1. Hypertension in renal parenchymal disease : Why is it so resistant to treatment? VM Campese1, N Mitra1 and D Sandee1 Kidney International 2006:69:967-973

2. Hypertension chronic renal disease Pathogenesis of HTN in CKD pts - complex and multifactorial - why it is resistant to treatment Traditional paradigm of HTN in CKD - excess of intravascular volume (volume dependent) - excessive activation of RAS system (renin-dependent) In recent years, alternative pathogenic mechanisms

3. Table 1. Factors implicated in the pathogenesis of hypertension in kidney disease

4. This review - Importance of less established mechanisms - Therapeutic interventions aimed at those alternative mechanisms may represent the key for adequate BP control in many CKD patients.

5. ROLE OF INCREASED SNS ACTIVITY Increased SNS activity in pts with renal disease Kidney is a sensory organ - target of the SNS activity - also origin and modulator of this activity Ischemic metabolites (adenosine), uremic toxins (urea) ->stimulation of afferent nerves ->increases in SNS activity and BP

6. Ischemic injury or renal damage -> increased renal sensory impulses from kidney -> transmitted to CNS -> activate brain regions involved in the noradrenergic control of BP -> important role in pathogenesis of HTN in CKD

7. Fig 1. This schema summarize current concepts linking renal damage with increased SNS activity.

8. Antiadrenergic drugs - important component of HTN management in CKD - ACEI, ARB : partially reduce SNS activity by interfering with effects of ANGII on SNS transmission both at pph and central sites

9. SLEEP APNEA AND CIRCADIAN VARIABILITY OF BLOOD PRESSURE IN CKD Dippers – 10-25% BP reduction at night Nondippers - prevalence is 74–82% among CKD pts - risk of cardiac concentric hypertrophy, cardiovascular events in ESRD pts Mechanisms for non-dipping in pts with CKD pts - extracellular volume expansion, uremic neuropathy, restless leg syndrome, sleep apnea syndrome

10. Sleep apnea - 21–47% of ESRD pts - oxygen desaturation : raising BP through the activation of chemoreceptors - removal of excessive volume with dialysis - nasal continuous positive pressure => improve nocturnal oxygen desaturation reduce SNS activity and BP

11. ROLE OF THE VASCULAR ENDOTHELIUM The role of endothelium in vascular and renal physiology and pathology : well recognized Endothelium-derived relaxing factors endothelium-derived constricting factors : play a role in HTN associated with kidney disease

12. ENDOTHELIUM-DERIVED VASOCONSTRICTOR FACTORS Role of ET in CKD-related HTN - active research and controversy - variety of action, maintenance of vascular tone ET-A receptor - predominantly on vascular smooth muscle cells - mediates vasoconstriction ET-B receptor - predominantly on endothelial cells - promotes vasodilation via NO and prostacyclin

13. ET-A receptor blockade - results in vasodilatation ET-B receptor blockade - results in vasoconstriction ET - also effects on renal tubular sodium handling Predominant receptor in kidney - ET-B receptor : results in natriuresis ET-B receptor-deficient rats - exacerbate HTN in high salt diet rats - develop salt-sensitive hypertension

14. Some pts with essential HTN and HTN pts with CKD - higher plasma ET-1 (affinity for ETA receptor↑) ET1 receptor antagonists - significantly reduce BP and proteinuria in CKD pts - Place of ET1 antagonists in management of HTN in CKD and ESRD pts remain to be futher explored

15. ENDOTHELIUM-DERIVED VASODILATOR FACTORS Vascular endothelial cells cause vasodilatation NO by NO synthase (NOS) in endothelium Endothelial NOS (eNOS) - regulates endothelial function and vascular tone Neuronal NOS (nNOS) - modulates SNS activity

16. CKD and ESRD pts - impaired endothelium-dependent vasodilation - higher asymmetrical dimethylatginine (NO synthesis inhibitor) : NO synthesis ↓ : this may contribute to HTN in CKD pts - asymmetrical dimethylatginine level : correlate with atherosclerosis, cardiovascular mortality

17. ROLE OF ARTERIAL STRUCTURAL CHANGES Distensibility of large vessels - protective mechanism on HTN, cardiovascular disease Increased aortic stiffness - advancing age, smoking, DM, CKD - coincides with systolic BP↑, pulse pressure ↑ - independent predictor of cardiovascular mortality Two factors that determine distensibility - pressure and the vessel wall structure

18. Uremic pts with CKD - functional and morphologic changes of arteries - hyperplasia of smooth muscle cells, calcification of media and intima-media thickness ↑ - disturbed Ca-P balance and 2’ hyperparathyroidism => Sustaining BP, increasing severity, reducing response to phamarcologic intervention

19.  Therapeutic modalities to decrease structural changes  Inhibitors of RAS - decrease aortic collagen production in animal  Statins - also decrease arterial stiffness  Drugs that interfere with the advanced glycation end products of collagen  Hormone replacement Tx

20. OXIDATIVE STRESS AND HYPERTENSION Reactive oxygen species (ROS) on BP and cardiovascular toxicity ROS is increased in HTN models, in uremic rats ROS in HTN - result of vasoconstriction? causative?

21. ROS - may stimulate vascular contraction directly or through vasodilator NO ↓ - may play a role in regulation of noradrenergic transmission in the brain The role of antioxidants in the management of HTN in CKD remains speculative

22. ROLE OF IATROGENIC FACTORS Several iatrogenic factors may contribute to HTN in pts with CKD Erythropoietin, Cyclosporine, Steroids, NSAIDS Divalent ions and vitamin D, Sympathomimetic agents Recombinant human erythropoietin - Hct ↑, worsen BP control - increased blood viscosity - pressor responsiveness to NE, angiotensin-II ↑ - direct vasoconstrictor action