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Introduction: For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed. Methods: We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. Results: The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively. Conclusions: In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion In 2015, a selective decrease in the glomerular filtration of middle‐sized molecules such as cystatin C compared to small molecules such as creatinine was first described and tentatively termed “Shrunken pore syndrome.” Numerous studies have thereafter found an association between this syndrome (defined by a low eGFRcystatin C to eGFRcreatinine ratio) and mortality and morbidity. In 2023, the syndrome was renamed selective glomerular hypofiltration syndromes (SGHS) as shrunken pores are not the only pathophysiological mechanism. Recently, some studies have used the difference between eGFRcystatin C and eGFRcreatinine to describe a similar disorder, and this investigation compares the two measures.Using a cohort of 2781 adults with a median follow‐up of 5.6 years, referred for determination of glomerular filtration rate (GFR), estimated GFR (eGFR) was determined using four equations. SGHS was defined using the eGFRdifference and the eGFRratio and association to mortality investigated through adjusted Cox proportional hazard models. From each adjusted regression model, Harrell's C‐index and 95% confidence intervals were calculated.Both measures were associated with mortality. No significant differences concerning hazard ratios or Harrell's C‐index were found between the two measures to estimate mortality, and both identified SGHS and increased mortality in a subpopulation of 567 “healthy” individuals with no prior diagnosis and with no kidney disorder according to the kidney disease improving global outcomes‐criteria.The eGFRdifference is not superior to the eGFRratio in diagnosing SGHS or estimating mortality. However, as the two measures do not identify the same subpopulation, using them simultaneously might improve risk stratification. [ABSTRACT FROM AUTHOR]

Backgrounds: Crush syndrome (CS) is the leading cause of death after earthquakes, second only to direct trauma. Acute kidney injury (AKI) is the most severe complication of CS. Research based on the CS-AKI mouse model and kidney function assessment by glomerular filtration rate (GFR) helps to elucidate the pathogenesis of CS-AKI, which contributes to effective treatment measures. Methods: Mice were modeled by the multi-channel small animal crushing platform. We set up different CS-AKI modeling parameters by applying different crushing weights (0.5 kg, 1.0 kg, 1.5 kg), crushing durations (6 h, 12 h, 16 h), and decompression durations (6 h, 12 h, 24 h). The GFR, serum creatinine (SCr), blood urea nitrogen (BUN), kidney tissue Kim-1 mRNA and Ngal mRNA expression levels, and HE staining were examined to evaluate the results of different protocols. Results: The results showed that with the crushing weight increased, the kidney function assessment's gold standard GFR significantly decreased, and the levels of SCr and BUN increased. Meanwhile, the longer crushing durations found a higher extension of inflammatory cell infiltration in the kidney. The degree of kidney injury continued to worsen with the duration of decompression, indicating severe damage after reperfusion, which was associated with tubular injury and a sustained elevation of the inflammatory state. Conclusion: We successfully constructed CS-AKI mouse models with different severities under the above parameters. Applying 1.5 kg for 16 h and then decompressing for 24 h induced severe AKI. These findings provide clues for further exploration of the mechanism and treatment of traumatic AKI. [ABSTRACT FROM AUTHOR]

BACKGROUND Inhibitors of the Na+-coupled glucose transporter SGLT2 (SGLT2i) primarily shift the reabsorption of large amounts of glucose from the kidney's early proximal tubule to downstream tubular segments expressing SGLT1, and the non-reabsorbed glucose is spilled into the urine together with some osmotic diuresis. How can this protect the kidneys and heart from failing as observed in individuals with and without type 2 diabetes? GOAL Mediation analyses identified clinical phenotypes of SGLT2i associated with improved kidney and heart outcome, including a reduction of plasma volume or increase in hematocrit, and lowering of serum urate levels and albuminuria. This review outlines how primary effects of SGLT2i on the early proximal tubule can explain these phenotypes. RESULTS The physiology of tubule-glomerular communication provides the basis for acute lowering of GFR and glomerular capillary pressure, which contributes to lowering of albuminuria but also to long term preservation of GFR, at least in part by reducing kidney cortex oxygen demand. Functional co-regulation of SGLT2 with other sodium and metabolite transporters in the early proximal tubule explains why SGLT2i initially excrete more sodium than expected and are uricosuric, thereby reducing plasma volume and serum urate. Inhibition of SGLT2 reduces early proximal tubule gluco-toxicity and by shifting transport downstream may simulate "systemic hypoxia", and the resulting increase in erythropoiesis, together with the osmotic diuresis, enhances hematocrit and improves blood oxygen delivery. Cardio-renal protection by SGLT2i is also provided by a fasting-like and insulin-sparing metabolic phenotype and, potentially, by off-target effects on the heart and microbiotic formation of uremic toxins. [ABSTRACT FROM AUTHOR]

Backgrounds: Crush syndrome (CS) is the leading cause of death after earthquakes, second only to direct trauma. Acute kidney injury (AKI) is the most severe complication of CS. Research based on the CS-AKI mouse model and kidney function assessment by glomerular filtration rate (GFR) helps to elucidate the pathogenesis of CS-AKI, which contributes to effective treatment measures. Methods: Mice were modeled by the multi-channel small animal crushing platform. We set up different CS-AKI modeling parameters by applying different crushing weights (0.5 kg, 1.0 kg, 1.5 kg), crushing durations (6 h, 12 h, 16 h), and decompression durations (6 h, 12 h, 24 h). The GFR, serum creatinine (SCr), blood urea nitrogen (BUN), kidney tissue Kim-1 mRNA and Ngal mRNA expression levels, and HE staining were examined to evaluate the results of different protocols. Results: The results showed that with the crushing weight increased, the kidney function assessment’s gold standard GFR significantly decreased, and the levels of SCr and BUN increased. Meanwhile, the longer crushing durations found a higher extension of inflammatory cell infiltration in the kidney. The degree of kidney injury continued to worsen with the duration of decompression, indicating severe damage after reperfusion, which was associated with tubular injury and a sustained elevation of the inflammatory state. Conclusion: We successfully constructed CS-AKI mouse models with different severities under the above parameters. Applying 1.5 kg for 16 h and then decompressing for 24 h induced severe AKI. These findings provide clues for further exploration of the mechanism and treatment of traumatic AKI. [ABSTRACT FROM AUTHOR]

What mechanisms can link the inhibition of sodium-glucose cotransporter 2 (SGLT2) in the early proximal tubule to kidney and heart protection in patients with and without type 2 diabetes? Due to physical and functional coupling of SGLT2 to other sodium and metabolite transporters in the early proximal tubule (including NHE3, URAT1), inhibitors of SGLT2 (SGLT2i) reduce reabsorption not only of glucose, inducing osmotic diuresis, but of other metabolites plus of a larger amount of sodium than expected based on SGLT2 inhibition alone, thereby reducing volume retention, hypertension and hyperuricemia. Metabolic adaptations to SGLT2i include a fasting-like response, with enhanced lipolysis and formation of ketone bodies that serve as additional fuel for kidneys and heart. Making use of the physiology of tubulo-glomerular communication, SGLT2i functionally lower glomerular capillary pressure and filtration rate, thereby reducing physical stress on the glomerular filtration barrier, tubular exposure to albumin and nephrotoxic compounds, and the oxygen demand for reabsorbing the filtered load. Together with reduced gluco-toxicity in the early proximal tubule and better distribution of transport work along the nephron, SGLT2i can preserve tubular integrity and transport function and, thereby, glomerular filtration rate in the long-term. By shifting transport downstream, SGLT2i may simulate systemic hypoxia at the oxygen sensors in the deep cortex/outer medulla, which stimulates erythropoiesis and, together with osmotic diuresis, enhances hematocrit and thereby improves oxygen delivery to all organs. The described SGLT2-dependent effects may be complemented by off-target effects of SGLT2i on the heart itself and on the microbiome formation of cardiovascular-effective uremic toxins. [ABSTRACT FROM AUTHOR]

Background: Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results. Methods: In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury. Results: Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group. Conclusion: The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups. [ABSTRACT FROM AUTHOR]

Abstract Background Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results. Methods In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury. Results Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman’s rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group. Conclusion The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.

Abstract Chronic Kidney Disease (CKD) stands as a substantial challenge within the global health landscape. The elevated metabolic demands essential for sustaining normal kidney function have propelled an increasing interest in unraveling the intricate relationship between mitochondrial dysfunction and CKD. However, the authentic causal relationship between these two factors remains to be conclusively elucidated. This study endeavors to address this knowledge gap through the Mendelian Randomization (MR) method. We utilized large-scale QTL datasets (including 31,684 eQTLs samples, 1980 mQTLs samples, and 35,559 pQTLs samples) to precisely identify key genes related to mitochondrial function as exposure factors. Subsequently, we employed GWAS datasets (comprising 480,698 CKD samples and 1,004,040 eGFRcrea samples) as outcome factors. Through a comprehensive multi-level analysis (encompassing expression, methylation, and protein quantification loci), we evaluated the causal impact of these genes on CKD and estimated glomerular filtration rate (eGFR). The integration and validation of diverse genetic data, complemented by the application of co-localization analysis, bi-directional MR analysis, and various MR methods, notably including inverse variance weighted, have collectively strengthened our confidence in the robustness of these findings. Lastly, we validate the outcomes through examination in human RNA sequencing datasets encompassing various subtypes of CKD. This study unveils significant associations between the glycine amidinotransferase (GATM) and CKD, as well as eGFR. Notably, an augmentation in GATM gene and protein expression corresponds to a diminished risk of CKD, whereas distinct methylation patterns imply an increased risk. Furthermore, a discernible reduction in GATM expression is observed across diverse pathological subtypes of CKD, exhibiting a noteworthy positive correlation with GFR. These findings establish a causal relationship between GATM and CKD, thereby highlighting its potential as a therapeutic target. This insight lays the foundation for the development of potential therapeutic interventions for CKD, presenting substantial clinical promise.

Safely expanding the use of extended-criteria organ donors is critical to increase access to kidney transplantation and reduce wait list mortality. We performed a retrospective analysis of 24 pediatric en-bloc (PEB) compared to 13 dual-kidney transplantations (DKT) and 39 living donor kidney transplants (LDKT) at the University of Virginia hospital, performed between 2011 and 2019. All living donor kidney transplants were performed in 2017. This year was chosen so that 5-year outcomes data would be available. Primary outcomes were glomerular filtration rate and serum creatinine at 12 and 24 months postoperatively. Secondary outcomes were patient and graft survival. The 1-year creatinine levels (mL/min/1.73 m2) were lower in the PEB group (median 0.9, IQR 0.8–1.4) when compared to the DKT (median 1.4, IQR 1.2–1.5) and LDKT (median 1.3, IQR 1.1–1.5) groups (p < 0.001). The 2-year creatinine levels (mL/min/1.73 m2) were also lower in the PEB group (median 0.8, IQR 0.7–1.08) compared to the DKT (median 1.3, IQR 1.1–1.5) and LDKT (median 1.3, IQR 1.0–1.5) groups (p < 0.001). The glomerular filtration rates demonstrated similar results. Graft survival at 1, 3, and 5 years was 100/100/90, 100/92/69, and 96/96/91 for LDKT, DKT, and PEB, respectively (p = 0.27). Patient survival at 1, 3, and 5 years was 100/100/90, 100/100/88 and 100/100/95 for LDKT, DKT, and PEB, respectively (p = 0.78). Dual KT and PEB transplantation are two alternative techniques to safely expand the donor pool. PEB kidney transplantation, though technically more demanding, provides the best long-term graft function.

Background: Familial Mediterranean fever (FMF) is the most frequent form of inherited periodic fever syndromes. It is caused by a mutation in the MEFV gene and is transmitted by autosomal recessive mode. It is marked by recurring fever episodes with a range of symptoms due to inflammation in the pleura, synovium, and peritoneum. In FMF patients, subclinical inflammation frequently persists throughout the attack-free periods. Uric acid is a product of purine nucleotides catabolism. It is elevated in tissue damage. Aim of the work: To assess uric acid levels and glomerular filtration rate (GFR) in children with FMF during the attack-free period. Subjects and Methods: This cross-sectional study assessed uric acid levels and GFR in 40 children with FMF during the attack-free period. They were enrolled from the Pediatric Rheumatology Outpatient Clinic, Children's Hospital, Faculty of Medicine, Cairo University. Their uric acid levels were compared to a control group of 40 healthy age and sex-matched children. Results: The mean ± SD age of FMF patients was 12.65 ± 1.82 years and 50% were males while thecontrolgroupmeanagewas12.6±1.82years(p=0.903)and52.5%weremales(p=0.823). The mean± SD GFR among FMF patients was 124.75 ± 43.91(ml/min/1.73m2), while among the control group it was 155.48 ± 63.17 ml/min/1.73m2 (p =0.054). Seven (17.5%) FMF patients had reduced GFR (mean ± SD = 84.29± 3.15 ml/min/1.73m2). The mean ± SD uric acid folds of upper level of normal was 0.55 ± 0.13 among the control group, 0.75±0.21in the FMF group, 0.49 ± 0.21 among those with normal GFR and 0.74 ± 0.21 among those with reduced GFR respectively (p=0.286). Three (7.5%) of the FMF patients had microalbuminuria and normal GFR. Conclusion: Uric acid levels were within normal range for age among children with FMF during the attack-free periods and were not predicative of impaired GFR or presence of albuminuria. In a subset of FMF patients, GFR was impaired and others had microalbuminuria during the attack-free periods despite having normal kidney functions. More studies are needed to highlight the risk factors and value of GFR and microalbuminuria in follow up of children with FMF. SUA levels were not elevated in children with FMF during the attack-free period.

Lengnan Xu,1 Chen Yu,1 Aiqun Chen,1 Chuanbao Li,2 Yonghui Mao1 1Department of Nephrology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Laboratory Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yonghui Mao; Chuanbao Li, Tel +86-10-85133880, Email maoyonghui0214@bjhmoh.cn; lichuanbao3662@bjhmoh.cnBackground: This study aims to investigate GFR decline in elderly subjects with varying physical conditions and analyze key risk factors impacting renal function changes.Methods: We obtained data from patients between 2017 and 2019, and matched healthy elderly subjects based on gender and age. Data collected for all subjects included annual measurements of fast blood glucose (GLU), glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c), blood albumin (ALB), blood uric acid (UA), urine protein (UP), and systolic blood pressure (SBP). Additionally, information on coexisting diseases was gathered. The Full Age Spectrum (FAS) equation was used to calculate eGFR.Results: A total of 162 patients with complete 3-year renal dynamic imaging were included, including 84 patients in the kidney disease group (K group) and 78 patients in the non-kidney disease group (NK group). Ninety individuals were selected as the healthy group (H group). The annual decline rate in the K group was the fastest, which exceeded 5mL/min/1.73m2 (P < 0.05). Group (K group: β=− 40.31, P< 0.001; NK group: β=− 26.96, P< 0.001), ALB (β=− 0.38, P=0.038) and HbA1c (β=1.36, P=0.029) had a significant negative impact on the eGFR changes. For participants who had negative proteinuria: K group had the most significant annual eGFR decline.Conclusion: The presence of kidney disease, along with proteinuria nor not, can lead to a marked acceleration in kidney function decline in elderly. We categorize elderly individuals with an annual eGFR decline of more than 5 mL/min/1.73m2 as the “kidney accelerated aging” population.Keywords: elderly, GFR, kidney accelerated aging, risk factors

Chronic Kidney Disease (CKD) stands as a substantial challenge within the global health landscape. The elevated metabolic demands essential for sustaining normal kidney function have propelled an increasing interest in unraveling the intricate relationship between mitochondrial dysfunction and CKD. However, the authentic causal relationship between these two factors remains to be conclusively elucidated. This study endeavors to address this knowledge gap through the Mendelian Randomization (MR) method. We utilized large-scale QTL datasets (including 31,684 eQTLs samples, 1980 mQTLs samples, and 35,559 pQTLs samples) to precisely identify key genes related to mitochondrial function as exposure factors. Subsequently, we employed GWAS datasets (comprising 480,698 CKD samples and 1,004,040 eGFRcrea samples) as outcome factors. Through a comprehensive multi-level analysis (encompassing expression, methylation, and protein quantification loci), we evaluated the causal impact of these genes on CKD and estimated glomerular filtration rate (eGFR). The integration and validation of diverse genetic data, complemented by the application of co-localization analysis, bi-directional MR analysis, and various MR methods, notably including inverse variance weighted, have collectively strengthened our confidence in the robustness of these findings. Lastly, we validate the outcomes through examination in human RNA sequencing datasets encompassing various subtypes of CKD. This study unveils significant associations between the glycine amidinotransferase (GATM) and CKD, as well as eGFR. Notably, an augmentation in GATM gene and protein expression corresponds to a diminished risk of CKD, whereas distinct methylation patterns imply an increased risk. Furthermore, a discernible reduction in GATM expression is observed across diverse pathological subtypes of CKD, exhibiting a noteworthy positive correlation with GFR. These findings establish a causal relationship between GATM and CKD, thereby highlighting its potential as a therapeutic target. This insight lays the foundation for the development of potential therapeutic interventions for CKD, presenting substantial clinical promise. [ABSTRACT FROM AUTHOR]

Background: Recent clinical studies suggest protective effects of SGLT2 inhibitors on kidney disease outcome. Chronic hypoxia has a critical role in kidney disease development, thus we speculated that canagliflozin, an SGLT2 inhibitor, can improve kidney oxygenation. Methods: A single-arm study was conducted to investigate the effects of canagliflozin on T2* value, which reflects oxygenation level, in patients with type 2 diabetes (T2D) using repeated blood oxygenation level-dependent MRI (BOLD MRI) examinations. Changes in cortical T2* frombefore (Day 0) to after single-dose treatment (Day 1) and after five consecutive treatments (Day 5) were evaluated using 12-layer concentric objects (TLCO) and region of interest (ROI) methods. Results: In the full analysis set (n=14 patients), the TLCO method showed no change of T2* with canagliflozin treatment, whereas the ROI method found that cortical T2* was significantly increased on Day 1 but not on Day 5. Sensitivity analysis using TLCO in 13 well-measured patients showed that canagliflozin significantly increased T2* on Day 1 with no change on Day 5, whereas a significant improvement in cortical T2* following canagliflozin treatment was found on both Day 1 and 5 using ROI. Conclusions: Short-term canagliflozin treatment may improve cortical oxygenation and lead to better kidney outcomes in patients with T2D. [ABSTRACT FROM AUTHOR]

Background In this secondary analysis of the STOP-ACEi trial, we explored the impact of discontinuing or continuing renin–angiotensin system inhibitor therapy in people with advanced chronic kidney disease on cystatin C estimated glomerular filtration rate (eGFR). Methods Cystatin C eGFRs were calculated at baseline, 12, 24 and 36 months using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin 2012, European Kidney Function Consortium and CKD-EPI Combined 2021 equations. We excluded samples obtained after the initiation of kidney replacement therapy. Primary analysis used complete case analysis and mixed-effects linear regression model, adjusting for minimization variables, baseline value, time-point and treatment by time interaction. Sensitivity analysis was conducted using a pattern mixture model to account for missing data that was not at random. To model the longitudinal cystatin C data with time-to-event data, a joint model was utilized which incorporated the cystatin C measurements at various time points and accounted for the occurrence of kidney replacement therapy. Results The mean cystatin C eGFRs (CKD-EPI 2012) at baseline were 17.8 mg/L [standard deviation (SD 6.3)] and 17.9 mL/min/1.73 m2 (SD 6.3) in the STOP and CONTINUE arms, respectively. The estimated least squares mean difference at 12 months between STOP and CONTINUE arm was –1.46 [95% confidence interval (CI) –2.39 to –0.52, P = .002]. The estimated least squares mean difference at 24 months was –2.27 (95% CI –3.48 to –1.06, P < .001). The estimated least squares mean difference at 36 months was –1.72 (95% CI –3.48 to 0.03, P = .05). Conclusion Our results are consistent with the primary study's analysis and sensitivity analyses support these findings and provide additional insights. Our findings demonstrate the similarity of creatinine and cystatin eGFR results and therefore support the use of cystatin C as an alternative marker of eGFR in advanced CKD, particularly in those in whom creatinine is likely to be less accurate. [ABSTRACT FROM AUTHOR]

Background: Limited direct comparative studies exist in terms of the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) on the kidney outcomes in Japanese individuals with type 2 diabetes. Methods: This retrospective cohort study included 561 Japanese adults with type 2 diabetes, who were newly prescribed either an SGLT2i or a DPP4i and had an eGFR ≥ 30 mL/min/1.73 m2. The cohort comprised 207 women and 354 men, with a mean (± standard deviation) age of 63 (± 12) years. The exposure and outcome were SGLT2i or DPP4i initiation and eGFR slope during the overall follow-up period, restricted to participants who were followed for ≥2 years. We adopted the on-treatment analysis. Analysis of covariance was used to compare the adjusted eGFR slope between the two groups, incorporating 10 variables at baseline. Results: During the median follow-up period of 3.4 years, least square mean (95% CI) eGFR slopes were −1.91 (−2.15, −1.67) and −1.12 (−1.58, −0.67) mL/min/1.73 m2/year in individuals treated with a DPP4i (n = 460) and an SGLT2i (n = 101), respectively, demonstrating statistical significance (p = 0.002). The robustness of this finding was strengthened by sensitivity analyses. Conclusions: This study provides potential evidence of the superiority of SGLT2is over DPP4is in slowing kidney function decline in Japanese adults with type 2 diabetes and eGFR ≥ 30 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Background Glomerular filtration rate (GFR) estimation by Gates protocol using the gamma camera for diethylenetriaminepentaacetic acid (DTPA) dynamic renography has not compared well with the gold standard GFR by plasma sampling method. This is because depth of the kidneys is generally not considered. Our aim was to study whether manual depth correction using the skin to middle of kidney distance in lateral view and posterior aspect-lateral posterior method would reduce the bias in the Gates GFR as compared with the gold standard. Materials and Methods Retrospective study of 27 adult prospective renal donors who underwent GFR by plasma sampling and DTPA dynamic renography at Inlaks and Budhrani Hospital, Pune, Maharashtra, India between January 2022 and April 2023. The entire data was statistically analyzed using Statistical Package for Social Sciences (SPSS ver 21.0, IBM Corporation, United States) for MS Windows. Results There is no significant agreement between plasma sampling versus gamma camera method and plasma sampling versus lateral posterior method for depth correction for GFR measurements; however, the evidence of systemic bias is lower for the gamma camera method compared with the lateral posterior method for depth correction as against the plasma sampling method. Conclusion The lateral posterior method for depth correction while using the gamma camera-based Gates protocol is not a reliable method for depth correction in the western Indian adult population with preserved renal function. [ABSTRACT FROM AUTHOR]

Safely expanding the use of extended-criteria organ donors is critical to increase access to kidney transplantation and reduce wait list mortality. We performed a retrospective analysis of 24 pediatric en-bloc (PEB) compared to 13 dual-kidney transplantations (DKT) and 39 living donor kidney transplants (LDKT) at the University of Virginia hospital, performed between 2011 and 2019. All living donor kidney transplants were performed in 2017. This year was chosen so that 5-year outcomes data would be available. Primary outcomes were glomerular filtration rate and serum creatinine at 12 and 24 months postoperatively. Secondary outcomes were patient and graft survival. The 1-year creatinine levels (mL/min/1.73 m2) were lower in the PEB group (median 0.9, IQR 0.8–1.4) when compared to the DKT (median 1.4, IQR 1.2–1.5) and LDKT (median 1.3, IQR 1.1–1.5) groups (p < 0.001). The 2-year creatinine levels (mL/min/1.73 m2) were also lower in the PEB group (median 0.8, IQR 0.7–1.08) compared to the DKT (median 1.3, IQR 1.1–1.5) and LDKT (median 1.3, IQR 1.0–1.5) groups (p < 0.001). The glomerular filtration rates demonstrated similar results. Graft survival at 1, 3, and 5 years was 100/100/90, 100/92/69, and 96/96/91 for LDKT, DKT, and PEB, respectively (p = 0.27). Patient survival at 1, 3, and 5 years was 100/100/90, 100/100/88 and 100/100/95 for LDKT, DKT, and PEB, respectively (p = 0.78). Dual KT and PEB transplantation are two alternative techniques to safely expand the donor pool. PEB kidney transplantation, though technically more demanding, provides the best long-term graft function. [ABSTRACT FROM AUTHOR]

The impact of physiological changes during aging on drug disposition has not always been thoroughly assessed in clinical studies. This has left an open question such as how and to what extent patho- and physiological changes in renal function can affect pharmacokinetics in the geriatric population. The objective of this work was to use a physiologically based pharmacokinetic (PBPK) model to quantify the impact of aging and renal impairment (RI) separately and together on ceftazidime pharmacokinetics (PK). The predicted plasma concentrations and PK parameters from the PBPK model were compared to the observed data in individuals of different ages with or without RI (16 independent studies were investigated in this analysis). Apart from clearance in one study, the predicted ceftazidime PK parameters of young adults, elderly, and in individuals with different levels of renal function were within 2-fold of the observed data, and the observed concentrations fell within the 5th–95th prediction interval from the PBPK model simulations. The PBPK model predicted a 1.2-, 1.5-, and 1.8-fold increase in the plasma exposure (AUC) ratio in individuals aged 40, 60, and 70 years old, respectively, with normal renal function for their age compared to 20-year-old individuals with normal renal function. The impact of RI on ceftazidime was predicted to be less marked in older individuals (a 1.04-, 1.43-, and 2.55-fold change in mild, moderate, or severe RI compared to a healthy age-matched control) than in younger individuals (where a 1.47-, 2.03-, and 3.50-fold increase was predicted in mild, moderate, or severe RI compared to a healthy age-matched control). Utilization of the applied population-based PBPK approach allows delineation of the effects of age from renal disease and can better inform future study design and dosing recommendations in clinical study of elderly patients depending on their age and renal function. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is associated with the progressive loss of functional nephrons and hypertension (HTN). Clinical studies demonstrate calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN. However, there are few long-term clinical studies that determine the impact of CCBs in patients with hypertensive CKD. African Americans (AA) have a higher prevalence of CKD and a faster progression to total kidney failure as compared to the white population but the mechanisms are poorly understood. Both clinical evidence (the African American Study of Kidney Disease and Hypertension, or AASK trial) and experimental studies have demonstrated that CCB may expose glomerular capillaries to high systemic pressures and exacerbate CKD progression. Therefore, using a large physiological model, we set out to replicate the AASK trial findings, predict renal hemodynamic responses and the role of the renin-angiotensin system during CCB antihypertensive therapy in a virtual population, and hypothesize mechanisms underlying those findings. Our current mathematical model, HumMod, is comprised of integrated systems that play an integral role in long-term blood pressure (BP) control such as neural, endocrine, circulatory, and renal systems. Parameters (n = 341) that control these systems were randomly varied and resulted in 1,400 unique models that we define as a virtual population. We calibrated these models to individual patient level data from the AASK trial: BP and glomerular filtration rate (GFR) before and after 3 years of amlodipine (10 mg/day). After calibration, the new virtual population (n = 165) was associated with statistically similar BP and GFR before and after CCB. Baseline factors such as elevated single nephron GFR and low tubuloglomerular feedback were correlated with greater declines in renal function and increased glomerulosclerosis after 3 years of CCB. Blocking the renin-angiotensin system (RAS) in the virtual population decreased glomerular pressure, limited glomerular damage, and further decreased BP (-14 ± 8 mmHg) as compared to CCB alone (-11 ± 9 mmHg). Our simulations echo the potential risk of CCB monotherapy in AA CKD patients and support blockade of the renin angiotensin system as a valuable tool in renal disease treatment when combined with CCB therapy. [ABSTRACT FROM AUTHOR]

Background: The prevalence of chronic kidney disease is increasing worldwide. Most common cause being diabetic nephropathy secondary to type 2 diabetes mellitus The population of India is projected to become the major reservoir of chronic diseases like diabetes mellitus and hypertension also 25-40% of them are likely to develop CKD which increases the mortality and morbidity risks thereby raising the ESRD burden. An association has been found between hemodialysis and pulmonary hypertension (PH) which is estimated to be around 19-69% and also ESRD with PH (9-39%). Aim: To study the prevalence of pulmonary hypertension in CKD patients and compare prevalence of pulmonary hypertension in dialysis dependent and independent CKD patients Material and Methods: It is a prospective observational and cross-sectional study conducted on 120 (60 non dialysis and 60 hemodialysis dependent) CKD patients of age ≥18 years coming to Department of General Medicine & Nephrology of M.K.C.G. Medical College and Hospital, Berhampur between April 2021 to March 2023. Results: Maximum (43.3%) patients were more than 60 years and mean age was 58.8 years. There were 40 male and 20 female in dialysis dependent group and 38 male and 22 female in non-dialysis dependent groups. 41(34.2%) patients had diabetes and 69 (57.5%) had systemic hypertension and 33(27.5%) had PH. Mean eGFR was 17.68 with mean duration of dialysis 12.72 months. The mean Hb was 7.53 gm% in dialysis group and 10.1 gm% in non-dialysis group. Mean urea level was 150 mg/dl and 80 mg/dl and mean creatinine level 7 and 2.4 mg/dl in dialysis and non-dialysis group respectively. 62 patients were in ESRD, 30.8% patients were in stage 4 and 17.5% in stage 3 of CKD. LVH was found in 35.83% of dialysis group and 16.67% of non-dialysis group. Conclusion: Prevalence of PH is high among patients on dialysis owing to their AVFs and other factors rather than those on conservative management. It linearly increases with the duration of hemodialysis, so this complication should be anticipated and addressed early and alternate mode of dialysis must be considered. [ABSTRACT FROM AUTHOR]

Background There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite–mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < −0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite–mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < −0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions The majority of metabolite–mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR. [ABSTRACT FROM AUTHOR]

Background: Children with chronic kidney disease (CKD) are at risk for abnormalities in pubertal development. We aimed to describe the timing of pubertal onset by luteinizing hormone (LH) levels and the association between hormonal onset of puberty with changes in GFR. Methods: Data from the Chronic Kidney Disease in Children (CKiD) study were collected prospectively. GFR was estimated at annual visits and measured by iohexol clearance every other year. LH was measured from stored repository serum samples in a nested sample of 124 participants. Hormonal onset of puberty was defined as LH level greater than or equal to 0.3 IU/L. A mixed effects model with random intercepts and slopes was used to compare the slope of decline of GFR before and after hormonal onset of puberty. The model was adjusted for age, glomerular disease diagnosis, baseline proteinuria on the log scale, and BMI. Results: Median age at hormonal onset of puberty was 9.9 years (IQR 8.1, 11.9) in girls and 10.2 years (IQR 9.2, 11.0) in boys. The mixed effects model showed faster decline in both estimated GFR and measured GFR in boys after hormonal onset of puberty (p < 0.001), and a similar but attenuated accelerated estimated GFR decline was observed for girls with no difference for measured GFR. Conclusions: LH levels in the post-pubertal range were observed prior to clinical manifestations of puberty in children with CKD. Hormonal onset of puberty was associated with faster decline in GFR, particularly among boys with CKD. [ABSTRACT FROM AUTHOR]

The homeostatic and excretory functions of the kidney are dependent on its perfusion, totalling 20–25% of cardiac output, and the process of glomerular ultrafiltration. Renal blood flow (RBF) is directly proportional to the trans-renal gradient which is autoregulated across a mean arterial pressure of 50–150 mmHg in a normotensive person. Selective molecular filtration in the glomerulus is achieved by the glomerular filtration barrier and is related to the size, shape, and electrical charge of molecules. The process of ultrafiltration is determined by the balance between hydrostatic and colloid osmotic pressures in the glomerular capillary and Bowman's space, and is affected by renal plasma flow, altered surface area and changes in afferent and efferent renal arteriole vascular resistance. The phenomenon of renal plasma flow autoregulation minimizes changes in the volume of ultrafiltration through myogenic and tubuloglomerular feedback mechanisms. Glomerular filtration rate can be measured using exogenous inulin, or estimated (eGFR) from creatinine clearance, several equations can be used to calculate eGFR but their limitations in estimating the true excretory function of the kidney need to be taken into consideration. [ABSTRACT FROM AUTHOR]

Background: When applying Pierce U25 formula for estimating glomerular filtration rate (eGFR), we observed a higher proportion of eGFR < 90 mL/min/1.73 m2 (chronic kidney disease (CKD) stage 2). We compared agreement and accuracy of the Pierce U25 (ages 2–25), Pottel (ages 2–100), and CKD-EPI (ages 18–100) formulae to GFR measurements. Methods: Post hoc analysis of the three eGFRs compared to 367 99m technetium-diethylene-triamine penta-acetic acid (99Tc DTPA) GFR measurements (240 patients) using 3 sampling points and Brockner/Mørtensen correction (body surface area calculation based on ideal weight) on simultaneous serum creatinine and cystatin C measurements. Results: Overall, the U25 formula performed well with a Spearman r of 0.8102 (95% confidence interval 0.7706 to 0.8435, p < 0.0001) while diagnostic accuracy was low in patients with normal mGFR. The U25 formula reclassified 29.5% of patients with normal mGFR as CKD stage 2; whereas the average of the modified Schwartz formula based on serum creatinine and the Filler formula based on cystatin C, only over-diagnosed CKD stage 2 in 8.5%, 24.5% within 10% and 62.7% within 30%. We therefore combined both. The average Schwartz/Filler eGFR had 36.5% of results within 10%, 84.7% within 30%, and normal mGFR accuracy was 26.8%, 63.9% for 10% and 30%, respectively, outperforming the CKD-EPI and Pottel formulae. Conclusions: The Pierce U25 formula results correlated well with mGFR < 75 mL/min/1.73 m2. Over the entire GFR range, accuracy was better for patients with a higher mGFR, when averaging the combined Schwartz/Filler formulae. More work is needed to prospectively confirm our findings in other centers. [ABSTRACT FROM AUTHOR]

Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted ceftazidime concentrations in non-pregnant and pregnant subjects of different gestational weeks were within 2-fold of the observations, and the observed concentrations fell within the 5th–95th prediction interval from the PBPK simulations. The calculated transplacental clearance (0.00137 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 0.7 after the first dose, increasing to about 1.0 at a steady state, which also agrees well with clinical observations. The developed maternal PBPK model adequately predicted the observed exposure and kinetics of ceftazidime in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study and, in addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, and improving the efficacy and safety of drugs in target populations. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a metal with no nutritional value or physiological role. However, it is found in the body of most people because it is a contaminant of nearly all food types and is readily absorbed. The body burden of Cd is determined principally by its intestinal absorption rate as there is no mechanism for its elimination. Most acquired Cd accumulates within the kidney tubular cells, where its levels increase through to the age of 50 years but decline thereafter due to its release into the urine as the injured tubular cells die. This is associated with progressive kidney disease, which is signified by a sustained decline in the estimated glomerular filtration rate (eGFR) and albuminuria. Generally, reductions in eGFR after Cd exposure are irreversible, and are likely to decline further towards kidney failure if exposure persists. There is no evidence that the elimination of current environmental exposure can reverse these effects and no theoretical reason to believe that such a reversal is possible. This review aims to provide an update on urinary and blood Cd levels that were found to be associated with GFR loss and albuminuria in the general populations. A special emphasis is placed on the mechanisms underlying albumin excretion in Cd-exposed persons, and for an accurate measure of the doses–response relationships between Cd exposure and eGFR, its excretion rate must be normalised to creatinine clearance. The difficult challenge of establishing realistic Cd exposure guidelines such that human health is protected, is discussed. [ABSTRACT FROM AUTHOR]

BackgroundRecent clinical studies suggest protective effects of SGLT2 inhibitors on kidney disease outcome. Chronic hypoxia has a critical role in kidney disease development, thus we speculated that canagliflozin, an SGLT2 inhibitor, can improve kidney oxygenation.MethodsA single-arm study was conducted to investigate the effects of canagliflozin on T2* value, which reflects oxygenation level, in patients with type 2 diabetes (T2D) using repeated blood oxygenation level-dependent MRI (BOLD MRI) examinations. Changes in cortical T2* from before (Day 0) to after single-dose treatment (Day 1) and after five consecutive treatments (Day 5) were evaluated using 12-layer concentric objects (TLCO) and region of interest (ROI) methods.ResultsIn the full analysis set (n=14 patients), the TLCO method showed no change of T2* with canagliflozin treatment, whereas the ROI method found that cortical T2* was significantly increased on Day 1 but not on Day 5. Sensitivity analysis using TLCO in 13 well-measured patients showed that canagliflozin significantly increased T2* on Day 1 with no change on Day 5, whereas a significant improvement in cortical T2* following canagliflozin treatment was found on both Day 1 and 5 using ROI.ConclusionsShort-term canagliflozin treatment may improve cortical oxygenation and lead to better kidney outcomes in patients with T2D.

Chronic kidney disease (CKD) is associated with the progressive loss of functional nephrons and hypertension (HTN). Clinical studies demonstrate calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN. However, there are few long-term clinical studies that determine the impact of CCBs in patients with hypertensive CKD. African Americans (AA) have a higher prevalence of CKD and a faster progression to total kidney failure as compared to the white population but the mechanisms are poorly understood. Both clinical evidence (the African American Study of Kidney Disease and Hypertension, or AASK trial) and experimental studies have demonstrated that CCB may expose glomerular capillaries to high systemic pressures and exacerbate CKD progression. Therefore, using a large physiological model, we set out to replicate the AASK trial findings, predict renal hemodynamic responses and the role of the renin-angiotensin system during CCB antihypertensive therapy in a virtual population, and hypothesize mechanisms underlying those findings. Our current mathematical model, HumMod, is comprised of integrated systems that play an integral role in long-term blood pressure (BP) control such as neural, endocrine, circulatory, and renal systems. Parameters (n = 341) that control these systems were randomly varied and resulted in 1,400 unique models that we define as a virtual population. We calibrated these models to individual patient level data from the AASK trial: BP and glomerular filtration rate (GFR) before and after 3 years of amlodipine (10 mg/day). After calibration, the new virtual population (n = 165) was associated with statistically similar BP and GFR before and after CCB. Baseline factors such as elevated single nephron GFR and low tubuloglomerular feedback were correlated with greater declines in renal function and increased glomerulosclerosis after 3 years of CCB. Blocking the renin-angiotensin system (RAS) in the virtual population decreased glomerular pressure, limited glomerular damage, and further decreased BP (−14 ± 8 mmHg) as compared to CCB alone (−11 ± 9 mmHg). Our simulations echo the potential risk of CCB monotherapy in AA CKD patients and support blockade of the renin angiotensin system as a valuable tool in renal disease treatment when combined with CCB therapy.

Background: Cisplatin is a chemotherapeutic drug commonly used in the treatment of many childhood solid malignancies. It is known to cause long-term nephrotoxicity, most commonly manifesting as reduced glomerular filtration rate and hypomagnesaemia. Existing literature regarding the epidemiology of long-term nephrotoxicity in childhood cancer describes large variation in prevalence and risk factors. Objectives: This study is to evaluate the prevalence of, and risk factors for, long-term cisplatin nephrotoxicity after treatment for childhood cancer. Study eligibility criteria: Studies were eligible for inclusion if they: (i) evaluated participants treated with cisplatin who were diagnosed with cancer < 18 years of age; (ii) investigated any author-defined measure of nephrotoxicity; and (iii) performed this evaluation 3 or more months after cisplatin cessation. Studies whose scope was broader than this were included if appropriate subgroup analysis was performed. Results: Prevalence of reduced glomerular filtration rate (GFR) ranged between 5.9 and 48.1%. Pooled prevalence of reduced GFR using studies with a modern consensus threshold of 90 ml/min/1.73 m2 was 29% (95% CI 0.0–58%). Prevalence of hypomagnesaemia ranged between 8.0 and 71.4%. Pooled prevalence of hypomagnesaemia was 37% (95% CI 22–51%). Substantial heterogeneity was present, with I2 statistics of 94% and 73% for reduced GFR and hypomagnesaemia respectively. All large, long-term follow-up studies described increased risk of reduced GFR with increasing cumulative cisplatin dose. Included studies varied as to whether cisplatin was a risk factor for proteinuria, and whether age was a risk factor for cisplatin nephrotoxicity. Limitations: A wide range of study methodologies were noted which impeded analysis. No studies yielded data from developing health-care settings. No non-English studies were included, further limiting generalisability. Conclusions: Both of the most common manifestations of long-term cisplatin nephrotoxicity have a prevalence of approximately a third, with increasing cumulative dose conferring increased risk of nephrotoxicity. Further work is needed to characterise the relationship between reduced GFR and hypomagnesaemia, investigate other risk factors and understand the interindividual variation in susceptibility to nephrotoxicity. [ABSTRACT FROM AUTHOR]

Objective: To identify the association between the changes in intestinal microflora and renal function in patients with chronic renal failure (CRF). Methods: This retrospective case-control study included 50 patients with CRF (study group), admitted to the Clinical Laboratory Department of Shenzhen People’s Hospital from March 2021 to May 2022, and 50 healthy individuals (control group). The association between the distribution of intestinal microflora and the glomerular filtration rate (GFR), levels of serum creatinine (SCr), blood urea nitrogen (BUN), and serum cystatin C (CysC) were analyzed. Results: Intestinal microflora of CRF patients had significantly higher levels of Enterococci compared to the control group (p-Value <0.05), while the levels of Bifidobacterium spp. and Escherichia coli were lower in the study group (p-Value <0.05). GFR was lower, and the levels of BUN, SCr, and CysC were higher in the study group compared to the control group (all p-Value <0.05). GFR, BUN, SCr and CysC levels in the study group negatively correlated with the levels of Bifidobacterium spp. and Lactobacillus spp. (r<0, P<0.05), and positively correlated with the abundance of Enterococcus spp. and Escherichia coli (r>0, P<0.05) in the intestinal microflora. Conclusions: Changes in intestinal microbiota are associated with a significant decrease in GFR and a marked increase in serum levels of renal function indicators, and alterations in the balance of intestinal microbiota may lead to further aggravation of the renal function damage in patients with CRF. [ABSTRACT FROM AUTHOR]

Background: The objective was to investigate the correlation between ADC values of DW-MRI and Renal Resistivity Index (RI)of the renal parenchyma in assessing various stages of chronic kidney disease. Materials and Methods: It is a single institutional prospective study in Govt General hospital, Kurnool. Approval got from by institutional ethical committee. The informed consent from the patients and controls have been obtained Patients who came for MRI abdomen and spine both non renal and the renal disorder and to renal Doppler study with normal and elevated renal parameters were identified and included in the study. Results: In our study, there has been steady decreasing trend in ADC values with the decrease in eGFRi .e., with the progression of severity(stage) of CKD. The level of serum creatinine and the stage of chronic kidney disease are inversely correlated with the ADC value, which also demonstrated a decreasing tendency. In conclusion, RI ≥ 0.79 on the renal duplex ultrasonography can be a helpful predictor for renal progression in patients with moderate renal dysfunction, regardless of their ACE inhibitors and ARB as angiotensin receptor blockers usage. Therefore, checking the RI value is helpful when we evaluate kidney ultrasonography in patients with moderate renal dysfunction. Conclusion: The value of the apparent diffusion coefficient can be used as an extra marker to determine the level of renal function. ADC can be used to determine the degree of renal impairment. ADC values continues to decrease with increase in severity (stage) of chronic kidney disease. DWI is recognized as a promising imaging tool that can take part in the assessment of the morphological and functional changes in diffuse renal parenchymal disease, hence playing an important role in the early diagnosis and staging of chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. Methods All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000–31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. Results During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P  < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5–5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4–2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6–4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8–3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. Conclusions Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints. [ABSTRACT FROM AUTHOR]

ObjectiveDespite the need, measuring glomerular filtration rate (mGFR) is not routinely performed for adults with cerebral palsy (CP), possibly due to unknown feasibility given the secondary complications of CP. This study aimed to assess the feasibility and reliability of mGFR and explore factors associated with eGFR-mGFR discordance among young adults with mild-to-moderate CP.MethodsThis single-center, cross-sectional study included 18- to 40-year-olds with CP gross motor function classification system (GMFCS) I-III. The participants were excluded if they were pregnant/lactating, had cognitive impairments, or had contraindications to mGFR. A routine clinical protocol for mGFR and eGFR was used. mGFR feasibility was assessed based on the number of participants who completed testing. mGFR reliability was assessed using the coefficient of variation (CV) across the four 30 min intervals. The association between age, sex, and GMFCS and the percentage of eGFR-mGFR discordance was assessed.ResultsOf the 19 participants enrolled, 18 completed the testing [mean age (SD), 29.9 (7.4) years, n = 10 female participants, n = 10/3/5 for GMFCS I/II/III] and most (n = 15) of the participants had an mGFR >90 mL/min; 14 participants (77.8%) had a CV 50%. eGFR overestimated mGFR by a median (interquartile range) of approximately 17.5% (2–38%); the full range of mis-estimation was −20.5 to 174.3%. Increasing age and GMFCS levels exhibited notable, but weak-to-modest, associations with a larger eGFR-mGFR discordance.DiscussionObtaining mGFR was feasible and reasonably reliable within this small sample. eGFR overestimated mGFR by a notable amount, which may be associated with patient-level factors.

The impact of physiological changes during aging on drug disposition has not always been thoroughly assessed in clinical studies. This has left an open question such as how and to what extent patho- and physiological changes in renal function can affect pharmacokinetics in the geriatric population. The objective of this work was to use a physiologically based pharmacokinetic (PBPK) model to quantify the impact of aging and renal impairment (RI) separately and together on ceftazidime pharmacokinetics (PK). The predicted plasma concentrations and PK parameters from the PBPK model were compared to the observed data in individuals of different ages with or without RI (16 independent studies were investigated in this analysis). Apart from clearance in one study, the predicted ceftazidime PK parameters of young adults, elderly, and in individuals with different levels of renal function were within 2-fold of the observed data, and the observed concentrations fell within the 5th–95th prediction interval from the PBPK model simulations. The PBPK model predicted a 1.2-, 1.5-, and 1.8-fold increase in the plasma exposure (AUC) ratio in individuals aged 40, 60, and 70 years old, respectively, with normal renal function for their age compared to 20-year-old individuals with normal renal function. The impact of RI on ceftazidime was predicted to be less marked in older individuals (a 1.04-, 1.43-, and 2.55-fold change in mild, moderate, or severe RI compared to a healthy age-matched control) than in younger individuals (where a 1.47-, 2.03-, and 3.50-fold increase was predicted in mild, moderate, or severe RI compared to a healthy age-matched control). Utilization of the applied population-based PBPK approach allows delineation of the effects of age from renal disease and can better inform future study design and dosing recommendations in clinical study of elderly patients depending on their age and renal function.

ObjectiveHigh levels of psychological distress increase the risk of a wide range of medical diseases. In this study, we investigated the association between posttraumatic stress disorder (PTSD) and kidney disease.MethodsWorld Trade Center (WTC) responders were included if they had two or more measures of estimated glomerular filtration rate (eGFR). The PTSD Checklist (PCL) was used to define no PTSD (PCL < 40), "mild" PTSD (40 ≤ PCL

Thalassemia is one of the most prevalent genetic disorders worldwide and has previously been found to have an association with several physiological and organ complications. Several studies have found both its positive and inverse correlation with the glomerular filtration rate (GFR). Therefore, in this meta-analysis, we tried to assess the accurate correlation of β-thalassemia major (β-TM) with GFR. We searched in Google Scholar, PubMed, and ScienceDirect, and from the initial 96 articles, we finally included 12 studies. The quality and publication bias assessment confirmed that all the studies were of high to moderate quality with no publication bias. The main outcome of the mean difference (MD) was −6.94, 95%CI: −20.69, 6.80 (p < 0.00001), which indicated a negative correlation of the GFR with β-TM. The sensitivity analyses found one study to be a slight outlier, and reanalyzing the data excluding that study, an MD was achieved of −16.46, 95%CI: −26.81, −6.11 (p < 0.00001), which provides even stronger support for our main outcome. Our result determined that the GFR is generally higher in healthy people as compared to β-TM patients.

Background: Observational studies have shown an association between reduced renal function and the risk of sarcopenia. However, the causal relationship and the underlying biological mechanisms remain uncertain. Using a Mendelian randomization (MR) framework, we investigated the causal role of 27 hypothetical risk mediators, including metabolites, hormones, inflammation, and stress traits, on the risk of sarcopenia. Methods: Instrumental variables (IVs) to proxy renal function were identified by selecting single nucleotide polymorphisms (SNPs) reliably associated with creatinine and cystatin C-based glomerular filtration rate (GFR) in CKDGen summary data. IVs for putative risk traits and sarcopenia traits were constructed from relevant genome-wide association studies (GWAS). MR estimated effects were obtained using an inverse-variance weighted effects model, and various sensitivity analyses were performed. The mediating role of hypothetical risk factors in the relationship between GFR and sarcopenia was assessed through multivariate MR. Results: Genetically predicted reduced GFRcrea was associated with higher odds of appendicular lean mass (ALM) (odds ratio (OR): 0.64, 95% confidence interval (CI) 0.37 to 0.68) and grip strength (OR: 0.67; 95% CI 0.58 to 0.78). Likewise, GFRcys highlighted a causal relationship with ALM (OR: 0.52; 95% CI 0.42 to 0.65) and grip strength (OR: 0.66; 95% CI 0.59 to 0.74). Both estimated GFR (eGFR) were negatively associated with IGF-1, IL-16, 25(OH)D, triglycerides (range of effect size per standard deviation: -0.81 to -0.30), and positively correlated with HDL cholesterol (0.62, 0.31). There was a positive correlation between IGF-1, fasting insulin and ALM as well as grip strength (OR range: 1.04–1.67) and a negative correlation between serum CRP and ALM (OR: 0.95) as well as grip strength (OR: 0.98). Additionally, genetically predicted IL-1β (OR: 0.95) and total cholesterol (OR: 0.96) were negatively associated with ALM. We found evidence that IGF-1 mediates the relationship between eGFR and risk for muscle mass and strength. Conclusions: This MR study provides insight into the potential causal mechanisms between renal function and the risk of sarcopenia and proposes IGF-1 as a potential target for the prevention of renal sarcopenia.

Introduction The abrupt loss of renal function to the point that bodily fluid equilibrium is impossible to maintain is known as acute kidney injury. Serum creatinine levels rise to about twice the usual amount for the patient's age due to a decrease in GFR, which is the condition's primary characteristic1. Its frequency, morbidity pattern, diagnostic challenges, treatment options, prognosis, and final results in individual instances have all been forecasted to make it a significant issue for the paediatric age range. Due to the high occurrence of infections, sepsis, acute glomerulonephritis, and gastroenteritis in hot and humid climates, it is still a prevalent ailment in underdeveloped nations, but in western countries, the main causes are trauma, surgery, alcohol, and narcotics. AKI has been becoming more common, and other investigations have shown varying degrees of mortality as well. Material And Method Children throughout the newborn period who were at high risk of developing AKI or those who came with AKI to the paediatric ward of the S.C.B. Medical College and Hospital and the S.V.P. Post Graduate Institute of Paediatrics in Cuttack were included in the study's material. The instances chosen for the research and the methods used are described in full below. Laboratory parameters were used to test for signs of AKI in all children older than 28 days who had clinical indications of developing oligouria or anuria. They also included those who showed signs of AKI while they were in the hospital. Serum creatinine levels of 1.5 mg/dl or higher in children older than one year, and 1 mg/dl or higher in children less than one year, were used to include those who were clinically suspected. Result Indicates age incidence of AKI cases in the present study. Majority of cases, 38.8% were observed in the age group of 5-10 years followed by 31.3% in 1-5years. 44% cases occurred in the under 5 age group in our study. In the present study male children outnumbered females (M:F=1.4:1). Indicates the various clinical features observed in AKI cases in the present work. Oliguria / anuria was present in approx. 86% of cases, next most common presenting feature was fever in 67.2% followed by H/O snake bite in 14.9%, loose stool in 16.9% cases amongst the study group. We observed presence of skin infection as a marker of AGN(4%), altered sensorium(9%), hematuria(14.4%), convulsion (15.4%), abdominal distension (20%), bleeding manifestation and bloody stool(5%) cases amongst the study population. Conclusions This study demonstrated the etiological patterns in this region of the state and certain areas of Eastern India, and it focused on the many domains of Acute Kidney Injury in children who presented to the hospital. The study population was well-characterized and heterogeneous. Children's AKI has a heterogeneous aetiology that differs not only between countries but even between areas within the same nation. Contemporary medical services have the potential to promptly reverse impaired kidney function; nonetheless, rapid intervention, early identification, and clinical awareness are crucial. [ABSTRACT FROM AUTHOR]

Background In 2021, an updated Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimated glomerular filtration rate (eGFR) without a coefficient for race (CKD-EPI21) was developed. The performance of this new equation has yet to be examined among specific patient groups. Methods We compared the performances of the new CKD-EPI21 equation and the 2009 equation assuming non-Black race (CKD-EPI09-NB) in patients with GFR measured by chromium-51-EDTA plasma clearance at Aarhus University Hospital in Denmark during 2010–18. We examined bias, accuracy, precision and correct classification of chronic kidney disease (CKD) stage using chromium-51-EDTA clearance as the reference standard. We assessed the performance in the total cohort, cancer patients and potential living kidney donors. We also assessed the performance stratified by CKD stage in the total cohort. Results In this predominantly white population, the CKD-EPI21 equation performed slightly better than the CKD-EPI09-NB equation in both the total cohort (N  = 4668), and in cancer patients (N  = 3313) and potential living kidney donors (N  = 239). In the total cohort, the CKD-EPI21 equation demonstrated a slightly lower median absolute bias (−0.2 versus −4.4 mL/min/1.73 m2), and a similar accuracy, precision and correct classification of CKD stage compared with the CKD-EPI09-NB equation. When stratified by CKD stage, the CKD-EPI09-NB equation performed slightly better than the CKD-EPI21 equation among patients with a measured GFR (mGFR) <60 mL/min/1.73 m2. Conclusions In a selected cohort of Danish patients with mGFR, the CKD-EPI21 equation performed slightly better than the CKD-EPI09-NB equation except for patients with a mGFR <60 mL/min/1.73 m2, where CKD-EPI09-NB performed slightly better although the differences were considered clinically insignificant. [ABSTRACT FROM AUTHOR]

Studies into the functions and mechanisms of action of quercetin may be able to help dispel the negative effects of toxicants on renal toxicity due to its anti-inflammatory potential, as well as provide a simple, low-cost alternative for treating renal toxicity in developing nations. Therefore, the present study evaluated the ameliorative and renal protective activities of quercetin dihydrate in potassium bromate-induced, renal-toxic Wistar rats. Forty-five (45) mature female Wistar rats (180–200 g) were randomly grouped into nine (9) (n = 5). Group A served as general control. Nephrotoxicity was induced in groups B to I with the administration of potassium bromate. While group B served as a negative control, groups C–E received graded doses of quercetin (40, 60, and 80 mg/kg, respectively). Group F received 2.5 mg/kg/day of vitamin C, while groups G–I received vitamin C (2.5 mg/kg/day) and co-administration of a graded dose of quercetin (40, 60, and 80 mg/kg, respectively). Daily urine levels and final blood samples by retro-orbital techniques were collected for GFR, urea, and creatinine level assessment. The collected data were subjected to ANOVA and Tukey's post hoc test, and the results were presented as mean SEM with a p < 0.05 level considered significant. Body and organ weight and GFR were significantly reduced (p < 0.05), while serum and urine creatinine and urea were decreased in renotoxic animals. However, treatment with QCT reversed the renotoxic effects. We, therefore, concluded that quercetin administered alone or with vitamin C conferred renal protection by reversing KBrO3-induced renal toxicity in rats. Further studies to corroborate the present findings are recommended. [ABSTRACT FROM AUTHOR]

Background:Thyroid hormones have a very crucial role in the regulation of metabolism, proteins synthesis and influencing functions of various other hormones in the human body. While both kidneys play an essential role in the metabolism of thyroid hormone by conversion of thyroxine (T4) to triiodothyronine (T3). In patients with chronic kidney diseases, frequent abnormal thyroid functions are observed. Aim:To study the pattern of thyroid dysfunction in chronic kidney disease population and to evaluate the correlation existing in between severity of kidney failure and thyroid dysfunction Methods:This cross sectional observational study was conducted in the department of internal medicine in a tertiary care hospital, central India. 100 chronic kidney disease patients were included in the study. Diagnosis of chronic kidney failure was performed as per criteria laid down by Kidney Disease Outcome Quality Initiative. Blood was drawn for estimation of serum creatinine, GFR and thyroid profile. Results: Among 100 CKD patients, most of them (64%) were male with age ranging from 18 to 80 years with mean age of 57.08±10.35 years. Of the total patients, 6%, 12%, 29%, 26% & 27% patients belonged to CKD Stages 1,2,3,4 & 5 respectively. Low T3 is the most common thyroid dysfunction & the earliest abnormality noticed in CKD patients. The prevalence of low T3 syndrome in this study was 48%. Increasing trend for Low T3 prevalence with increasing severity of CKD was noticed in this study and was statistically significant (P

Background Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified. Methods Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 μg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid. Results The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2 , and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR. Conclusion In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to summarize the surgical experience of renal artery cold perfusion combined with laparoscopic nephron preserving surgery for the treatment of complex renal angiomyolipoma and to evaluate the safety and feasibility of this surgical protocol. Materials and methods: Clinical data of nine patients who received renal artery cold perfusion combined with laparoscopic nephron preserving surgery for complex renal angiomyolipoma in our hospital from February 2017 to August 2020 were retrospectively analyzed. The study parameters included imaging findings, total renal function before and after surgery, glomerular filtration rate (GFR) of affected kidney before and after surgery, and related complications. Results: Eight of the nine patients successfully completed the operation, one patient was intolerant to renal artery balloon implantation, and the success rate of the operation was 88.89%. The mean maximum tumor diameter was 6.8 cm, and RENAL score was 7 points. Postoperative total renal function and GFR of the affected kidney had no significant changes compared with that before surgery, and imaging examination showed no tumor residue or recurrence. Conclusion: This surgical procedure is safe and feasible for complex renal angiomyolipoma and can be used as a surgical option for renal hamartoma. The long-term effect needs to be confirmed by further studies. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. Materials and Methods: In this prespecified substudy of the randomized, placebo‐controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between‐group change in mGFR, measured by the 51Cr‐EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. Results: From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention‐to‐treat analysis. Treatment with empagliflozin reduced mGFR by −7.9 mL/min (95% confidence interval [CI] −11.1 to −4.7; P < 0.001), estimated ECV by −192.5 mL (95% CI −318.0 to −66.9; P = 0.003) and estimated PV by −128.9 mL (95% CI −218.0 to 39.8; P = 0.005) at Week 13. Conclusions: Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity. The spectrum of disease includes phenotypes ranging from "classic" to "later-onset," with varying kidney disease progression. Identifying patterns of declining kidney function and involvement of other major organs in patients with FD is important to guide therapy decisions. Methods Clusters of patients with FD and similar estimated glomerular filtration rate (eGFR) decline and age were created using agglomerative clustering of data captured between 2007 and 2020 in the United States Optum Market Clarity database. Male patients with a diagnosis of FD and two or more eGFR values ≥6 months apart were included. Disease progression was compared with a control cohort of patients without an FD diagnosis. Results eGFR values from 234 male patients with FD were analysed, yielding seven clusters. Five clusters demonstrated disease progression from "natural" eGFR decline, with a slight decrease in kidney function and eGFR usually within the normal range, to rapid, early decline in eGFR and cardiac complications. When compared with the control cohort, a more rapid decline and a higher percentage of cardiac hypertrophy, heart failure, arrhythmias and stroke were noted in the study group. An inflection point was observed in each cluster when deterioration of kidney function accelerated. Conclusions Clustering of male patients with FD by decline in kidney function, organ involvement and phenotype through analysis of real-world data provides a reference that could help determine the optimal time for initiation of FD-specific treatment and facilitate management decisions made by healthcare professionals. [ABSTRACT FROM AUTHOR]