Sorot Phisitkul

Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR

Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

Vaccines in the management of hypertension

Importance of the field: In the USA only 35% of patients with hypertension achieve adequate blood pressure control. Non-compliance is one of the main barriers to treatment. Vaccine against hypertension is an innovative treatment, injected every 4 – 6 months, to combat non-compliance. Areas covered in this review: Pathogenesis of hypertension and progress towards developing a hypertension vaccine, including the virus-like-particle-based approach, new adjuvant molecules and the potential toxicity of hypertension vaccine. What the reader will gain: The pathogenesis of hypertension is multifactorial. The most common cause is disruption of the Renin–angiotensin–aldosterone system (RAAS), and the first vaccine study was carried out against renin. While the vaccine reduced blood pressure in animal models, it also caused autoimmune disease. In the last decade, vaccines against angiotensin I, angiotensin II, and angiotensin II-type 1 receptors have demonstrated acceptable safety profiles in animal and human studies. Take home message: Reduction in blood pressure can be achieved by inducing immunity against targets in the RAAS. The target antigen and selection of adjuvant are crucial factors determining effectiveness and safety of the vaccine. CYT006-AngQb (angiotensin II vaccine) reduced blood pressure in humans but the results were not reproducible with more frequent dosing. Vaccines for hypertension are still in the early phase. We hope for an effective vaccine for hypertension in the years to come.

Review of Catheter Thrombectomy Devices

Acute massive pulmonary embolism (PE) is a frequently fatal event that causes significant compromise of hemodynamic stability. Unfortunately, mortality rates for PE have remained relatively constant despite advances in prophylactic and treatment measures. In addition to embolus size, symptom recognition for diagnosis and emergent treatment are two distinct factors that dictate survival. Treatment generally includes thrombolytic agents; however, not all patients are candidates for aggressive thrombolytic management. Development of catheter thrombectomy devices provides an alternative treatment modality for severe cases when thrombolytics are contraindicated. Catheter thrombectomy devices have undergone major advances over the last decade, but literature support of their success is limited.

Blood Pressure Vaccines

Hypertension is widespread and causes incalculable misery. Much of the population at risk of hypertension is not in regular contact with healthcare providers. The idea of a vaccine for hypertension that could ameliorate or cure the disease with a single procedure is innately appealing. The discovery that renin increased blood pressure raised the possibility that renin could be the key to the etiology of hypertension. Administering renin from one species to another resulted in the recipient developing anti-renin antibodies sparking interest in a vaccine against renin. Some of these renin vaccines were successful at lowering blood pressure but resulted in severe vasculitis and kidney damage. This turned the scientific focus downstream in the renin–angiotensin–aldosterone system, angiotensin I, angiotensin II, and the angiotensin II receptor all have tested as vaccine targets. Many of these peptides are small and unable to initiate an immune response by themselves. This stimulated research into possible adjuvants. Viral-like particle (VLP) showed strong immune response and has a good safety profile. The CYT006-AngQb vaccine combines angiotensin II and VLP. This is the only hypertension vaccine shown to significantly reduce blood pressure in hypertensive humans (mean − 9/− 4 mmHg). This was considered an ineffective response and has not been improved by larger or more frequent doses. Angiotensin II receptor vaccines are now undergoing active research. The chapter will discuss each vaccine and the future outlook for the field.

DIETARY PROTEIN INDUCES REMNANT KIDNEY INJURY BY INCREASED INTRINSIC ACID PRODUCTION MEDIATED THROUGH ENDOTHELIN RECEPTORS.: 266

Purpose We tested the hypothesis that acid-producing dietary protein induces endothelin-mediated parenchymal injury in the 5/6 nephrectomized rat by increasing intrinsic acid production. Methods Munich-Wistar rats underwent surgical 5/6 nephrectomy (Nx) and were studied 12 weeks after eating diets with either acid-producing protein (casein) or non-acid-producing protein (soy). Intrinsic acid production in the casein group was reduced by added Ca ++ citrate with Ca ++ phosphate as a control. Intrinsic acid production in the soy group was increased by added (NH 4 ) 2 SO 4 with Na 2 SO 4 as a control. Both casein-eating Nx and soy + (NH 4 ) 2 SO 4 -eating Nx received either the oral endothelin A/B receptor antagonist bosentan or the oral endothelin A antagonist darunsentan. Distal nephron Net HCO 3 reabsorption (Net J HCO3 ) was measured at 4 weeks by in vivo microperfusion. Urine endothelin 1 excretion (U ET-1 V), urine albumin excretion (U alb V), kidney glomerulosclerosis (GS), and tubulointerstitial injury (TII) were measured at 12 weeks. Results (1) Casein-eating Nx versus soy-eating Nx had higher U ET-1 V (315 ± 52 vs 78 ± 13 fmol/d, p alb V (180 ± 22 vs 74 ± 10 mg/d, p p p ++ citrate versus Ca ++ phosphate had lower U ET-1 V (89 ± 22 vs 341 ± 56 fmol/d, p alb V (105 ± 11 vs 177 ± 20 mg/d, p p p 4 ) 2 SO 4 versus Na 2 SO 4 had higher U ET-1 V (350 ± 40 vs 211 ± 26 fmol/d, p alb V (145 ± 16 vs 86 ± 10 mg/d, p p p HCO3 in acid-ingesting groups. By contrast, the endothelin A but not endothelin A/B antagonist reduced U alb V and TII in acid-ingesting groups. Conclusions Acid-producing dietary protein induces endothelin B-mediated increased acidification and endothelin A-mediated TII in the 5/6 nephrectomized rat through increased intrinsic acid production.

241 ORAL ALKALI REDUCES URINE ENDOTHELIN EXCRETION IN CHRONIC KIDNEY DISEASE ASSOCIATED WITH PRIMARY HYPERTENSION.

Purpose Renal endothelin 1 (ET-1) production is increased in the 5/6 nephrectomy experimental model of chronic kidney disease (CKD) and in rats with normal GFR ingesting mineral acid or acid-producing dietary protein. Unpublished data from our laboratory support that amelioration of the acid retention in experimental CKD with dietary alkali decreases renal ET-1 production as measured by urine excretion of endothelin 1 (UET-1V). We hypothesized that the same is true in human CKD. Methods We recruited 18 healthy controls, 21 subjects with primary hypertension without CKD, and 19 subjects with CKD (plasma creatinine 1.5-6.0 mg/dL) and primary hypertension without diabetes, evidence of glomerulonephritis, or history of renal replacement therapy. We reduced systolic blood pressure (SBP) in the latter 2 groups toward 130 mm Hg over 6 months. We then prescribed oral Na+ citrate to CKD subjects with TCO2 < 22 mM (n = 12) but not to those with TCO2

Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors

22 mM (n = 7) and followed each for an additional 6 months. We measured UET-1V (ng/g creatinine or ng/g Cr) in a spot am specimen and venous blood TCO2 at 0, 6, and 12 months. Summary UET-1V was higher than healthy controls (3.1 6 0.4 ng/g Cr) in hypertensives without CKD (5.9 6 1.1 ng/g Cr, p < .03 vs controls) and in hypertensives with CKD (5.1 6 0.7 ng/g Cr, p < .02 vs controls). After SBP reduction, UET-1V in hypertensives without CKD (3.5 6 0.4 ng/g Cr) was not different from healthy controls (p = .23) but that for hypertensives with CKD (5.3 6 0.5 ng/g Cr) remained higher than control (p < .001) and was now higher than hypertensives without CKD (p < .007). TCO2 increased in CKD subjects prescribe Na+ citrate (20.1 6 0.4 to 23.9 6 0.4 mM, p < .001 paired t) but decreased in those not prescribed Na+ citrate (23.6 6 0.5 to 23.0 6 0.5 mM, p < .03 paired t). Although UET-1V was not different between CKD subjects before Na+ citrate (p = .85), UET-1V decreased in those prescribed Na+ citrate (5.4 6 0.6 to 4.1 6 0.4 ng/g Cr, p < .02, paired t) but did not change in those not prescribed Na+ citrate (5.2 6 1.0 to 6.1 6 1.0 ng/g Cr, p = .10, paired t). Follow-up UET-1V was lower in CKD subjects prescribed compared to those not prescribed Na+ citrate (p < .04). Conclusions The data show that primary hypertensives with compared to those without CKD have higher UET-1V despite improved BP control that is decreased by oral Na+ citrate. These studies support the contention that subjects with CKD have increased renal ET-1 production that is mediated by the associated positive acid balance.