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Hypertension and Chronic Kidney Disease
Chronic kidney disease (CKD) is defined by laboratory findings of a decreased estimated glomerular filtration rate (eGFR) to less than 60 mL per minute per 1.73 m 2 or evidence of renal parenchymal injury (i.e., albuminuria > 300 mg/day) present for 3 months or more. Both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) classify CKD into five stages based on the degree of remaining renal function ( Fig. 33.1 ). The stages range from histologic and/or laboratory evidence of parenchymal injury (very high albuminuria) with preserved eGFR to end-stage renal disease (ESRD) and need for renal replacement therapy.
Classification of chronic kidney disease by glomerular filtration rate and albuminuria.
(From Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013; 3:1-150.)
CKD is a worldwide public health problem with an increasing international prevalence, primarily related to diabetes and hypertension. According to the 2012 National Health and Nutrition Examination Survey (NHANES) data, approximately 29% of the population of the United States suffers from hypertension. In contrast, hypertension affects one-third of those with stage 1 CKD, and 85% of those with stage 5 CKD.
The prevalence of hypertension among hemodialysis patients is less clear, owing to variations in the threshold value for diagnosis and the timing of measurement (i.e., preceding, during, or following dialysis). In one report, 85% of the 2000 dialysis patients recruited into an iron supplementation trial possessed a predialysis blood pressure in excess of 150/85 mm Hg despite having started dialysis four years prior, a rate slightly higher than a prevalence rate of 75% observed in other studies.
Pathophysiology of Hypertension in Kidney Disease
The key components of hypertension in patients with kidney disease include excess activation of the renin-angiotensin-aldosterone system (RAAS), inappropriately elevated sympathetic nervous activity, impaired renal salt and water excretion, increased arterial stiffness, and reduced nitric oxide release. Sympathetic overactivity results in additional efferent arteriolar vasoconstriction with increases in intraglomerular pressure and a greater plasma filtration fraction. Enhanced filtration leads to elevated oncotic pressures, further increasing intravascular volume. Sympathetic activity also up-regulates the renin-angiotensin-aldosterone cascade, ultimately increasing angiotensin II. Angiotensin II promotes efferent arteriolar vasoconstriction, giving rise to hyperfiltration (increased glomerular filtration). In healthy individuals, increased sodium intake raises blood pressure and GFR, which in turn promotes sodium loss. However, in those with a GFR less than 60 mL per min, the pressure-natriuresis curve is shifted to the left such that sodium balance is only achieved at the expense of a higher blood pressure. High salt loads are also poorly tolerated in such populations because of reductions in nitric oxide release, thereby blunting the vasodilatory response to increases in volume ( Fig. 33.2 ).
The pathogenesis of hypertension among dialysis patients, although related to the aforementioned mechanisms in CKD patients, is primarily related to volume overload. Among dialysis patients there is an inability to excrete sodium and water; hence, volume expansion is the driving force for hypertension. Bioelectrical impedance assessment of volume status and the reduction in blood pressure realized after volume removal confirm this precept. Derangements in the sympathetic nervous system are also implicated as both the rates of sympathetic discharge and vascular resistance are more than two-fold higher among dialysis patients when compared with normotensive individuals. This elevation in vascular resistance is, in part, mediated by dysfunction of the endothelial-derived compounds nitric oxide and endothelin.
Nitric oxide, a potent vasodilator, is inhibited by the endogenously produced molecule asymmetric dimethyl arginine (ADMA). Because ADMA is excreted in the urine, levels in anuric individuals are elevated and would be associated with depressed nitric oxide levels and, in experimental models, arterial constriction. However, studies in dialysis patients failed to correlate ADMA concentrations with mean arterial pressure, indicating an incomplete understanding of its causal role. Among endothelin subtypes, animal data demonstrate that increased levels of endothelin-1 results in elevations in systemic blood pressure. Moreover, hypertensive hemodialysis patients demonstrate elevations in endothelin-1 compared with normotensive dialysis-dependent individuals.
Another contributor to persistent elevation of BP among dialysis patients includes erythropoietin-stimulating agents (EPO), provoking elevations in blood pressure in both normotensive and hypertensive individuals. Although the effect is both dose and hemoglobin-target dependent, it cannot be simply explained by elevated blood volume because increases in red blood cell volume trigger compensatory reductions in plasma cell volume such that total blood volume remains unchanged. Putative pathways include endothelin-1 and enhanced adrenergic sensitivity.
Blood Pressure Goals in Chronic Kidney Disease
Treatment of hypertension in CKD is directed at two goals: prevention or slowing of CKD-progression and reducing the elevated cardiovascular morbidity and mortality seen among CKD patients. The target blood pressure for individuals with CKD has been established by KDIGO and the Expert Panel Report (also known as Joint National Committee Report [JNC 8]); in those with albuminuric CKD, goal blood pressure is 140/90 or lower mm Hg, and 130/80 or lower mm Hg in those with 300 mg per day or higher of albuminuria. Despite these recommendations, the efficacy of the tighter blood pressure target has failed to show additional slowing of CKD progression (at least in nondiabetic patients with advanced CKD). Conversely, post hoc analyses of all randomized trials have demonstrated a further reduction in cardiovascular mortality including heart failure, stroke, and coronary heart events in advanced CKD patients with blood pressure levels below 130/80 mm Hg in both those with and without diabetes.
Among dialysis patients, evidence for specific BP goals remain unclear given the paucity of randomized trials. As such, recommendations have been extrapolated from observational studies among dialysis patients and the larger hypertension literature. The most recent (2005) KDOQI guidelines for dialysis patients recommend a predialysis and postdialysis blood pressure of less than 140/90 mm Hg and 130/80 mm Hg, respectively, acknowledging a weak level of evidence and a recommendation based on expert opinion. More recent evidence suggests that blood pressure measurements obtained on the morning after dialysis are the most prognostic and reproducible.
Hypertension and Risk for Chronic Kidney Disease
Blood pressure has long been recognized as a manifestation and mediator of chronic kidney disease. Multiple retrospective studies have found that uncontrolled blood pressure is an independent predictor of CKD progression and the development of ESRD. The Multiple Risk Factor Intervention Trial (MRFIT) of over 12,000 men prospectively studied the effects of various interventions on the incidence of coronary artery disease, and by post hoc analysis, on progression to ESRD. Individuals developing ESRD had higher baseline mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) than individuals without ESRD (SBP 142 versus 135 mm Hg; DBP 93 mm Hg versus 91 mm Hg, both p < 0.001). For every increase in systolic blood pressure of 10 mm Hg, the hazard ratio of developing ESRD increased by a factor of 1.3. These results are even more remarkable considering those individuals with baseline diastolic blood pressure in excess of 115 mm Hg were excluded.
Studies in cohorts with CKD of any etiology confirm the above association. Among more than 200 patients from the Veterans Affairs hospital population, a systolic blood pressure of 150 or greater mm Hg carried a hazard ratio of 9.1 for progression to a renal endpoint. Furthermore, rates of progression to ESRD were a function of blood pressure control with incidence rates of 7.2%, 27.7%, and 71.4% among those with systolic pressures of less than 130 mm Hg, less than 150 mm Hg, and more than 150 mm Hg, respectively. Although the aforementioned studies focused on those with GFRs greater than 60 mL per minute (stages 1 to 3), studies of those with more advanced CKD show a similar association. An analysis of 4000 Canadian patients found participants’ GFR declined at a rate of more than 5.0 mL per minute over the study period in those with a mean blood pressure of 145/80 mm Hg compared with reductions in GFR of less than 2.2 mL per minute in those with pressures of 137/74 mm Hg.
CKD progression is even more rapid among those with diabetes and uncontrolled blood pressures ( Fig. 33.3 ). The reduction of endpoints in noninsulin-dependent diabetes mellitus with the angiotensin II antagonist losartan (RENAAL) trial examined the effects of losartan on renal outcomes among those with diabetic nephropathy (albuminuria ≥ 300 mg/g; serum creatinine 1.3 to 3.0 mg/dL). Baseline systolic blood pressure in excess of 160 mm Hg and pulse pressure greater than 70 mm Hg were both independently associated with progression to a doubling of serum creatinine, ESRD, or death. Additionally, the lower the blood pressure achieved the slower the progression of CKD ( Fig. 33.4A ) and to ESRD ( Fig. 33.4B ). There was no association between diastolic hypertension and renal outcome. Among the more than 1600 hypertensive patients with diabetic nephropathy enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT), the achieved systolic BP at study completion (average follow-up: 2.6 years) was the strongest predictor of renal outcomes. Those with a systolic blood pressure of more than 149 mm Hg saw a 2.2-fold increase in the risk of a doubling of serum creatinine or ESRD when compared with those with a systolic pressure of less than 134 mm Hg. Furthermore, progressive lowering of systolic BP to 120 mm Hg was associated with improved renal and patient survival, an effect independent of baseline renal function. Similar to data from the RENAAL trial, there was no correlation between diastolic BP and renal outcomes.
Magnitude of Blood Pressure Lowering and Chronic Kidney Disease Progression
Although the role of hypertension in the development and progression of CKD is well documented, tight control of high blood pressures has yet to be unequivocally linked to slowing the progression of CKD in either the diabetic or nondiabetic population. In the modification of diet in renal disease (MDRD) study, individuals with nondiabetic CKD (mean GFR 39 mL/min; mean proteinuria 1.1 g/d) were randomized to tight or usual mean arterial pressure (MAP) with achieved MAP of 91 mm Hg (125/75 mm Hg) or 96 mm Hg (130/80 mm Hg), respectively. After three years, the rate of GFR decline was identical in both arms at 11.5 mL per minute. However, among those with greater than 3 grams per day of proteinuria, GFR decline was 10.2 mL per minute in the usual blood pressure group but 6.7 mL per minute in those treated to the lower target. Upon an additional 6 years of passive follow-up, during which no blood pressure goal was specified and blood pressures were not measured, those randomized to the intensive arm were 33% less likely to require dialysis. However, this benefit was driven exclusively by lower rates of ESRD in those with at least 1 gram per day of proteinuria.
The African American Study of Kidney Disease (AASK), a trial that excluded those with diabetes, also evaluated the effects of intensive blood pressure control on CKD progression. Almost 1100 African Americans with a mean GFR of 46 mL per minute and 600 mg of proteinuria achieved a blood pressure goal of either 128/78 mm Hg (intensive therapy) or 141/85 mm Hg (usual care) with metoprolol, ramipril, or amlodipine. Over four years of follow-up, the rate of GFR decline was nearly identical in both groups at 2.1 mL per minute per year; there was no difference when stratified by antihypertensive agent. The ramipril efficacy in nephropathy-2 (REIN-2) tested a similar premise with ramipril in patients with immunoglobulin a nephropathy (mean GFR 35 mL/min; mean proteinuria 2.9 g/d). Achieved blood pressures were 130/80 mm Hg (intensive group) and 134/82 (usual care). Intensive blood pressure control failed to result in further slowing of GFR decline (mean decline 2.6 mL/min in both groups) over 18 months of follow-up, an outcome noted irrespective of degree of pretreatment proteinuria. In aggregate, the results of these studies indicate that control of blood pressure to less than 130/80 fails to further slow progression of nondiabetic CKD; however, there may be a modest benefit among those with proteinuria in excess of 2 to 3 grams per day. Moreover, unlike glycemic control there is no legacy effect of BP reduction on CVD outcomes.
The lack of prospective trials evaluating the effects of lower blood pressure targets on the progression of diabetic nephropathy has resulted in a limited understanding of optimal blood pressure goals. One trial evaluating patients with type I diabetes with nephropathy (mean creatinine 1.2 mg/dL; mean proteinuria 1.2 mg/dL) found that both those randomized to intensive (MAP: 92 mm Hg) or usual (MAP: 100 to 107 mm Hg) blood pressure experienced a yearly decline of 10% in GFR.
The appropriate blood pressure control (ABCD) trial has been the only attempt at prevention of CKD progression in type 2 diabetic patients. The study evaluated the effects of achieved blood pressure goals of 128/75 mm Hg (intensive) versus 137/81 mm Hg (usual care) among 500 normotensive individuals with type 2 diabetes, one-third of whom had diabetic nephropathy. After five years of follow up, no change in the rate of GFR decline was noted between groups. Moreover, the study was extended by 2.5 years and still no difference was noted, albeit both groups had very slow decline in glomerular filtration rate.
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