Renal function, proteinuria and ACE‐inhibitor therapy as determinants of plasma levels of endothelial markers

Nephrology Dialysis Transplantation, Mar 2002

Beata Naumnik, Jacek Borawski, Krystyna Pawlak, Michał Myśliwiec

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Renal function, proteinuria and ACE‐inhibitor therapy as determinants of plasma levels of endothelial markers

- Renal function, proteinuria and ACE-inhibitor therapy as determinants of plasma levels of endothelial markers Sir, Dysfunction of vascular endothelial cells (ECs) is of growing importance in chronic renal failure (CRF) patients in view of its deleterious link with haemostatic abnormalities w1x and accelerated atherosclerosis w2x. Elevated blood levels of some EC-derived substances are established markers of endothelial activation anduor injury in various disorders w2x, including CRF itself w3x. However, plasma levels of these molecules could vary depending on reduced glomerular filtration rate and increased permeability of the glomeruli. Associations between circulating EC markers and progression of renal failure and proteinuria have been the main interest of our study. We measured the plasma concentrations of soluble thrombomodulin (sTM), antigens (Ag) of tissue factor (TF) and of the main TF inhibitor (tissue factor pathway inhibitor, TFPI), as well as plasma activities (Act) of TF, TFPI, and von Willebrand factor (vWF). Commercially available immunoenzymatic or chromogenic (TF Act and TFPI Act) assays were used. The vWF assay estimates functional activity of this molecule based on the amount of epitopes capable of binding to glycoprotein Iba on platelet membrane. The EC markers were determined in 38 patients (15 females) with a mean age of 50.4"16.7 years. The median creatinine clearance (Ccr) measured using 24 h total creatinine excretion was 20.9 (range 2.9288.4) mlumin, and median proteinuria (determined by the biuret method) was 2.0 (07.2) gu24 h. Renal diagnoses were chronic glomerulonephritis (n s 20), diabetic nephropathy (n s 4), polycystic kidney disease (n s 3), secondary amyloidosis (n s 3), hypertensive nephropathy (n s 2), chronic pyelonephritis (n s 2), and unknown (n s 4). Eighteen patients had nephrotic range proteinuria. At the time of the evaluation, 16 patients were treated with ACE inhibitors (ACEI). None of the patients received glucocorticosteroids, immunosuppressive agents, oral anti-coagulants or lipid-lowering drugs, none were positive for HIV, hepatitis C or B viruses and none had evidence of severe liver injury. The control group consisted of 15 (eight females) healthy, non-smoking volunteers with a mean age of 47.9"8.5 years. They did not receive any drugs on a regular basis and denied accidental usage during the month preceding the study. None of the patients or controls had suffered from any inflammatory or infectious diseases during this period of time. Data were shown as mean"1 SD or median (range) depending on their distribution. The skewed data were normalized by transformation to log10 (zeros were assigned values equal to one third of detection limits). For statistical analysis, we used unpaired Students t-tests, and bivariate and stepwise multiple linear regression models. As presented in Table 1, the plasma levels of most EC markers, except TFPI Act, were higher in the patients than in controls. Only TF Act was found to be lower in the patients. Ccr was inversely correlated with sTM, and directly with TF Act. The only statistically significant positive correlates of proteinuria were TF Act and vWF Act. There was no association between Ccr and proteinuria (b s 0.067, P s 0.688). The correlation between sTM and Ccr remained significant when adjusted for proteinuria (b s 0.433, P s 0.007), and the relationship between vWF Act and proteinuria was significant when adjusted for Ccr (b s 0.367, P s 0.023). Both Ccr and proteinuria were independent predictors of TF Act (b s 0.064, P s 0.032 and b s 0.041, P s 0.039, respectively). There were positive associations between plasma levels of TFPI Ag and TFPI Act (b s 0.398, P s 0.006), and between the former marker and vWF Act (b s 0.469, P s 0.001). The only difference found between the nephrotic vs nonnephrotic patients was a higher level of vWF Act in the former group (189.4"49.1% vs 125.5"44.0%, P s 0.0003). None of the EC markers differed between patients categorized by the use of ACEI therapy. However, when the comparative analyses were performed within the nephrotic 134.1 (0.0588) 0.04 (00.15) 139.3"27.1 2.93"0.70 6.39"2.79 155.8"56.1 69.0 (0.0118) 0.07 (0.020.14) 86.7"16.9 2.44"1.01 1.30"0.21 85.5"26.1 P valuea Regression coefficient Creatinine clearance Proteinuria 0.083 Data are shown as mean"1 SD for normally distributed variables, and median (range) for non-normally distributed variables. Ag, antigen; Act, activity; sTM, soluble thrombomodulin; vWF, von Willebrand factor; TF, tissue factor; TFPI, tissue factor pathway inhibitor. aP value from unpaired Students t-test between patients and controls. bP s 0.004, cP s 0.037, dP s 0.002, eP s 0.014. group, the ACEI-treated patients (n s 9) were found to have median TF Ag level lower by a factor of 2 (88.9 (0235.9) pguml vs 171.2 (0285.5) pguml, P s 0.016) and marginally decreased vWF Act levels (164.0"35.2% vs 207.0"52.9%, P s 0.061) compared with the untreated group (n s 9). The median Ccr in the nephrotic group was 20.5 (3.088.4) mlumin and lower in the ACEI-treated subgroup than in the untreated one (36.5"25.6 mlumin vs 14.1"9.0 mlumin, P s 0.029). The mean proteinuria was 4.87"1.18 gu24 h and did not differ between the subgroups (P s 0.136). In the stepwise multivariable analyses, with ACEI therapy, Ccr and proteinuria entered as independent variables, the ACEI treatment was the only predictor of low vWF Act (b s 0.633, P s 0.014). It also tended to be independently associated with decreased TF Ag levels (b s 0.493, P s 0.062) in our nephrotic patients. This study shows for the first time that plasma activity of TF, a key factor in the activation of extrinsic pathway of blood coagulation, decreases progressively with the impairment of renal function. None of the other EC markers studied, except sTM, were associated with the severity of renal failure. This confirms previous findings w3,4x of the negative relationship between Ccr and sTM in conservatively treated CRF patients. Mezzano et al. w3x suggest that this dependency does not necessarily rule out the use of sTM as an EC marker in CRF patients because its increase in plasma could reflect genuine endothelial damage, independently of a possible defect in tubular secretion. Our observations of increased plasma TF Ag levels that were unrelated to glomerular filtration in CRF patients are in line with data by Kario et al. w5x. It is important to note, however, that the TF Ag concentration did not correspond to its decreased pro-coagulant activity. It is unlikely that increased availability of TFPI was the cause of decreased plasma activity of TF because neither TFPI Ag concentration nor its activity was associated with TF Act. The apparent disparity between the high levels of TF antigen and the relatively low functional activity of this molecule, found in our study, might be due to enhanced fragmentation of circulating complexes between TF and coagulation factors VII and X. This could result from abnormal activation of multiple proteolytic enzymes, which is a common feature in uraemia w1,3x. Another possibility is the accumulation of unspecified uraemic inhibitors of TF activity in plasma, as described previously for anti-coagulant protein C, coagulation factor VIII and vWF w6,7x. Proteinuria was an independent positive predictor of both plasma vWF activity and TF activity in our patients. On the other hand, hypoalbuminaemia due to nephrosis is known to be involved in EC dysfunction and blood hypercoagulability w8x. Proteinuria is also an independent factor in the progression of renal failure in both diabetic nephropathy and non-diabetic kidney disease w9x. However, we found no association between proteinuria and Ccr in our patients. In this study, the use of ACEI therapy was independently associated with lower plasma vWF Act in nephrotic patients, which confirms the findings by Hernandez et al. w10x. Although the independent association between the ACEI treatment and decreased plasma TF Ag was marginally nonsignificant, we suggest that this potentially clinically significant effect should be re-evaluated in a larger group and confirmed prospectively. In conclusion, the activity of pro-coagulant TF decreases while anti-coagulant sTM accumulates in plasma along with the progression of renal failure. These events may be involved in the development of bleeding diathesis in CRF patients. On the other hand, the plasma activity of TF and that of the platelet-bridging vWF molecule increase in conjunction with proteinuria, which may enhance the risk of thrombosis in proteinuric kidney disease. ACEI treatment is associated with decreased vWF activity in nephrotic patients, and may protect against endothelial injury in this high-risk population. Department of Nephrology and Internal Medicine Medical Academy Biakystok, Poland Email: Beata Naumnik Jacek Borawski Krystyna Pawlak Michak Mysliwiec

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Beata Naumnik, Jacek Borawski, Krystyna Pawlak, Michał Myśliwiec. Renal function, proteinuria and ACE‐inhibitor therapy as determinants of plasma levels of endothelial markers, Nephrology Dialysis Transplantation, 2002, 526-528, DOI: 10.1093/ndt/17.3.526