Pathogenesis of HTN and resistant to treatment in CKD

Dr. Ahmadi

NIPEC Annual ConferenceProfessional Standards Enhancing Person-Centred Care

Dr. Ahmadi

Professor OF Nephrology

TUMS

• Elevated blood pressure can occur as a result of, and be a potent risk factor for, chronic kidney disease (CKD) progression

• CKD is associated with dysregulation of various • CKD is associated with dysregulation of various blood pressure control systems, including the ability to excrete the daily sodium load, sympathetic activation, renin–angiotensinsystem activity, and endothelial function

An overview of the pathogenesis of CKD progression

Current Blood Pressure and CKD Progression

Jafar TH et al. Ann Intern Med 2003

• HTN is found in 80–85% of all CKD patients, with a higher prevalence being seen in those with worse kidney function.

• The MDRD study showed HTN prevalence increasing from65% to 95% as glomerularincreasing from65% to 95% as glomerularfiltration rates (GFR) decreased from 85% to 15%

• Among CKD patients, and those on maintenance hemodialysis, the prevalence of non-dippers is 74–82%

• The CRIC study, a cohort study of 3612 CKD patients in 2010, showed that 67% of patients reached their blood pressure goal of 140/90 mmHg and 46% reached their goal of 130/90 mmHgmmHg

• This is compared to HTN control rates in the general population of 50% from 2007 to 2008

• The prevalence of hypertension is high in CKD,

reaching nearly 90% in National Kidney Foundation stage 5 CKD

• In the largest cohort study of CKD in the United States, more than half of the patients were States, more than half of the patients were treated with at least 3 antihypertensive drugs

• The higher incidence of drug-resistant hypertension in CKD likely identifies patients with more severe vascular damage

Prevalence of Hypertension in Renal Parenchymal Disease

Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4

Arterial Hypertension in Chronic Kidney Disease

Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4

Factors implicated in the pathogenesis of hypertension in kidney disease

Traditional factors• Sodium retention and

volume excess

• Activation of the renin–

Iatrogenic factors• Erythropoietin

• Cyclosporine

• Steroids• Activation of the renin–angiotensin system

• Steroids

• Divalent ions and vitamin D

• Sympathomimeticagents

• NSAIDS

Less recognized factors

• Activation of the sympathetic nervous system

• Renal ischemia• Sleep apnea• Deficit of endothelium-derived

vasodepressor substances

• Aldosterone• Oxidative stress• Structural changes of the

arteries• Obesity/metabolic syndrome• Leptinvasodepressor substances

• Increased endothelinproduction

• Reduced central dopaminergictone

• Reduced baroreceptorsensitivity/abnormal vagalfunction

• Leptin• Increased plasma [beta]-

endorphin• Increased [beta]-lipotropin• Serotonin

Considerations for Mechanisms of Antihypertensive Drug Resistance

• Age• Arterial stiffness• Diabetes• Chronic kidney disease• Chronic kidney disease• Salt and interfering substances• Sympathetic nervous system• Systolic pressure• Vascular calcification

The final pathway result: resistant hypertension

Target organ damage caused by high intake of sodium chloride

Salt-Induced Alterations That May Impair Sodium Excretion and Promote Renal Vasoconstriction

• Increased sympathetic activity

• Decreased renal medullary blood flow

• Increased formation of reactive oxygen species

• Low bioavailability of nitric oxide• Low bioavailability of nitric oxide

• Enhanced vasoconstrictive effects of angiotensinII and vasopressin

• Increased intrarenal formation of angiotensin II

• Overexpression of angiotensinogen in proximal tubule

Salt-Induced Alterations That May Impair Sodium Excretion and Promote Renal Vasoconstriction

• Increased expression of aldosterone synthetase• Activation of the mineralocorticoid receptor• Decreased production of

20hydroxyeicosatetraenoic acid, an arachidonic20hydroxyeicosatetraenoic acid, an arachidonicacid metabolite

• Failure of atrial natriuretic peptide to potentiatemarinobufagenin-induced inhibition of Naþ/KþATPase

• Defective dopamine-receptor function

Cause and effect diagram of forces that increase total body sodium content

J Am Soc Nephrol25:1148-1155, 2014

Rac1 is a modulator of MR activity and serves as a determinant of salt-sensitive hypertension. The paradoxical response of MR to salt loading in salt-sensitive hypertensionsalt-sensitive hypertension

Is caused by Rac1activation.Rac1activation induces nuclear translocation of MR, leading to the increased transcriptional activity of MR-dependent genes, such as Sgk1

J Am Soc Nephrol25:1148-1155, 2014

The potential involvement of aberrant b-adrenergic stimulation oftheGR-WNK4-NCC pathway in salt-sensitive hypertension. Arrowhead lines and T-shaped lines lines and T-shaped lines indicate activation and inhibition, respectively. HDAC8, histonedeacetylase 8; nGRE, negative glucocorticoidresponse element; PKA, protein kinas

• This schema summarizes current concepts linking renallinking renaldamage with increased sympathetic nervous system (SNS)

Afferent and efferent sympathetic innervations of the kidney

Pathophysiologic mechanisms of hypertension

Advances in Chronic Kidney Disease, Vol21, No 6 (November), 2014: pp 489-499

The renin-angiotensin-aldosterone system and sympathetic nervous systems

Advances in Chronic Kidney Disease, Vol 21, No 6 (November), 2014: pp 489-499

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• Curr Opin NephrolHypertens 2012, 21:1–6

• Dietary nitrate supplementation may provide a novel and economic treatment for kidney and cardiovascular disease.

• Whereas plasma asymmetric dimethylarginine(ADMA) predicts cardiovascular risk in chronic (ADMA) predicts cardiovascular risk in chronic kidney disease (CKD), the role of the kidney damage in the elevation and the variability of plasma ADMA remains unclear

Summary of asymmetric dimethyl arginine-induced molecular pathways predisposing development of endothelial dysfunction

Summary of homocysteine-induced molecular pathways predisposing to development of endothelial dysfunction

• CurreNt Opinion In Nephrology AndHypertension2010,19:134–139

Regulation ofendothelin-1 production in the vasculature and kidney

Pathophysiological role of endothelin in chronic kidneydisease (CKD) development

Kidney International(2014)86 896–90

Endothelin receptor antagonists inhypertension

• Darusentan

• Sitaxsentan

Atrasentan , in addition to lowering • Atrasentan , in addition to lowering BP, was associated with improvements in glucose and lipid metabolism , side effects : nasal stuffiness, headache, and edema

Endothelin receptor antagonists in chronic kidney disease

• The largest study of the antiproteinuric effects of endothelin antagonism was the Avosentan on Doubling of Serum Creatinine, End Stage Renal Disease, and Death in Diabetic Nephropathy (ASCEND) trial, which involved 1395 CKD stage 3 Disease, and Death in Diabetic Nephropathy (ASCEND) trial, which involved 1395 CKD stage 3 or 4 patients (estimated glomerular filtration rate15 -60ml/min/1.73m2)with diabetic nephropathy and macroalbuminuria, whichwasdefinedasaurinaryalbumin excretion rate (UAER) of 0.2–5.6mg/min

Adverse effects of endothelin receptorantagonists

• Headaches, rhinitis, flushing, and syncope.Theseeffects do not tend to be dose-dependent

• ERAs are also associated with elevations in liver function tests, and the severity of this effect function tests, and the severity of this effect varies from ERA to ERA, but in general it appears to be more severe at higher doses(Sitaxsentan)

• Most importantly, ERAs also cause a dose-dependent fluid and sodium retention, resulting in edema and potentially worsening of conges-tive heart failure symptoms

• Curr Opin NephrolHypertens 2016, 25:100–106

• Activation of Wnt/b-catenin signaling is a common pathologic finding in a wide variety of CKD, which is accompanied by intrarenalupregulation of RAS components.

• Wnt/b -catenin, as a master upstream • Wnt/b -catenin, as a master upstream regulator, controls the expression of multiple RAS genes in the kidney

• Blockade of Wnt/ b-catenin signaling by small molecule ICG-001 inhibits RAS activation and attenuates renal fibrosis after chronic injury

• Klotho is an endogenous Wnt antagonist, and loss of Klotho is associated with derpression of loss of Klotho is associated with derpression of Wnt/ b-catenin signaling, which leads to RAS activation, hypertension, and kidney fibrosis

As Wnt/b-catenin regulates many RAS components, targeted inhibition of this signaling could simultaneously signaling could simultaneously inhibit multiple RAS genes, thereby displaying superior therapeutic efficacy

Wnt/b-catenin signaling regulates the rennin–angiotensin system in CKD

JNC 8

CKD

James PA et al. JAMA 2014

SBP <140 mmHg DBP <90 mmHg

ACEI/ARB alone or in combination with other drug class

ESH/ESC

2013 ESH/ESC Guidelines. J Hypertens 2013

SBP <140 mmHg DBP <90 mmHg

CKD

Recent guidelines on blood pressure targets