Normotensive Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

Echocardiographic Abnormalities in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Patients.

Cardiovascular abnormalities, such as left ventricular hypertrophy and valvular disorders, particularly mitral valve prolapse, have been described as highly prevalent among adult patients with autosomal dominant polycystic kidney disease (ADPKD). The present study aimed to assess echocardiographic parameters in a large sample of both normotensive and hypertensive ADPKD patients, regardless of kidney function level, and evaluate their association with clinical and laboratorial parameters. A retrospective study consisted of the analysis of clinical, laboratorial, and transthoracic echocardiograms data retrieved from the medical records of young adult ADPKD outpatients. A total of 294 patients (120 M/174 F, 41.0 ± 13.8 years old, 199 hypertensive and 95 normotensive) with a median estimated glomerular filtration rate (eGFR) of 75.5 mL/min/1.73 m2 were included. The hypertensive group (67.6%) was significantly older and exhibited significantly lower eGFR than the normotensive one. Increased left ventricular mass index (LVMI) was seen in 2.0%, mitral valve prolapse was observed in 3.4%, mitral valve regurgitation in 15.3%, tricuspid valve regurgitation in 16.0%, and aortic valve regurgitation in 4.8% of the whole sample. The present study suggested that the prevalence of mitral valve prolapse was much lower than previously reported, and increased LVMI was not seen in most adult ADPKD patients.

SAT-259 DIFFERENT MARKERS OF ENDOTHELIAL DYSFUNCTION ARE ALTERED IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PATIENTS WITH EARLY AND LATE DISEASE

Patients with autosomal dominant polycystic kidney disease (ADPKD) have a high incidence rate of hypertension and cardiovascular disease. Endothelial dysfunction (ED) has been reported in some patient ADPKD cohorts although published studies have been confounded by the inclusion of patients with significant chronic kidney disease (CKD), hypertension, anti-hypertensive drugs and other co-morbidities (age, smoking, high BMI). The major aim of this study was to test the hypothesis that ED was present in normotensive ADPKD patients with early disease (≥60ml/min/1.73m2) without confounding risk factors by assessing vascular function, serum and urine biomarkers in a single centre prospective study.

Abstract 124: Nadph Oxidase 4 and Mitochondrial Abnormalities Contribute to Oxidative Stress and Endothelial Dysfunction in Young Normotensive Patients With Autosomal Dominant Polycystic Kidney Disease

Background: Fifty percent of patients with autosomal dominant polycystic kidney disease (ADPKD) present hypertension (HTN) early on, which increases to nearly 100% at end-stage, and is associated with faster renal functional decline. Endothelial dysfunction (ED) accompanied by oxidative stress (OS) precedes the development of HTN, but the mechanisms responsible remain unknown. The aim of this study was to determine whether NADPH oxidase (NOX4) and mitochondrial dysfunction contribute to OS and ED preceding HTN in early ADPKD. Methods: We prospectively measured plasma levels of homocysteine (Hcy), 8-isoprostane, NOX4 and the mtDNA genes COX3 and ND1 in young normotensive (without BP medication) ADPKD patients, and age-matched healthy volunteers (HV) (n=10, each). Total kidney volume (TKV) and Renal Blood Flow (RBF) were evaluated by MRI. Results: BP levels were higher in ADPKD, and HtTKV was twofold higher in ADPKD vs. controls. eGFR and RBF were similar between the groups (Table). Plasma Hcy, 8-isoprostanes and NOX4 were higher in ADPKD, and correlated directly with HtTKV (p<0.05, Figure), but the correlation with RBF was not significant. Plasma mtDNA copy number were lower in ADPKD compared to controls, and correlated inversely with HtTKV(R 2 0.397 and 0.392 respectively). Conclusion: Early ADPKD is associated with elevation in Hcy, 8-isoprostane, and NOX4 levels, and decreased mtDNA copy numbers, which precede the reduction in RBF and the development of HTN, and are associated with disease severity. NOX4 and mitochondrial abnormalities may contribute to oxidative stress, endothelial dysfunction, and possibly the development of HTN and disease progression in ADPKD.

Early atherosclerosis in normotensive patients with autosomal dominant polycystic kidney disease: the relation between epicardial adipose tissue thickness and carotid intima-media thickness.

Epicardial adipose tissue thickness (EATT) is suggested as a novel marker of subclinical atherosclerosis. Despite increased carotid intima-media thickness (CIMT) in autosomal dominant polycystic kidney disease (ADPKD) patients, the extent of the relationship between CIMT and EATT is unknown. The main purpose of our study was to evaluate the relation between EATT and CIMT in normotensive ADPKD patients with well-preserved renal function. Fifty-five normotensive ADPKD patients with normal renal function and 50 healthy control subjects were included in the study. EATT and CIMT were measured by echocardiography in all subjects. Correlation between EATT and CIMT was evaluated in ADPKD patients, while multivariate linear regression analysis was performed to determine factors predicting EATT and CIMT. ADPKD patients had significantly higher levels CIMT [0.7 (0.4–1.2) vs. 0.5 (0.4–0.8) mm, p < 0.001] and EATT (6.8 ± 2.7 vs. 4.8 ± 1.2 mm, p < 0.001) as compared with control subjects. Significant positive correlation was found between EATT and CIMT (r = 0.58, p < 0.001). Higher CRP levels (OR 54.7, 95 % CI 37.44–72.01, p < 0.001) and having ADPKD (OR 10.2, 95 % CI 2.53–17.86, p = 0.01) were the only independent factors associated with a higher EATT. A higher age (OR 0.35, 95 % CI −0.02 to 0.71, p = 0.06) tended to be independently associated with a higher EATT. In conclusion, our findings suggest that EATT, being simply measured by echocardiography and correlated with CIMT, can be used to detect subclinical atherosclerosis in normotensive ADPKD patients.

Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans

Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.

Pentraxin 3 as a novel bio-marker of inflammation and endothelial dysfunction in autosomal dominant polycystic kidney disease

Cardiovascular disease (CVD) is the main cause of mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Prior to hypertension early vascular changes and inflammation have been reported. We aimed to investigate long pentraxin 3 (PTX-3), which has been recently described as a biomarker of inflammation, and its relation with endothelial dysfunction in early ADPKD patients. Twenty-five ADPKD patients without hypertension and 25 healthy controls were studied cross-sectionally. Hypertension was diagnosed with ambulatory blood pressure monitoring. Plasma concentrations of PTX-3 and proteinuria levels were obtained from each participant. Endothelial dysfunction was assessed using ischemia-induced forearm flow-mediated vasodilation (FMD). PTX-3 levels were higher in ADPKD patients compared to healthy controls (4.2 [1.2-10.1] vs. 1.4 [0.4-3.1] ng/ml, p < 0.001). Additionally, C-reactive protein (CRP) and proteinuria levels were higher in ADPKD patients than in healthy subjects. In the whole cohort, PTX-3 correlated negatively with FMD (r: -0.58, p < 0.001) and positively with proteinuria (r: 0.56, p < 0.001) and uric acid (r: 0.57, p < 0.001). In all subjects, FMD was independently predicted by PTX-3, but not by uric acid, CRP or proteinuria. PTX-3 may be a better biomarker of inflammation than CRP to predict endothelial dysfunction in normotensive ADPKD patients with well-preserved kidney function. Hence, inflammation which is demonstrated by PTX-3 may potentially be used to predict future CVD in this population.

A Link between the Intrarenal Renin Angiotensin System and Hypertension in Autosomal Dominant Polycystic Kidney Disease

Background/Aims: Early onset of hypertension and its consequences account for the great majority of deaths in patients with autosomal dominant polycystic kidney disease (ADPKD). Renin-angiotensin system (RAS) components have been shown in ADPKD kidneys independent of systemic RAS. Thus, we examined the urinary angiotensinogen (UAGT) levels as a biomarker of intrarenal RAS status in ADPKD patients with/without hypertension and healthy subjects. Methods: Eighty-four ADPKD patients (43 with hypertension and 41 without hypertension) and 40 healthy controls were studied cross-sectionally. Patients with glomerular filtration rate <60 ml/min were excluded from the study. Hypertension was diagnosed with ambulatory blood pressure monitoring. Urinary and plasma concentration of angiotensinogen, spot urine microprotein and creatinine (UCre) levels were recorded for each participant. Results: UAGT/UCre levels were higher in hypertensive ADPKD patients (23.7 ± 8.4) compared with normotensive ADPKD patients (16.6 ± 5.2) and healthy controls (6.9 ± 3.3; p < 0.001). In univariate analysis, UAGT correlated with systolic blood pressure, diastolic blood pressure (DBP) and proteinuria. The independence of these correlations was analyzed in a regression model, and UAGT was shown to be significantly predicted by proteinuria and DBP. Conclusion: Intrarenal RAS activation which is monitored by UAGT levels clinically may be a harbinger of hypertension and kidney disease in ADPKD patients.

Neutrophil-to-lymphocyte ratio, insulin resistance, and endothelial dysfunction in patients with autosomal dominant polycystic kidney disease

Endothelial dysfunction (ED), insulin resistance (IR), and inflammation are risk factors for increased cardiovascular morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD). ADPKD patients may have increased carotid intima-media thickness (CIMT) and decreased coronary flow velocity reserve (CFVR). The neutrophil-to-lymphocyte ratio (NLR) was introduced as a marker to determine inflammation in various disorders. We aimed to investigate the relationship between NLR and IR, CFVR, CIMT, and the left ventricular mass index (LVMI) in normotensive ADPKD patients. Twentynine ADPKD patients (age 38.8 ± 10.2 years; 8 men and 21 women) and 19 healthy controls (age 33.8 ± 7.4 years; 8 men and 11 women) were included in this cross-sectional study. CFVR was calculated with echocardiography as the ratio of hyperemic to baseline diastolic peak coronary flow velocities. CIMT was measured in the distal common carotid artery by using a 10-MHz linear echocardiography probe. HOMA-IR was calculated NLR was calculated as the ratio of the neutrophil and lymphocyte counts. Age, sex, body mass index, and levels of glucose, creatinine, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, C-reactive protein (CRP), microalbuminuria, and creatinine clearance were similar between ADPKD patients and healthy subjects. NLR, CIMT, LVMI, and HOMA-IR were significantly higher and CFVR values were significantly lower in patients with ADPKD compared to that in healthy subjects. NLR showed positive correlation with CIMT, HOMA, insulin, glucose, and HDL cholesterol levels, while it was inversely correlated with CFVR and albumin level in all subjects. In patients with ADPKD, NLR showed positive correlation with HDL cholesterol level and inverse correlation with LVMI and albumin level. NLR that was found to be increased in patients with ADPKD may be a readily available marker of inflammation and ED.

Impairment of heart rate recovery index in autosomal-dominant polycystic kidney disease patients without hypertension

Background. We aimed to determine the status of the autonomic nervous system in patients with autosomal-dominant polycystic kidney disease (ADPKD) who were normotensive and had normal renal function. Methods. A total of 28 normotensive ADPKD patients with normal renal function and 30 healthy control subjects consented to participate in the study. Heart rate recovery (HRR) indices were defined as the reduction in heart rate from the rate at peak exercise to the rate at the 1st, 2nd, 3rd and 5th minutes after the cessation of the exercise stress test; these results were indicated HRR1, HRR2, HRR3 and HRR5, respectively. Results. The 1st- and 2nd-minute HRR indices of patients with ADPKD were significantly lower than those of the healthy control group (27.1±7.9 vs 32.0±7.9; p=0.023 and 46.9±11.5 vs 53.0±9.0; p=0.029, respectively). Similarly, HRR indices after the 3rd and 5th minutes of the recovery period were significantly lower in patients with ADPKD when compared with indices in the control group (56.7±12.0 vs 65.1±11.2; p=0.008 and 62.5±13.8 vs 76.6±15.5; p =0.001, respectively). Conclusion. Impaired HRR index is associated with normotensive early-stage ADPKD patients. Increased renal ischemia and activation of the renin–angiotensin–aldosterone system (RAAS) may contribute to impairment in the autonomic nervous system in these patients before the development of hypertension. Even if ADPKD patients are normotensive, there appears to be an association with autonomic dysfunction and polycystic kidney disease.

Insulin resistance and coronary flow velocity reserve in patients with autosomal dominant polycystic kidney disease

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to investigate coronary flow velocity reserve (CFVR) as a marker of endothelial dysfunction, carotid intima media thickness (CIMT) as a marker of subclinical organ damage and insulin resistance (IR) as a cardiovascular risk factor in patients with ADPKD. Twenty-two normotensive ADPKD patients with well-preserved renal function and 19 healthy subjects were included in the study. Creatinine clearances were calculated by the Cockcroft-Gault formula. The homeostasis model of IR (HOMA-IR) was used to measure IR. CIMT was measured by high-resolution vascular ultrasound. CFVR was calculated as the ratio of hyperaemic to baseline diastolic peak velocities by echocardiography. There was no significant difference between the two groups regarding age, gender, body mass index, systolic and diastolic blood pressures, cholesterol and triglyceride levels. However, CIMT and HOMA-IR were significantly increased and CFVR was significantly decreased in patients with ADPKD compared with healthy subjects. The findings of decreased CFVR, increased CIMT and increased IR suggest that cardiovascular risk is elevated even in the early stages of ADPKD.

Peripheral augmentation index and vascular inflammation in autosomal dominant polycystic kidney disease

Cardiovascular disease is the leading cause of premature mortality in autosomal dominant polycystic kidney disease (ADPKD). We examined peripheral augmentation index (AIx) as a measure of systemic vascular function and circulating markers of vascular inflammation in patients with ADPKD. Fifty-two ADPKD patients with hypertension and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), 50 ADPKD patients with hypertension and eGFR ≥ 60 mL/min/1.73 m(2), 42 normotensive ADPKD patients with eGFR ≥ 60 mL/min/1.73 m(2) and 51 normotensive healthy controls were enrolled in this study. AIx was measured from peripheral artery tone recordings using finger plethysmography. Serum levels of soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, P-selectin, E-selectin, soluble Fas (sFas) and Fas ligand (FasL) were measured as markers of vascular inflammation. AIx was higher in all three patient groups with ADPKD compared to healthy controls (P < 0.05). AIx was similar between the normotensive ADPKD patients with eGFR ≥ 60 mL/min/1.73 m(2) and hypertensive ADPKD patients with eGFR < 60 mL/min/1.73 m(2) (P > 0.05). ICAM, P-selectin, E-selectin and sFas were higher and FasL lower in all ADPKD groups compared to controls (P < 0.05). ICAM, P-selectin and E-selectin were similar between the normotensive ADPKD patients with eGFR ≥ 60 mL/min/1.73 m(2) and hypertensive ADPKD patients with eGFR < 60 mL/min/1.73 m(2) (P > 0.05). According to multiple regression analysis, predictors of AIx in ADPKD included age, height, heart rate and mean arterial pressure (P < 0.05). Vascular inflammatory markers were not predictors of AIx in ADPKD. Systemic vascular dysfunction, manifesting as an increase in AIx and vascular inflammation is evident in young normotensive ADPKD patients with preserved renal function. Vascular inflammation is not associated with elevated AIx in ADPKD.

Ultrasonic Characterization (Integrated Backscatter) of Myocardial Tissue in Patients with Autosomal Dominant Polycystic Kidney Disease

Objective: To study changes in myocardial wall texture in autosomal dominant polycystic kidney disease (ADPKD) patients by ultrasonic integrated backscatter (IBS) analysis. Methods: Hypertensive and normotensive ADPKD patients, essential hypertension (EHP) patients and healthy volunteers were included in the study. All the subjects underwent conventional echocardiography and ultrasonic IBS of the myocardial wall. Both the calibrated IBS (C-IBS) and the systolic-diastolic cyclical variations in IBS (CV-IBS) were evaluated. Results: Mean C-IBS in hypertensive ADPKD patients was significantly higher than that in EHP patients and normotensive ADPKD patients. Mean C-IBS in normotensive ADPKD patients was significantly higher than that in healthy subjects. Mean CV-IBS in hypertensive ADPKD patients was significantly lower than that in EHP patients and normotensive ADPKD patients. Mean CV-IBS in normotensive ADPKD patients was significantly lower than that in healthy subjects. Multivariate analysis showed that the mean C-IBS was positively related to the systolic and diastolic blood pressure (SBP, DBP) and left ventricular mass index (LVMI); mean CV-IBS was positively correlated with contractile performance and transmitral E/A ratio and inversely correlated with SBP, DBP and LVMI. Conclusions: ADPKD patients experienced myocardial interstitial collagen deposition and impairment to myocardial contractile performance, which were both aggravated by hypertension. IBS seems to be a useful tool for the assessment of myocardial changes in ADPKD patients.

Early renal and vascular changes in ADPKD patients with low-grade albumin excretion and normal renal function

Autosomal dominant polycystic kidney disease (ADPKD) shows an increase in both urine monocyte chemoattractant protein-1 (MCP-1) and carotid intima-media thickness (CIMT) before changes in serum creatinine concentration. Although microalbuminuria is an index of disease progression, data on whether renal alterations and vascular remodelling are already present at normal or minimally increased levels of urine albumin excretion in early stages of the disease are lacking. Forty-eight ADPKD patients (24.8 +/- 0.8 years) with normal renal function (MDRD 108.1 +/- 3.1 ml/min) and 21 age-matched controls were studied in a cross-sectional study. The urine albumin/creatinine ratio (UACR) above the upper range of controls (6.8 mg/g) was taken as the predictor of renal alterations and vascular remodelling. Urine MCP-1, MCP-1 fractional excretion (FE(MCP-1)), endothelial-dependent vascular relaxation (EDVR), aortic pulse-wave velocity (Ao-PWV) and CIMT were chosen as biological markers. No differences between ADPKD with UACR <or=6.8 mg/g and controls were observed in urine MCP-1 (77.7 +/- 13.9 versus 57.8 +/- 6.3 ng/g), FE(MCP-1) (91 +/- 19 versus 74 +/- 8%) and CIMT (0.47 +/- 0.06 versus 0.44 +/- 0.07 mm), respectively. Conversely, ADPKD with UACR >6.8 mg/g showed values that were different from the two other groups. In addition, patients with UACR >6.8 and <20 mg/g showed greater values for urine MCP-1, FE(MCP-1) and CIMT (131.8 +/- 21.7 ng/g, 159 +/- 31% and 0.55 +/- 0.05 mm, respectively), as compared with patients with UACR <or=6.8 mg/g. The same pattern was found in a subset of normotensive ADPKD patients. No differences were found in EDVR and Ao-PWV. In young ADPKD patients, normal levels of UACR suggest that renal interstitium is comparable to that in healthy subjects and indicate an absence of subtle atherosclerotic changes in the carotid arteries. Likewise, early renal and vascular changes may be present at UACR below the levels defined as microalbuminuria.

Carotid vascular remodelling in patients with autosomal dominant polycystic kidney disease

To study carotid vascular wall remodelling in patients with autosomal dominant polycystic kidney disease (ADPKD) using integrated backscatter signal (IBS) analysis. Included in the study were: 60 ADPKD patients with preserved renal function, including 32 patient with hypertension and 28 with normotension; 25 patients with essential hypertension; and 30 healthy volunteers. Carotid intima-media thickness (IMT) was measured by 2-D conventional ultrasonography. Acoustic tissue characterization of the carotid wall was assessed by IBS analysis, and the percentage of regions considered as fibromatosis was calculated in all groups. Carotid IMT in hypertensive ADPKD patients (0.8 +/- 0.05 vs 0.68 +/- 0.02 mm, P < 0.01 and 0.8 +/- 0.05 vs 0.56 +/- 0.04 mm, P < 0.01 respectively) and patients with essential hypertension (0.79 +/- 0.03 vs 0.68 +/- 0.02 mm, P < 0.01 and 0.79 +/- 0.03 vs 0.56 +/- 0.0 4 mm, P < 0.01 respectively) was significantly greater than that of normotensive patients and healthy subjects. Carotid IMT in normotensive ADPKD patients was also significantly greater than that in healthy subjects (0.68 +/- 0.02 vs 0.56 +/- 0.04 mm, P < 0.01). Calibrated IBS (C-IBS) in hypertensive ADPKD patients was significantly greater than that in patients with essential hypertension and normotensive ADPKD patients (-21.2 +/- 1.51 dB vs -23.1 +/- 1.61 dB, P < 0.05; -21.2 +/- 1.51 dB vs -24.5 +/- 1.34 dB, P < 0.01). C-IBS in normotensive ADPKD patients was significantly greater than that in healthy subjects (-24.5 +/- 1.34 dB vs -26.2 +/- 1.69 dB, P < 0.01). The percentage of regions that could be considered as fibromatosis in hypertensive ADPKD patients was significantly greater than that in patients with essential hypertension and normotensive ADPKD patients (30.0% vs 22.4%, P < 0.05; 30.0% vs 17.9%, P < 0.01). The percentage of regions that could be considered as fibromatosis in normotensive ADPKD patients was significantly greater than that in healthy subjects (15.2% vs 10.3%, P < 0.01). Carotid remodelling occurs in the early stage of ADPKD and can be aggravated by hypertension. Fibrosis contributes to the vascular rearrangement.

Biventricular diastolic dysfunction in patients with autosomal-dominant polycystic kidney disease

Left ventricular diastolic dysfunction has been shown in patients with autosomal-dominant polycystic kidney disease (ADPKD). However, there is no study evaluating right ventricular functions in these patients. In the present study, diastolic functions of both ventricles in normotensive and hypertensive ADPKD patients with well-preserved renal function were investigated. Fifteen hypertensive and 16 normotensive patients with ADPKD with well-preserved renal function, 16 patients with essential hypertension, and 24 healthy subjects were included in the study. Conventional left and right ventricular echocardiographic measurements were performed in all subjects. Left and right ventricular functions were investigated both by myocardial performance index (MPI) [calculated by dividing the sum of isovolumic contraction time and isovolumic relaxation time (IVRT) by ejection time] and by tissue Doppler imaging (TDI). Left ventricular deceleration time and IVRT were significantly prolonged in hypertensive patients with ADPKD compared with patients with essential hypertension and even in normotensive patients with ADPKD compared with healthy subjects. Left and right MPIs were significantly higher in patients with ADPKD compared with healthy subjects, showing systolic and diastolic dysfunction. Moreover, by using TDI, the peak early diastolic mitral annular velocity (Em) to peak late diastolic mitral annular velocity (Am) ratio and the peak early diastolic tricuspid annular velocity (Et) to peak late diastolic tricuspid annular velocity (At) ratio were decreased in patients with ADPKD, suggesting biventricular diastolic dysfunction. Both hypertensive and normotensive patients with ADPKD show significant biventricular diastolic dysfunction, suggesting cardiac involvement very early in the course of ADPKD.

Candesartan Reduces Urinary Fatty Acid-Binding Protein Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease

Free fatty acids (FFAs) bound to albumin are overloaded in renal proximal tubules and exacerbate tubulointerstitial damage. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of FFAs that is expressed in renal proximal tubules in humans. Urinary L-FABP reflects the clinical prognosis of chronic glomerulonephritis. The aim of the present study was to determine whether urinary L-FABP excretion is altered in patients with autosomal dominant polycystic kidney disease (ADPKD) and whether candesartan cilexetil, an angiotensin II receptor antagonist, affects these levels. Subjects comprised 20 normotensive ADPKD patients (8 men and 12 women, mean age 42.6 years) and 20 age-matched healthy volunteers (8 men and 12 women, mean age 44.0 years). The 20 ADPKD patients participated in a randomized double-blind placebo-controlled study of candesartan cilexetil for 6 months. Urinary L-FABP levels were measured by a newly established ELISA method. Urinary L-FABP levels were significantly higher in ADPKD patients (154.5 +/- 110.6 microg/g Cr) than in healthy subjects (5.5 +/- 3.8 microg/g Cr) (P < 0.001). Candesartan cilexetil reduced urinary L-FABP levels from 168.5 +/- 104.5 microg/g Cr to 98.5 +/- 68.5 microg/g Cr after 3 months (P < 0.01) and to 44.6 +/- 30.8 microg/g Cr after 6 months (P < 0.001). Placebo had no effect on L-FABP levels (before, 140.5 +/- 100.5 microg/g Cr; at 3 months, 148.5 +/- 108.5 microg/g Cr; at 6 months, 150.5 +/- 110.8 microg/g Cr). During the 6 months, serum creatinine, blood urea nitrogen, 24-hour creatinine clearance and blood pressure showed little change in either group. Increased urinary L-FABP levels may be associated with the development of ADPKD, and candesartan cilexetil has a beneficial effect on reducing these levels.

A comparative study of three kidney biomarker tests in autosomal-dominant polycystic kidney disease

The relationship between the progress of tubular damage and renal insufficiency in autosomal-dominant polycystic kidney disease (ADPKD) is a subject of doubtless interest, and is the object of this present work. A total of 92 adult ADPKD patients of both genders were studied, none of which presented end-stage renal disease (ESRD), and classified according to an ultrasound score based on kidney size and number of cysts. Urinary albumin and beta-N-acetylhexosaminidase (Hex) and its isoenzymes were determined, together with serum glutathione peroxidase, cystatin C, creatinine, and urea. A frequent elevation of the urinary Hex was found and an alteration of its isoenzymatic profile, with 31% of the normotensive patients with normoalbuminuria already presenting an increased proportion of Hex B isoenzyme. Keeping age constant, a partial significant correlation was found between the ultrasound score and the proportion of Hex B (r = 0.352, P < 0.05), but not with albuminuria or cystatin C. In 42 patients the different biochemical variables were again determined after 1 year, finding that in the 13 normotensive patients with normoalbuminuria there had been a significant decrease in the concentration of cystatin C (P < 0.05), and a significant increase in the urinary excretion of albumin and Hex B isoenzyme (P < 0.05). By the other hand, in the other 29 patients with micro- or macroalbuminuria and hypertension, no significant differences were found. The results point toward an important participation of tubular damage in the pathogenesis of this disease. It may also be suggested that in normotensive and normoalbuminuric ADPKD patients, a gradual increase of glomerular filtration would be produced. After the start of hypertension and microalbuminuria, the glomerular filtration rate (GFR) would decrease progressively, although more slowly.

Effect of Dilazep Dihydrochloride on Urinary Albumin Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 ± 52 to 46 ± 26 µg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD patients with microalbuminuria.

Endothelium-dependent relaxation of small resistance vessels is impaired in patients with autosomal dominant polycystic kidney disease.

Impaired endothelium-dependent relaxation has been demonstrated previously in resistance vessels of Han:SPRD polycystic kidney disease rats. The aim of the present study was to investigate whether endothelium-dependent relaxation is reduced also in patients with autosomal dominant polycystic kidney disease (ADPKD) and whether this is influenced by the nitric oxide (NO) system. Small subcutaneous resistance vessels from normotensive ADPKD patients with normal or near-normal renal function (n = 9) and from healthy control subjects (n = 10) were mounted in a Mulvany-Halpern myograph. The morphology of the vessels and acetylcholine (ACh)-induced endothelium-dependent relaxation, as well as 3-morpholino-sydnonimine (SIN-1, NO donor)-induced endothelium-independent relaxation were investigated. The results showed that: (1) there were no significant differences in morphologic parameters of resistance vessels between the two groups; (2) the maximal ACh-induced relaxation rate was decreased in ADPKD patients compared with control subjects (71.5 +/- 12.1 versus 85.2 +/- 8.7%, P < 0.01); (3) in the presence of L-arginine (a substrate of NO synthase), a left shift of the ACh dose-response curves was found in control subjects, but not in ADPKD patients; (4) in the presence of the N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase), a right shift of the ACh dose-response curve was found in control subjects, but not in ADPKD patients; and (5) endothelium-independent relaxation rate induced with SIN-1 was similar in patients and control subjects. In conclusion, endothelium-dependent relaxation was impaired in resistance vessels from patients with ADPKD. The reduced response of the vessels to both the substrate and inhibitor of NO synthase in ADPKD suggests that an impairment of NO synthase may be involved in the mechanism of endothelial dysfunction in ADPKD.

Ambulatory blood pressure and left ventricular mass in normotensive patients with autosomal dominant polycystic kidney disease.

Higher left ventricular mass (LVM) has been found in early stages of autosomal dominant polycystic kidney disease (ADPKD). The mechanisms involved in the increase of LVM are unknown. To investigate whether LVM in ADPKD may be influenced by abnormal diurnal BP variations, the 24-h ambulatory BP profile was analyzed in a group of young normotensive ADPKD patients. Ambulatory BP monitoring and two-dimensional echocardiography were performed in 26 young normotensive ADPKD with normal renal function and in 26 healthy control subjects. LVM index was higher in ADPKD patients than in controls (90.8+/-19.6 g/m2 versus 73.9+/-16.1 g/m2, P = 0.001). Average 24-h and daytime systolic, diastolic, and mean BP were similar in both groups. Nighttime diastolic and mean BP, but not systolic BP, were greater in ADPKD patients. The average and percent nocturnal decrease of systolic BP was lower in ADPKD patients than in control subjects (10.0 mm Hg [-3 to 24] versus 15.5 mm Hg [-4 to 31], P = 0.009, and 9.0% [-2 to 22] versus 14.2% [-2 to 25], P = 0.016, respectively). On the basis of their profile BP patterns, 54% of ADPKD subjects and 31% of controls were classified as nondippers (P = 0.092). There were no differences between dippers and nondippers in left ventricular wall thickness, chamber dimensions, and mass indexes. In ADPKD patients, simple regression analysis showed that LVM index was correlated with 24-h, daytime, and nighttime systolic BP. On multiple regression analysis, the 24-h systolic BP was the only variable linked to LVM index. It is concluded that young normotensive ADPKD patients have higher LVM that is closely related to the ambulatory systolic BP. The nocturnal fall in BP is attenuated in these patients, although it is not associated with the higher LVH that they present.