Hypertension In Autosomal Dominant Polycystic Kidney Disease Research Articles

Screening of QTc interval and global autonomic activity in autosomal dominant polycystic kidney disease and atherosclerotic renal artery stenosis hypertensive patients.

Arterial hypertension (AH) represents a major risk factor for cardiovascular disease and is associated to several complications, such as prolonged corrected QT (QTc) interval and impaired heart rate variability (HRV). Secondary causes of AH include autosomal dominant polycystic kidney disease (ADPKD) and atherosclerotic renal artery stenosis (ARAS), both known to be related to arrhythmic risk and autonomic imbalance. The aim of the study is to evaluate whether global autonomic activity and QTc interval differently affect ADPKD and ARAS hypertensive patients. An observational study was performed on 59 patients: 16 ADPKD patients and 19 diagnosed with ARAS, compared to 24 healthy controls (HC). All patients underwent clinical evaluation, biochemical lab tests, 24-hour electrocardiogram (ECG) and renal Doppler ultrasound. HRV was assessed through the analysis of 24-hour ECG to detect standard deviation of normal-to-normal RR intervals (SDNN). QTc interval was defined as prolonged when > 440 msec. SDNN was significantly lower in ADPKD and ARAS patients than HC (p < 0.0001) and no significant differences were found between ADPKD and ARAS patients (p > 0.05). QTc was found significantly higher in ARAS patients than HC (p = 0.001) and in ARAS patients than ADPKD patients (p = 0.004). The pathogenesis of hypertension in ADPKD and ARAS patients is related to the activation of the renin angiotensin aldosterone system (RAAS). In ADPKD, cyst enlargement leads to kidney ischemia and renin release, associated to endothelial dysfunction, low nitric oxide and sympathetic tone activation. Differently, reduction in renal perfusion pressure activates RAAS and renal adrenergic nerves in ARAS patients. We can speculate that prolonged QTc interval is more present in ARAS vs. ADPKD hypertensive patients due to a greater activation of RAAS. We suggest adding 24-hour HRV evaluation in association with traditional risk factors in course of ADPKD and ARAS hypertension to better stratify cardiovascular risk in these groups of patients.

Evaluation of common polymorphisms of eNOS gene and ACE gene in autosomal dominant polycystic kidney disease patients and their association with hypertension and renal failure

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most hereditary renal disease that leads to end-stage renal disease (ESRD). Objectives: Since there is no available parameter to assess the clinical course of ADPKD and its outcome, yet, the aim of our study was evaluation of the association of common polymorphisms of eNOS and ACE genes with clinical manifestations (kidney failure and hypertension) in ADPKD. Patients and Methods: Seventy-five ADPKD patients and 100 control subjects participated in our study. Around 7.5 cc of whole blood was taken from each participant and sent to the genetic laboratory. DNA was obtained from them by the phenol chloroform extraction and ethanol precipitation techniques. Then genotyping for I/D polymorphism of ACE gene and Glu298 ASP and T786C polymorphisms of eNOS gene was performed by PCR electrophoresis and molecular evaluation by special primers for two genes. Results: The frequency of DD polymorphism of ACE gene and TC polymorphism of T786C of eNOS were considerably elevated in ADPKD individuals than control subjects. No significant difference between groups regarding Glu298 ASP polymorphisms of eNOS gene was detected. In ADPKD patients, 29 patients (39%) had hypertension, 5 patients (6.7%) had diabetes and 43 patients (57%) had glomerular filtration rate (GFR) below 60 mL/min/1.73 m2 . The polymorphisms of ACE and eNOS genes were not meaningfully different regarding diabetes, high blood pressure, GFR and plasma creatinine in ADPKD individuals (P&gt;0.05). Conclusion: In our study, we could not find any association between polymorphisms of ACE and eNOS genes with renal insufficiency and hypertension in ADPKD patients.

Systemic Succinate, Hypoxia-Inducible Factor-1 Alpha, and IL-1β Gene Expression in Autosomal Dominant Polycystic Kidney Disease with and without Hypertension

Background and Objectives: Cyst pressure induces renin-angiotensin-aldosterone system activation and kidney hypoxia in autosomal dominant polycystic kidney disease (ADPKD). Lipopolysaccharide-induced Toll-like receptor activation causes metabolic disturbances that are triggered by increased succinate levels and hypoxia inducible factors, which results in inflammation via IL-1β activation. Since we aimed to investigate the role of both inflammation and hypoxia in the clinical course of ADPKD, via succinate levels from sera samples, HIF-1α gene expression from whole blood and urine samples and IL-1βgene expression from whole blood were measured. Methods: One hundred ADPKD patients and 100 matched healthy controls were enrolled to this cross-sectional study. Twenty-four-hour ambulatory blood pressure monitoring was conducted in all participants. Blood, serum, and urine samples were taken after 12-h fasting for the measurement of biochemical parameters and succinate levels. Whole blood and urine samples were used for HIF-1α and IL-1β geneexpression by using quantitative real-time PCR. Results: There were significant differences in whole blood HIF-1α, IL-1β geneexpression, and serumsuccinate levels between the ADPKD patients and the control subjects. Whole blood HIF-1αgene expression, IL-1β geneexpression, and serumsuccinate levels were also significantly different in ADPKD patients with hypertension in comparison with normotensive ones (p < 0.05). Serum succinate levels and blood IL-1β geneexpression were increased in ADPKD patients with high levels of HIF-1α geneexpression (p = 0.018 and p = 0.029, respectively). Conclusions: Increased age,low eGFR, and HIF-1α and IL-1β geneexpressions were also independently associated with hypertension in ADPKD patients. Inflammation and hypoxia are both relevant factors that might be associated with hypertension in ADPKD.

The association of endothelin-1 levels with renal survival in polycystic kidney disease patients

The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival. In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis. Endothelin levels and height-adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1-4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension. Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD.

Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease

Hypertension is a common early finding in autosomal dominant polycystic kidney disease (ADPKD). Improvements in screening and diagnosis of ADPKD have allowed earlier diagnosis, later onset of end-stage renal disease, and better survival. However, the main and most effective therapy remains control of hypertension. Hypertension is the most important modifiable risk factor in ADPKD. Therefore, early management of hypertension reduces the incidence of cardiovascular events in ADPKD patients. Stimulation of the renin-angiotensin-aldosterone system (RAAS) plays a central role in the pathogenesis of hypertension in ADPKD. Therapies that block the RAAS have improved patient management, blood pressure control, and ADPKD patient survival. This review highlights the current understanding of the epidemiology, potential pathogenetic mechanisms and proposes a strategy for the treatment and management of hypertension in ADPKD.

Cardiovascular risk in polycystic kidney disease

Hypertension is common and occurs in the majority of autosomal dominant polycystic kidney disease (ADPKD) patients prior to loss of kidney function. Hypertension relates to progressive kidney enlargement, and is a significant independent risk factor for progression to end-stage renal disease. The pathogenesis of hypertension in ADPKD is complex and depends on many factors that influence each other. High expression of PKD1 and PKD2 genes is present in the cilia of tubular epithelial cells, in endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin-1 or -2 expression is associated with abnormal vascular structure and function. PKD1/PKD2 deficiency results in reduced nitric oxide levels, altered endothelial response to shear stress with attenuation in vascular relaxation. Activation of the renin-angiotensin-aldosterone system occurs in ADPKD due to decreased nitric oxide production as well as bilateral cyst expansion and intra-renal ischemia. With increasing cyst size, further activation of the renin-angiotensin-aldosterone system occurs, blood pressure increases and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to end-stage renal disease. Inhibition of the angiotensin-aldosterone system is possible with angiotensin-converting enzyme inhibitors and seems to be the first-line treatment for hypertension in these subjects. As suggested by the HALT-PKD study, an aggressive blood pressure control is safe and recommended and is associated with preservation of kidney function and a reduction in total kidney volume over time. A collaborative multidisciplinary approach between nephrologists and cardiologists is necessary for the monitoring of kidney and heart complications.

Mechanisms and management of hypertension in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, characterized by progressive cyst growth and renal enlargement, resulting in renal failure. Hypertension is common and occurs early, prior to loss of kidney function. Whether hypertension in ADPKD is a primary vasculopathy secondary to mutations in the polycystin genes or secondary to activation of the renin-angiotensin-aldosterone system by cyst expansion and intrarenal ischemia is unclear. Dysregulation of the primary cilium causing endothelial and vascular smooth muscle cell dysfunction is a component of ADPKD. In this article, we review the epidemiology, pathophysiology and clinical characteristics of hypertension in ADPKD and give specific recommendations for its treatment.

Endothelial Nitric Oxide Synthase Gene Expression Is Associated with Hypertension in Autosomal Dominant Polycystic Kidney Disease

Background/Aims: Early occurrence of hypertension is the prominent feature of autosomal dominant polycystic kidney disease (ADPKD). The role of angiotensin-converting enzyme (ACE) gene polymorphism and endothelial nitric oxide synthase (eNOS) gene polymorphism in the clinical course of ADPKD is not well understood. However, data about the expression of these genes are lacking. Thus, we aimed to investigate the polymorphisms and expressions of both the ACE and eNOS genes that affect hypertension in ADPKD. Methods: Whole blood samples were obtained from all participants. ACE and eNOS gene polymorphisms and their expressions were analyzed in 78 ADPKD patients and 30 controls. Gene expressions were assessed by quantitative real-time PCR. Twenty-four-hour blood pressure monitoring was performed for the diagnosis of hypertension in all study participants. Results:eNOS expression and the estimated glomerular filtration rate were found to be significantly higher in ADPKD patients without hypertension than in those with hypertension. Each unit of increase in eNOS expression led to a 0.88-fold decrease (95% CI: 0.80-0.96) in the risk of hypertension in multiple logistic regression analysis. Conclusions:eNOS gene expression is independently predictive of hypertension in the ADPKD population. This study showed, for the first time, a novel link between eNOS gene expression and hypertension in ADPKD.

Effect of percutaneous renal denervation on blood pressure level and sympathetic activity in a patient with polycystic kidney disease

Sirs: The underlying mechanisms for the rise in blood pressure in individuals with autosomal dominant polycystic kidney disease (ADPKD) are complex, and experimental and clinical data support the concept that sympathetic hyperactivity may contribute to the pathogenesis of hypertension in ADPKD [1, 2]. More recently, a catheter-based percutaneous aimed at ablating both efferent and afferent renal nerve fibres has been introduced into clinical medicine and has been demonstrated to safely and effectively reduce blood pressure in patients with treatment resistant hypertension and normal renal function [3–6]. However, to our knowledge there is only one report of Shetty et al. [7] who observed after renal denervation resolution of chronic pain related to renal cysts and delayed fall in blood pressure in patient with ADPKD and resistant to treatment hypertension. No data on reduction of sympathetic activity has been shown. A 26-year-old male with polycystic kidney disease was referred to the Department of Hypertension by the end of 2012 for the consideration of percutaneous renal denervation due to resistant hypertension. At the age of 20, the patient was first diagnosed with hypertension and also with ADPKD. A family history of polycystic kidney disease was present in the mother and in addition to in a sister. At the time of referral, the patient had an office blood pressure of 162/77 mmHg and an average day-time ambulatory blood pressure of 138/73 mmHg despite four antihypertensive medications comprising valsartan 160 mg od, amlodipine 10 mg od, nebivolol 2.5 mg od, and hydrochlorothiazide 25 mg od. No history of cardiovascular disease or diabetes was reported, the patient has never smoked. The patient has normal renal function at baseline with a serum creatinine of 74 μmol/L and estimated glomerular filtration rate by MDRD formula of >60 mL/min/1.73 m2. The patient was not troubled by chronic flank pain. On Doppler duplex examination renal arteries were normal, renal resistive index values were 0.61 and 0.66 in the right and left kidney, respectively. Abdominal ultrasound showed enlarged size of right (145 mm) and left (180 mm) kidney with multiple simple renal cortical cysts with a maximum diameter of 3 cm. Hepatic cysts were not present. Abdominal MRI showed bilateral simple appearing renal cysts in the upper and lower poles. Microneurography was performed before and 3 months after the renal denervation. Muscle sympathetic-nerve activity (MSNA) signals were recorded by an electrode placed into the peroneal nerve at the popliteal fossa, posterior to the fibular head and the reference electrode was placed subcutaneously 2–3 cm from the recording electrode. Due to his uncontrollable blood pressure percutaneous renal sympathetic denervation using the Symplicity Catheter® system was performed as described previously [5], with five ablations in left and six in right renal artery (Fig. 1). The patient was discharged the following day on his pre-ablation antihypertensive regimen. The only complication of the procedure was transient stenosis of both arteries resulting from artery spasm and edema. Fig. 1 Symplicity Catheter® in the left renal artery. It was possible to perform five ablations in the left renal artery The patient was reviewed at 1 and 3 months post renal sympathetic denervation. At 1 month follow up he had improvement in his systolic blood pressure with an office reading of 129/60 mmHg and at 3 month follow up his blood pressure had dropped to 120/74 mmHg. A 24-h ambulatory blood pressure monitoring at 1 and 3 months confirmed blood pressure control with a mean day-time blood pressure of 131/68 and 128/65 mmHg, respectively. His renal function remained unchanged at 1 and 3 months. Microneurography at 3 months showed a reduction in MSNA (Fig. 2), as assessed in the peroneal nerve. Fig. 2 Reduction in blood pressure and muscle sympathetic-nerve activity (MSNA), as assessed in the peroneal nerve on microneurography 3 months after bilateral renal-nerves ablation Our case report confirms the safety and effectiveness of a catheter-based renal denervation approach for the treatment of resistant hypertension in patients with ADPKD. While a single case has its obvious limitations, the fall in blood pressure after the procedure was accompanied by the decrease in the sympathetic activity being likely mediated via ablations of different fibres responsible. However, it should be mentioned that MSNA may not give information specifically about renal sympathetic activity [8]. In our case, larger reductions in office than in ambulatory blood pressure were noticed. However, these changes were of comparable magnitude as reported in the prospective studies [5, 9, 10]. In these groups, also the discrepancy between reduction in office and ambulatory blood pressure was also noted, but is should be stressed that observed reductions provide an equivalent reduction in cardiovascular events [5, 8, 11]. Confirmation of substantial BP lowering via catheter-based renal afferent denervation in patients with ADPKD in future studies may provide a valuable and safe alternative for the management of this difficult clinical condition.

Cardiovascular Complications in Autosomal Dominant Polycystic Kidney Disease

Cardiovascular complications are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Hypertension is a common finding of ADPKD occurring in 50-70% of patients before the impairment of renal function. Stimulation of the renin-angiotensin-aldosterone system plays a major role in the development of hypertension in ADPKD. Hypertension is associated with an increased rate of progression to end-stage renal disease and is the most important potentially treatable variable in these patients. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with ADPKD. Both hypertension and left ventricular hypertrophy play a crucial role in the development of cardiovascular complications in these patients. Furthermore, endothelial dysfunction, impaired coronary flow velocity reserve, biventricular diastolic dysfunction, increased carotid intima-media thickness, and arterial stiffness are present even in young normotensive patients with ADPKD who have well-preserved renal function. These findings suggest that cardiovascular involvement starts very early in the course of ADPKD. Intracranial and extracranial aneurysms and cardiac valvular defects are other potential cardiovascular problems in patients with ADPKD. A multifactorial approach aiming at all cardiovascular risk factors, such as hypertension, smoking, dyslipidemia and obesity is extremely important in these patients. Early diagnosis and treatment of hypertension, with drugs that block the renin-angiotensin-aldosterone system, has the potential to decrease the cardiovascular complications and slow the progression of renal disease in ADPKD.

Delayed diagnosis of primary aldosteronism in patients with autosomal dominant polycystic kidney diseases

Hypertension is a frequent early manifestation of autosomal dominant polycystic kidney disease (ADPKD). Several mechanisms can cause hypertension in ADPKD patients, although, primary aldosteronism (PA) as a possible manifestation of hypertension in ADPKD is extremely rare. We retrospectively reviewed the Taiwan Primary Aldosteronism Investigation (TAIPAI) database, which listed a total of 346 patients diagnosed with PA. Of these 346 patients, only three cases of concurrent PA and ADPKD were identified. These patients presented with hypertensive crisis and hypokalemia, and subsequent testing revealed aldosterone-producing adenomas (APAs) that were removed by laparoscopic adrenalectomy. Postoperatively, aldosterone-renin ratios (ARRs) and potassium levels normalized, and blood pressure improved. The diagnosis of PA in ADPKD is extremely challenging because multiple renal cysts can obscure the identification of adrenal adenomas, and ADPKD is associated with hypertension in almost all cases.(1) Because of frequent delays in the diagnosis of PA in ADPKD patients, future prospective studies to screen PA in hypertensive ADPKD patients may be necessary to evaluate the exact prevalence of coexistence of PA and ADPKD.

The profile of hypertension in autosomal dominant polycystic kidney disease

The aim of this study was to evaluate the frequency of hypertension in autosomal dominant polycystic kidney disease (ADPKD) patients and its correlation with renal function, renal structure and its influence in left ventricular wall. Two hundred patients were included in the study. The patients were divided in two groups: first group of 92 patients with normal renal function, and second group of 108 patients with chronic renal failure. All patients performed an abdominal ultrasound and a M-mode echocardiography. Hypertension was observed in 140 ADPKD patients (70%): 56 of the first group (61%) and 84 of the second group (79%). Subjects who developed hypertension before age 35 had worse renal survival than those who remained normotensive after age 35 (50 years vs. 62 years; p<0.0001; risk ratio=4.3). Hypertensive patients had significantly higher serum creatinine concentration than those without hypertension (p<0.001). Left ventricular hypertrophy was present in 56 patients with hypertension (40%) and in 9 normotensive patients (16%) (p<0.005). Patients with LVH had a worse renal survival than those without LVH (p<0.001). Also, we have studied the role of renal cystic enlargement in initiating hypertension in ADPKD and on renal function. We conclude that hypertension is a common complication in our ADPKD patients, considering as an important factor of cardiac hypertrophy. LVH could be considered a more valid measure of blood pressure control than office blood pressure measurements. The blood pressure correlates with kidney size in ADPKD patients. With more increased kidney volume, the highest blood pressure is observed. These findings suggest that hypertension is a serious complication in ADPKD that may lead to both an increased incidence of cardiovascular complications and more rapid progression of renal functional impairment.

Approaches to Testing New Treatments in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by a prolonged subclinical course of gradual renal cyst expansion, resulting in massively enlarged kidneys and renal failure by the fifth to sixth decade. Renal cyst expansion results in intrarenal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS) and relates to the development and maintenance of hypertension in ADPKD. Hypertension relates to disease progression in ADPKD with regard to renal volume, proteinuria, cardiovascular complications, and progression to end-stage renal disease. Novel magnetic resonance imaging methods developed in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) provide accurate estimates of change in renal volume over a short period of time in ADPKD patients with intact renal function. In CRISP an increase in renal volume of 63.4 ml/yr was found. PKD1 status, male gender, hypertension, reduced renal blood flow, and proteinuria are associated with increased renal volume and change in renal volume over time. HALT-Polycystic Kidney Disease (HALT-PKD) is designed to test whether blockade of RAAS and/or rigorous blood pressure control play a role in slowing renal progression during early (using magnetic resonance imaging methods developed in CRISP) and during late (using measures, including composite of time to doubling of serum creatinine, onset of end-stage renal disease, or death) phases in ADPKD. Findings from CRISP and the rationale for interventions in ADPKD are described, and the design of the HALT-PKD clinical trial is outlined.

Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities

An increased understanding of the genetic, molecular and cellular mechanisms responsible for the development of polycystic kidney disease has laid out the foundation for the development of rational therapies. Many animal models where these therapies can be tested are currently available. This review summarizes the rationale for these treatments, the results of preclinical trials and the prospects for clinical trials, some already in early phases of implementation.

Role of endothelin and nitric oxide in the pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease

The pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease (ADPKD) is complex and likely dependent on interaction of hemodynamic, endocrine and neurogenic factors. We decided to evaluate the role of endothelin (ET1) and nitric oxide (NO) in the regulation of arterial blood pressure (BP) and to determine plasma levels of ET1 and NO in the group of patients with ADPKD. The ADPKD group (18 patients, 6 men + 12 women, mean age 44.611.7 years, with creatinine clearancecorrig &gt; 1.1 ml/s) was compared with a control group of 27 healthy volunteers of comparable age. Plasma levels of ET1 assessed by direct RIA determination in the group of ADPKD patients (11.031.8 fmol/ml) were significantly increased (p&lt;0.001) in comparison with the control group (2.660.58 fmol/ml), while no significant differences were observed between normotensive and hypertensive patients in the ADPKD group. Serum levels of NO were evaluated according to the determination of serum levels of their metabolites – nitrites/nitrates. Serum levels of NO in the group of ADPKD patients (39.85±6.38 μmol/l) were significantly higher (p&lt;0.05) in comparison with the control group (22.7±1.20 μmol/l), whereas in the ADPKD group no significant differences were observed between normotensive and hypertensive patients. Thus, our study supports the concept of complex alteration of both vasoconstrictor and vasodilator systems in the pathogenesis of arterial hypertension in ADPKD.

The pathogenesis of hypertension in autosomal dominant polycystic kidney disease.

Hypertension is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD), often occurring early in the disease before the renal function starts to decrease. The pathogenesis of this early hypertension is controversial. To review studies on the pathogenesis of early and late hypertension in ADPKD. Studies on ADPKD and hypertension were retrieved from Medline from the last 20 years, with an emphasis on the last 10 years. These studies, together with selected published abstracts from recent hypertension and nephrology meetings, were reviewed critically. Cyst growth, renal handling of sodium, activation of the renin-angiotensin-aldosterone system, volume expansion, an elevated plasma volume, and increased plasma atrial natriuretic peptide and plasma endothelin levels have all been found to be associated with hypertension in ADPKD. In some studies an inappropriate activity of the renin-angiotensin-aldosterone system that could be related to cyst growth and intrarenal ischemia was found. An increase in renal vascular resistance has been demonstrated and might be caused by intrarenal release of angiotensin II. Interestingly, the protective effect of angiotensin converting enzyme inhibitors on the renal function could not be demonstrated in ADPKD patients with a moderately decreased renal function. The importance, if any, of endothelial vasodilatory factors is not known. Sympathetic nervous activity seems to be increased in ADPKD, but the importance of this for the blood pressure level is not known. The pathogenesis of hypertension in ADPKD is complex and likely to be dependent on the interaction of hemodynamic, endocrine and neurogenic factors.

Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease.

Evidence suggests an important role for the renin-angiotensin system in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD). Therefore, we studied the presence of immunoreactive renin in renal biopsies and measured the concentrations of renin in cyst fluids. Normal kidneys and kidneys with renal artery stenosis were used for comparison. In ADPKD, immunoreactive renin was present in juxtaglomerular apparatus, associated arterioles, and in some cells within the connective tissue surrounding the cysts. Vascular immunoreactive renin was less prominent than in renal artery stenosis. Increased amounts of tubular immunoreactive renin were noted in polycystic kidneys, as compared to normal kidneys and kidneys with renal artery stenosis. Cyst fluids contained renin detected by Western analysis and enzymatic activity; concentrations were greater in gradient cysts than in nongradient cysts. Seventy-four percent of the renin in gradient cysts was active as compared to 23% in nongradient cysts and 15% in plasma. To determine whether cyst epithelial cells are capable of synthesizing renin, these cells were isolated in tissue culture. Enzymatic assay of extracts from these cells revealed the presence of renin-like enzymatic activity (1.3 +/- 0.8 ng AI/mg protein/hr). The synthesis of renin by tubulocystic epithelium was confirmed by [35S]-methionine radiolabeling of cyst-derived cells, followed by immunoprecipitation and SDS-PAGE and by detection of renin mRNA by the polymerase chain reaction. These results indicate that the tubulocystic epithelium has the potential to synthesize renin. Elevated levels of active renin in renal cysts may be linked to the pathogenesis of hypertension in ADPKD. The occurrence of renin in the lining epithelium of cyst walls raises the possibility that abnormal expression of the renin-angiotensin system may, by a paracrine or autocrine mechanism, regulate epithelial hyperplasia in growing renal cysts.

Effect of Inhibition of Converting Enzyme on Renal Hemodynamics and Sodium Management in Polycystic Kidney Disease

We compared the tubular transport of sodium and the erythrocyte sodium-lithium countertransport activity in hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) and in normotensive control subjects. In addition, we assessed the effects of inhibition of converting enzyme on renal hemodynamics and sodium excretion in hypertensive patients with ADPKD to provide information on mechanisms responsible for the increased renal vascular resistance and filtration fraction and the adjustment of the pressure-natriuresis relationship during saline expansion, observed in patients with ADPKD, hypertension, and preserved renal function. In comparison with normotensive control subjects, the hypertensive patients with ADPKD had lower renal plasma flows, higher renal vascular resistances and filtration fractions, and similar proximal and distal fractional reabsorptions of sodium. The administration of enalapril resulted in significant increases in the renal plasma flow and significant reductions in mean arterial pressure, renal vascular resistance, and filtration fraction, but the glomerular filtration rate remained unchanged. Despite the significant reduction in mean arterial pressure during inhibition of converting enzyme, the distal fractional reabsorption of sodium decreased while the total fractional excretion of sodium remained unchanged or increased slightly. No significant differences were detected between the normotensive control subjects and the hypertensive patients with ADPKD in erythrocyte sodium-lithium countertransport activity, plasma renin activity, plasma aldosterone concentration, or atrial natriuretic factor. These results suggest that the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.

Renal structure and hypertension in autosomal dominant polycystic kidney disease

Hypertension has been reported to occur in 50 to 75 percent of subjects with autosomal dominant polycystic kidney disease (ADPKD) prior to the onset of marked renal insufficiency but concurrent with cystic deformation of the renal parenchyma. The present study was undertaken to examine whether the renal structural abnormalities are greater in hypertensive (HBP) versus normotensive (NBP) male and female patients with ADPKD who were matched within gender groups for age, body surface area, serum creatinine concentration (males HBP 1.2 +/- 0.02 vs. NBP 1.1 +/- 0.03 mg/dl. NS: females HBP 0.9 +/- 0.03 vs. NBP 0.9 +/- 0.02 mg/dl, NS) and creatinine clearance (males HBP 100 +/- 3 vs. NBP 108 +/- 3 ml/min/1.73 m2, NS: females HBP 97 +/- 3 vs. NBP 96 +/- 2 ml/min/1.73 m2, NS). Renal volume was significantly greater in the HBP compared to the NBP group (males HBP 624 +/- 47 vs. NBP 390 +/- 43 cm3, P less than 0.0005; females HBP 446 +/- 32 vs. NBP 338 +/- 24 cm3, P less than 0.002). Since increased renal volume is due to increased cysts, the results indicate that the early high incidence of hypertension in ADPKD correlates with the renal structural abnormalities in this disorder.