In addition to these above changes, reduced GFR in elderly likewise results in impaired natriuresis, thereby fostering hypertension via volume expansion. Age-related arteriolosclerosis may result in renal artery stenosis, resulting in decreased renal perfusion and upregulation of the renin-angiotensin-aldosterone cascade. Further challenging treatment decisions is the frequent development of autonomic dysregulation in the elderly, a major risk factor for falls and cardiovascular events [40].
The result of these abnormalities is that roughly 65% of patients greater than the age of 60 have at least isolated systolic hypertension [42]. Similarly corresponding to the underlying physiology highlighted above, rising pulse pressure, rather than systolic or diastolic blood pressure, appears to be the greatest risk factor for cardiovascular events in the elderly population [43,44]. In an interesting analysis of the Framingham Heart Study by Franklin et al, the authors noted that in patients < 50 years of age, diastolic blood pressure was the strongest risk factor for events. However, at age 50 to 59, a change occurred where all 3 blood pressure indexes were comparable risk predictors, and then from age 60 years and on pulse pressure became the superior predictor, with diastolic blood pressure being negatively correlated to cardiovascular risk, highlighting the potential importance for organ perfusion during diastole in this group [45].
Likewise, in the elderly population pulse pressure also appears to be inversely related to GFR, suggesting that vascular stiffness and the reduced forward flow in diastole may contribute to microvascular damage and CKD [46]. In elderly patients with untreated isolated systolic hypertension, increasing systolic blood pressure (a reflection of rising pulse pressure) was associated with the greatest risk of renal decline when compared to diastolic blood pressure, pulse, and mean arterial pressure [47]. In the normal state, high renal blood flow and low renal arterial resistance can contribute to regular large intrarenal pressure variations. Because of vascular stiffness, these pressure variations increase with time, increasing up to 4-fold in the elderly compared with young peers, and likely contribute to renal damage seen in older patients [48].
Treatment
In comparison to the paucity of randomized trials examining CKD progression in the elderly, 4 very large, well designed randomized trials (SHEP, MRC trial, Syst-Eur trial, and HYVET) specifically examining the treatment of hypertension in the elderly have now been conducted [14–17] and confirmed earlier and smaller trials demonstrating the benefits of treatment of hypertension in the elderly [49,50]. In addition to this, several of the other large landmark hypertension trials such as ALLHAT, ACCOMPLISH, and the SPRINT trial included a considerable number of elderly patients [51–53]. Though the primary aim of those trials was not to determine the effects of hypertension treatment in the elderly per se, sub-analysis of this population in these trials has further added to our knowledge of this condition.
In the largest initial trial of hypertension in the elderly (SHEP), the researchers randomized 4376 patients over the age of 60 with an average blood pressure of 170/77 mm Hg into a treatment versus placebo arm. Such a study would be inconceivable today due to the consistent benefit derived from antihypertensive therapy now demonstrated in multiple trials. An achieved systolic blood pressure of 143 mm Hg in the treatment arm versus 155 mm Hg in the placebo arm was obtained. Stroke and nonfatal cardiac events were significantly reduced with treatment. The development of renal dysfunction occurred in 7 patients in the treatment arm and 11 patients in the placebo arm, a nonsignificant difference. As we have noted previously, however, patients with pre-existing kidney disease were excluded from the study [14]. A subsequent analysis of the SHEP trial results by Vaccarino et al, however, showed that in patients on treatment who developed an increase in pulse pressure of 10 mm Hg or more carried a 23% higher risk for developing heart failure and a 24% higher risk for stroke. This effect was not seen in the placebo arm [39].
Shortly following the publication of the SHEP results, the Medical Research Council trial of treatment of hypertension in older adults (MRC) further confirmed the initial findings by demonstrating a 25% reduction in stroke and a 17% reduction in all cardiac events in 4396 patients aged 65 to 74 with a systolic blood pressure greater than 160 mm Hg randomized to treatment of hypertension with either atenolol or a diuretic combination of amiloride and hydrochlorothiazide versus placebo. Like SHEP, however, patients with pre-existing renal disease were excluded, and no report of renal outcomes was published in the initial results [15]. Similarly, the Systolic Hypertension in Europe Trial (Syst-Eur) revealed a 42% reduction in stroke and a 26% reduction in all cardiac endpoints in 4695 patients with a systolic blood pressure of greater than 160 mm Hg randomized to receive nitrendipine with addition of enalapril and hydrochlorothiazide as required. However, CKD patients were likewise excluded in this trial [16].
Finally, the Hypertension in the Very Elderly Trial (HYVET) was unique in that it sought to enroll only patients greater than 80 years of age, a significant departure from the earlier hypertension in elderly trials. This trial randomized 3845 patients, again with a systolic blood pressure of 160 mm Hg or greater, to a placebo arm versus a treatment arm of the thiazide type diuretic indapamide, with addition of the ACE inhibitor perindopril if blood pressure was still greater than 150 mm Hg on monotherapy. Despite the older age of the participants in this trial, patients still benefited from blood pressure reduction with a 30% reduction in rate of stroke, a 21% reduction in the rate of death from any cause, and an impressive 64% reduction in the rate of heart failure [17]. These findings from HYVET, combined with the earlier SHEP, MRC and Syst-Eur trials, confirmed that treatment of hypertension in the elderly of any age should be attempted.