remission (CR) were compared. Factors associated with time to CR were evaluated by Cox regression models. NEPTUNE cases had more FSGS (53.9 vs. 17.0%) and family history of kidney disease (35.2 vs. 3.2%). N-KDR cases were older (median 56 vs. 43 years) and demonstrated greater levels of UPCR (7.73 vs. 6.65) and hypoalbuminemia (1.6 vs. 2.2 mg/dL). N-KDR cases showed higher proportion of CR (overall: 89.2 vs. 62.9%; FSGS: 67.3 vs. 43.7%; MCD: 93.7 vs. 85.4%). A multivariable model showed that FSGS (vs. MCD: HR=0.28, 95%CI 0.20-0.41), systolic blood pressure (per 10 mmHg: HR=0.93, 95%CI 0.86-0.99) and eGFR (per 10 mL/min/1.73m2: HR=1.16, 95%CI 1.09-1.24) were associated with time to CR. There were significant interactions in patient age (p=0.004) and eGFR (p=0.001) between the cohorts. The North American cohort had more FSGS and more frequent family history. Japanese patients showed more severe NS with better response to IST. FSGS, hypertension and lower eGFR were shared predictors of poor treatment response. Identifying shared and unique features across geographically diverse populations may help uncover biologically relevant subgroups, improve prediction of disease course and better design future multi-national clinical trials.

Beyond the kidney biopsy: genomic approach to undetermined kidney diseases.

According to data from large national registries, almost 20%-25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded, respectively, the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES "first" eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (P=.02) and in patients with a family history of kidney disease (P<.0001), reaching 56.8% when the patient had both first- and second-degree family history of renal disease. Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome "first" may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

Incorporation of Genetic Studies in the Kidney Transplant Evaluation Clinic: The Value of a Multidisciplinary Approach.

Recent studies identified underlying genetic causes in a proportion of patients with various forms of kidney disease. In particular, genetic testing reclassified some focal segmental glomerulosclerosis (FSGS) cases into collagen type 4 (COL4)-related nephropathy. This knowledge has major implications for counseling prospective transplant recipients about recurrence risk and screening biologically related donors. We describe our experience incorporating genetic testing in our kidney transplant multidisciplinary practice. Patients' DNA was analyzed using whole exome sequencing for a comprehensive kidney gene panel encompassing 344 genes associated with kidney diseases and candidate genes highly expressed in the kidney. Results were correlated with phenotype by a multidisciplinary committee of nephrologists, renal pathologists, geneticists, and genetic counselors. Between October 2018 and July 2020, 30 recipient and 5 donor candidates completed testing. Among recipient candidates, 24 (80%) carried the diagnosis of FSGS, 2 (6.7%) tubulointerstitial nephritis, and 1 (3.3%) nephrolithiasis, and 3 (10%) had an unknown cause of kidney disease. The yield for pathogenic/likely pathogenic variants was 43.3%, with majority being COL4 variants (53.8%). Among those with FSGS diagnosis, the yield was 10 of 24 (41.6%), with 29% reclassified into a COL4-related nephropathy. Family history of kidney disease was the only clinical characteristic difference between recipients with positive and negative results (76.9 versus 29.4%; P = 0.025). One of 5 donors tested positive for a pathogenic/likely pathogenic variant and was excluded from donation. We conclude that thoughtful use of genetic testing can be valuable for kidney donor selection and transplant recipient management.

Adult-Onset Genetic Focal Segmental Glomerulosclerosis: A Tale of Two Mutations

Focal segmental glomerulosclerosis (FSGS) is a kidney histologic lesion that may be caused by multiple aetiologies and pathophysiological mechanisms, with podocyte injury and depletion as the common denominator. FSGS may be subdivided into different subclasses: primary, secondary, genetic and unknown forms. Notwithstanding the overlapping clinical and histological characteristics across the different forms of FSGS, their management and response to treatment are strikingly different. Genetic FSGS may be suggested by the appearance of nephrotic syndrome during childhood, but it may also present in adulthood, where the diagnosis is rather challenging due to widely variable clinical and histological phenotypes. Herein we present the case of a 34-year-old female with a family history of chronic kidney disease of undetermined aetiology, referred for a Nephrology consultation due to haematoproteinuria and de novo arterial hypertension. Complementary evaluation revealed a urinary protein/creatinine ratio of 4.3 g/g and albumin/creatinine ratio of 3.9 g/g with hypoalbuminaemia. Kidney biopsy revealed lesions of FSGS, associated with extensive foot process effacement. The constellation of findings and family history of kidney disease raised the suspicion of a genetic cause, therefore genetic testing was performed. Two variants in the NPHS2 gene [c.686G&gt;A, p.(Arg229Gln) and c.855_856del, p(Arg286Thrfs*17)] were found in compound heterozygosity, compatible with the diagnosis of genetic FSGS. This case highlights the importance of a detailed evaluation of patients with FSGS lesions in order to identify the FSGS form, given its therapeutic and prognostic impact, including after kidney transplantation.

A novel heterozygous mutation of the NPHS1 gene in a Chinese child with congenital nephrotic syndrome: A case report.

Congenital nephrotic syndrome (CNS) is a heterogeneous disorder in which massive proteinuria, hypoproteinemia, and hyperlipidemia and marked edema are the main manifestations before 3 months-of-age. Here, we present a case involving the genetic diagnosis of a child with CNS. A 31-day-old male infant with diarrhea for 25 days and generalized edema for more than 10 days. There was no family history of kidney disease. On proband whole exome sequencing, a compound heterozygous mutation of the NPHS1 gene was identified, including a novel in-frame mutation in exon 14 (c.1864_1866dupACC p. T622dup) and a missense mutation in exon 8 (c.928G>A p. D310N). Based on the clinical and genetic findings, this patient was finally diagnosed with CNS. The main treatment options for the patient were 2-fold: anti-infective treatment and symptomatic treatment. The patient died in follow-up 2 months later; the specific reason for death was unclear. Whole exome sequencing and Sanger sequencing confirmed that the infant had CNS. Our study identified a novel mutation in an infant, thus expanding the gene-mutation spectrum of the NPHS1 gene, thus providing an efficient prenatal screening strategy and early genetic counseling.

Renal Genetics Clinic: 3-Year Experience in the Cleveland Clinic

There has been an increasing demand for the expertise provided by a renal genetics clinic. Such programs are limited in the United States and typically operate in a genomics research setting. Here we report a 3-year, real-world, single-center renal genetics clinic experience. Retrospective cohort. Outpatient cases referred to the renal genetics clinic of the Cleveland Clinic between January 2019 and March 2022 were reviewed. Clinical and laboratory characteristics were analyzed. All genetic testing was performed in clinical labs. 309 new patients referred from 15 specialties were evaluated, including 118 males and 191 females aged 35.1±20.3 years. Glomerular diseases were the leading presentation followed by cystic kidney diseases, electrolyte disorders, congenital anomalies of kidneys and urinary tract, nephrolithiasis, and tubulointerstitial kidney diseases. Dysmorphic features were noted in 27 (8.7%) patients. Genetic testing was recommended in 292 (94.5%) patients including chromosomal microarray (8.9%), single-gene tests (19.5%), multigene panels (77.3%), and exome sequencing (17.5%). 80.5% of patients received insurance coverage for genetic testing. 45% (115/256) of patients had positive results, 25% (64/256) had variants of unknown significance, and 22.3% (57/256) had negative results. 43 distinct monogenic disorders were diagnosed. Family history of kidney disease was present in 52.8% of patients and associated with positive genetic findings (OR, 2.28; 95% CI, 1.40-3.74). 69% of patients with positive results received a new diagnosis and/or a change in the diagnosis. Among these, 39.7% (31/78) of patients received a significant change in disease management. Retrospective and single-center study. The renal genetics clinic plays important roles in the diagnosis and management of patients with genetic kidney diseases. Multigene panels are the most frequently used testing modality with a high diagnostic yield. Family history of kidney disease is a strong indication for renal genetics clinic referral.

LBODP032 Case Report Of A 13 Years Old Female With A Novel Pathogenic Variant In The Hnf1b Gene

Abstract Background MODY5 results from mutations in the gene encoding hepatocyte nuclear factor 1 homeobox B (HNF1B), a transcription factor critical in development of the pancreas, liver, intestines, and the urogenital tract (1). We report the case of a pediatric patient with a novel frameshift variant (p. Phe309SerfsTer18) in the HNF1B gene accounting for the co-occurrence of diabetes mellitus and structural renal abnormalities. Clinical case: A 13-years-old female with chronic kidney disease stage 3 (eGFR = 48 ml/min/1.73m2) secondary to congenital dysplastic-appearing left kidney and surgical removal of a cystic dysplastic right kidney was referred to our diabetes clinic for hyperglycemia. She reported long-standing polyuria and polydipsia previously attributed to her kidney disease. She required laparoscopic right nephrectomy at age 5 years due to increasing cyst size. Her left kidney also has small renal parenchymal cysts which have been monitored over time. There is no known family history of kidney disease, and grandparents have a history of diabetes. Laboratory investigation revealed a random blood glucose of 478 mg/dL and a hemoglobin A1c of 12.2%. She was not in diabetic ketoacidosis. She had a detectable insulin level of 5.1 mcIU/mL and C-peptide was 3.4 ng/mL. She was initially presumed to have Type 1 diabetes based on a relatively low insulin level and started on basal-bolus insulin (up to 0.59 units/kg of weight/day). Glycosylated hemoglobin was 8.7% one month after diagnosis. Glutamic acid decarboxylase, zinc transporter, islet cell, and insulin autoantibodies were not detected, however, and she was then suspected to have either Type 2 diabetes or MODY. Approximately one year later, she was taken off insulin due to hypoglycemia and managed only with metformin 500 mg twice daily. Next-generation sequencing revealed a de novo pathogenic variant in HNF1B causing a frameshift deletion (p. Phe309SerfsTer18). Genetic testing of parents was negative. Once her diagnosis of MODY5 was made, she was started on glipizide 2.5 mg once daily which has been titrated up to a dose of 5 mg with some success. However, she has since been re-started on insulin (up to 0.2 units/kg/day) due to hyperglycemia keeping in line with the MODY5 phenotype likely causing destruction of beta cells over time (1). Conclusion We report a case of MODY5 with a novel frameshift mutation (p. Phe309SerfsTer18) in the HNF1B gene. This case highlights the importance of screening for HNF-1B mutations in those patients with structural renal abnormalities and hyperglycemia, as diagnosis can guide management decisions and provide prognostic information. Reference Bellanné-Chantelot C, Chauveau D, Gautier JF, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7): 510-517. doi: 10.7326/0003-4819-140-7-200404060-0000 Presentation: No date and time listed

Determinants of Chronic Kidney Disease among Diabetes Mellitus Patients at Gatundu Level 5 Hospital, Kiambu County, Kenya

The prevalence of chronic kidney disease (CKD) is rising alarmingly throughout the world, and it is one of the major public health menace due to the significant morbidity and mortality it is associated with. The burden of CKD inexplicably affects low-income nations like Kenya, where the two main public health concerns for the CKD growth rate are hypertension and diabetes mellitus. The aim of this study was to identify the determinants of chronic kidney disease diabetes mellitus patients and also assess their awareness, perspectives and prevalence of CKD. A hospital based cross-sectional study design was conducted at a rural hospital in central Kenya among adult (≥18 years) diabetes mellitus patients. Sample size was determined using Yamane Taro formula. Informed written consent was obtained from each participant and data was collected by interview and chart review; Glomerular filtration rate (GFR) was estimated from serum creatinine using modification of diet in renal disease (MDRD) formula, while CKD was defined as eGFR of less than 60mls/min/1.73m2 for more than three months. Multivariate logistic regression was used to identify independent determinants of CKD and a p-value of &lt;0.05 was considered to be statistically significant. Majority of the participants (43.42%) were aged between50-60 years and 95 (62.5%) of them were females. Participants with history of high blood pressure had a 129.4 %(AOR;1.29495% CI, 2.401-.698) risk of having CKD, while those who did not perform physical exercises were found to be 123.3% (AOR 1.233, 95% CL,1.889-.805) times more likely to have CKD Only 39 (25.8%) of the participants had average awareness about CKD and its risk factors. The overall unadjusted prevalence of CKD among diabetic patients was 78.2% (n= 119, 95% CI). The researcher found that existing history of hypertension, lack of physical exercises, family history of kidney disease, rural residency and low levels of education were independent determinants associated ......