Measurement Of Glomerular Filtration Rate Research Articles

Estimated glomerular filtration rate calculated by serum creatinine lacks precision and accuracy in adults with type 2 diabetes with preserved renal function

AimsWe evaluated the performance of creatinine-based equations that are currently used to estimate glomerular filtration rate (GFR) in people with type 2 diabetes compared to measured GFR using gold-standard methods. MethodsIn this post-hoc analysis, 32 participants underwent repeated measurement of GFR by inulin clearance (mGFR). GFR was estimated by serum creatinine using the MDRD (eGFRMDRD) and CKD-EPI (eGFRCKD-EPI) equations four times over the course of one month. Performance was evaluated using measurements of bias (mean difference), precision (SD), and inaccuracy (proportion of eGFR that differed by >20 % of mGFR). Treatment and time effects on bias were evaluated using linear mixed effects models. ResultsAt baseline, participants (38 % female) were age 60 ± 8 years, had diabetes duration of 9 ± 7 years, HbA1c 56 ± 9 mmol/mol (7.2 ± 0.8 %), and BMI 31.0 ± 6.2 kg/m2. Mean mGFR was 113 ± 24, mean eGFRMDRD was 93 ± 12, and mean eGFRCKD-EPI was 94 ± 9 mL/min/1.73 m2. When 128 observations (32 participants measured 4 times) were evaluated, both equations substantially underestimated mGFR. For eGFRMDRD, mean bias was −21.5 mL/min/1.73 m2, precision was 22.7 mL/min/1.73 m2, and 46 % of observations differed by >20 %. Results were similar for eGFRCKD-EPI. No time or treatment effects on bias were observed. ConclusionsIn adults with type 2 diabetes and preserved renal function, eGFR equations underestimated mGFR, lacked precision and accuracy, and performance was lower at higher ranges of mGFR. Current eGFR equations by serum creatinine are inaccurate in adults with type 2 diabetes with preserved renal function, highlighting the necessity to develop new methods to measure kidney function at earlier stages of diabetic kidney disease.

Data quality control in longitudinal epidemiologic studies: conditional studentized residuals from linear mixed effects models for outlier detection in the setting of pediatric chronic kidney disease

PurposeQuality control in longitudinal cohort studies is critical for valid epidemiologic inference. Conditional studentized residuals (CSRs) derived from linear mixed effects models offer efficient individual-specific quality control. We present the utility of CSRs for outlier detection in an applied example using data from the Chronic Kidney Disease in Children cohort. MethodsLongitudinal linear mixed effects models with glomerular filtration rate (GFR) as the outcome were fit for observations prior to kidney replacement therapy, stratified by nonglomerular or glomerular diagnosis, and for a subset after receiving a kidney transplant. For each model, CSRs were calculated and values ≥±5 were considered potential outliers for further investigation. ResultsA total of 1096 participants contributed 6881 annual measures of GFR across the two diagnostic groups and after transplant. In all models, the fixed effects captured progressive GFR decline. CSRs provided measures of individual-level deviations from the modeled trajectories (random + fixed effects) and were easily visualized in longitudinal plots. A total of 38 potential outliers from 32 participants were detected and further investigated for quality control. ConclusionsThis example demonstrated how longitudinal models can provide CSRs to detect individual-specific outliers. CSRs should be considered as part of quality control for longitudinal epidemiologic studies.

Direct mapping of kidney function by DCE-MRI urography using a tetrazinanone organic radical contrast agent

Chronic kidney disease (CKD) and acute kidney injury (AKI) are ongoing global health burdens. Glomerular filtration rate (GFR) is the gold standard measure of kidney function, with clinical estimates providing a global assessment of kidney health without spatial information of kidney- or region-specific dysfunction. The addition of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to the anatomical imaging already performed would yield a ‘one-stop-shop’ for renal assessment in cases of suspected AKI and CKD. Towards urography by DCE-MRI, we evaluated a class of nitrogen-centered organic radicals known as verdazyls, which are extremely stable even in highly reducing environments. A glucose-modified verdazyl, glucoverdazyl, provided contrast limited to kidney and bladder, affording functional kidney evaluation in mouse models of unilateral ureteral obstruction (UUO) and folic acid-induced nephropathy (FAN). Imaging outcomes correlated with histology and hematology assessing kidney dysfunction, and glucoverdazyl clearance rates were found to be a reliable surrogate measure of GFR.

Activation of renal vascular smooth muscle TRPV4 channels by 5-hydroxytryptamine impairs kidney function in neonatal pigs.

Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT1-5-HT7), with 5-HT2 predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca2+ levels ([Ca2+]i) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT2A is the predominant 5-HT2 receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca2+]i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT2 receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production.

A Predictive Model for Kidney Failure After Nephrectomy for Localized Kidney Cancer: The Kidney Cancer Risk Equation

Nephrectomy is the mainstay of treatment for individuals with localized kidney cancer. However, surgery can potentially result in the loss of kidney function or in kidney failure requiring dialysis/kidney transplantation. There are currently no clinical tools available to preoperatively identify which patients are at risk of kidney failure over the long term. Our study developed and validated a prediction equation for kidney failure after nephrectomy for localized kidney cancer. Population-level cohort study. Adults (n=1,026) from Manitoba, Canada, with non-metastatic kidney cancer diagnosed between January 1, 2004, and December 31, 2016, who were treated with either a partial or radical nephrectomy and had at least 1 estimated glomerular filtration rate (eGFR) measurement before and after nephrectomy. A validation cohort included individuals in Ontario (n=12,043) with a diagnosis of localized kidney cancer between October 1, 2008, and September 30, 2018, who received a partial or radical nephrectomy and had at least 1 eGFR measurement before and after surgery. Age, sex, eGFR, urinary albumin-creatinine ratio, history of diabetes mellitus, and nephrectomy type (partial/radical). The primary outcome was a composite of dialysis, transplantation, or an eGFR<15mL/min/1.73m2 during the follow-up period. Cox proportional hazards regression models evaluated for accuracy using area under the receiver operating characteristic curve (AUC), Brier scores, calibration plots, and continuous net reclassification improvement. We also implemented decision curve analysis. Models developed in the Manitoba cohort were validated in the Ontario cohort. In the development cohort, 10.3% reached kidney failure after nephrectomy. The final model resulted in a 5-year area under thecurve of 0.85 (95% CI, 0.78-0.92) in the development cohort and 0.86 (95% CI, 0.84-0.88) in the validation cohort. Further external validation needed in diverse cohorts. Our externally validated model can be easily applied in clinical practice to inform preoperative discussions about kidney failure risk in patients facing surgical options for localized kidney cancer. Patients with localized kidney cancer often experience a lot of worry about whether their kidney function will remain stable or will decline if they choose to undergo surgery for treatment. To help patients make an informed treatment decision, we developed a simple equation that incorporates 6 easily accessible pieces of patient information to predict the risk of reaching kidney failure 5 years after kidney cancer surgery. We expect that this tool has the potential to inform patient-centered discussions tailored around individualized risk, helping ensure that patients receive the most appropriate risk-based care.

Adsorption and Clearance of the Novel Fluorescent Tracer Agent MB-102 During Continuous Renal Replacement Therapy: In Vitro Results.

MB-102 is a novel fluorescent tracer agent that is exclusively removed from the body by glomerular filtration. This agent can be detected transdermally to provide a real-time measurement of glomerular filtration rate at the point-of-care and is currently in clinical studies for such. MB-102 clearance during continuous renal replacement therapy (CRRT) is unknown. Its plasma protein binding (~0%), molecular weight (~372 Da) and volume of distribution (15-20 L) suggest that it may be removed by renal replacement therapies. To determine the disposition of MB-102 during CRRT, an in vitro study assessing the transmembrane clearance (CL TM ) and adsorptive clearance of MB-102 was conducted. A validated in vitro bovine blood continuous hemofiltration (HF) and continuous hemodialysis (HD) models were performed using two types of hemodiafilters to evaluate CL TM of MB-102. For HF, three different ultrafiltration rates were evaluated. For HD, four different dialysate flow rates were evaluated. Urea was used as a control. No MB-102 adsorption to the CRRT apparatus or either of hemodiafilters was observed. MB-102 is readily removed by HF and HD. Dialysate and ultrafiltrate flow rates directly influence MB-102 CLTM. Hence MB-102 CLTM should be measurable for critically ill patients receiving CRRT.

Posterior Urethral Valves, Unilateral Vesicoureteral Reflux, and Renal Dysplasia (VURD) Syndrome: Long-Term Longitudinal Evaluation of the Kidney Function.

The presence of unilateral vesicoureteral reflux (VUR), and renal dysplasia associated with posterior urethral valves (PUV) (VURD syndrome) was believed to represent a pressure-released pop-off mechanism protecting kidney function. We aimed to investigate its role with respect to long-term kidney function in a cross-sectional and longitudinal analysis. We compared the iohexol glomerular filtration rate (GFR) measured at 5 (GFR5) and 10 (GFR10) years of age in children with (Group A) and without (Group B) VURD syndrome, who underwent PUV resection under 2 years of age. VURD syndrome was diagnosed in cases of unilateral loss of kidney function (<15% on nuclear medicine test) associated with ipsilateral grade IV-V VUR. VURD syndrome was diagnosed in 16 (12.8%) out of 125 patients who met the inclusion criteria. While the median GFR5 was similar in the 2 groups [Group A: 87.3 (74.7-101.2) mL/min/1.73 m2 vs. Group B: 99.6 (77-113) mL/min/1.73 m2, p-value: 0.181], the median GFR10 values were significantly lower in children with VURD syndrome [Group A: 75.7 (71.2-85.9) mL/min/1.73 m2 vs. Group B: 95.1 (81.2-114.2) mL/min/1.73 m2, p-value: 0.009]. Similar results were obtained in a longitudinal analysis of the children with GFR measurement available both at 5 and 10 years of age [GFR5 in Group A: 93.1 (76.9-103.5) mL/min/1.73 m2 vs. Group B: 97.5 (80-113) mL/min/1.73 m2, p-value: 0.460; GFR10: Group A: 71.9 (71.9-85.9) mL/min/1.73 m2 vs. Group B: 94.8 (81.5-110.6) mL/min/1.73 m2, p-value: 0.024]. In conclusion, VURD syndrome does not show a protective role in kidney function preservation. On the contrary, it seems to be associated with a deterioration of the kidney function on a long-term follow-up.

Kidney Function and Long-Term Risk of End-Stage Kidney Disease and Mortality in a Multiethnic Population

Contemporary differences between South Asian and White ethnicities in the incidence of end-stage kidney disease (ESKD) and mortality are poorly described. Data for all South Asian patients who had an estimated glomerular filtration rate (eGFR) measure after January 1, 2006, and 1 million randomly selected participants of other ethnicities were extracted from the Clinical Practice Research Datalink (CPRD). All participants were followed-up with from index date until ESKD, all-cause mortality, or end of study. All-cause mortality rate and ESKD incidence rate by age were described among Whites and South Asians, and adjusted hazard ratios (HRs) of these 2 outcomes by baseline eGFR estimated using Cox proportional hazard model. A total of 40,888 South Asians and 236,634 Whites were followed for a median of 5.3 and 9.4 years for ESKD incidence and mortality outcomes, respectively. All-cause mortality rates were higher among Whites than South Asians; South Asian women aged between 70 and 85 years had a slightly higher ESKD incidence rate compared to their White counterparts. Compared to Whites with a baseline eGFR of 90 ml/min per 1.73 m2, adjusted HRs for all-cause mortality were significantly lower among South Asians than Whites; however, adjusted HRs for ESKD incidence by baseline eGFR were similar in both ethnicities. Calculating South Asian eGFRs using an ethnicity-specific equation had no impact on the results. South Asians experience lower mortality than Whites but not substantially higher rates of ESKD. Further research is warranted to better understand the reasons for these ethnic differences and possible impacts on chronic kidney disease (CKD) service delivery and patient outcomes.

Comparison of Three Glomerular Filtration Rate Estimating Equations with 24-Hour Urine Creatinine Clearance Measurement in Potential Living Kidney Donors.

The accuracy of the measurement of renal function in potential living kidney donors (PLKD) is essential. The direct measurement of glomerular filtration rate (mGFR) has been considered the "gold standard." The estimated GFR (eGFR) with 24-hour urinary creatinine clearance (CrCl) is frequently used because of its availability. We aim to evaluate the correlation and agreement of eGFR using serum-based creatinine formulas (Cockcroft-Gault, MDRD, and CKD-EPI) and the eGFR based on 24-hour urinary CrCl to evaluate kidney function in PLKD. We evaluated the kidney function in 799 PLKD using 24-hour urinary CrCl method and compared the correlation and agreement with the eGFR based on creatinine formulas (Cockcroft-Gault, MDRD, and CKD-EPI). We calculated the mean bias (difference), precision (SD of this difference), accuracy, and performed Bland-Altman plots. A total of 799 PLKD were analyzed. The age of the PLKD ranged from 18 to 73 years. Weak to mild correlation was observed between 24-hour urinary CrCl and all formulas (ranged from 0.31 to 0.49). The three equations underestimated the GFR. Using the Bland-Altman graphic, we observed that the CKD-EPI was the least scattered and most precise; however, mean bias and the interval range (limits of agreement) of all formulas were too big to assume equivalence between 24-hour urinary CrCl method and eGFR based on creatinine. Results of mean bias were similar when comparing the three equations in patients with CrCl GFR <60. However, the accuracy of all formulas was better for the female group and the youngest individuals (≤40 years old). In this PLKD cohort, of all the three equations, the CKD-EPI was the least scattered and most precise. However, the correlation and the level of agreement between the three equations and 24-hour urinary CrCl were too low to assume the equivalence.

#4179 DIFFERENCES IN PROTOCOLS FOR MEASURING GLOMERULAR FILTRATION RATE USING IOHEXOL

Abstract Background and Aims When assessing kidney function, measurement of glomerular filtration rate (mGFR) using an exogenous marker such as iohexol is the gold standard. In this study, we aim to identify similarities and differences between iohexol-based mGFR protocols. Method Detailed data on iohexol measurement protocols were obtained using a standardized survey sent to centres in Europe and the US. It was completed by 15 participants. Data are reported as number and percentage (n, %). Results In the participating centres, measurements are performed after referral by a nephrologist (n=6, 40%), other specialties (n=5, 33%) or for research purposes (n=4, 27%). Most common indications for mGFR are evaluation of kidney donors (n=5, 33%), drug dosing (n=4, 27%), abnormal body composition (n=3, 20%) and transplant evaluation (n=4, 27%). Most participants perform measurements in the morning (n=10, 67%), with patients withholding caffeine (n=5, 33%), fasting (n=4, 27%) or avoiding heavy meals (n=3, 20%). Most centres use an IV iohexol dose of 5 mL 300 mg I/mL (n=10, 67 %) or a dose based on weight (n=2, 13%). The timing of sample collection is shown in Figure 1, most often a single sample per time point (n=12, 80%). Iohexol is measured by LC-MS (n=8, 53%) or LC-UV (n=7, 47%). Within-assay variability ranges between &amp;lt;2% (n=3, 20%) and 6-8% (n=1, 7%) and the between-assay variability ranges between &amp;lt;2% (n=2, 13%) and 6-8% (n=2, 13%). When asked about assumptions and corrections, most centres make a one-compartment assumption in their PK model (n=8, 53%), others making two-compartment (n=2, 13%) or measurement-dependent (n=1, 7%) assumptions. mGFR is standardized for body surface area according to the DuBois-formula (n=6 (40%), Haycock and Schwarz formula (n=2, 13%) or not-specified (n=7, 47%). Some participants correct their measurements for eGFR (n=9, 60 %). Most centres participate in external quality control (Equalis, n=12, 80%). Conclusion There is a large variation in protocols for iohexol-based mGFR, which highlights the need for a standardized mGFR protocol before widespread use in clinical routine.

#4145 ACLARA: AN ON-LINE CALCULATOR TO ESTIMATE CREATININE CLEARANCE IN RATS

Abstract Background and Aims Creatinine clearance (ClCr) is a standard method for the measurement of glomerular filtration rate in rats. Recently, we developed ACLARA, an open and freely available neural network (NN)-based calculator of ClCr in Wistar rats (http://idal.uv.es/aclara). By working solely on plasma creatinine concentration and body weight, ACLARA instantly and easily provides accurate ClCr estimations with an identical concept to that underlying human glomerular filtration rate (GFR)-estimating formulae utility in the clinical setting. In addition to saving costs and time, ACLARA aligns with the 3Rs principles by providing a methodological refinement tool that reduces experimental animal stress derived from avoiding confinement in metabolic cages for individual, 24-hour urine collection. As a potential limitation, ACLARA was developed with data from Wistar rats. Accordingly, the aim of this study is to study ACLARA's accuracy and utility in a different rat strain, namely the spontaneous hypertensive rat (SHR). Method In order to further validate the calculator, we used a dataset with 1,458 entries from unpublished experiments of AKI induced in Wistar and SHR male rats. Measured ClCr (mClCr) was determined with a standard procedure, as we previously described [1], and estimated ClCr (eClCr) was calculated using ACLARA. Calculator performance was assessed with the mean absolute error (MAE) and the Pearson product-moment correlation coefficient calculated as previously described [2]. Results of eCLCr were compared with their corresponding mClCr values in the context of individual experiments. Results Our study reveals that ACLARA performs with reasonably high accuracy at ClCr estimation in both Wistar and SHR rats as indicated by Pearson's product-moment correlation coefficient (Corr) and MAE. The global Corr for the 1,458 measured versus estimated data values reaches 0.9, and a MAE of 0.18 mL/min. In general, estimated data provide identical results to measured data for individual experiments considered in the whole and, if anything, depict more congruent behavior. We interpret this improvement as the consequence of bypassing experimental errors introduced by the well-known discrepancies between the real and measured urinary flow in metabolic cages. Interestingly, ACLARA performs with accuracy through the range of ages and for all experimental conditions tested, including pharmacological treatments. Figure 1 shows a representative experiment in which measured and estimated data are compared holistically. Conclusion ACLARA is an easy-to-use and reliable tool to estimate creatinine clearance in SHR and Wistar rats from plasma creatinine concentration and body weight data. Validation for a second rat strain suggests a potential, wider application of ACLARA through laboratory rats, which needs to be further studied. In this sense, collaboration and use by independent investigators and recruitment of additional data sets from other laboratories is strongly sought to further adjust the calculator in order to enhance its accuracy, extend its applicability and improve its utility to the scientific community. This study was supported by Project PI21/01226, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and a grant from the Consejería de Educación, Junta de Castilla y León (IES160P20), Spain, co-funded by FEDER funds; and a grant from the Valencian Government with reference number CIAICO/2021/184. Noelia Diaz-Morales is recipient of a Juan de la Cierva-Formación postdoctoral contract (FJC2020-043205-I) funded by MCIN/AEI/10.13039/501100011033 and European Union “NextGenerationEU/PRTR”.

#4420 EARLY DAPAGLIFLOZIN UTILIZATION FOR CHRONIC KIDNEY DISEASE TREATMENT IN JAPAN

Abstract Background and Aims In 2021, dapagliflozin was approved for the treatment of adults with chronic kidney disease (CKD) in Japan. This observational analysis is part of the multinational OPTIMISE-CKD study program and aims to describe early dapagliflozin utilization in CKD following approval in Japan, contextualized by contemporary CKD management. Method Adult patients with CKD in hospital claims data from the Medical Data Vision Co. Ltd database (MDV; Tokyo, Japan) during 1 March 2020 – 28 February 2022 were included. CKD was defined as any of the following: 2 estimated glomerular filtration rate (eGFR) measures ≥90 days apart of which the second was ≤75 ml/min/1.73 m2, or a CKD diagnosis code. Patients with type 1 diabetes, gestational diabetes, &amp;lt;365 days continuous enrolment or who were on dialysis were excluded. The remaining patients were considered eligible for dapagliflozin 10 mg treatment. Dapagliflozin initiators had a recorded prescription for dapagliflozin 10 mg on or after 26 August 2021, and no previous dapagliflozin 10 mg prescription. Results A total of 2,297 patients in MDV met the study criteria and had initiated dapagliflozin during the first 6 months since approval. The median age was 70 years (interquartile range; IQR 57-79 years), 33% were female and 50% had a recorded CKD diagnosis. For the 594 initiators who had eGFR data, the CKD stage distribution was as follows: 27% stage 1-2, 28% stage 3a, 28% stage 3b, 16% stage 4 and 1% stage 5 (non-dialysis). The average eGFR among these patients was 49 ml/min/1.73 m2 (standard deviation; SD 19 ml/min/1.73 m2). The most common comorbidities were heart failure (37%), hypertension (34%) and type 2 diabetes (34%). Renin-angiotensin system inhibitors (RASi; 58%), calcium channel blockers (37%) and lipid-lowering drugs (37%) were commonly prescribed. Dapagliflozin 10 mg was most commonly initiated in nephrology departments (42%), with a mean initial prescription duration of 41 days (SD 22.6 days). The 180,462 patients who did not initiate dapagliflozin 10 mg were older on average (median 78 years; IQR 69-85 years), and 42% were female. The comorbidity profiles were similar, except that 24% of patients had type 2 diabetes. The distribution of CKD stages among the 95,465 patients with available data was slightly different: 59% stage 1-2, 22% stage 3a, 11% stage 3b, 6% stage 4 and 3% stage 5 (non-dialysis). Only 23% of patients were prescribed RASi and 41% were prescribed any kind of cardiovascular treatment. Conclusion Early use of dapagliflozin in Japan was observed in a broad range of patients with CKD with respect to baseline characteristics. These preliminary data suggest that there is a large proportion of CKD patients who may be eligible, but not yet treated with dapagliflozin 10 mg, which has shown to attenuate disease progression and reduce adverse outcomes. Considering that the majority of prescriptions was made in nephrology departments, there might be opportunities in other healthcare specialties to improve CKD diagnosis and treatment. Additional analyses, including sensitivity analyses using more conservative CKD definitions, could further specify the unmet need and highlight activities that may increase prescriptions among patients who might benefit from treatment. Further analyses across more patients and countries in the OPTIMISE-CKD program will provide additional insight into the real-world experience of novel treatments for CKD and facilitate optimized CKD management.

GFR measurements and ultrasound findings in 154 children with a congenital solitary functioning kidney

Multicystic dysplastic kidney (MCDK) and unilateral renal agenesis (URA) are the most common reasons for a congenital solitary functioning kidney (SFK). We aimed to assess the presence of abnormalities in the congenital SFK and evaluate kidney function using chrome EDTA (CrEDTA) measurements. We retrospectively reviewed the medical records of 154 children with MCDK and URA in the period from 2005 to 2022 to analyze results from ultrasound scans and CrEDTA glomerular filtration rate (GFR) examinations. Of 154 children with a solitary kidney due to MCDK (62%) or URA (38%), abnormalities on the congenital SFK were found in 13 children (8%). The abnormalities spontaneously resolved in 6 children (46%). The most common abnormality was hydronephrosis. Compensatory hypertrophy was found in 17% of the children within the first 6 months of life. 116 children (90%) had a standard GFR (sdGFR) above 75% of expected for the age. Out of those with a sdGFR below 75% of expected, 3 (23%) had abnormalities in the congenital SFK. There was no difference in sdGFR between children with MCDK and URA. Our study is the first using CrEDTA for GFR measurements and suggests that most children with a congenital SFK due to MCDK or URA have a kidney function within expected for the age. Compensatory hypertrophy of the SFK is found in a minority of children within the first six months of life, suggesting that this process is developing over time. The prevalence of abnormalities in the SFK seems low, however those with abnormalities (e.g. hydronephrosis) are at higher risk of reduced sdGFR.

Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study

ObjectiveTo compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DesignDevelopment...

Energy Metabolism Dysregulation in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a significant contributor to morbidity and mortality. A better understanding of mechanisms underlying CKD progression is indispensable for developing effective therapies. Towards this goal, we addressed specific gaps in knowledge regarding tubular metabolism in the pathogenesis of CKD using the subtotal nephrectomy (STN) model in mice. Weight- and age-matched male 129X1/SvJ mice underwent sham or STN surgeries. We conducted serial glomerular filtration rate (GFR) and hemodynamic measurements up to 16 weeks after sham and STN surgery and established the 4-week timepoint for subsequent studies. For a comprehensive assessment of renal metabolism, we conducted transcriptomic analyses, which showed significant enrichment of pathways involved in fatty acid metabolism, gluconeogenesis, glycolysis, and mitochondrial metabolism in STN kidneys. Expression of rate-limiting fatty acid oxidation and glycolytic enzymes was increased in STN kidneys, and proximal tubules in STN kidneys exhibited increased functional glycolysis but decreased mitochondrial respiration, despite an increase in mitochondrial biogenesis. Assessment of the pyruvate dehydrogenase complex pathway showed significant suppression of pyruvate dehydrogenase suggesting decreased provision of acetyl CoA from pyruvate for the citric acid cycle to fuel mitochondrial respiration. In conclusion, metabolic pathways are significantly altered in response to kidney injury and may play an important role in the disease progression.

A back propagation neural network approach to estimate the glomerular filtration rate in an older population

BackgroundThe use of creatinine-based glomerular filtration rate (GFR)-estimating equations to evaluate kidney function in elderly individuals does not appear to offer any performance advantages. We therefore aimed to develop an accurate GFR-estimating tool for this age group.MethodsAdults aged ≥ 65 years who underwent GFR measurement by technetium-99 m-diethylene triamine pentaacetic acid (99mTc-DTPA) renal dynamic imaging were included. Data were randomly split into a training set containing 80% of the participants and a test set containing the remaining 20% of the subjects. The Back propagation neural network (BPNN) approach was used to derive a novel GFR estimation tool; then we compared the performance of the BPNN tool with six creatinine-based equations (Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI], European Kidney Function Consortium [EKFC], Berlin Initiative Study-1 [BIS1], Lund-Malmö Revised [LMR], Asian modified CKD-EPI, and Modification of Diet in Renal Disease [MDRD]) in the test cohort. Three equation performance criteria were considered: bias (difference between measured GFR and estimated GFR), precision (interquartile range [IQR] of the median difference), and accuracy P30 (percentage of GFR estimates that are within 30% of measured GFR).ResultsThe study included 1,222 older adults. The mean age of both the training cohort (n = 978) and the test cohort (n = 244) was 72 ± 6 years, with 544 (55.6%) and 129 (52.9%) males, respectively. The median bias of BPNN was 2.06 ml/min/1.73 m2, which was smaller than that of LMR (4.59 ml/min/1.73 m2; p = 0.03), and higher than that of the Asian modified CKD-EPI (-1.43 ml/min/1.73 m2; p = 0.02). The median bias between BPNN and each of CKD-EPI (2.19 ml/min/1.73 m2; p = 0.31), EKFC (-1.41 ml/min/1.73 m2; p = 0.26), BIS1 (0.64 ml/min/1.73 m2; p = 0.99), and MDRD (1.11 ml/min/1.73 m2; p = 0.45) was not significant. However, the BPNN had the highest precision IQR (14.31 ml/min/1.73 m2) and the greatest accuracy P30 among all equations (78.28%). At measured GFR < 45 ml/min/1.73 m2, the BPNN has highest accuracy P30 (70.69%), and highest precision IQR (12.46 ml/min/1.73 m2). The biases of BPNN and BIS1 equations were similar (0.74 [-1.55−2.78] and 0.24 [-2.58−1.61], respectively), smaller than any other equation.ConclusionsThe novel BPNN tool is more accurate than the currently available creatinine-based GFR estimation equations in an older population and could be recommended for routine clinical use.

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Evaluating the effectiveness of an apelin analog as a potential treatment for pulmonary arterial hypertension using a sugen-hypoxia rat model

Background: Pulmonary arterial hypertension (PAH) is a debilitating syndrome characterized by heightened pulmonary arterial pressures, and adverse pulmonary vascular remodeling. Eventually, the right ventricle (RV) decompensates, and fatal right heart failure ensues. Existing treatments for PAH are ineffective at improving survival. Apelin is an endogenous cardioprotective peptide, and disruption of apelin signaling was associated with the development of PAH. Restoring the activity of the apelin pathway is a promising approach in reversing the arteriopathy underlying PAH to protect the RV. The salutary actions of apelin are limited by its short half-life; recently, apelin analogs designed with extended half-lives offer a novel therapeutic avenue requiring further testing. Objective: Our project aims to evaluate the effectiveness of an apelin analog as a potential treatment for PAH using a Sugen-Hypoxia (SuHx) rat model of PAH which recapitulates disease characteristics seen in humans. We hypothesize that the apelin analog treatment will improve pulmonary hemodynamics and preserve RV adaptation in rats exposed to SuHx and assuage the pulmonary arteriopathy seen in PAH rats. Experimental design: Male Sprague Dawley rats aged 9 weeks were randomly split into a placebo or treated PAH group. For 3 weeks, a control group was kept within normal room air while the placebo and treated PAH rats were kept in a hypoxia chamber (10% O 2 ). Placebo and treated rats were injected with SU5416 (20 mg/kg, SQ) once at the start of the 3 weeks to induce disease. The normoxic period lasted 5 weeks following the 3 weeks of hypoxia. Treated rats received apelin analog (0.5 μmol/kg, IV, b.i.d.) for the final 3 weeks of normoxia; the placebo group received the same dose of saline. Results: At endpoint, glomerular filtration rate (GFR) measurements showed that placebo treated (PAH-P) PAH rats had reduced GFR while apelin treated (PAH-A) PAH rats had recovered GFR. Echocardiography revealed that PAH-A rats had improved cardiac function compared to PAH-P rats. RV Pressure-volume loop surgeries showed that PAH-A rats had ameliorated RV hemodynamic pressures in contrast to PAH-P rats. Histological analysis demonstrated reduced cardiac fibrosis and hypertrophy, and fewer formations of pulmonary vascular lesions within PAH-A rats compared to PAH-P rats. Single nucleus RNA sequencing performed on RV and lung tissue delineated mitigation of disease progression within the PAH-A group compared to PAH-P rats. Electrocardiography recordings showed more severe electrical remodeling in the PAH-P group compared to the PAH-A rats. Conclusions &amp; significance: Rats with PAH treated with apelin had overall improved cardiopulmonary health outcomes compared to placebo treated PAH rats. The results of this study provide insight into the beneficial role of the apelin pathway in the setting of PAH to propose a new treatment for patients with PAH to improve their duration and quality of life. Canadian Institutes of Health Research Grant 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.

Prevalence of undiagnosed stage 3 chronic kidney disease in France, Germany, Italy, Japan and the USA: results from the multinational observational REVEAL-CKD study

ObjectivesREVEAL-CKD aims to estimate the prevalence of, and factors associated with, undiagnosed stage 3 chronic kidney disease (CKD).DesignMultinational, observational study.SettingData from six country-specific electronic medical records and/or insurance claims databases...

Benefits of direct glomerular filtration rate (GFR) determination versus creatinine-based tests for evaluating renal function.

To diagnose renal disease earlier and thereby reduce the number of patients with end-stage renal disease, accurate, specific diagnostic tests are necessary. The author explains the benefits of using tests that rely on the glomerular filtration rate measurement rather than on traditional creatinine-based diagnostic tests.