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.
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.
Reduction in Albuminuria
Despite the apparent lack of benefit of intensive BP lowering on CKD progression, there is consensus as to the salutary effects of albuminuria reduction associated with renal outcomes. Of note, there is considerable debate as to whether or not high albuminuria (formerly microalbuminuria; defined as 30 to 300 mg/day of urinary albumin excretion) indicates the presence of nephropathy ( Fig. 33.5 ). This is consistent with the Renin-Angiotensin System Study (RASS). It found that among normotensive normo-albuminuric patients with type I diabetes, angiotensin-converting enzyme inhibitor (ACEi) therapy suppressed albuminuria but angiotensin II receptor blocker (ARB) therapy increased it. However, neither therapy failed to alter morphologic progression of diabetic nephropathy, as documented by serial renal biopsy.
The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study further highlighted the limitations of microalbuminuria as a surrogate for kidney disease. Although the primary outcome was the rate of cardiovascular events in those randomized to benazepril/hydrochlorothiazide compared with benazepril/amlodipine, the prespecified secondary endpoint of progression to ESRD was less common in benazepril/amlodipine-treated patients, despite higher rates of albuminuria.
In contrast, very high albuminuria, that is more than 300 mg per day, is an unequivocal sign of renal parenchymal injury, a risk factor for CKD progression and a heightened rate of cardiovascular events. In a post hoc analysis of the aforementioned AASK trial, every two-fold increase in baseline proteinuria was associated with an 80% increase in the risk of progression to ESRD. Moreover, a strong association between the degree of proteinuria reduction during the first six months, and the progression to dialysis, was noted. Compared with patients who failed to achieve a reduction in proteinuria, those who achieved a 50% reduction had a slowing of progression to ESRD ( Table 33.1 ). Results from the MDRD study further reinforce this precept as only those with heavy proteinuria treated to an aggressive BP goal had a slowing of GFR decline.
| Slowing of Progression to Dialysis | No Change Over Control or Faster Progression to Dialysis | |
|---|---|---|
| 30%-35% Reduction in Proteinuria | No Proteinuria Reduction Monotherapy | 20%-35% Greater Reduction in Proteinuria vs. RAS |
| Captopril Trial | DHPCCB arm-IDNT | ALTITUDE |
| AASK | DHPCCB arm-AASK | ONTARGET |
| RENAAL | ACCOMPLISH | |
| IDNT | ||
Cardiovascular Risk Modification
Chronic kidney disease is as an independent risk factor for cardiovascular mortality with the risk proportionate to disease severity. As such, for risk stratification purposes, the KDOQI guidelines state that those with depressed GFRs should be considered high risk for cardiovascular events. The Systolic Blood Pressure Intervention Trial (SPRINT) was an open-label randomized control trial that evaluated the effects of intensive versus usual blood pressure control among 9300 patients at an increased risk of cardiovascular events (those with a history of stroke, coronary artery disease, or CKD) without diabetes. Those in the active arm achieved a systolic blood pressure of 121 mm Hg, and those in the standard treatment arm an SBP of 135 mm Hg. 75% and 55% of patients, respectively, were on RAAS blockade. Among the 28% of patients with CKD (mean GFR 48 mL/min per m 2 ), there was no difference between groups with respect to the prespecified outcomes of doubling of serum creatinine, progression to ESRD, or reduction in proteinuria over a follow-up of 3.3 years. There was also no reduction in cardiovascular events such as myocardial infarction, stroke, or death from a cardiovascular cause among this subgroup. Those treated to a tighter blood pressure control also had higher rates of syncope, acute kidney injury, and hypotension. Limitations include a short duration of follow-up and a mean age of only 68 years.
The excess cardiac event rates attributable to kidney disease also extend to those on dialysis with 50% of patient deaths related to cardiovascular disease, specifically, heart failure and sudden death. Despite this, the relationship between hypertension and mortality remains opaque as a result of the lack of prospective studies and inconsistent interstudy methodology. Because the overwhelming majority of studies are observational in nature, the influence of confounders, notably that of different classes of antihypertensive therapy, dialysis adequacy, and the possibility that predialysis hypertension may be a surrogate for interdialytic weight gain or compliance, cannot be excluded as the cause for differences in cardiovascular mortality. Moreover, variable duration of follow-up and a reliance on predialysis blood pressures as a measure of hypertension, render accurate interpretation of such studies challenging.
Among the more recent and larger positive studies, Mazzuchi and colleagues found both systolic and diastolic hypertension to be associated with heightened all-cause mortality. However, the study population excluded those who had been on dialysis for less than two years, thereby introducing considerable bias. By far the largest study, that of Port et al, found no relationship between predialysis blood pressure and mortality. Again, patients were included only if they had been on dialysis for one or more years. In contrast to the lack of consensus regarding systolic blood pressure and mortality, low diastolic pressures, defined as less than 60 to 70 mm Hg, appear to uniformly enhance all-cause mortality, a phenomenon also observed in nondialysis dependent individuals. Possible explanations include a high burden of comorbidities, myocardial dysfunction, and patient frailty. Finally, some data support the hypothesis that moderate levels of hypertension are cardioprotective, or, perhaps, simply a manifestation of more robust health. This paradox, that low blood pressure is associated with adverse outcomes and high blood pressure with survival, has been termed the reverse epidemiology of blood pressure among those with renal failure.
An analysis of 25,000 hemodialysis patients participating in the international Dialysis Outcomes and Practice Patterns Study (DOPPS) revealed an all-cause mortality hazard ratio of 1.14 for those with a predialysis systolic blood pressure of 110 to 119 mm Hg and 1.11 for pressures of 120 to 129 mm Hg, compared with a reference pressure of 130 to 139 mm Hg. Among hypertensive individuals, those with a predialysis systolic measurement of 150 to 159 mm Hg had a lower all-cause mortality (hazard ratio: 0.90) than the reference population; moreover, no correlation was noted between mortality and pressures in excess of 160 mm Hg. Similar U-shaped curves were noted for diastolic pressures, with a hazard ratio of 1.0 for predialysis values of 60 to 99 mm Hg. Other post hoc analyses have confirmed this observation, suggesting that low-normal predialysis blood pressures are a marker of a higher burden of comorbid conditions, rather than a deleterious effect from lowering pressures to these levels. Nonetheless, in the absence of prospective trials, confounding variables and the cause-effect relationship between blood pressure and mortality remain unclear.
Selection of Antihypertensive Agent
Volume Control in Chronic Kidney Disease
Given the salt-avid state characteristic of CKD, appropriately dosed diuretics remain the cornerstone of hypertension management and should be instituted irrespective of the detection of edema on physical exam. This is consistent with observational data that demonstrates an association between early expansion of extracellular fluid volume and cardiac remodeling in the predialysis CKD patient. In contrast to the dosing of most medications in patients with advanced CKD, diuretics require a higher dose to be effective, given decreased tubule delivery of such agents.
Before adding an antihypertensive medication to those on dialysis, optimization of the patient’s volume status is critical and results in normotension in greater than 85% of patients. The dry weight, the lowest blood pressure that does not result in symptoms of hypotension (rather than the absence of edema) should be sought. In the prospective randomized Dry Weight Reduction in Hypertensive Hemodialysis Patients (DRIP) study, additional ultrafiltration of 0.1 kg per 10 kg body weight per session resulted in a further 0.9-kg weight loss at one month with a decrease in blood pressure of 6.9/3.1 mm Hg by ambulatory monitoring versus control patients ( Fig. 33.6 ). Although participants in the DRIP trial benefited from a rapid decline in blood pressure, the presence of a lag phenomenon is well documented such that up to one month may be required to see an improvement in hemodynamic parameters. Although no direct evaluation of dry weight reduction on left ventricular (LV) mass has been undertaken, a study comparing six-nights per week hemodialysis versus conventional thrice-weekly sessions showed improvement in this parameter.
Agents That Modify the Renin-Angiotensin-Aldosterone System
As the presence of macroalbuminuria and the reduction therein has become an important consideration when selecting an antihypertensive, class differences among agents emerge. The best-studied and most effective agents are those that block the RAAS. As detailed earlier, ACEi and ARBs are effective antialbuminuric agents in kidney disease of any etiology. The aforementioned REIN-2 study, although not demonstrating the salutary effects of aggressive blood pressure control on CKD progression over 36 months of follow-up, indicated that those on ramipril therapy had significantly lower rates of GFR decline (0.53 mL/min versus 0.88 mL/min per month). Furthermore, the ramipril group demonstrated significant reductions in albuminuria that continued to improve over time: 23% reduction at 1 month of treatment, 33% at 12 months, and 55% at 36 months. This benefit was independent of blood pressure control. Similarly, the Captopril Trial evaluated the effect of an ACEi compared with placebo on progression of nephropathy among those with insulin-dependent diabetes. Patients randomized to placebo experienced a 17% decline in creatinine clearance compared with 11% in the captopril arm. Doubling of creatinine occurred in 43% of placebo-treated patients versus 25% receiving captopril over three years of follow-up. The largest benefit was seen in those with the most advanced stages of CKD.
Angiotensin receptor blockers appear to carry a similar benefit. The ARB irbesartan was studied in a randomized controlled trial of patients with hypertension and diabetic nephropathy. Compared with amlodipine and placebo, irbesartan reduced proteinuria to a greater degree and was associated with a 30% to 35% lower risk of doubling of serum creatinine compared with placebo or amlodipine. The risk reduction was not explained by differences in blood pressure. Similarly, the previously cited RENAAL study examined the effect of losartan versus placebo in patients with type 2 diabetes and greater than 300 mg of albuminuria per day. Individuals treated with losartan achieved a 16% risk reduction of progressing to the primary endpoint of doubling of serum creatinine and an absolute, 35%, reduction of proteinuria. As in the study examining irbesartan, the benefit was not explained by differences in blood pressure.
The renin inhibitor, aliskerin, was tested for both blood pressure reduction and renal outcomes in combination with the ARB, valsartan. Nearly 1150 hypertensive participants with type 2 diabetes and stage 1 or 2 CKD were randomized to receive the combination of aliskiren/valsartan 150/160 mg or valsartan 160 mg monotherapy for 2 weeks, with force-titration to 300/320 mg and 320 mg, respectively, for another 6 weeks. Changes in ambulatory blood pressure (ABP), the primary outcome, were available for 665 participants. Reductions from baseline to week 8 in 24-hour ABP were −14.1/−8.7 mm Hg with aliskiren/valsartan versus −10.2/−6.3 mm Hg among those on valsartan monotherapy. Although adverse events were noted in one-third of participants in both groups, no subject developed acute kidney injury or a serum potassium in excess of 6.0 mEq/L.
In contrast, the Aliskerin Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) Trial evaluated the aforementioned dual therapy on cardiovascular and renal outcomes. Although there was superior proteinuria reduction among those patients on combination therapy, the trial was terminated prematurely because of significantly higher incidence of hyperkalemia, acute kidney injury, and hypotension. Moreover, there was a trend toward worse cardiovascular outcomes in those on dual therapy. It is worthwhile to note that the mean eGFR in the ALTITUDE trial was below 45 mL per minute.
In addition to the ALTITUDE trial, other trials have failed to uniformly support a direct link between reduction of proteinuria and improved renal outcomes. The Gauging Albuminuria Reduction with Lotrel in Diabetic Patients with Hypertension (GUARD) study tested the combination of benazepril with either hydrochlorothiazide or amlodipine on the degree of urinary protein reduction and blood pressure decline among diabetics. Despite twice the proteinuria reduction in the diuretic arm, progression to overt nephropathy was similar between groups. As a prespecified secondary analysis of the aforementioned ACCOMPLISH trial, those at high risk for a cardiovascular event were randomized to the combination of either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. Ten percent of the 11,000 enrolled patients suffered from chronic kidney disease, more than half of which was attributed to diabetes. Over a 3-year period, those randomized to the ACEi with calcium channel blocker (CCB) arm achieved only half as much proteinuria reduction, yet the rate of progression to renal endpoints such as ESRD or a doubling of serum creatinine was also 50% less.
Further enthusiasm for maximal proteinuria reduction has been tempered by a series of high quality trials demonstrating double RAAS blockade, while further reducing proteinuria, does so at the cost of hyperkalemia, hypotension, and increased rates of acute kidney injury. The Ongoing Telmisartan Alone or in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the first large (>15,000 participants) study to compare ramipril with combination therapy with telmisartan on cardiovascular events among those with diabetes or vascular disease. Although there was no difference in the number of cardiac endpoints reached between groups, the incidence of hyperkalemia, hypotension, and renal impairment was significantly more common in those assigned to combination therapy. The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial/study specifically evaluated the effects of combination therapy with lisinopril and losartan on renal outcomes such as GFR and progression to ESRD. The trial was halted early because despite improvements in levels of proteinuria, patients randomized to ARB plus ACEi therapy experienced more hyperkalemia and acute kidney injury. Moreover, there was also a trend toward worse renal outcomes compared with placebo-treated patients. In summary, the current evidence strongly supports the use of ACEi or ARB monotherapy to achieve proteinuria reduction as a means of slowing CKD progression. However, combination therapy to further reduce proteinuria, be it by double RAAS blockade or with diuretic therapy, paradoxically appears to hasten CKD progression or results in additional short-term adverse events.
Aldosterone antagonists such as spironolactone and eplerenone have grown in popularity as a means of achieving further reductions in albuminuria when used as add-on therapy among those treated with ACEi or ARB monotherapy. Physiologic grounds for their use is derived from the agents’ ability to halt the aldosterone escape that occurs despite treatment with RAAS blockade. This lack of suppression of the aldosterone escape pathway has been linked to persistent declines in GFR. Evidence for the antiproteinuric effects of spironolactone have been demonstrated in both diabetic and nondiabetic populations. In a randomized controlled trial of 80 individuals with persistent diabetic nephropathy (mean GFR 65 mL/min; mean albuminuria 1.0 g/d) despite lisinopril (80 mg) monotherapy, either spironolactone (25 mg), losartan (100 mg), or placebo were instituted as add-on therapy. As shown in Fig. 33.7 , at 2-year follow-up, only spironolactone therapy resulted in a statistically significant reduction (34%) in urinary protein excretion. Of note, nearly 50% of patients in both arms had at least one serum potassium in excess of 6.0 mEq/L. Using the selective mineralocorticoid receptor blocker eplerenone, 275 diabetics with a GFR of 75 mL per min and 300 mg of albuminuria were randomly assigned to enalapril monotherapy or dual therapy with eplerenone (doses: 50 to 100 mg/day). At three months, albuminuria had decreased by 41% and 48%, respectively. However, 10% of those on low-dose and 25% on high-dose eplerenone were noted to have a serum potassium greater than 6.0 mEq/L.
