[CATHETER-BASED RENAL DENERVATION FOR THE TREATMENT OF HYPERTENSION].

INTRODUCTION: Hypertension is a significant risk factor for cardiovascular morbidity and mortality. Despite a large variety of pharmacological treatment options, many patients remain uncontrolled. Medical inertia and patients' non-adherence to medications are the main reasons for lack of control. Experimental evidence shows that increased renal sympathetic nerve activity increases blood pressure and surgical denervation lowers blood pressure. In studies published between the years 2010-2013, radiofrequency endovascular ablation of renal sympathetic nerves (RDN) seemed to produce antihypertensive effects. However, a randomized sham-control study failed to prove active treatment-specific benefit. One of the main reasons for failure was the small number of ablations in each procedure. In recent years, technological progress has been made with the possibility to quadruple the number of ablation sites and extend them to the branches of the main renal arteries. Small sham-controlled studies were conducted in patients with grade 1-2 hypertension, either untreated or treated with up to three drugs. At three to six months follow-up, modest yet significant decrease of blood pressure was found, both in office and ambulatory measurements. Data from the Global SYMPLICITY Registry, which collects data from consecutive patients undergoing RDN with Medtronic radiofrequency ablation catheters, most of them with resistant hypertension, also showed significant improvement in blood pressure. However, in the absence of a control group, these real-life results should be interpreted with caution. Selection criteria of patients more likely to benefit from RDN have not been defined and will be discussed in the current review. In summary, RDN is a promising new treatment for hypertension. Randomized sham-controlled studies with a longer follow-up are still needed to confirm long-lasting treatment-specific effects and to show cardiovascular protection and safety.

Translating clinical trial results into personalized recommendations by considering multiple outcomes and subjective views.

Currently, clinicians rely mostly on population-level treatment effects from RCTs, usually considering the treatment's benefits. This study proposes a process, focused on practical usability, for translating RCT data into personalized treatment recommendations that weighs benefits against harms and integrates subjective perceptions of relative severity. Intensive blood pressure treatment (IBPT) was selected as the test case to demonstrate the suggested process, which was divided into three phases: (1) Prediction models were developed using the Systolic Blood-Pressure Intervention Trial (SPRINT) data for benefits and adverse events of IBPT. The models were externally validated using retrospective Clalit Health Services (CHS) data; (2) Predicted risk reductions and increases from these models were used to create a yes/no IBPT recommendation by calculating a severity-weighted benefit-to-harm ratio; (3) Analysis outputs were summarized in a decision support tool. Based on the individual benefit-to-harm ratios, 62 and 84% of the SPRINT and CHS populations, respectively, would theoretically be recommended IBPT. The original SPRINT trial results of significant decrease in cardiovascular outcomes following IBPT persisted only in the group that received a "yes-treatment" recommendation by the suggested process, while the rate of serious adverse events was slightly higher in the "no-treatment" recommendation group. This process can be used to translate RCT data into individualized recommendations by identifying patients for whom the treatment's benefits outweigh the harms, while considering subjective views of perceived severity of the different outcomes. The proposed approach emphasizes clinical practicality by mimicking physicians' clinical decision-making process and integrating all recommendation outputs into a usable decision support tool.

Animal models of preeclampsia.

There have been many attempts to produce animal models that mimic the hypertensive disorders of pregnancy, especially preeclampsia, but most are incomplete when compared to the full spectrum of the human disease. This review assesses a number of these models, organized according to the investigators attempt to focus on a specific pathogenic mechanism believed to play a role in the human disease. These mechanisms include uterine ischemia, impairments in the nitric oxide system, insulin resistance, overactivity of the autonomic nervous and/or renin-angiotensin systems, activation of a systemic inflammatory response, and most recently, activation of circulating proteins that interfere with angiogenesis. In addition a model of renal disease that mimics superimposed preeclampsia is discussed. Defining these animal models should help in our quest to understand the cause, as well as to test preventative and therapeutic strategies in the management of these hypertensive disorders of pregnancy.

Insulin-induced hypertension, L-arginine, and endothelial nitric oxide synthase in pregnant rats.

Pregnancy-induced hypertension in rats with chronic exogenous hyperinsulinemia is associated with reduced urinary excretion of nitric oxide metabolites. We tested the hypothesis that there are perturbations of endothelial nitric oxide synthase in their kidneys. We studied three groups of rats: control pregnant rats (n = 6); pregnant rats with hyperinsulinemia by subcutaneous sustained-release insulin pellet (n = 5); and hyperinsulinemic pregnant rats treated with l-arginine 2 gL in drinking water (n = 5). By the end of pregnancy blood pressure was 78 +/- 12 mm Hg in controls, 119 +/- 15 mm Hg in hyperinsulinemic rats, and 77 +/- 8 mm Hg in l-arginine-treated hyperinsulinemic rats, p < 0.007. Serum creatinine was 0.4 mg/dl in controls, 0.6 mg/dl in hyperinsulinemic rats, and 0.5 mg/dl in l-arginine-treated rats, p < 0.05. Corresponding urinary excretion of nitric oxide metabolites was 2.1 +/- 0.5, 1.2 +/- 0.2, and 1.5 +/- 0.2 micromols/mg creatinine, p < 0.01. Expression of endothelial nitric oxide synthase protein in kidneys by Western blot was not different between controls and hyperinsulinemic rats, 5.6 +/- 2.4 and 5.8 +/- 3.4 OD x mm2, but was nearly doubled in l-arginine-treated rats, 10.8 +/- 2.3, p < 0.03. Thus, the salutary effect of l-arginine on hyperinsulinemic pregnancy-induced hypertension (PIH) may be mediated, in part, by endothelial nitric oxide synthase in their kidneys.

Effect of tetrahydrobiopterin on blood pressure in rats after subtotal nephrectomy.

BACKGROUND: Previous studies have shown that endothelial dysfunction after 5/6 nephrectomy (5/6 Nx) in rats is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. Blood pressure is significantly increased by day 10 after surgery. Tetrahydrobiopterin (BH4) is a key cofactor of NO synthase. Suboptimal levels of BH4 result in uncoupling of NO synthase, low NO synthesis and augmented production of superoxide anions. The aim of this study was to evaluate whether BH4 supplementation may improve NO production and prevent the increase of blood pressure after 5/6 Nx. METHODS: Three groups were evaluated: 5/6 Nx (untreated rats), BH4 (5/6 Nx rats treated with BH4, 10 mg/day i.p. for 10 days) and L-ARG (5/6 Nx rats treated with L-arginine, 260 mg/kg BW, p.o for 10 days). Systolic blood pressure (SBP), urinary nitrate excretion (UNO(3)) and creatinine clearance (CCR) were measured before surgery and on days 3 and 10 after surgery. Endothelial NO synthase (eNOS) protein content of mesenteric resistance vessels was measured at the end of the study. RESULTS: SBP increased from 107 +/- 2 to 127 +/- 4 mm Hg in untreated 5/6 Nx rats (p < 0.01). By contrast, rats treated with BH4 or L-ARG remained normotensive. Ten days after 5/6 Nx, creatinine clearance decreased similarly in all groups. Both BH4 and L-ARG supplementation markedly increased UNO(3) excretion. The mesenteric vascular expression of eNOs protein was significantly higher in BH4 but not in L-ARG, compared with Nx rats. CONCLUSIONS: BH4 supplementation prevents the earlier increase in blood pressure observed in rats after 5/6 Nx, possibly by upregulating eNOS in resistance vessels.

Normokalemic hyperaldosteronism in patients with resistant hypertension.

BACKGROUND: Primary aldosteronism is a common cause of non-renal secondary hypertension. A correct diagnosis results in curing the hypertension or targeting appropriate pharmacotherapy. In patients with low renin resistant hypertension (after treatment with three or more different anti-hypertensive drugs the blood pressure remains above 140/90 mmHg), screening for aldosteronism is mandatory. OBJECTIVES: To demonstrate that normal blood levels of potassium in resistant hypertensive patients do not exclude the possible presence of hyperaldosteronism, and to suggest the use of the plasma aldosterone concentration (ng/dl)/plasma renin activity (ng/ml/hour) ratio in screening for hyperaldosteronism. METHODS: Blood tests, suppression and stimulation tests (2 L normal saline i.v./4 hours and 20 mg furosemide i.v. for 60 minutes in a standing position) were systematically performed in 20 low renin normokalemic resistant hypertensive patients. None had renal disorders, known endocrine abnormalities or heart failure. They did not receive anti-hypertensive drugs affecting PAC or PRA. Basal PRA and PAC were measured twice: PAC after saline infusion and PAC/PRA after stimulation. RESULTS: PAC/PRA above 50 was used to denote hyperaldosteronism. Serum K was 4 +/- 0.07 mM/L, PAC 22.8 +/- 1.8 ng/dl, PRA 0.13 +/- 0.02 ng/ml/hour, PAC/PRA 190 +/- 22 (above 100 in 17). After suppression PAC decreased from 25 +/- 1.8 to 11 +/- 1 ng/dl (normal < 5 ng/dl). Stimulation did not affect PRA and PAC/PRA. Abdominal computed tomography scan revealed normal adrenal glands in 15 patients. Spironolactone (116 +/- 60 mg/day) normalized blood pressure in all patients; it was used as a single therapy in 8, and in association with only one anti-hypertensive drug in the remaining 12 patients. In one patient the treatment was discontinued due to the presence of hyperkalemia. CONCLUSIONS: Low renin resistant hypertension associated with normokalemia may be due to hyperaldosteronism. Normal aldosterone levels in the basal condition do not exclude the possibility of hyperaldosteronism. Using a PAC/PRA ratio above 50 as a screening test can aid the physician in deciding when to perform dynamic tests, thus increasing the sensitivity of the diagnosis of hyperaldosteronism. CT scan is frequently normal. Targeted pharmacotherapy leads to a normalization of blood values.

Additive renoprotective effect of candesartan and tetrahydrobiopterin in rats after 5/6 nephrectomy.

BACKGROUND: Chronic treatment with candesartan cilexetil (C) improves the outcome of rats after 5/6 nephrectomy (Nx). Tetrahydrobiopterin (BH4), an essential cofactor for appropriate endothelial nitric oxide synthase (eNOS) activity, prevents an increase in blood pressure (BP) in Nx rats when given immediately after surgery. In the present study, we evaluated the renoprotective effect of a combined treatment. METHODS: Five groups of rats were studied: SHAM (sham-operated rats, n=12); SNx (untreated 5/6 nephrectomized rats, n=15); C (SNx rats treated with candesartan cilexetil, 5 mg/kg/day per os, n=11); C+BH4 (SNx rats treated with candesartan cilexetil and BH4, 10 mg/kg/day intraperitoneally, n=11); and BH4 (SNx rats treated with BH4, 10 mg/kg/day intraperitoneally, n=11). Treatment began 30 days after surgery, when hypertension and renal insufficiency have developed. This day was considered as day 1 of treatment for statistical comparisons. The study was continued until 50% mortality was achieved in the SNx rats (4 months after surgery). RESULTS: The survival rates were 100% for SHAM, 47% for SNx, 50% for BH4, 64% for C and 80% for C+BH4 (P<0.05 vs all). Untreated Nx rats developed hypertension, proteinuria (UP) and severe renal insufficiency. Mortality was associated with a lower renal function and increased urine protein excretion. In C and C+BH4 rats, systolic blood pressure (SBP) decreased significantly. BH4 alone had a mild non-significant effect on SBP. C and C+BH4 treatments attenuated significantly the increase in proteinuria found in SNx animals. The weight of the remnant kidneys as well as the severity of glomerulosclerosis were significantly lower in the C+BH4 rats. CONCLUSION: This study shows that in subnephrectomized rats, addition of BH4 to a treatment with candesartan had an additive renoprotective effect. The mechanism of such action may include a better control of BP associated with a blockade of actions of angiotensin II (Ag II), an improvement in nitric oxide synthesis and a balanced redox.

Human erythropoietin gene therapy for patients with chronic renal failure.

Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical condition is anemia. Patients with anemia of chronic renal failure are treated with erythropoietin. The objective of this study was to develop a therapeutic platform for serum-secreted proteins like erythropoietin. We developed a tissue protein factory based on dermal cores (Biopump) harvested and implanted autologously. In this study, an adenovector was designed to express the human erythropoietin under the control of the cytomegalovirus (CMV) promoter. This vector transduced the harvested dermal cores ex vivo. The transduced cores were implanted, and erythropoietin and reticulocyte counts were measured. Dermal cores were harvested from 13 patients with chronic renal failure, and implantation was performed in 10. There were no significant drug-related side effects to this procedure. Erythropoietin serum levels increased significantly to therapeutic levels from day 1 after implantation reaching a peak during the first week of follow-up. The expression period was transient for up to 14 days. The rise of erythropoietin was followed by a transient significant increase in reticulocyte counts. The decrease of erythropoietin expression coincided with a significant dermal infiltrate of CD8 cytotoxic T cells. Antierythropoietin antibodies were not detected until day 90 following implantation. Implantation of dermal cores ex vivo transduced with human genes could eventually be used in the clinical setting to express therapeutic serum proteins. However, nonimmunogenic delivery system should be tested as gene vehicles.

Effect of chronic tetrahydrobiopterin supplementation on blood pressure and proteinuria in 5/6 nephrectomized rats.

BACKGROUND: Tetrahydrobiopterin (BH4) is a key cofactor of nitric oxide (NO) synthase. Reduced BH4 levels may mediate endothelial NO synthase uncoupling, resulting in reduced NO synthesis and enhanced oxidative stress. In rats after 5/6 nephrectomy (Nx), administration of BH4 prevents the onset of hypertension, typically observed 10 days after Nx. This effect is associated with an increased synthesis of NO. The aim of the present study was to evaluate the effect of chronic BH4 therapy on blood pressure and renal morphology. METHODS: During an 8 week period, five groups of rats were studied: untreated 5/6 Nx rats, BH4-treated Nx rats (BH4, 10 mg/kg body weight/day administered intraperitoneally), l-arginine treated Nx rats (LA, 130 mg/kg/day), diltiazem-treated Nx rats (DILT, 30 mg/kg/day) and sham-operated rats. Treatments were commenced 24 h after surgery. Systolic blood pressure values (SBP), 24 h proteinuria (UP) and creatinine clearance rate (CCR) were assessed before and at weeks 4 and 8 of the study period. Histological changes in the kidney were evaluated at the end of the study (week 8). RESULTS: Compared with baseline, in Nx rats both SBP and UP increased significantly (112+/-1 to 136+/- 1.4 mmHg, P<0.01 and 23+/-2 to 127 +/- 26 mg/day, P<0.01, respectively). Treatment with BH4 normalized SBP values as did treatment with LA and DILT (109+/-3, 115+/-2 and 114+/-2 mmHg, respectively). UP was markedly reduced by BH4, the reduction being similar to that obtained by LA and significantly more marked than that of DILT rats (20+/-2, 28+/-3 and 62+/- 14 mg/day, respectively). CCR was equally decreased in all Nx groups. Histological evaluation showed the development of mesangial expansion in Nx rats, an effect that was significantly blunted by all treatments. CONCLUSIONS: In rats after 5/6 nephrectomy, BH4 supplementation initiated 24 h after surgery and maintained for 8 weeks preserved SBP, reduced UP and prevented the development of glomerular mesangial expansion.