Hypertension in Chronic Kidney Disease: Navigating the Evidence
Background/Aims: Hypertension (HT) is a common complication in patients with chronic kidney disease (CKD). However, the relationship. Relationship between hypertension and renal function and its therapeutic renal disease, a very significant relationship exists between hypertension and. Hypertension (HTN) is ubiquitous in the renal failure patient. vessel in HTN is consistent with the close correlation of vascular disease to HTN (because HTN is .
Based on these findings, guidelines recommend ACE inhibitor or ARB therapy as first-line treatment for those with diabetes or those presenting with nondiabetic kidney disease, HTN, and proteinuria. Therefore, selection of one agent over another will depend on patient-specific factors such as potential for side effects and cost.
Pathophysiology of hypertension in renal failure.
Treatment with both an ACE inhibitor and an ARB is not recommended, as this combination has been shown to worsen kidney function. ACE inhibitors may cause a dry cough, which unfortunately often requires a change in therapy. ARBs are not associated with dry cough. Angioedema is very rare; however, patients started on ACE inhibitors or ARBs should be informed of the signs and symptoms that may present with angioedema.
For patients without proteinuria, a preferred first-line therapy has not been clearly established, and other agents, such as a thiazide, may be considered. As a result, diuretics are often necessary in their treatment regimen.
- Pathophysiology of hypertension in renal failure.
- Chronic Kidney Disease and Hypertension: A Destructive Combination
This increase in fluid loss may lead to electrolyte imbalance. It is important for patients on these agents to have their electrolytes monitored to ensure they do not experience electrolyte abnormalities such as hyperkalemia or hypomagnesemia. Orthostatic hypotension may occur in response to any antihypertensive agents; however, it is common with diuretics.
It is important to counsel patients initiating diuretic therapy on the need to rise slowly from a sitting or lying-down position. Common adverse effects include edema and constipation with ND-CCBs especially verapamil and flushing and peripheral edema with dihydropyridine agents. Aldosterone plays a severely deleterious role in the progression of CKD. Aldosterone receptor antagonists e. It is important for patients initiated on potassium-sparing diuretics to have their potassium levels checked to ensure they do not experience electrolyte abnormalities.
Symptoms of hyperkalemia include heart arrhythmia and severe muscle weakness. Unfortunately, hyperkalemia may present asymptomatically, which underscores the importance of monitoring. Aliskiren is the only renin inhibitor currently available on the market.High Blood Pressure and Your Kidneys - A to Z Guide
It is indicated for the treatment of HTN as monotherapy or as combination therapy with valsartan. Data that evaluate the effect of beta-blockers on the progression of CKD and proteinuria are limited.
This type of therapy takes into consideration circadian BP patterns, and institutes administration of antihypertensive medication in respect to the daily patterns, moving away from administration of all antihypertensive medications in the morning.
Trials have demonstrated improved hour BP control in patients administering CCBs in the evening rather than in the morning. If patients are on more than two antihypertensive agents, it may be appropriate to administer two agents in the morning and the additional agents in the evening.
Increased physical activity, weight loss, and dietary modifications are recommended for all patients with HTN. The Dietary Approaches to Stop Hypertension DASH diet emphasizes an increased consumption of fruits and vegetables, inclusion of low-fat dairy and lean protein, and a restriction of saturated fats; this meal plan has been shown to significantly lower systolic BP nearly equivalent to the reduction achieved by antihypertensive monotherapy.
Agents that reduce proteinuria in addition to BP are generally first line, but patients may often require three to four antihypertensive agents in order to achieve their goals and minimize their risk for CVD and ESRD. In addition, healthy lifestyle modifications should always be considered as a vital component of any antihypertensive therapy regimen. Prevalence of chronic kidney disease in the United States. Am J Kidney Dis. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: The case for chronic kidney disease, diabetes mellitus, and myocardial infarction being equivalent risk factors for cardiovascular mortality inpatients older than 65 years.
Hypertension in cardiovascular and kidney disease. Segura J, Ruilope L. Hypertension in moderate-to-severe nondiabetic CKD patients. Adv Chronic Kidney Dis. Standards of medical care in diabetes— Preserving renal function in adults with hypertension and diabetes: Analyses of registry data show a U-shaped relationship between blood pressure and mortality.
By contrast, studies of selected patients at low risk for cardiovascular disease replicate the observation in the general population that the risk of adverse cardiovascular outcome increases with blood pressure.
While the exact pathophysiologic basis for this discrepancy is unclear, it has been suggested that high mortality in dialysis patients with lower blood pressure is due to coexisting severe cardiac disease.
In support of this explanation is the favorable outcome seen in the intervention arm of the Frequent Hemodialysis Network FHN Daily Trial despite having lower pressure than the control group [ 20 ]. In renal transplant recipients, observational studies suggest that post-transplant hypertension is an independent risk factor for graft failure and death, and that adequate blood pressure control reduces this risk [ 2122 ]. Pathophysiologic Considerations The kidneys play such a vital role in long-term blood pressure regulation that Guyton argued that sustained hypertension could not occur in the absence of impairment of renal handling of sodium [ 23 ].
In fact, virtually all forms of experimental and human hypertension exhibit impaired sodium excretion by the kidneys at normal blood pressure [ 24 ].
In his seminal experiments using large animals and isolated perfused kidneys, Guyton showed that acute rise in blood pressure results in brisk increase in renal sodium excretion and normalization of blood pressure. Under these circumstances, rise in blood pressure was initially mediated by expansion of extracellular fluid ECF volume, despite reduction in total peripheral resistance.
At this stage, the rise in blood pressure is mediated by increased cardiac output; this manifests as predominantly systolic hypertension. Over time, however, ECF volume and cardiac output normalize and high blood pressure results from elevated peripheral resistance, which increases diastolic blood pressure.
International Journal of Hypertension
That subtle renal defects may underlie the pathogenesis of essential hypertension in humans is supported further by several lines of evidence.
In a series of patients with renal failure due to histologically proven hypertensive nephrosclerosis, transplant with kidneys from normotensive donors resulted in the resolution of their hypertension [ 25 ]. It has also been shown that normotensive individuals with family history of hypertension respond to salt loading with less natriuresis and higher blood pressure than those with no family history [ 26 ].
Finally, hypertensive victims of fatal accidents were endowed with fewer nephrons than normotensive controls in an autopsy series [ 27 ]. The exact nature of renal defect or defects responsible for inappropriate sodium excretion, or of factors that mediate the subsequent rise in peripheral resistance, remains unclear. The critical role of volume expansion in hypertension due to CKD is underscored by the effect of ultrafiltration or diuretics on blood pressure control in CKD patients.
Dialysis units that employ eight-hour thrice-weekly or short daily hemodialysis report that only a minority of patients require antihypertensive medications for blood pressure control [ 28 ]. This observation is confirmed in the FHN Daily Trial, which also showed improvement in the composite outcome of death or left ventricular hypertrophy in the more frequent dialysis group [ 20 ].
Similarly, better volume and blood pressure control could be achieved by peritoneal dialysis [ 29 ], or use of loop diuretics in earlier stages of CKD [ 30 ]. Positive salt balance is the dominant but not the sole factor in the genesis of hypertension in CKD. As noted above, experimental evidence has clearly demonstrated that hypertension due to retention of salt and water is maintained by increased peripheral resistance. This has been replicated in hypertensive uremic humans [ 31 ].
Table 1 shows a list of factors proposed to cause hypertension in CKD along with their corresponding mechanisms. Activation of the renin-angiotensin system RAS has been well documented in dialysis patients with uncontrolled hypertension despite optimized ultrafiltration [ 32 ].
Treatment of such patients with bilateral nephrectomy or inhibitors of RAS has been shown to result in control of blood pressure, suggesting failing kidneys as the source of excess renin [ 3233 ]. In addition to its direct pressor effect, it is possible that the activation of the RAS may contribute to hypertension in CKD by stimulating the sympathetic nervous system.
In microneurographic studies, patients with CKD have increased sympathetic nerve activity that responds to angiotensin-converting enzyme ACE inhibition or bilateral nephrectomy [ 34 ]. Even when renal function is well preserved, activation of the RAS is an important factor in the pathogenesis of hypertension in polycystic kidney disease, and is believed to be due to compression of the renal vasculature by enlarging cysts [ 35 ].
Other factors proposed to explain increased vascular resistance in CKD include increased production of endothelin [ 36 ] and endogenous digitalis-like substance [ 37 ]; reduced generation of vasodilators such as nitric oxide [ 38 ] and kinins [ 39 ]; and imbalance between vasodilator and vasoconstrictor prostaglandins [ 40 ].
While the primacy of oxidative stress in hypertension and chronic kidney disease is unknown, it commonly accompanies both disorders and is believed to contribute in part to their pathogenesis [ 41 ]. Graft function is an important predictor of hypertension after renal transplant [ 18 ]. In addition, calcineurin inhibitors tacrolimus and cyclosporine and glucocorticoids contribute to the pathogenesis of hypertension in kidney transplant recipients.
Calcineurin inhibitors possess vasoconstrictor properties, but the exact mechanism is not known. Disturbances in the biology of vasoactive substances discussed above and the effect on smooth muscle calcium metabolism have been described [ 1842 ]. Stenosis of the renal artery of a transplant, or of arteries proximal to the arterial anastomosis, is an infrequent but potentially reversible cause of hypertension after renal transplant.
Treatment of Hypertension in Chronic Kidney Disease Patients with CKD are more likely to die, largely from cardiovascular disease, than require dialysis [ 4344 ]. It is, therefore, critically important to control modifiable risk factors e. As discussed below, there is consistent evidence that attainment of this blood pressure goal retards progression of renal disease in patients with CKD and proteinuria. It is, however, questionable whether this blood pressure goal is applicable to all patients with CKD.
Second, the safety of intensive blood pressure lowering in patients older than 70 years, who have been largely excluded from most clinical trials examining the benefit of blood pressure control, is not established.
Third, secondary analyses of prospective studies indicate that patients with CKD may incur excess risk of stroke when systolic blood pressure is lowered below mm Hg, or of myocardial infarction when diastolic blood pressure is lowered below 80 mm Hg. The benefit of treating isolated systolic hypertension in patients with CKD has not been directly tested in a clinical trial.
The Systolic Hypertension in the Elderly Program, which excluded patients with renal dysfunction, has shown that treatment of systolic hypertension reduces morbidity and mortality; it is however, important to note that the mean systolic blood pressure attained in the active treatment arm was mm Hg [ 50 ].
Since patients with CKD tend to be older and have more cardiovascular risk factors, it is advisable to individualize treatment in some patients, especially those who do not have significant proteinuria.
Most clinical trials that examined control of blood pressure in patients with CKD used progression of renal disease as their primary endpoint, and stratified their study population by the degree of proteinuria or etiology of kidney disease.
In the following sections, the evidence for benefits of blood pressure treatment will be discussed separately for diabetic nephropathy, other proteinuric renal diseases, and nonproteinuric nephropathy. Table 2 summarizes treatment of hypertension in CKD according to the nature of kidney disease. Most [ 51 — 55 ], but not all [ 56 — 58 ], clinical trials that examined the impact of specific class of antihypertensive agents on worsening of proteinuria or renal function in diabetic nephropathy found that ACE inhibitors or ARBs are renoprotective.
In patients with type 1 diabetes, treatment with captopril retarded progression of microalbuminuria daily urinary excretion of albumin of 30— mg to overt proteinuria [ 5152 ], and of overt nephropathy to ESRD [ 53 ].
Two large clinical trials also showed that use of the ARBs irbesartan and losartan in patients with overt diabetic nephropathy due to type 2 diabetes reduced the risk of progression of renal disease [ 5455 ].
Secondary analyses of existing trials, however, suggest that lowering blood pressure to this level may improve renal and cardiovascular outcomes. In a posthoc analysis of the original data, the authors found no blood pressure threshold for the beneficial effect of blood pressure lowering and recommended aiming for systolic blood pressure of mm Hg or lower in diabetic patients with hypertension [ 60 ]. The Irbesartan in Diabetic Nephropathy Trial IDNT assessed the renoprotective effects of adding irbesartan, amlodipine, or placebo to standard antihypertensive regimens [ 54 ].
All three groups had a median daily urinary protein excretion of 1. Secondary analyses of IDNT showed that progressive lowering of blood pressure up to systolic blood pressure of mmHg protects against cardiovascular events and deterioration of renal function, but further reduction in blood pressure is deleterious; a similar trend up to diastolic blood pressure of 85 mmHg was observed for cardiovascular but not renal endpoints [ 4961 ]. The normotensive ABCD trial compared intensive with moderate blood pressure lowering using nisoldipine or enalapril in normotensive patients with type 2 diabetes.
There was no difference in the rate of decline of renal function—the primary endpoint—but lesser degree of proteinuria was noted with intensive therapy. No difference was noted between the nisoldipine and enalapril arms. The MDRD study largely consisted of nondiabetic patients; it compared the effect of intensive versus usual blood pressure control, and low versus high protein intake on renal function. This large trial of diabetic patients with cardiovascular disease or at least two additional risk factors for cardiovascular disease evaluated the impact of lowering systolic blood pressure below or mm Hg.
Study participants had mean serum creatinine of 0. Despite attaining systolic blood pressure of and mm Hg with intensive and standard therapy, there was no difference in the composite primary endpoint nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death or all-cause mortality between the two groups.
The intensive control group had lower risk of stroke, but at the expense of higher rates of serious side effects.