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Genetic overlap between estimated glomerular filtration rate and cardiovascular disease identifies potential targets for cardiorenal syndrome.

Heart and kidney diseases frequently coexist, but the genetic basis of this relationship remains unclear. We analyzed genetic data from large-scale studies to investigate how kidney function (estimated glomerular filtration rate, eGFR) and six common cardiovascular diseases share genetic risk factors. Using MiXeR method, and conjunctional false discovery rate (conjFDR) to identify overlapping genetic regions, we found 478 shared genomic loci between eGFR and cardiovascular diseases. These shared genes are involved in tissue development and structure. We also identified 29 genes that could be targeted by existing medications approved by the US Food and Drug Administration, such as PRKAG2, PDE1A, and IGF1R. Among these, genetically predicted higher level of IGF1R expression is associated with a higher eGFR, which reflects good kidney function and is protective against cardiorenal diseases, such as atrial fibrillation, and myocardial infarction. These findings reveal genetic overlap between kidney function and cardiovascular diseases, highlighting potential targets for understanding and treating cardiorenal syndrome.

Humans

Genome-wide association study of estimated glomerular filtration rate using repeated measurements in the Taiwan Biobank.

BACKGROUND: Chronic kidney disease (CKD) is a major global public health issue, with genetic factors playing a significant role in kidney function. Although genome-wide association studies (GWAS) have identified numerous loci associated with estimated glomerular filtration rate (eGFR), most studies relied on a single time-point measurement, which limits the capacity to account for within-individual measurement variability. METHODS: We performed a repeated-measurement GWAS in the prospective Taiwan Biobank (Taiwanese ancestry; n = 25,004) using two repeated creatinine-based eGFR measurements. Repeated eGFR values were analyzed using a linear mixed-effects model with a subject-specific random intercept and time-varying covariates, providing a more precise estimate of eGFR level. Identified loci underwent functional annotation (expression quantitative trait locus, deleteriousness prediction, and epigenetic markers) and were compared with results from a single-measurement GWAS. RESULTS: Six loci associated with eGFR were identified, including four previously reported regions (1q22, 4q21.1, 11p14.1, and 17q21.2) and two additional loci (6p21.32 and 15q24.2). Functional annotation implicated several candidate genes-such as MUC1/EFNA1, SHROOM3, HLA-DQB1, MPPED2, NRG4, and PGAP3/FBXL20-in the regulation of kidney function. CONCLUSION: Incorporating repeated eGFR measurements into GWAS may improve phenotypic precision for identifying genetic associations with kidney function. This study identified eGFR-associated loci and biologically plausible candidate genes in a Taiwanese population, which require further replication and functional validation.

Chronic kidney disease

A single-injection method for measuring glomerular filtration rate.

A method for estimating glomerular filtration rate (GFR) has been developed that is based on an analysis of the total area under the plasma radioactivity-time curve after a single intravenous injection of [125I]iothalamate. Glomerular filtration rates obtained by this method (method A) and those obtained with two widely used single-injection techniques, the slope-intercept method (method B), and the two-compartment method (method C), were compared with GFRs obtained by standard inulin clearance techniques in 14 dogs. Method B consistently over. estimated inulin clearances more than 30%. Method C also overestimated inulin clearance considerably in dogs with an increased extracellular fluid volume, but was fairly reliable in normal dogs. Glomerular filtration rates obtained by the new method (method A) were in excellent agreement with inulin clearances in all dogs, regardless of the state of body hydration. The mean inulin clearance for all 14 experiments was 72.7+/-6.0 SE ml/min, while GFRs obtained by method A averaged 75.1+/-6.0 ml/min. The data from this study suggest that method A is a reliable means for estimating GFR that is especially useful in chronic experiments.

Animals

A simple method for the estimation of glomerular filtration rate.

A simple method is presented for indirect estimation of the glomerular filtration rate from two venous blood samples, drawn after a single injection of a small dose of [125I]sodium iothalamate (10 muCi). The method does not require exact dosage, as the first sample, taken a few minutes (t = 5 min) after injection, is used to normalize the value of the second sample, which should be taken in between 2-4 h after injection. The glomerular filtration rate, as measured by standard inulin clearance, may then be predicted from the logarithm of the normalized value and linear regression formulas with a standard error of estimate of the order 1-2 ml/min/1.73 m2. The slope-intercept method for direct estimation of glomerular filtration rate is also evaluated and found to significantly underestimate standard inulin clearance. The normalized 'single-point' method is concluded to be superior to the slope-intercept method and more sophisticated methods using curve fitting technique, with regard to predictive force and clinical applicability.

Adult

The technetium-99m-DTPA renal uptake-plasma volume product: a quantitative estimation of glomerular filtration rate.

An image-based method for estimating quantitative renal glomerular filtration rates (GFR) by calculating the product of the renal uptake rate and plasma volume is presented. By using the relationship GFR = F.PV/t, F represents renal 99mTc-DTPA uptake after bolus injection, PV is the plasma volume and t is time. This GFR evaluation was carried out on 96 patients and compared to GFR values determined in the same patients using radiotracer blood clearance techniques relying on two venous blood samples. When estimating patient plasma volumes using patient's weight and measured hematocrit values, the image-based method for calculating GFR accurately approximates the values obtained from blood samples (linear regression slope = 1.03; y-intercept = -2.81 ml/min). The two techniques correlate with a value of r = 0.89.

Adult

The renal plasma flow and glomerular filtration rate as estimated through double radiocompound renography.

In order to estimate the renal plasma flow and glomerular filtration rate during the course of renography, a method was developed using simultaneously 131I Hippuran and 169Yb DTPA. First results obtained in a survey of approximately 200 patients are encouraging. The method permits an accurate evaluation of the renal function. In addition, by comparing the clearance rate of the two radiocompounds one can also obtain some interesting diagnostic information which can contribute usefully to the interpretation of renographic tracings and/or gamma camera sequential images.

Acute Disease

Creatinine for estimation of glomerular filtration rate.

The aim of this study was to evaluate the plasma creatinine concentration (PCr) and creatinine clearance (CCr) for estimation of glomerular filtration rate (GFR). Inulin clearance (Cin) was used as the reference standard for GFR. Thirty-nine concurrent Cin and CCr studies provided data for comparing Cin with the measured CCr and with the calculated CCr (calc-CCr). (Calc-CCr = k.L/PCr, where L = height in centimeters and k is the proportionality constant.) Thirty-one children 5.3-20.8 years of age, with Cin ranging from 2.8 to 138.8 ml/min per 1.73 m2, participated in these studies at The Children's Mercy Hospital. The measured CCr was 16.7 +/- 10.3 ml/min per 1.73 m2 (P < 0.001) greater than the Cin, and the calc-CCr overestimated Cin by a mean of 31.6 +/- 20.8 ml/min per 1.73 m2 (P < 0.001). Although there is good correlation between Cin and CCr (r = 0.96), and Cin and calc-CCr (r = 0.90), the 95% confidence intervals are quite broad. Hence, the CCr and the calc-CCr, derived using Schwartz values for k, consistently overestimate GFR. However, if the k value in the equation GFR = k.L/PCr is derived from k = Cin/L, rather than from k = CCr.PCr/L, a more accurate estimate of GFR may be obtained.

Adolescent

The estimate of glomerular filtration rate during urography. Acceptability of a nonionic contrast medium as a marker of renal function.

RATIONALE AND OBJECTIVES: An estimate of glomerular filtration rate (GFR) may be obtained at the same time as urography by measuring the plasma clearance of the radiographic contrast medium using an x-ray fluorescence technique. It must be established whether the function measured or one modified by an effect of the contrast medium itself represents a true value. METHODS: Technetium 99m-DTPA (99mTc-DTPA) plasma clearance was measured in 21 patients using a single-injection technique, before, during, and after an intravenous injection of 50 mL of 350 mg I/mL iohexol. Iohexol clearance also was determined using an alternative single-injection, two-sample technique. RESULTS: The mean 99mTc-DTPA clearances before, during, and after contrast were 71.2, 71.5, and 70.7 mL/minute, respectively. The within-patient standard deviation in clearance values was 3.84 mL/minute. One factor repeat measures analysis of variance indicated no significant difference between the three measurements (F ratio = 0.24). Contrast and 99mTc-DTPA clearances performed simultaneously agreed closely (r = .976; ClDTPA = 1.02ClCon - 1.35). CONCLUSION: The authors conclude that no change in function is observed during or 48 hours after contrast injection. Imaging doses of iohexol can be used for GFR measurement during urography.

Aged

A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine.

Based on statistical analysis of data in 186 children, a formula was derived which allows accurate estimation of glomerular filtration rate (GFR) from plasma creatinine and body lenght (GFR(ml/min/1.73 sq m) = 0.55 length (cm)/Per (mg/dl). Its application to clearance data in a separate group of 223 children reveals excellent agreement with GFR estimated by the Ccr (r = .935) or Cin (r = .905). This formula should be useful for adjusting dosages of drugs excreted by the kidney and detecting significant changes in renal function.

Adolescent

Accurate estimation of glomerular filtration rate in diabetic nephropathy from age, body weight, and serum creatinine.

OBJECTIVE: To assess, in diabetic nephropathy, the accuracy of a method that estimates glomerular function with age, body weight, and serum creatinine as parameters. RESEARCH DESIGN AND METHODS: Glomerular filtration rate (GFR) was measured 57 times in 20 subjects with insulin-dependent diabetes mellitus and nephropathy with a single injection of 51Cr-EDTA. At the same time, the estimated creatinine clearance (ml/min) was calculated with the Cockroft-Gault formula (140 - age [yr]) x body wt [kg] x K/serum creatinine [mumol/L]) K = 1.23 for men, 1.05 for women These values were then corrected for body surface area (1.73 m2). RESULTS: For GFR measurements less than 100 ml.min-1.1.73 m-2 (n = 41), there was a strong positive correlation with the estimated creatinine clearance corrected for body surface area (r = 0.94, P less than 0.0001). The slope of this regression line did not differ significantly from identity or the y-intercept from zero. On average, the Cockroft-Gault formula (corrected for body surface area) underestimated the GFR by only 3.1 ml.min-1.1.73 m-2 (9.7 SD). CONCLUSIONS: This formula, corrected for body surface area, gives accurate estimates of GFR when GFR less than 100 ml.min-1.1.73 m-2. This formula could be used with an acceptable degree of confidence when repeated isotope assessments of renal function in diabetic nephropathy are impracticable.

Adult

Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate.

Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/Cll) ranged from 1.14 to 2.27. With cimetidine, ClC/Cll approached unity in 8 patients (mean 1.02 [SD 0.03]), but considerably exceeded unity in 8 others (1.33 [0.14]). Plasma cimetidine/creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p = 0.01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibited previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures GFR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.

Adolescent

Effect of levothyroxine therapy on albuminuria and glomerular function in patients with type 2 diabetes and subclinical Hypothyroidism: a randomized controlled pilot trial.

AIMS: To evaluate the effect of levothyroxine therapy on renal outcomes in patients with type 2 diabetes mellitus (T2DM) and subclinical hypothyroidism (SCH) with background SGLT2 inhibitor therapy. METHODS: In this hypothesis generating open-label, randomized controlled pilot trial, adults with T2DM and SCH were assigned (1:1) to levothyroxine or no levothyroxine therapy and followed for 6&#xa0;months. Primary outcomes were changes in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). RESULTS: Sixty participants were randomized (30 per group); 24 and 27 completed follow-up in the treatment and control groups respectively. UACR decreased with levothyroxine (-13.09&#xa0;mg/g) and increased in controls (31.84&#xa0;mg/g). The difference was significant in per-protocol (PP)(-44.93&#xa0;mg/g; 95% CI -77.6 to -12.26; p&#xa0;=&#xa0;0.008) but insignificant in intention to treat (ITT)(-35.61&#xa0;mg/g; 95% CI -77.31 to 6.08; p&#xa0;=&#xa0;0.092). eGFR changes were statistically insignificant in both ITT(4.65&#xa0;mL/min/1.73&#xa0;m2; 95% CI -8.3 to 17.6; p&#xa0;=&#xa0;0.472) and PP(7.35&#xa0;mL/min/1.73&#xa0;m2; 95% CI -1.68 to 16.37; p&#xa0;=&#xa0;0.108). Thyroid-stimulating hormone decreased significantly in treatment arm in comparison to control arm (p&#xa0;<&#xa0;0.001) in ITT and PP. No adverse event was reported. CONCLUSIONS: Levothyroxine treatment showed trend toward improving albuminuria and eGFR without reaching statistical significance, suggesting possible renoprotective effect warranting further studies. CLINICAL TRIAL REGISTRATION: This trial is registered with Clinical Trial Registry of India (CTRI/2025/06/089606).

Humans

Unilateral estimation of glomerular filtration rate with 99mTc-DTPA.

There is one renal disease in which unilateral estimation of GFR is desirable for clinical purposes: chronic pyelonephritis. Considering the possibilities for complications to determine unilateral renal function by ureter catheter just in this group of patients, we tried to estimate unilateral GFR with 66mTc-DTPA after a single injection of 5 mCi i.v. on the basis of blood samples at 90, 110 and 130 min after injection and evaluation of gamma-camera data from 25 to 35 min after administration of the dose. 31 patients were studied. In arenal patients clearance values were 7.5 ml/min (+/- 10.47 ml/min), unilaterally nephrectomized patients showed zero values for the removed kidney. Normal patients had a mean GFR of 107 +/- 17.7 ml/min with a partition between right and left kidney of 54.2 +/- 10 to 52.75 +/- 8.5 ml/min. Patients without urinary tract obstruction and unilateral renal disease had values of 27.1 +/- 11 ml/min for the diseased kidney while the normal kidneys gave a mean value of 59.6 ml/min (+/- 13 ml/min). In the presence of urinary tract obstruction, data could not be correlated to the state of renal function. This shows that unilateral estimation of GFR using 99mTc-DTPA is basically possible, but that it is useless in obstructive kidney disease.

Chronic Disease

Estimation of glomerular filtration rate from plasma creatinine concentration in children.

The relation between the true plasma creatinine concentration (Pc) and the glomerular filtration rate corrected for body surface area (GFR/SA) was investigated in 108 individuals, and the following formula was derived: GFR/SA (ml/min per 1-73m2SA) = 0-43 Ht (cm)/Pc (mg/100 ml). This formula was tested in a second group of 83 children, and its accuracy and precision was compared to the 24-hour creatinine clearance. It was found to be superior to the creatinine clearance overall, and was as good, even if all results involving suspect 24-hour-urine collections were eliminated from analysis. The formula in SI usage is: GFR/SA (ml/min per 1-73 m2SA) = 38 Ht (cm)1Pc (mumol/l).

Adolescent