Abnormal blood pressure dipping in diabetic kidney disease: A black‐race nightmare?

Diabetic kidney disease (DKD) is the leading cause of end‐stage renal disease and renal replacement therapy worldwide.1 Despite the proportional stability of patients with diabetes mellitus who have this microvascular complication, there is an increase in absolute number of patients with DKD, as diabetes mellitus has become progressively more prevalent over the past decades.2 Accumulating data suggest that patients with DKD are at increased risk for cardiovascular disease and mortality. A post hoc analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron‐MR Controlled Evaluation) study3 (conducted among 10 640 individuals with type 2 diabetes mellitus) evaluated the impact of albuminuria and estimated glomerular filtration rate (eGFR) level on cardiovascular and renal outcomes. It was observed that both macroalbuminuria and eGFR <60 mL/min/1.73 m² were associated with a significant 3.2‐fold increase in cardiovascular adverse events. Specifically, every halving of eGFR level and 10‐fold increase in urine albumin to creatinine ratio resulted in a statistically significant increase in cardiovascular events with a hazard ratio of 2.48 and 2.20, respectively. Moreover, in a post hoc analysis of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) blood pressure (BP) arm, it was found that DKD was significantly associated with a higher risk for cerebrovascular events compared with participants free of nephropathy,4 featuring a stroke incidence of 0.66% and 0.28% per year, respectively.

Currently, several significant differences in the prevalence, pathophysiology, risk stratification, and management of cardiovascular, metabolic, and renal disorders have been identified between individuals of black and white race.5, 6 The International Society of Hypertension in Blacks6 stated that black persons are more prone to BP‐related cardiovascular and renal complications such as left ventricular hypertrophy, heart failure, stroke, chronic kidney, and end‐stage renal disease. Moreover, black patients with hypertension have target organ damage to a greater extent than white patients with hypertension.6 Type 2 diabetes mellitus, chronic kidney disease, and obesity are also more prevalent in blacks.7, 8, 9 Importantly, a higher death rate from hypertension was found in black vs white individuals (>41 vs 15.1 per 100 000 persons, respectively).10 Race also influences the efficacy of different antihypertensive agents.11 Particularly, calcium channel blockers and diuretics result in a greater reduction in BP levels than renin‐angiotensin system inhibitors and β‐blockers in blacks, potentially attributable to the salt‐sensitive profile of such patients. Thus, a calcium channel blocker or a diuretic as monotherapy or in combination with an angiotensin‐converting enzyme inhibitor or an angiotensin receptor blocker is recommended for the initiation of antihypertensive treatment in blacks6, 11 even if an individualized antihypertensive strategy is preferred.

Several hypotheses have been proposed to explain the abovementioned disorders in blacks, including socioeconomic, educational, physical activity, dietary, environmental, and genetic factors, as well pathogenetic mechanisms (eg, salt sensitivity and suppressed plasma renin activity, vascular abnormalities, and abnormal diurnal BP variation).6 Normal diurnal BP variation is characterized by a decrease in nocturnal systolic and diastolic BP of 10% to 20% of daytime levels and so‐called dipping status.12 A lower decrease or even increase in nighttime BP values, which in everyday clinical practice could be identified by ambulatory BP monitoring (ABPM), is called nondipping and rising or reverse‐dipping status, respectively.12 Both conditions are characterized by enhanced hypertension‐related target organ damage and cardiovascular morbidity and mortality. In a meta‐analysis of 16 perspective studies of 23 853 patients with hypertension who underwent ABPM, the risk of cardiovascular events and total mortality was evaluated.13 After adjustment for a wide cluster of traditional risk factors, nondipping status was significantly associated with a higher risk of cardiovascular events (hazard ratio, 1.29; 95% confidence interval, 1.12–1.48) and total mortality (hazard ratio, 1.26; 95% confidence interval, 1.11–1.44).

It is well established that black individuals are more likely to exhibit a nondipping pattern than white individuals, irrespective of the presence of hypertension.6, 14 In a post hoc analysis of the AASK (African American Study of Kidney Disease Cohort) trial15 which included 617 black patients with hypertension and nondiabetic chronic kidney disease, it was found that 80% of the participants were nondippers. These findings arose concerns about whether the increased cardiovascular and target organ damage in blacks could be attributed to nondipping status and generated expectations of ameliorating the management of such patients who are commonly treated in primary care units.

In the current issue of the Journal, Zullig and colleagues16 conducted a cross‐sectional analysis of the baseline data from STOP‐DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) study, in order to assess racial differences in diurnal BP variation among individuals with DKD. A total of 108 participants with type 2 diabetes mellitus, DKD (eGFR >45 mL/min/1.73 m²), and poorly controlled hypertension sufficiently underwent 24‐hour ABPM evaluation and were included in the analysis. Approximately 49% of the participants were black and 58% were men. It was found that more than half were nondippers (n=58), 22% were reverse dippers, and only 24% were dippers. Moreover, blacks had a significantly higher daytime and nighttime diastolic (but not systolic) BP level by 3 mm Hg and 5.1 mm Hg, respectively. Women were more likely to be dippers than men (33.3% vs 17.5%; P=.01), whereas men were more frequently reverse dippers than women (31.7% vs 8.9%; P=.01). Participants who were defined as dippers had a substantially lower overall and sleeping systolic BP (P=.04 and P<.01, respectively), as well lower sleeping diastolic BP (P<.01). Of great importance, blacks were found to have a higher risk of being nondippers or reverse dippers than whites (odds ratio, 2.63; 95% confidence interval, 1.19–5.83). In addition, men were more commonly reverse and nondippers than women, and this became more obvious in the presence of eGFR values <60 mL/min/1.73 m². Last, black race, male sex, and eGFR <60 mL/min/1.73 m² were associated with a lower decrease rate in systolic BP from wake to sleep compared with white race, female sex, and higher eGFR values, respectively (by 3.32%, P=.02; 3.98%, P<.01; and 5.39%, P<.01, respectively).

The study by Zullig and colleagues is an interesting clinical study that addresses dipping status in the settings of DKD, unveiling a high prevalence of reverse dipping and nondipping status (in total 76%) and significant racial differences in the diurnal BP variance.16 The findings of the study underline the need for a wider use of ABPM in primary care. In addition, data confirm the greater cardiovascular and hypertension‐related target organ damage of blacks and suggests that certain pathophysiological mechanisms could be potentially implicated in these deteriorations. The punctilious design of the study by using an adequate ABPM procedure, excluding patients with poor medication adherence, and the conduction of the trial in a DUKE center that guaranties high scientific standards are significant strengths of the study. However, there are several limitations in the analysis by Zullig and colleagues. First, the small sample size limits the generalization of their study findings. Second, the poorly controlled hypertension of participants raises concerns about adequate antihypertensive treatment. Specifically, factors that could affect the outcomes include the use of an inadequate number and dosage of antihypertensive agents, inappropriate combinations, and drugs without 24‐hour activity. Finally, given that extreme dipping status, defined as a decrease in nighttime BP of >20%, exerts relatively unknown effects on cardiovascular risk,12 it would be preferable if a separate group of extreme dippers was included in the analysis.

Collectively, the study findings highlight the necessity for ABPM in patients with poorly controlled hypertension and in individuals with high cardiovascular risk (such as patients with DKD). Future randomized clinical trials need to be conducted in order to investigate whether these findings could lead to optimizing the management of hypertension and cardiovascular risk by testing alternative strategies such as the nighttime administration of antihypertensive agents, especially in black individuals and patients with DKD.

CONFLICTS OF INTEREST

The authors report no specific funding in relation to this research and have no conflicts of interest to disclose.

Stavropoulos K, Imprialos KP, Doumas M. Abnormal blood pressure dipping in diabetic kidney disease: A black‐race nightmare? J Clin Hypertens. 2017;19:1336–1338. 10.1111/jch.13078