Blood pressure of <120/70 mm Hg linked to lower risk of chronic kidney disease, macroalbuminuria
For patients with type 1 diabetes, blood pressure (BP) of <120/70 mm Hg is associated with a substantially reduced risk of adverse renal outcomes, according to a study published online Nov. 21 in Diabetes Care.
Elaine Ku, M.D., from the University of California in San Francisco, and colleagues compared BP levels and their association with the risk of renal outcomes among 1,441 participants with type 1 diabetes aged 13 to 39 years who had been randomized to receive intensive versus conventional glycemic control. Time-updated systolic BP (SBP) and diastolic BP (DBP) were the exposures of interest.
The researchers identified 84 cases of stage III chronic kidney disease (CKD) and 169 cases of macroalbuminuria during a median follow-up of 24 years. Compared with SBPs between 130 and 140 mm Hg, SBP in the <120 mm Hg range correlated with a 0.59 times risk of macroalbuminuria and a 0.32 times risk of stage III CKD, in adjusted models. Compared with DBPs between 80 and 90 mm Hg, DBP in the <70 mm Hg range correlated with a 0.73 times risk of macroalbuminuria and a 0.47 times risk of stage III CKD. There was no interaction between BP and glycemic control strategy.
"A lower BP (<120/70 mm Hg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy," the authors write.
OBJECTIVE To compare different blood pressure (BP) levels in their association with the risk of renal outcomes in type 1 diabetes and to determine whether an intensive glycemic control strategy modifies this association.
RESEARCH DESIGN AND METHODS We included 1,441 participants with type 1 diabetes between the ages of 13 and 39 years who had previously been randomized to receive intensive versus conventional glycemic control in the Diabetes Control and Complications Trial (DCCT). The exposures of interest were time-updated systolic BP (SBP) and diastolic BP (DBP) categories. Outcomes included macroalbuminuria (>300 mg/24 h) or stage III chronic kidney disease (CKD) (sustained estimated glomerular filtration rate <60 mL/min/1.73 m2).
RESULTS During a median follow-up time of 24 years, there were 84 cases of stage III CKD and 169 cases of macroalbuminuria. In adjusted models, SBP in the <120 mmHg range was associated with a 0.59 times higher risk of macroalbuminuria (95% CI 0.37–0.95) and a 0.32 times higher risk of stage III CKD (95% CI 0.14–0.75) compared with SBPs between 130 and 140 mmHg. DBP in the <70 mmHg range were associated with a 0.73 times higher risk of macroalbuminuria (95% CI 0.44–1.18) and a 0.47 times higher risk of stage III CKD (95% CI 0.21–1.05) compared with DBPs between 80 and 90 mmHg. No interaction was noted between BP and prior DCCT-assigned glycemic control strategy (all P > 0.05).
CONCLUSIONS A lower BP (<120/70 mmHg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy. Interventional trials may be useful to help determine whether the currently recommended BP target of 140/90 mmHg may be too high for optimal renal protection in type 1 diabetes.
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The Joint National Committee and American Diabetes Association guidelines currently recommend a blood pressure (BP) target of <140/90 mmHg for all adults with diabetes, regardless of type (1–3). However, evidence used to support this recommendation is primarily based on data from trials of type 2 diabetes (4–6). The relationship between BP and adverse outcomes in type 1 and type 2 diabetes may differ, given that the type 1 diabetes population is typically much younger at disease onset, hypertension is less frequently present at diagnosis (3), and the basis for the pathophysiology and disease complications may differ between the two populations.
Prior prospective cohort studies (7,8) of patients with type 1 diabetes suggested that lower BP levels (<110–120/70–80 mmHg) at baseline entry were associated with a lower risk of adverse renal outcomes, including incident microalbuminuria. In one trial of antihypertensive treatment in type 1 diabetes (9), assignment to a lower mean arterial pressure (MAP) target of <92 mmHg (corresponding to ∼125/75 mmHg) led to a significant reduction in proteinuria compared with a MAP target of 100–107 mmHg (corresponding to ∼130–140/85–90 mmHg). Thus, it is possible that lower BP (<120/80 mmHg) reduces the risk of important renal outcomes, such as proteinuria, in patients with type 1 diabetes and may provide a synergistic benefit with intensive glycemic control on renal outcomes (10–12). However, fewer studies have examined the association between BP levels over time and the risk of more advanced renal outcomes, such as stage III chronic kidney disease (CKD) or end-stage renal disease (ESRD), during long-term follow-up. One recent report (13) in a large cohort of patients with type 1 diabetes with established diabetic nephropathy indicated that survival has improved and the loss of renal function has diminished over time, along with better control of modifiable risk factors such as BP. Given the typical long duration before the onset of more serious renal complications in type 1 diabetes, the use of observational data to help support or refute the potential use of future BP-lowering trials on the risk of renal outcomes would be useful in this population.
The primary objective of this study was to determine whether there is an association between lower BP levels and the risk of more advanced diabetic nephropathy, defined as macroalbuminuria or stage III CKD, within a background of different glycemic control strategies using data from the Diabetes Control and Complications Trial (DCCT). We hypothesized that exposure to BPs <120/80 mmHg would be associated with a lower risk of macroalbuminuria and CKD and that there would be a stepwise increase in the risk of adverse renal outcomes with stepwise increases in BP levels. We also hypothesized that the association of BP and outcomes would be weaker in participants formerly assigned to receive intensive glycemic control during the DCCT.
The primary objective of this study was to determine the stepwise association between lower BPs (to levels <120/80 mmHg) and the risk of adverse renal outcomes. We also aimed to determine whether exposure to intensive glycemic control would modify any benefit associated with lower BPs. We hypothesized and found that SBPs <120 mmHg were associated with a statistically significant lower risk of our primary outcomes of macroalbuminuria and incident stage III CKD compared with reference BPs in the range of 130 to <140 mmHg range. DBPs <70 mmHg trended toward lower risk of macroalbuminuria and stage III CKD, although this finding did not achieve statistical significance. Contrary to our hypothesis, these results were independent of assigned glycemic control strategy during DCCT or achieved hemoglobin A1c levels during the DCCT and EDIC. We also found that lower BPs were associated with a lower risk of microalbuminuria and milder declines in renal function.
Recently, both the Joint National Committee and the American Diabetes Association revised recommendations for BP targets in patients with type 1 and type 2 diabetes from <130/80 to <140/90 mmHg (1,2,17). The rationale for this change stemmed primarily from the lack of solid trial-based evidence to support the benefit of a lower BP target in patients with diabetes (1,2). For example, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, intensive BP lowering (to an SBP goal of 120 vs. 140 mmHg) did not reduce the risk of a composite outcome of cardiovascular events and death among patients with type 2 diabetes (6). However, few trials have been conducted to test the benefit of alternate BP targets on the risk of adverse renal outcomes in the type 1 diabetes population. It is possible that patients with type 1 diabetes could have a different association between BP level and renal outcomes compared with patients with type 2 diabetes, given the younger age of disease onset, the earlier diagnosis, and the lower prevalence of comorbidities, such as obesity at the time of type 1 diabetes onset (18). In the absence of randomized controlled trials on outcomes, such as incident CKD in type 1 diabetes, the observational data in DCCT and EDIC could serve to provide support for the conduct of interventional trials to further test the hypothesis that tight BP control would delay the onset and progression of clinical renal disease in this population.
In randomized controlled trials of normotensive persons (defined as DBP of <90 mmHg) with type 1 diabetes treated with RAAS blockade, persons randomized to receive RAAS blockade (who achieved a 3–7 mmHg lower BP compared with the placebo arm) had a lower risk of worsening overt proteinuria, thus suggesting the benefit of lower BP levels on renal outcomes (19,20). Another small trial demonstrated a benefit to lowering MAP to <92 mmHg (corresponding to ∼125/75 mmHg) on the reduction of proteinuria (mean 535 mg/24 h vs. 1,723 mg/24 h in the MAP target of 100–107 mmHg) but not on renal function decline during 2 years of follow-up (9). Observational studies (21) have shown that persistent microalbuminuria is more likely to develop in normotensive normo-albuminuric patients with higher baseline BP values who have type 1 diabetes during follow-up. Elevations in SBP during sleep have been found to precede the onset of microalbuminuria in otherwise normotensive normoalbuminuric adolescents and young adults with type 1 diabetes (21–23).
Our study expands upon the results from prior studies by providing data from a larger and well-characterized population on the risk of more advanced renal end points, including stage III CKD, during nearly 30 years of follow-up. Our study is also unique in the use of time-updated BPs and hemoglobin A1c measures, which may reduce the misclassification bias of BP status and glycemic control during long-term follow-up. In fact, we found that baseline SBP and DBP values at DCCT entry were poorly predictive of the long-term risk of adverse renal outcomes in our study (24–27).
Multiple follow-up studies using the DCCT/EDIC cohort (10–12,24) have demonstrated the importance of glycemic control in preventing long-term renal sequelae, including the onset of hypertension, microalbuminuria, macroalbuminuria, and CKD. It is plausible, however, that intensive glycemic control and BP control may provide synergistic and additive renal protection in patients with type 1 diabetes. The results of animal studies (25,26) have suggested an additive interaction between diabetes and hypertension, in which both contribute to enhanced vascular permeability to albumin and monocyte adhesiveness to the endothelium (a first step in atherogenesis). Our study suggests that even in participants who had been previously exposed to intensive glycemic control, lower BP was still associated with a lower risk of adverse renal outcomes. We believe this finding to be important, as the traditional focus in type 1 diabetes research and clinical practice has been on the effects of intensive glycemic control (10,11). We would suggest that our finding between lower BP and renal outcomes supports the need for future interventional studies, because BP treatment may be less costly and more achievable than other treatment options.
The large effect size of lower BPs observed in our study may be due to the long duration of follow-up, and the accurate assessment of both the predictor of interest and other confounding factors that are likely to change over time, such as antihypertensive use, hemoglobin A1c level, and BMI, all of which were prospectively collected per the research protocol.
When restricting our analyses to the duration of follow-up when patients actively received antihypertensive drug therapy, we
observed similar effect sizes for renal protection in those patients treated to lower BP levels, suggesting a potential benefit to antihypertensive therapy. We note that, in our sensitivity analysis with a 7-year imposed lag, the association between lower BP and lower risk of adverse outcomes only achieved statistical significance for incident CKD, and not for macroalbuminuria. Whether this attenuation is due to diminished power (given the obligatory exclusion of >25% events from our analysis when we enforce a 7-year lag between BP and outcome ascertainment), reverse causation (in that worsened renal injury and/or function can also lead to worsened BP) or the tendency for BP levels to have shorter-term associations with albuminuria (due to hemodynamic responses to BP changes or albuminuria-lowering effects of BP medications) are unclear.
Finally, our fully adjusted models may be overly conservative in their adjustment for time-updated albuminuria and eGFR, given that our primary outcomes of interest are macroalbuminuria and stage III CKD.
Although the results of this study are compatible with the hypothesis that lower BP targets may reduce complications in the younger type 1 diabetes population, other explanations are also possible. For example, it is known that there is a strong familial component to diabetic nephropathy risk in type 1 diabetes (27,28) and that a family history of hypertension is a significant predictor of diabetic nephropathy risk (29–31). It is possible that the propensity to hypertension is associated with a genetic predisposition to diabetic nephropathy through pathways that are, at least in part, independent of systemic BP (32).
The strengths of our study include the well-characterized cohort, the long duration and completeness of follow-up, the detailed collection of covariates that may potentially confound the association between BP and renal outcomes, and the use of models that account for changes in time-varying covariates.
We also recognize a number of limitations. Because these data are observational, they cannot prove causation. It remains possible that subtle kidney disease may lead to early elevations in BP, and we cannot rule out the potential for reverse causation in our findings. However, we note similar trends in our data even when imposing a 7-year lag between BP and CKD ascertainment. Other limitations include the use of a study cohort that is predominantly white, which may limit the ability to apply our results to other races. The urinary measurements may also be limited in their ability to capture potential diurnal variations in albumin excretion.
In conclusion, there is an association between BP levels that are significantly below the current treatment guidelines and the risk of adverse renal outcomes in patients with type 1 diabetes, independent of glycemic control. We believe that these data provide a rationale for future interventional trials designed to test the hypothesis that more aggressive lowering of BP could reduce the renal morbidities associated with type 1 diabetes.