Urinary tetrahydrodeoxycorticosterone excretion is a significant independent predictor of LV mass in patients with chronic kidney disease
Emily P. McQuarriePatrick B. MarkRajan PatelRobert FraserE.A. DaviesTracey SteedmanJohn ConnellE. Marie Freel
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The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy.In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine.Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, 18 U/g urinary Cr; FSGS and MCD, 24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs.Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.
Albuminuria
Beta-2 microglobulin
Minimal change disease
Glomerular hyperfiltration
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BACKGROUND :
Chronic kidney disease is the growing epidemic of the 21st century. With the rising burden of diabetes and hypertension, chronic kidney disease is becoming rampant in our country. About 40 – 50% of the death in chronic kidney disease patients is attributed to cardiovascular causes. Individuals with the most severe form of chronic kidney disease have a risk for cardiac death 15 times higher than patients with preserved glomerular filtration rate. The two classical features of cardiac disease in end stage renal disease (ESRD) are atherosclerotic vascular disease and left ventricular hypertrophy. The prevalence of left ventricular hypertrophy is around 80% in a dialysis population. Multiple afterload and preload related factors act in the pathogenesis of this uremic cardiomyopathy, which once initiated, lead on to myocyte ischemia and myocardial fibrosis and eventually death. Hence if the risk factors which contributed to left ventricular hypertrophy in chronic kidney disease patients could be lined out, it would be possible to prevent and regress the left ventricular wall thickness. In our study, two variables glomerular filtration rate and the amount of proteinuria are used to predict the left ventricular mass index in chronic kidney disease.
AIMS AND OBJECTIVES :
1. To calculate the left ventricular mass index in CKD patients who are maintained on conservative medical management.
2. To calculate the glomerular filtration rate of CKD patients using 24 hour creatinine clearance and Cockcroft Gault formula and the amount of proteinuria using urine spot PCR and 24 hour quantification.
3. To study whether there is a significant correlation between the amount of proteinuria and glomerular filtration rate to the left ventricular mass index.
4. To also correlate the association between other variables in chronic kidney disease and left ventricular mass index.
MATERIALS AND METHODS :
A total of 75 patients attending the Nephrology OP and admitted in the Nephrology ward satisfying the inclusion and exclusion criteria were included in the study over a period of 6 months. Blood samples and urine samples were drawn at the time of admission and in the Outpatient department for urine spot protein creatinine ratio calculation and renal function test. 24 hour urine collection was scrutinized and analysed for proteinuria quantification and creatinine clearance. Left ventricular mass was measured using 2D Echocardiography. Devereux formula was used for the calculation of left ventricular mass index.
OBSERVATION AND RESULTS :
Among the variables studied age and sex of the patient, prevalence of diabetes and hypertension in the study population, systolic blood pressure, diastolic blood pressure, serum albumin and hemoglobin, serum alkaline phosphatase, total cholesterol and serum triglycerides, blood urea of the patients in the study group did not have a significant p value, suggesting that all these variables did not influence or predict the development of left ventricular hypertrophy in chronic kidney disease patients in our study.
The variables duration of chronic kidney disease, serum creatinine, creatinine clearance (24 hour urine estimation, Cockcroft Gault equation, and MDRD equation), and urine spot PCR and 24 hour proteinuria all had a significant p value demonstrating their predictive potential for left ventricular hypertrophy in chronic kidney disease.
Among the significant parameters, a statistically highly significant negative correlation was observed between declining GFR (Stage 4/5) and increased left ventricular mass index (p value < 0.001). Highly significant positive correlation was also observed with serum creatinine values and increased left ventricular mass (p value < 0.001). Regarding proteinuria, a highly significant positive correlation was obtained between urine spot protein creatinine ratio, 24 hour urine protein and the left ventricular wall thickness (p value < 0.001). These parameters were found to be significant in both univariate and multivariate regression analysis.
CONCLUSION:
1. Glomerular filtration rate and the amount of proteinuria significantly influence the left ventricular wall thickness in chronic kidney disease patients.
2. Declining GFR had a strong negative correlation with left ventricular mass, where the amount of protein excreted positively predicted the significant risk of left ventricular hypertrophy in these patients.
3. These predictors of LV mass could be easily measured and are highly sensitive and specific for the same.
4. Hence routine measurement of these variables, and its correlation to left ventricular thickness could be easily ascertained compared to the costly investigations like cardiac MRI and Echocardiography.
5. On arriving at a suspicion of possible LV hypertrophy, rigorous measures to reduce protein excretion and frequent hemodialysis session could improve patients survival from the deadly cardiovascular diseases.
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Urine sodium
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Background
Even the earliest subclinical renal dysfunction is an important independent risk factor for cardiovascular disease [1]. It is cardiovascular complications associated with atherosclerotic vascular disease that are the leading causes of premature mortality in rheumatoid arthritis (RA) [2].Objectives
To determine the urinary excretions of albumin in patients with RA, to identify the relationship of this indicator with risk factors for cardiovascular disease.Methods
The study included 73 patients with RA at the age 18 to 60 years, who were treated at the rheumatology department of the regional hospital. Exclusion criteria were an associated kidney diseases, hypertension stage III, any kind of secondary nephropathy and pregnancy. We investigated the urinary excretions of albumin (Al) by immunoturbidimetric method in a morning urine sample. The urinary albumin excretion was considered normal for the index of Al/urine creatinine less than 17 mg/g in men and 25 mg/g in women. The arterial stiffness was detected using a Tensioclinic arteriograph (Tensiomed, Hungary). The pulse wave velocity in the aortaand augmentation index were measured. The ultrasound measuring of the carotid intima-media thickness was performed to study subclinical atherosclerosis.Results
The urinary excretion of Al in the patients with RA was significantly higher than in control subjects matched for age, body mass index, blood pressure (50.27 [23.2, 100.82] mg/g and 23.43 [17.92, 30.42] mg/g, respectively, p<0.001). Increased urinary albumin excretion was found in 52 (71%) patients. The correlation was found of the urinary excretion of Al with age (r = 0.266; p = 0.023), the multiplicity of nonsteroid anti-inflammatory drugs (NSAIDs) in the month prior to the study (r = 0.271; p = 0.027), glomerular filtration rate, which was calculated by using the Modification of Diet in Renal Disease (r = -0.282; p = 0.016), low density lipoprotein (r= 0.367; p = 0.005), atherogenic index (r = 0.415; p = 0.001), pulse wave velocity in the aorta (r = 0.258; p = 0.039), augmentation index in the aorta and brachial artery (r = 0.346; p = 0.005), the carotid intima-media thickness (r = 0.270; p = 0.021).Conclusions
The urinary excretion of Al in the patients with RA is significantly higher than in the control group. Increased urinary albumin excretion correlates with risk factors for cardiovascular disease (hypertension, dyslipidemia, the arterial stiffness) and with the features of the development of the RA (multiple NSAIDs).References
Astor B.C., Hallan S.I.Miller E.R. et al. Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population. American Journal of Epidemiology2008;167:1226-1233 CaplanM. J. Cardiovasculardiseaseinrheumatoidarthritis. Curr. Opin. Rheumatol., 2006;18:289-97.Disclosure of Interest
None DeclaredSubclinical infection
Microalbuminuria
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<b><i>Background:</i></b> While higher blood pressure is known to increase proteinuria, whether increased dietary sodium as estimated from 24-hour urinary excretion correlates with increased proteinuria in patients with chronic kidney disease (CKD) is not well studied. <b><i>Methods:</i></b> We measured 24-hour urinary sodium, potassium and protein excretion in 3,680 participants in the Chronic Renal Insufficiency Cohort study, to determine the relationship between urinary sodium and potassium and urinary protein excretion in patients with CKD. We stratified our data based on the presence or absence of diabetes given the absence of any data on this relationship and evidence that diabetics had greater urinary protein excretion at nearly every level of urinary sodium excretion. Multiple linear regressions were used with a stepwise inclusion of covariates such as systolic blood pressure, demographics, hemoglobin A1c and type of antihypertensive medications to evaluate the relationship between urinary electrolyte excretion and proteinuria. <b><i>Results:</i></b> Our data demonstrated that urinary sodium (+1 SD above the mean), as a univariate variable, explained 12% of the variation in proteinuria (β = 0.29, p < 0.0001), with rising urinary sodium excretion associated with increasing proteinuria. The significance of that relationship was only partially attenuated with adjustment for demographic and clinical factors and the addition of 24-hour urinary potassium to the model (β = 0.13, R<sup>2</sup> = 0.35, p < 0.0001). <b><i>Conclusions:</i></b> An understanding of the relationship between these clinical factors and dietary sodium may allow a more tailored approach for dietary salt restriction in patients with CKD.
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BackgroundBlockade of the mineralocorticoid receptor (MR) in patients with chronic kidney disease (CKD) improves surrogate cardiovascular outcomes, such as left ventricular mass. Animal models of renal disease support a pathological role of mineralocorticoids, in the context of a high sodium intake. We aimed to assess the regulation of mineralocorticoid biosynthesis in patients with CKD.
Mineralocorticoid
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Serum p-cresyl sulfate (PCS) associates with cardiovascular disease in patients with chronic kidney disease. PCS concentrations are determined by intestinal uptake of p-cresol, human metabolism to PCS and renal clearance. Whether intestinal uptake of p-cresol itself is directly associated with cardiovascular disease in patients with renal dysfunction has not been studied to date. We performed a prospective study in patients with chronic kidney disease stage 1 – 5 (NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24 h urinary excretion of PCS. Primary endpoint was time to first cardiovascular event, i.e., cardiac death, myocardial infarction/ischemia, ventricular arrhythmia, cardiovascular surgery, ischemic stroke or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan-Meier estimates and Cox proportional hazard analyses. In a cohort of 200 patients, median 24 h urinary excretion of PCS amounted to 457.47 μmol (IQR 252.68 – 697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.037). Higher urinary excretion of PCS was directly associated with cardiovascular events (univariate hazard ratio per 100 μmol increase: 1.112, P 0.002). In multivariate analysis, urinary excretion of PCS remained a predictor of cardiovascular events, independent of eGFR (hazard ratio 1.120, P 0.002). In patients with chronic kidney disease, intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. The intestinal generation and absorption of p-cresol may be therapeutic targets to reduce cardiovascular disease risk in patients with renal dysfunction.
Univariate analysis
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Presently, scientific knowledge on the association between urinary lead concentration and renal profile is limited, especially on the characteristic of urinary lead that could aggravate existing kidney disease. This study aims to determine the concentration of urinary lead with serum creatinine and blood urea nitrogen in chronic kidney disease patients and to identify the influences of confounding factors and the blood pressure on the chronic kidney disease patients. Graphite Furnace Atomic Absorption Spectrometer was used to determine the urinary lead concentration. The differences and correlation of urinary lead with serum creatinine, blood urea nitrogen and diastolic blood pressure between the chronic kidney disease patients and control groups were assessed using Mann Whitney U and Spearman correlation tests. Our findings indicated a significantly higher urinary lead concentration in the chronic kidney disease group compared to the control group (p-=0.002). Nevertheless, there is a weak relationship between urinary lead with serum creatinine, blood urea nitrogen and diastolic blood pressure in the chronic kidney disease group (r values: -0.123, 0.101, and 0.127). In addition, sociodemographic factors did not influence the concentration of urinary lead (p>0.05). The urinary lead concentration in the chronic kidney disease group is not substantial, thus the evidence of urinary lead accumulation in chronic kidney disease group who have yet to start renal replacement therapy is inconclusive.
Blood urea nitrogen
Nephrology
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Introduction: Patients with chronic kidney disease (CKD) are at an increased risk of CVD compared to the general population. Left ventricular hypertrophy (LVH) is an independent risk factor for CVD in the general population and in CKD patients. In the general population, sodium (Na) excretion is directly associated with LVH. However, this association has not been examined in patients with CKD. Hypothesis: We hypothesized that in CKD patients, urinary Na excretion would be directly and urinary potassium (K) would be indirectly associated with development of ejection fraction (EF) < 50% and LVH and longitudinal changes in EF and left ventricular mass index (LVMI). Methods: The Chronic Renal Insufficiency Cohort Study (CRIC) is a prospective cohort study of 3,939 participants with CKD. Dietary Na and K excretion were assessed by averaging three 24-hour urinary measures (over 2 years) and calibrated to sex-specific mean 24-hour urinary creatinine excretion. Echocardiograms (ECHO) were conducted at follow-up years 1, 4, and 7 and centrally analyzed to quantify EF and LVMI. LVH is defined as LVMI ≥ 47 g/m 2.7 in women and LVMI ≥ 50 g/m 2.7 in men. Log-linear binomial and linear mixed effects models were used. Results: During follow-up, 676 participants developed EF <50% and 238 developed LVH among those with EF ≥ 50% or free of LVH at the first ECHO, respectively. After multivariate adjustment, participants in the highest quartile of adjusted sodium excretion (>196.2 mmol/24 hours) had a relative risk of 1.31 (95% CI 1.08, 1.59) of developing an EF < 50% during follow-up compared to those in the lowest quartile (<127.8 mmol/24 hours). Furthermore, participants in the highest quartile of adjusted urinary sodium excretion had a greater annual decrease in ejection fraction (-1.36%, 95 CI: -1.53, -1.19%) compared to those in the lowest quartile (-0.95%, 95% CI: -1.11, -0.79%; p for trend across quartiles 0.0003). No significant association was observed between K excretion and development of EF < 50% or change in EF. In addition, no association was observed between adjusted Na or K excretion and development of LVH or change in LVMI during follow-up. Conclusions: Higher Na excretion is associated with a greater likelihood of developing an EF <50% and a greater annual decrease in EF. Further studies are needed to determine if interventions to reduce high dietary sodium could slow the decline in left ventricular structure and function in patients with CKD.
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Salt intake not only elevates the levels of blood pressure, glomerular capillary pressure and proteinuria, but also increases oxidative stress within the renal cortex in animal models. We examined the effect of salt intake on the rate of renal function decline, urinary protein and oxidative stress in patients with chronic kidney disease (CKD).Clinical data including systolic blood pressure (SBP)and diastolic blood pressure (DBP), serum creatinine, uric acid, total cholesterol, triglyceride, urinary protein, salt intake, protein intake of non-diabetic CKD 53 patients were observed for one year. At the end of the observation period, we measured 8-hydroxydeoxy guanosine (8-OHdG) in spot urine. We calculated the slope of reciprocal serum creatinine as the rate of renal function decline (delta1/Cr). We then investigated the relationship between those clinical factors and delta1/Cr, and urinary 8-OHdG, and also selected clinical factors that significantly influence delta1/Cr and urinary 8-OHdG by stepwise multiple regression analysis. In addition, we investigated the gender difference in urinary 8-OHdG.Annual mean SBP and DBP of all patients were 121.5 +/- 9.3 mmHg and 72.5+/- 6.2 mmHg, respectively. delta1/Cr was negatively correlated with salt intake, urinary protein and urinary protein was a significant predictor of delta1/Cr in a multiple regression analysis. Salt intake was positively correlated with protein intake and urinary protein. Urinary 8-OHdG of all patients was positively correlated with urinary protein and it was a significant predictor. Urinary 8-OHdG of male patients was positively correlated with salt intake and was a significant predictor; in female patients, it was positively correlated with urinary protein and total cholesterol and these two factors were significant predictors.Salt intake increases urinary protein and promotes the progression of renal failure in CKD patients.
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