What is the first line medication therapy for a patient with chronic kidney failure?

Chronic kidney disease [CKD] is increasingly prevalent, with an estimated 26 million adults with CKD in the US.1 Hypertension is the most common comorbidity in chronic kidney disease. At least 85% of patients with stage 3 CKD or greater have hypertension, making parenchymal kidney disease the most common ‘secondary’ form of hypertension. Treatment of hypertension can often be challenging, as these patients often have severe hypertension requiring the use of multiple medications to achieve target blood pressure [BP] goals. Target BP goals are lower in patients with CKD than in the general population. Ideally, BP should be less than 130/80mmHg and less than 125/75mmHg if patients also have significant proteinuria [>1g/ 24 hours].

Hypertension is very common in CKD, with more than 80% of CKD patients having coexistent hypertension. Patients with more severe CKD are more likely to have more severe hypertension2 that is more difficult to control, requiring a greater number of medications. Conversely, patients with more severe hypertension are more likely to develop CKD.3 The type of renal disease also influences the likelihood of hypertension, and classically tubulo-interstitial diseases have had less prevalence of elevated BP than glomerular diseases.4

A large and growing number of factors influence BP regulation in CKD, as shown in Table 1. Most of the increase in BP results from a subset of three primary systems, which include:

• salt retention;
• renin–angiotensin–aldosterone axis activation; and
• sympathetic nervous system activation.

These factors are all potentially treatable and the physician should take these into account when selecting medications in CKD patients.

Volume expansion is common in hypertension of CKD. As renal function declines, so does the ability to excrete sodium. If heart failure occurs, this adds to the challenge of maintaining euvolemia. Sodium increases BP, so as kidney function declines it does so to an even greater extent than simple volume expansion would predict at the lowest levels of kidney function.5 This finding suggests that the effect of salt intake on BP as further kidney function loss occurs is likely to be enhanced by the CKD milieu. Moreover, salt administration is well known to abet the pro-hypertensive effects of angiotensin-II6 and norepinephrine.7

The renin–angiotensin system plays a major role in hypertension, especially in patients with CKD. This is clear in the antihypertensive response to both ACE inhibitors and angiotensin II receptor blockers [ARBs] in patients with CKD. Aside from the hemodynamic consequences of renin activation, the excess angiotensin II produced probably contributes to progressive renal function loss and other target organ damage. It does this through its stimulation of aldosterone release, potentiation of the effects of various growth factors, and, in particular, its stimulating effects on the fibrogenic cytokine transforming growth factor-β.8,9

Some of the increase in renin system activation may be the result of sympathetic input into the juxtaglomerular apparatus through the β1-adrenoreceptor.6 The sympathetic nervous system also appears to be overactive in CKD.10 Like the renin–angiotension system, the kidney is both the source and the recipient of neurogenic activity.11 There is a fairly extensive network of sensory nerve fibers in the kidney, and many laboratory data indicate that sympathetic activation plays a role in hypertension in CKD through direct vascular constriction and the aforementioned interactions with renin and salt. The recent investigation showing that renal sympathetic nerve ablation improves BP control in drug-resistant hypertension is further evidence of the importance of this system.12 Several other systems are also active to a pathological degree in some patients with CKD. Among those amenable to potential drug treatment are endothelin13 and aldosterone.14 Finally, there is also some progress on the genetic front. Several rare phenotypes in which the kidney and hypertension are linked have been described, shedding light on important intra-renal BP regulation pathways.15 Aside from diagnostic value, there has been little benefit achieved to date from genetic studies with respect to guiding intervention.

The evaluation of patients with hypertension and CKD requires some additional consideration aside from the standard hypertensive work-up suggested by JNC-716, in the following ways:

• In addition to the usual history taken for determining primary versus secondary hypertension, target organ damage, and presence of other cardiovascular risk factors,17 historical details should focus on prior drug therapies and why they were stopped. This should include issues such as drugs that caused hyperkalemia, worsening renal function, edema or dyspnea, and intolerable side effects.
• In addition to the usual exam findings that may suggest secondary forms of hypertension, document the presence of rales, presence of an S3, pedal edema, and carotid bruits. These findings are more common in CKD patients, and their subsequent clinical course may guide diuretic management.
• In addition to the standard lab tests [detailing target organ damage, suggesting secondary hypertension, or reflecting drug side effects], consider checking for presence/degree of anemia. Proteinuria should also be quantified since erythropoietin [which can raise BP] may be necessary and because the antihypertensive benefits and treatment goals of intervention are more impressive and lower, respectively, when proteinuria is present.18

The importance of hypertension in CKD rests on two management principles. The first principle is that hypertension confers a substantial risk for heart disease, stroke, peripheral arterial disease, and further kidney failure.16 This risk is amplified when proteinuria is present.19 The second is that although hypertension ranks technically as the second most common cause of end-stage renal disease behind diabetes, it is clear that the majority of patients with diabetes and CKD also have hypertension. Therefore, the decision to lower BP in CKD is undertaken to preserve target organ function on several fronts. Moreover, it is more likely that a CKD patient will die from heart disease than reach end-stage renal disease.20 Therefore, it is critical to adequately manage hypertension in CKD, as this plays a central role in reducing the likelihood of developing cardiovascular disease.

Restricting dietary sodium intake to 2,400mg/day is strongly recommended. So is weight loss [in the overweight] or weight management [in those not overweight], frequent physical activity, and restricting alcohol intake to a maximum of two drinks/day for men and one drink/day for women.16 The Dietary Approaches to Stop Hypertension [DASH] diet is often recommended.21 The greatest experience in this intervention category is with salt-intake reduction. In addition to helping to control BP, reducing salt intake can enable better reduce proteinuria when present22 and perhaps slow progressive kidney function loss.23

The first step is defining the goal BP. This is recommended by both JNC-7 and the National Kidney Foundation as 130/80mmHg or less in patients with CKD.16 A lower BP of 125/75mmHg is recommended in patients with CKD and more than 1g of proteinuria/24 hours.24

Figure 1 represents a useful scaffold for sorting pharmacological therapy into a physiological approach to BP reduction. There are four basic inter- related mechanisms by which BP is regulated. Most drug therapies principally address one of these influences. Hypertension associated with CKD frequently requires treatment that addresses several of these mechanisms. It is not uncommon for patients to require three or four drugs, and sometimes even more, to achieve BP goals. BP goals are based on risk stratification from JNC-6:25