Cause Of Chronic Kidney Disease Research Articles

#3250 RENAL HAEMODYNAMIC PARAMETERS IN DIABETIC NEPHROPATHY

Abstract Background and Aims Diabetic nephropathy is the leading cause of chronic kidney disease in modern world. Timely diagnosis is of paramount importance, especially after the recent introduction of novel therapies. The presence of an already altered renal haemodynamic profile was investigated in all patients referred with suspected diabetic nephropathy, upon their initial presentation to our renal department. Method During the past seven years, from January 2015 to December 2022, 578 patients were referred to the Renal Department for ultrasound assessment. Additionally to their standard assessment, they underwent renal ultrasound and triplex examination. Diabetic nephropathy (DN) was diagnosed in 149 patients. A group of patients with an estimated GFR> 60 ml/min, without diabetic nephropathy, was randomly selected from the same pull of patients for comparison reasons (control group). Renal haemodynamics assessment, including renal arteries, aorta and intrarenal resistive indexes (RI) of both kidneys, estimated glomerular filtration rate (CKDEPI) and 24h albuminuria, were evaluated in all patients. Results The mean age of the patients was 72.5 ±10.4 vs 65.8 ±6.9 years, for the DN and control group respectively. Renal length was comparable in both groups, renal diameter of left kidney was 10.61 ±1.28 vs. 10.59 ±1.44 cm and renal diameter of right kidney was 10.53 ±1.38 vs. 9.85 ±2.89 cm for DN group and control respectively. The estimated GFR was significantly lower in the DN group, 42.1±23.6 vs. 82.7 ±11.3 ml/min (p<0.05). Both renal arteries presented higher velocity values in the DN group, 53.4 ±22.2 vs. 21.7 ±28.9 cm/sec (p<0.0001) and 52.4 ±23.9 vs. 24.8 ±32.3 (p<0.0001), for the left and right renal artery. DN patients showed RI values above upper normal limit of 0.70, being at the same time significantly higher compared to control group, 0.73 ±0.06 vs. 0.61 ±0.17 (p<0.0001) and 0.72 ±0.06 vs. 0.59 ±0.20 (p<0.0001), for the left and right kidney respectively. Conclusion The presence of significantly increased renal artery velocity in diabetic nephropathy patients compared to control patients has not been described earlier to the best of our knowledge. It represents a new finding that is mainly attributed to the presence of arteriopathy. Evaluation of renal haemodynamics using triplex ultrasound, represents a non – invasive, readily available, inexpensive examination. When performed at initial patient presentation, constitutes an invaluable tool, timely assisting to diagnosis and treatment of diabetic patients.

#5114 THE GENOTYPE DISTRIBUTION IN A SINGLE-CENTRE COHORT OF PATIENTS WITH POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Polycystic kidney disease (PKD) is one of the most common causes of chronic kidney disease (CKD) and could lead to the end-stage kidney disease (ESKD) both in adulthood and in childhood. In the last few years many genes were discovered to be associated with PKD beyond the classical genes PKD1 and PKD2, that account for the majority of patients with ADPKD (Autosomal Dominant Polycystic Kidney Disease), and PKHD1 and DZIPIL that are responsible of ARPKD (Autosomal Recessive Polycystic Kidney Disease). The new genes are associated with different type of extra-renal involvement and with variable chance to develop CKD or ESKD. Thus, it is important for clinicians to define what mutation is involved in each patient to improve care in a context of precision medicine. We here describe a cohort of 65 consecutive patients followed at our PKD outpatient clinic who underwent the genetic analysis. Method We conducted a retrospective study of patients followed at our PKD outpatient clinic who underwent a genetic test for clinical reasons. We recorded why test was performed, with which modality and what was the result. If the analysis was positive we analyzed if only one or more genes were found mutated and if they belong to new genes described as being involved in PKD or if they are usually described in association with different diseases. Then, we collected demographic and clinical information (age, sex, renal function/presence of absence of ESKD) and the radiological description of kidneys in order to distinguish between typical and atypical PKDs. Results Among the 65 patients of our cohort 28 (43%) were males and 37 (57%) were females, the mean age was 56±18.6 years old; 20% had ESKD. They underwent genetic analysis for different reasons: 31 because of atypical PKD forms, 6 to define a suspected de novo mutation, 14 as a familiar screening and 14 for a better prognosis definition or when they approached the kidney transplant. The genetic analysis was conducted in two main ways: sequencing of PKD1 and PKD2 genes according to modern standards or exome sequencing. The first type of analysis was used for typical ADPKD forms whereas the second type was used when patients displayed an atypical presentation for both cysts distribution and kidney diameter (usually not enlarged kidneys with multiple bilateral cysts) and in two patients in which PKD1 and PKD2 sequencing was negative despite the PKD phenotype. We found that 25% of patients were negative, and the others are almost equally distributed between typical gene mutations and mutations in other genes (40% and 35% respectively) (Figure 1A). Of those with typical mutation, 81% was PKD1 positive and 19% PKD2 positive, a distribution that reflects that of literature (Figure 1B). Of those with other genes positivity: 52% had a DNAJB11 mutation, 17% a mutations in other PKD genes (ALG8, LRP5, PKHD1, COL4A1, IFT140), 32% had a mutation in genes usually associated with CAKUT (congenital anomalies of kidney and urinary tract) or with syndromic or extra-renal diseases (Figure 1C). 18 patients presented with multiple mutations, usually 2, in one case three and in another 4. Of them, the 22% had a double PKD1 mutation, while the others showed mutations in different genes associated with syndromic or extra-renal diseases (Figure 1D). Conclusion Our cohort revealed a wide variety of genetic mutations and also an almost equal distribution between typical genes and atypical/other genes. This could be the result of the small number of patients involved and of the monocentric design of the study (we have a cluster of patients with DNAJB11 belonging to the same small geographical area), but also of the larger inclusion of patients presenting with atypical PKDs. Unfortunately a 25% of patients remained genetically unresolved despite the use of exome sequencing.

#6143 FAMILIAL LECITHIN: CHOLESTEROL ACYLTRANSFERASE (LCAT) DEFICIENCY AS A CAUSE OF CHRONIC KIDNEY DISEASE – A CASE REPORT

Abstract Background and Aims Genetic causes of chronic kidney disease are becoming more recognized. Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disorder caused by loss of function mutations in LCAT gene. Patients present with abnormal lipid profile characterized with markedly reduced HDL-C, corneal opacification, anemia, and renal disease, which eventually progresses to kidney failure. Several studies reported genetic variants in LCAT gene that are associated with FLD, and others in certain apolipoprotein genes that act as risk factors for the disease. Incomplete form of FLD, caused by certain mutation, leads to fish-eye disease characterized by progressive corneal opacification. FLD was described in studies from Europe, Latin and North America, Australia and Japan. In Jordan, genetic and clinical studies in FLD patients are absent. Method We present a 36-year-old female who presented with nephrotic-range proteinuria, high serum creatinine, hypertension and corneal opacity. Further examination showed a severely reduced HDL level, an increased triglycerides level, anemia and mild thrombocytopenia. Patient's laboratory values at presentation are shown in Table 1. Her blood film showed normocytic and normochromic red blood cells, anisopoikilocytosis and target cells. Light and electron microscopy examination of the kidney biopsy revealed intramembranous, subendothelial and mesangial lipid deposition and vacuolization. In addition, the patient was found to have a family history of corneal opacity and chronic kidney disease. Therefore, FLD was suspected. Whole exome sequencing was employed to identify FLD variants. Results The patient was found to be homozygous at 154+5delG in LCAT gene, heterozygous at 388T>C in apolipoprotein E gene (APOE) and homozygous at 1114G>C in WW domain-containing oxidoreductase gene (WWOX). The patient's chronic kidney disease was managed supportively with low salt diet, moderate protein intake, statins, angiotensin receptor blockers and blood pressure control. After one year of follow up, her serum creatinine is 220 μmol/l and estimated proteinuria is 1.2 gm/24 hrs. Conclusion FLD should be suspected in patients who present with kidney disease associated with significantly low HDL cholesterol and corneal opacity. Family members should also be screened for kidney disease and genetic mutation in LCAT gene. To date, treatment is mainly supportive and enzyme replacement therapy is not yet widely available.

#5431 THE VALUE OF MANAGING DIABETIC KIDNEY DISEASE: CONTRASTING FINDINGS FROM THE INDIVIDUAL PATIENT AND POPULATION LEVEL PERSPECTIVES

Abstract Background and Aims The management of diabetic kidney disease (DKD) is associated with considerable resource utilisation. Within the context of the broader healthcare system, understanding the health economic implications of adopting strategies to ameliorate the progression of DKD is imperative for fully informed decision-making. The objective of this study was to estimate the UK whole healthcare system economic value, from the individual patient and population perspectives, associated with modifying the progression of DKD through attenuating the decline in eGFR by values consistent with those observed in recent randomised clinical outcome trials. Method Since type 2 diabetes (T2D) is the commonest single cause of chronic kidney disease (CKD), we developed a deterministic model utilising published estimates of disease progression stratified by stages: stage 1/2, stage 3a, stage 3b and stage 4/5. Patient characteristics and mean annual decline in eGFR were aligned to the placebo arm of DECLARE-TIMI 58 (-2.44 ml/min/1.732). We explored scenarios where a sustained attenuation in the rate of eGFR decline by 1 and 2ml/min/1.732 per year was realised. T2D specific and all-cause mortality were captured using UKPDS risk equations. CKD stage specific costs and changes in health utility were drawn from NICE guidelines (NG203). Per-patient and population level costs (indexed to 2022) and quality adjusted life years (QALYs) were estimated, and both discounted at 3.5%. Results We estimated there were 3.2M, 0.6M, 0.2M and 0.04M DKD patients in stages 1/2, 3a, 3b and 4/5 respectively. Declining kidney function was associated with increasing per-patient lifetime costs and decreasing QALYs: stage 1/2 £36,714, 8.1 QALYs; stage 3a £90,666, 6.5 QALYs; stage 3b £126,931, 5.2 QALYs; stage 4/5 £168,604, 3.7 QALYs. A sustained attenuation in the rate of eGFR decline by 1 and 2ml/min/1.732 per year had the greatest impact in those in stage 3b: with cost savings of £23,690 and £47,463 and gains in QALYs of 0.68 and 1.46 for 1 and 2ml/min/1.732 respectively. At the population level, however, total lifetime cost for DKD was greatest in those in stage 1/2 £30.3Bn; followed by stage 3a, £19.2Bn; stage 3b £9.5Bn; stage 4/5 £146M. A sustained attenuation in eGFR resulted in the largest cost savings in those in stage 1/2: £16.9 Bn and £22.3Bn for 1 and 2ml/min/1.732 respectively, and the greatest gains in QALYs of 0.8M and 1.1M for 1 and 2ml/min/1.732 respectively. In contrast, population level stage 4 cost savings and QALY gains were modest at £70.7M and £281.6M and 0.02M and 0.4M for 1 and 2ml/min/1.732 respectively. Conclusion The notion of value in healthcare is influenced by stakeholder perspective. From the clinician's and patient's perspective the greatest value in attenuating the progression of DKD is in those with more advanced disease. However, from the health care provider perspective, at the population level, modest cost-savings and QALY gains are realised in such patients. By contrast, those at an earlier disease stage deliver much greater population level return on investment consequent upon larger numbers of such individuals. This study illustrates that attenuating DKD progression provides value at both the individual and public health levels, irrespective of disease stage.

#3895 COMPARABLE RENO-CARDIAC PROTECTIVE EFFECTS OF SGLT2 INHIBITION VERSUS DPP-4 INHIBITION IN DIABETIC KIDNEY TRANSPLANT RECIPIENTS: KUWAIT EXPERIENCE

Abstract Background and Aims Diabetes is the most common cause of chronic kidney disease (CKD) globally. The renal and cardio-vascular benefits of the new anti-diabetic agents are not assessed comprehensively. We aimed to evaluate the short term renal and cardio-protective effects of Sodium-Glucose Cotransporter-2 Inhibition (SGLT2i) Vs. Dipeptidyl peptidase-4 Inhibition (DPP4i) among diabetic kidney transplant recipients. Method In this observational trial, 222 diabetic kidney transplants recipients (NODAT or type 2 diabetes) were enrolled and were categorized into two groups. Group 1 (n = 99) received SGLT2i while group 2(n = 123) received DPP4i as an add on antidiabetic medications. All patients in the two groups were followed up for 12 months. Results Most patients in the two groups (1&2) were men (59.6 vs. 61.7%, p = 0.73) in their middle age (58.5±11.9 vs. 54.4±12.9, p = 0.016) years respectively. The two groups were matched regarding their demographics especially the type of donor, type of immunosuppression (induction or maintenance), number of cardiovascular events before enrollment in the study and the number of patients who were maintained on ACEi or ARB(p>0.05). The minority of patients were smokers (12.9 vs.8.7%), and chronic glomerulonephritis was the original disease in 36.4 vs. 35.4% in the two groups, respectively. Most of the enrolled patients (72.8 vs. 78.6%) underwent hemodialysis pre-transplant. During follow up period, patients in both groups were comparable regarding mean blood pressure, body weight, HbA1C, 24-hour urine protein, and graft function (represented by the mean serum creatinine) at different time intervals and compared to base line values(p>0.05). However, the mean HbA1C was significantly higher in group 1 during the whole follow up period of the study (p<0.05) but it did not drop significantly compared to baseline values (p>0.05). We did not report any macroangiopathic events (cerebral stroke, acute myocardial infection, or peripheral arterial disease) in the two groups during the study. Conclusion Both GLT2i and DPP-4 I are comparable regarding renal and cardio-vascular protection among diabetic kidney transplant recipients.

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation

BackgroundDiabetic kidney disease (DKD) has been the leading cause of chronic kidney disease in developed countries. Evidence of the benefits of resveratrol (RES) for the treatment of DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against DKD are limited.MethodsDrug targets of RES were obtained from Drugbank and SwissTargetPrediction Databases. Disease targets of DKD were obtained from DisGeNET, Genecards, and Therapeutic Target Database. Therapeutic targets for RES against DKD were identified by intersecting the drug targets and disease targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were performed using the DAVID database and visualized by Cytoscape software. Molecular docking validation of the binding capacity between RES and targets was performed by UCSF Chimera software and SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, and western blot were used to verify the reliability of the effects of RES on target proteins.ResultsAfter the intersection of the 86 drug targets and 566 disease targets, 25 therapeutic targets for RES against DKD were obtained. And the target proteins were classified into 6 functional categories. A total of 11 cellular components terms and 27 diseases, and the top 20 enriched biological processes, molecular functions, and KEGG pathways potentially involved in the RES action against DKD were recorded. Molecular docking studies showed that RES had a strong binding affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, and CYP2C9 domains. The HG-induced podocyte injury model was successfully constructed and validated by RT-qPCR and western blot. RES treatment was able to reverse the abnormal gene expression of PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR.ConclusionsRES may target PPARA, SHBG, AKR1B1, PPARG, IGF1R, MMP9, AKT1, and INSR domains to act as a therapeutic agent for DKD. These findings comprehensively reveal the potential therapeutic targets for RES against DKD and provide theoretical bases for the clinical application of RES in the treatment of DKD.

Evidence Linking Cadmium Exposure and β2-Microglobulin to Increased Risk of Hypertension in Diabetes Type 2.

The most common causes of chronic kidney disease, diabetes, and hypertension are significant public health issues worldwide. Exposure to the heavy metal pollutant, cadmium (Cd), which is particularly damaging to the kidney, has been associated with both risk factors. Increased levels of urinary β2-microglobulin (β2M) have been used to signify Cd-induced kidney damage and circulating levels have been linked to blood pressure control. In this study we investigated the pressor effects of Cd and β2M in 88 diabetics and 88 non-diabetic controls, matched by age, gender and locality. The overall mean serum β2M was 5.98 mg/L, while mean blood Cd and Cd excretion normalized to creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L and 0.0084 µg/L of filtrate (0.95 µg/g creatinine), respectively. The prevalence odds ratio for hypertension rose by 79% per every ten-fold increase in blood Cd concentration. In all subjects, systolic blood pressure (SBP) showed positive associations with age (β = 0.247), serum β2M (β = 0.230), and ECd/Ccr (β = 0.167). In subgroup analysis, SBP showed a strong positive association with ECd/Ccr (β = 0.303) only in the diabetic group. The covariate-adjusted mean SBP in the diabetics of the highest ECd/Ccr tertile was 13.8 mmHg higher, compared to the lowest tertile (p = 0.027). An increase in SBP associated with Cd exposure was insignificant in non-diabetics. Thus, for the first time, we have demonstrated an independent effect of Cd and β2M on blood pressure, thereby implicating both Cd exposure and β2M in the development of hypertension, especially in diabetics.

Gene therapy for pediatric genetic kidney diseases

AbstractGenetic kidney disease is the main cause of chronic kidney disease in children. While the pathogenic genes associated with most genetic kidney diseases have been identified, the underlying mechanisms of disease initiation remain ambiguous, and effective treatment modalities are limited. Gene therapy has emerged as a promising approach for treating genetic diseases. Several gene therapy drugs have been successfully launched to treat genetic diseases affecting the eyes and muscles. However, the development of gene therapy agents for kidney diseases lags behind that of other genetic disorders. In this review, we first comprehensively summarize the main gene therapy strategies. Next, we provide an overview of current treatment options as well as the latest research on gene therapy approaches for pediatric genetic kidney diseases with a particular emphasis on Alport syndrome and polycystic kidney disease. Finally, we discuss the challenges and potential solutions for gene therapy of pediatric genetic kidney diseases.

Interstitial Nephritis: Wherefrom, Wherein, and Whereto.

Abnormalities of the renal interstitium were noted early while identifying chronic kidney disease in 1827; however, interest in glomerular and vascular lesions was then distracted from their further study. As a complication of scarlet fever, interstitial lesions attracted attention in 1859 and came to be defined as acute interstitial nephritis in 1898. The chronic form of interstitial nephritis was traditionally attributed to pyelonephritis until the advent of kidney biopsy in the 1950s, when interstitial lesions were recognized as an independent primary cause of chronic kidney disease from studies of analgesic nephropathy and vesico-ureteral reflux. The term tubulointerstitial nephritis was introduced in 1963 and promoted to denote the role of the tubules in the pathogenesis and the clinical presentation of interstitial nephritis as tubular dysfunction. Studies since then have established that fibrotic tubulointerstitial nephritis lesions correlate best with the severity and progression of kidney diseases independent of their etiology.

Chronic Kidney Disease Prediction using Machine Learning Algorithms

Abstract: Diabetes and high blood pressure are the primary causes of Chronic Kidney Disease (CKD). A person with CKD has a higher chance of dying young. Doctors face a difficult task in diagnosing the different diseases linked to CKD at an early stage to prevent the disease. Early discovery of CKD empowers sufferers to get the opportunity remedy to decorate the motion of this infection. CKD is among the top 20 causes of death worldwide and affects approximately 10% of the world's adult population. CKD is a disorder that disrupts normal kidney function. The novelty of this study lies in developing a diagnosis system to detect chronic kidney diseases. This study focused on evaluating a dataset collected from 400 patients containing 24 features. The mean and mode statistical analysis methods were used to replace the missing numerical and nominal values. To choose the most important features, Recursive Feature Elimination (RFE) was applied. Three classification algorithms applied in this study were k-nearest neighbors (KNN), Random Forest Classifier (RFC), and Ada Boost Classifier (ABC). All the classification algorithms achieved promising performance. The RFC and ABC Algorithm outperformed all other applied algorithms, reaching an accuracy, precision, recall, and F1-score of 100% for all measures. Therefore, Machine Learning techniques are of great importance in the early detection of CKD. These techniques are supportive of experts and doctors in early diagnosis to avoid developing kidney failure.

End-stage renal disease due to retroperitoneal fibrosis in neurofibromatosis type I.

Retroperitoneal fibrosis (RF) commonly leads to renal impairment due to compression of ureters, and around 8% of patients eventually progress to end-stage renal disease (ESRD). We present a case of RF in a 61-year-old female patient with neurofibromatosis type 1 (NF1) who developed ESRD. She presented with a postrenal acute kidney injury, being initially treated with an ureteral catheter. A magnetic resonance imaging of the abdomen showed parietal thickening of the right ureter, and she underwent right ureter reimplantation through bladder flap and psoas hitch. There was an extensive area of fibrosis and inflammation over the right ureter. Biopsy disclosed nonspecific fibrosis, which was consistent with RF. Although the procedure was successful, she developed ESRD. We review atypical presentations of RF and causes of renal injury in NF1. RF should be considered a possible cause of chronic kidney disease in patients with NF1, perhaps due to an unknown underlying mechanism.

The prevalence of chronic kidney disease among type 2 diabetes mellitus patients in central South Africa.

Type 2 diabetes mellitus (T2DM) is a leading cause of chronic kidney disease (CKD). The prevalence of CKD among T2DM patients in Africa is 22.0%. The cut-off age for dialysing diabetic patients in the resource-limited state sector in South Africa is 50 years. Type 2 diabetes mellitus patients who develop CKD are likely to be excluded from chronic dialysis and rely on control of risk factors, including blood pressure and blood glucose levels, to prevent CKD progression. We aimed to determine the prevalence of CKD among T2DM patients attending the diabetes clinic at Pelonomi Academic Hospital, Bloemfontein. In this retrospective cross-sectional study, medical records of patients (January 2016 and December 2018) were reviewed to collect demographic and clinical information. In total, 244 records were reviewed. Sixty-one (25.0%, 95% confidence interval [CI]: 20% - 30.8%) T2DM patients had CKD. The rate of CKD was slightly higher in males (n= 24/81; 29.6%) compared with females (n= 37/163; 22.7%). Most patients with CKD (n= 58; 95.1%) were 50 years of age. Only 17.8% of patients achieved a glycosylated haemoglobin (HbA1c) of 7.0%. Blood pressure was controlled in 14.3% of hypertensive patients. Renin-angiotensin-aldosterone system inhibitors were used by 78.6% of patients. A high prevalence of clinically significant CKD among T2DM patients with poor prospects of chronic dialysis in a resource-limited setting was observed. The risk factors for CKD development and progression should be adequately managed in T2DM patients.Contribution:This study emphasises the need for further research and innovation to improve outcomes of T2DM patients with CKD in resource-constrained settings.

A cohort study on the correlation between serum uric acid trajectory and the progression of renal function in patients with Type 2 diabetes mellitus.

Diabetic kidney disease is one of the most serious complications of diabetes mellitus (DM), and it is a main cause for chronic kidney disease and end-stage kidney disease (ESRD). It is important to find out the factors that cause the progression of renal function. The study aims to explore the relationship between serum uric acid (SUA) trajectory and the progression of renal function in patients with Type 2 diabetes mellitus (T2DM). A total of 846 patients with T2DM, who were admitted to the Department of Nephrology and Endocrinology, the Third Xiangya Hospital of Central South University, from January 2009 to December 2021 and met the criteria of baseline estimated glomerular filtration rate (eGFR)≥60 mL/(min·1.73 m2), were selected as the research subjects. The SUA data of multiple measurements were collected and identified as different SUA trajectories by group-based trajectory modeling (GBTM). According to the SUA trajectories, the patients were divided into a low trajectory group (105 cases), a middle trajectory group (396 cases), a middle high trajectory group (278 cases), and a high trajectory group (67 cases). Cox regression analysis was used to examine the effect of SUA trajectory on the progression of renal function in patients with T2DM. Subgroup analysis was performed by sex, age, course of disease, body mass index (BMI) and hemoglobin A1c (HbA1c). The median follow-up was 4.8 years. At the end of follow-up, 158 patients had different degrees of decline in renal function. After adjusting for multiple confounding factors by Cox regression analysis, the risks of eGFR<60 mL/(min·1.73 m2), eGFR reduction rate≥50%, serum creatinine (Scr) doubling and composite endpoint (eGFR reduction rate≥50%, Scr doubling or ESRD) in the high trajectory group were significantly higher than those in the low trajectory group, with HR of 3.84 (95% CI 1.83 to 8.05), 6.90 (95% CI 2.27 to 20.96), 6.29 (95% CI 2.03 to 19.52), and 8.04 (95% CI 2.68 to 24.18), respectively. There was no significant difference in the risk of ESRD among the above 4 groups (all P>0.05). Subgroup analysis showed that: compared with the low trajectory group, the risks of eGFR<60 mL/(min·1.73 m2) in patients with high trajectory in the subgroup of male, female, age<65 years, course of disease<10 years, BMI≥24 kg/m2 and HbA1c≥7% were increased (all P<0.05). The SUA trajectory had no interaction with sex, age, course of disease, BMI and HbA1c (all interactive P>0.05). The high SUA trajectory increases the risk for progression of renal function in patients with T2DM. Long-term longitudinal changes of SUA should be paid attention to.

Metformin and Canagliflozin Are Equally Renoprotective in Diabetic Kidney Disease but Have No Synergistic Effect.

Diabetic Kidney Disease (DKD) is a major microvascular complication for diabetic patients and is the most common cause of chronic kidney disease (CKD) and end-stage renal disease. Antidiabetic drugs, such as metformin and canagliflozin, have been shown to exert renoprotective effects. Additionally, quercetin recently showed promising results for the treatment of DKD. However, the molecular pathways through which these drugs exert their renoprotective effects remain partly unknown. The current study compares the renoprotective potential of metformin, canagliflozin, metformin + canagliflozin, and quercetin in a preclinical rat model of DKD. By combining streptozotocin (STZ) and nicotinamide (NAD) with daily oral N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration, DKD was induced in male Wistar Rats. After two weeks, rats were assigned to five treatment groups, receiving vehicle, metformin, canagliflozin, metformin + canagliflozin, or quercetin for a period of 12 weeks by daily oral gavage. Non-diabetic vehicle-treated control rats were also included in this study. All rats in which diabetes was induced developed hyperglycemia, hyperfiltration, proteinuria, hypertension, renal tubular injury and interstitial fibrosis, confirming DKD. Metformin and canagliflozin, alone or together, exerted similar renoprotective actions and similar reductions in tubular injury and collagen accumulation. Renoprotective actions of canagliflozin correlated with reduced hyperglycemia, while metformin was able to exert these effects even in the absence of proper glycemic control. Gene expression revealed that the renoprotective pathways may be traced back to the NF-κB pathway. No protective effect was seen with quercetin. In this experimental model of DKD, metformin and canagliflozin were able to protect the kidney against DKD progression, albeit in a non-synergistic way. These renoprotective effects may be attributable to the inhibition of the NF-κB pathway.

Optimizing Multidisciplinary Care of Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus.

Diabetes is the leading cause of chronic kidney disease (CKD), a condition associated with significant morbidity and mortality. As these patients have a high risk of developing cardiovascular disease and end-stage kidney disease, there is a need for early detection and early initiation of appropriate therapeutic interventions that slow disease progression and prevent adverse outcomes. Due to the complex nature of diabetes and CKD management, a holistic, patient-centered, collaborative care approach delivered by a coordinated multidisciplinary team (ideally including a clinical pharmacist as part of a comprehensive medication management program) is needed. In this review, we discuss the barriers to effective care, the current multidisciplinary approach used for CKD prevention and treatment, and the potential ways that the multidisciplinary management of CKD associated with type 2 diabetes mellitus can be refined to improve patient outcomes.

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.

Challenges of Glycemic Control in People With Diabetes and Advanced Kidney Disease and the Potential of Automated Insulin Delivery.

Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease in the world. It is known that maintaining optimal glycemic control can slow the progression of CKD. However, the failing kidney impacts glucose and insulin metabolism and contributes to increased glucose variability. Conventional methods of insulin delivery are not well equipped to adapt to this increased glycemic lability. Automated insulin delivery (AID) has been established as an effective treatment in patients with type 1 diabetes mellitus, and there is emerging evidence for their use in type 2 diabetes mellitus. However, few studies have examined their role in diabetes with concurrent advanced CKD. We discuss the potential benefits and challenges of AID use in patients with diabetes and advanced CKD, including those on dialysis.

In situ assessment of Mindin as a biomarker of podocyte lesions in diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal failure worldwide. Several mechanisms are involved in the pathogenesis of this disease, which culminate in morphological changes such as podocyte injury. Despite the complex diagnosis and pathogenesis, limited attempts have been made to establish new biomarkers for DN. The higher concentration of Mindin protein in the urine of patients with type 2 diabetes mellitus suggests that it plays a role in DN. Therefore, this study investigated whether in situ protein expression of Mindin can be considered a potential DN biomarker. Fifty renal biopsies from patients diagnosed with DN, 57 with nondiabetic glomerular diseases, including 17 with focal segmental glomerulosclerosis (FSGS), 14 with minimal lesion disease (MLD) and 27 with immunoglobulin A nephropathy (IgAN), and 23 adult kidney samples from autopsies (control group) were evaluated for Mindin expression by immunohistochemistry. Podocyte density was inferred by Wilms' tumor 1 (WT1) immunostaining, while foot process effacement was assessed by transmission electron microscopy. Receiver operative characteristic (ROC) analysis was performed to determine the biomarker sensitivity/specificity. Low podocyte density and increased Mindin expression were observed in all cases of DN, regardless of their class. In the DN group, Mindin expression was significantly higher than that in the FSGS, MCD, IgAN and control groups. Higher Mindin expression was significantly positively correlated with foot process effacement only in class III DN cases. Furthermore, Mindin protein presented high specificity in the biopsies of patients with DN (p < 0.0001). Our data suggest that Mindin may play a role in DN pathogenesis and is a promising biomarker of podocyte lesions.

Free fatty acid exacerbates diabetic kidney injury by suppressing autophagy-lysosomal function via ER stress

Diabetic kidney disease (DKD), the leading cause of chronic kidney disease, is characterized by accumulation of renal tubule free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets (LDs) and cell death. The present study aimed to investigate how FFA or TG induces renal tubular cell apoptosis, thereby contributing to the progression of DKD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated ER stress and organelle dysfunction in tubular cell injury. Six-week-old wild-type (WT) and eNOS-deficient C57BL/6J mice were placed on normal diet (ND, 5% fat calories) or high-fat diet (HFD, 42% fat calories) for two weeks, and then rendered diabetic with alloxan. Alloxan injection resulted in equivalent hyperglycemia in ND and HFD-fed WT and eNOS-deficient mice. However, a massive increase in urinary albumin was observed in HFD plus alloxan-treated eNOS-deficient mice, which was accompanied by excessive accumulation of neutral lipids in damaged proximal tubules. Moreover, in the diabetic eNOS-deficient kidneys, HFD feeding resulted in suppression of autophagy-lysosomal function and increase in tubular cell apoptosis. Cell studies revealed that saturated FFA palmitate but not unsaturated oleate induced eukaryotic initiation factor (eIF)2α phosphorylation, and then stimulated the activating transcription factor (ATF)4 and C/EBP homologous protein (CHOP), which, in turn, impaired autophagy-lysosomal function, leading to cell apoptosis. In addition, we observed a dramatic upregulation of LD-associated protein ADRP expression and TG-enriched LD formation in oleate-treated renal tubular cells, which was not apparent in palmitate-treated ones. Together, this study demonstrates that accumulation of renal FFA, rather than TG, plays a crucial role in the pathogenesis of diabetic kidney injury by suppressing autophagy-lysosomal function through ER stress signaling. This work was supported by the National Institutes of Health Grants SC1DK112151 and S21MD000101. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical Implications and Risk Factors for Erectile Dysfunction in Kidney Transplant: A Single-Center Assessment.

Erectile dysfunction (ED) affects the great majority of people undergoing dialysis and also the majority of patients undergoing kidney transplantation. In this study, we investigated the degree of erectile dysfunction (ED), as well as its prevalence, contributory variables, and overall impact after renal transplant. Adult male kidney transplant patients were the subject of an observational, non-interventional study that was conducted at a single center. Age, time and type ofdialysis before transplantation, comorbidities, factors associated with cardiovascular risk, data on sexual history, physical examination, and laboratory results were among the clinical data we examined. In addition to gathering clinical and demographic characteristics, the International Index of Erectile Function (IIEF) questionnaire was used to evaluate sexual function. A total of 170 renal transplanted patients between 20 and 70 years old (mean age: 45.40±11.5) were included in this study. All of the patients had immunosuppressive treatment with a calcineurin inhibitor (cyclosporine or tacrolimus) and had a normalglomerular filtration rate (GFR). The prevalence of sexual dysfunction increased with age (42.6% of patients under 40, 47.4% of patients in the 40-60 age group, and 78.9% of patients over 60). Mild, moderate, and severe ED was noted in 33.5%, 20.6%, and 10.6% of cases, respectively, and 51 (30%) patients reported having a normal sexual function.While calcium channel blockers (122 cases) were the most commonly used antihypertensive medication and chronic glomerulosclerosis (55.3%) was the most common cause of chronic kidney disease (CKD) before transplantation, none of these variables appear to have affected the severity of erectile dysfunction. The only medications associated with sexual dysfunction were alpha-blockers and aspirin (75 mg)(p=0.026 and p=0.013, respectively). Although kidney transplantation has positive impacts on the quality of life, erectile dysfunction is a frequent condition among patients with renal transplants, and it has an increased frequency with age. In our study, it has been observed that only a small percentage of the research group had a normal sexual function, although most of the patients were young, and that alpha-blockers and aspirin (75 mg) are associated with erectile dysfunction.