Blood Pressure Control in Patients With Diabetic Kidney Disease Ⅰ

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease. Blood pressure (BP) control can reduce the risks of cardiovascular (CV) morbidity, mortality, and kidney disease progression. Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines have suggested the implementation of a more intensive BP control with a target systolic BP (SBP) of <120 mmHg based on the evidence that the CV benefits obtained is outweighed by the kidney injury risk associated with a lower BP target. However, an extremely low BP level may partially aggravate renal function and CV outcomes. Herein, we aimed to review the existing literature regarding optimal BP control using medications for DKD. 

Key Words: Blood pressure, Diabetes, Kidney, Mortality

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INTRODUCTION

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) worldwide1). According to the Korean ESKD registry (Korean Renal Data System, KORDS), its incidence has exponentially increased from 10% in 1985 to 49.8% in 20202). The initial clinical manifestations of DKD include glomerular hyperfiltration, albuminuria, and arterial hypertension, which eventually lead to a lower esti-mated glomerular filtration rate (eGFR)3). The progression of chronic kidney disease (CKD) is considerably faster in patients with diabetes than in patients without diabetes4) .

The renin-angiotensin-aldosterone system (RAAS) is the most important treatment target. RAAS activation increases the glomerular capillary hydraulic pressure and disrupts the renal vascular autoregulation, causing further renal damage). Hence, rigorous control of RAAS activation is crucial for blood pressure (BP) and urinary albumin level control in DKD management.

Recent clinical studies have shown that strict BP control can reduce cardiovascular (CV) morbidity and mortality rates, as well as the progression of kidney diseases. However, a considerable decrease in BP levels may paradoxically agitate the renal damage6,7). Accordingly, when determining the optimal BP control for the prevention of CV events and all-cause death, the renal function status and risk of ESKD should be taken into consideration. Currently, the target BP for patients with diabetes is frequently used, as no randomized controlled trials (RCTs) have determined the target BP for patients with DKD.

A multidisciplinary approach is recommended to delay the deterioration of renal function in patients with DKD. Although this study examined the antihypertensive medications used in patients with DKD, lifestyle modifications, including a low-salt diet, exercise, smoking cessation, and weight control, require prioritization. In addition, recent clinical trials on the use of sodium-glucose cotransporter 2 inhibitors, finer enone, and selective endothelin A receptor antagonists have shown promising results. Sodium-glucose cotransporter 2 inhibitors and finer enone have been recommended in the latest Kidney Disease Improving Global Outcomes (KDIGO) guidelines8). Although these agents are beyond the scope of this review, their use may attenuate the progression of renal disease in patients with type 2 diabetes. Hence, we aimed to review the existing literature on optimal BP control using medications in these patients.

Renal hemodynamics in diabetic kidney disease: The relationship between albuminuria, hypertension, and renal function

In patients with type 1 diabetes, hypertension develops concurrently with albuminuria or overt nephropathy; in patients with type 2 diabetes, hypertension often precedes albuminuria, and the eGFR declines). Hypertension coexists with other CV risk factors, such as insulin resistance, dyslipidemia, and obesity. These risk factors can further exacerbate systemic hypertension and may be a cause as well as a consequence of the deterioration of renal function. Systemic hypertension increases intraglomerular pressure, inducing hyperfiltration and proteinuria). Furthermore, the overproduction of vasoactive factors disrupting renal vascular autoregulation worsens glomerular hyperfiltration, in which RAAS activation plays a crucial role10,11). The local production of angiotensin II induces intraglomerular hypertension, proteinuria, and inflammatory pathways, which contribute to the development of the pathognomonic features of DKD, such as glomerular hypertrophy and sclerosis, tubulointerstitial inflammation, and fibrosis12). An increase in urinary albumin excretion (UAE) is an early renal manifestation of generalized vascular dysfunction and may serve as an indicator of renal and CV risks). The UAE rate, even within the normal range, is associated with changes in BP levels, development of hypertension, and renal vascular resistance, which are particularly evident in the presence of renal dysfunction14,15). An increase in albuminuria is a predictor of ESKD progression). Recent studies have confirmed that an increase in the UAE rate leads to poor CV and renal outcomes, while reduction of albuminuria attained through optimal BP control is associated with a favorable prognosis16,17). Therefore, the reduction of albuminuria may serve as a treatment target because alterations in urinary albumin levels may reflect parallel changes in both CV and renal risks).

Patients with diabetes and normoalbuminuria may present with different clinical manifestations. CKD may present heterogeneously in patients with type 1 and type 2 diabetes, with differing histological patterns and variations in the extent of fibrosis and ischemia involving the tubules, glomeruli, and interstitium19). Albuminuria may be absent or minimal in a significant proportion of patients with diabetes with declining renal function). Higher BP levels determine renal function regardless of the albuminuria status21). For instance, the United Kingdom Prospective Diabetes Study (UKPDS) showed that each 10 mmHg increase in mean BP caused a 15% increase in the hazard ratios for CKD development or a twofold increase in the serum creatinine levels in patients with normoalbuminuria22). Although the renal outcomes in patients with diabetes with traditional “albuminuric” phenotype have improved by maximal RAAS inhibition and BP lowering, the utility of corresponding treatments when albuminuria is not present remains unclear. For patients with non-classic phenotypes of DKD presenting with minimal albuminuria, the appropriate antihypertensive treatment and antihypertensive drug combinations should be determined based on the target BP values).

Albuminuria is generally recognized as an indicator of and a treatment target for slowing the progression of kidney disease, and renoprotection is achieved by the reduction of albuminuria). The United States Food and Drug Administration recently accredited the changes in albuminuria as the target marker for kidney disease progression in various clinical trials). In addition, persistent hypertension may cause albuminuria, which may precede and even predict the development of hypertension, particularly in patients with low eGFR14). Considering the bidirectional relationship between hypertension and albuminuria, the optimal BP may require the reduction of albuminuria and tolerable decline in eGFR in patients with DKD.

Adequate measurement of blood pressure: Standardized versus routine office blood pressure measurement

In the 2021 KDIGO BP guidelines, the standardized office BP measurement was recommended over routine office measurement). This recommendation was also previously incorporated in the 2017 American College of Cardiology/ American Heart Association guidelines). As BP levels based on office measurements tend to be higher than standardized BP measurements), overtreatment and hypotensive events may be possible.

Several considerations should be taken into account when performing the standardized office BP measurements, that is, from the preparation to the actual measurement) . For instance, the patients are required to empty their bladders and refrain from consuming caffeine, exercising, and smoking for at least 30 min before the BP measurement. Additionally, patients should attempt to relax for more than 5 minutes while seated in a chair with back support and place both feet on the ground. Neither the patient nor the observer may talk during the 5-minute rest period and throughout the procedure. The cuff is placed directly on the skin, away from the patient’s clothing. During the measurement, adequate arm support is provided, and an adequately sized cuff, with a bladder length that covers 80% of the patient’s arm circumference should be placed on the upper arm of the patient. BP measurements are taken once in both arms, and subsequent measurements are taken in the arm with a higher BP level. A minimum of two BP measurements at 1- to 2-minute intervals were required, and the average of the measurements are recorded. Both systolic BP (SBP) and diastolic BP levels are recorded along with the antihypertension medication that the patient recently took before the BP measurement.

Notably, the American Diabetes Association (ADA) consensus panel has indicated that a 24-hour ambulatory BP measurement is relevant in identifying the at-risk subgroups of patients with diabetes). This may be due to the fact that masked hypertension and nocturnal non-dipping BP status are possible confounding variables in the relationship between office BP measurement and DKD progression). Furthermore, standing or seated BP should be used as a target for treatment as some patients with diabetes and hypertension may develop autonomic neuropathy manifested as orthostatic hypotension and impaired systemic hemodynamics).

Target blood pressure for patients with diabetic kidney disease

For the past two decades, the target BP levels in patients with and without albuminuria have been <130/80 mmHg and <140/90 mmHg, respectively). Recent results from the Systolic Blood Pressure Intervention Trial (SPRINT) challenge this traditional school of thought). This study demonstrated favorable results of intensive BP control, with a target SBP of <120 mmHg (mean BP, 121.4 mmHg), compared with that of the conventional target of <140 mmHg (mean BP, 136.2 mmHg). Adopting the results from the SPRINT, the KDIGO 2021 guidelines updated their recommendation to a target SBP of <120 mmHg in patients with CKD8). However, given the negative results of intensive BP control from several key studies6,31,32), other guidelines do not subscribe to the use of strict target BP levels and still recommend different targets for patients with CKD (Table 1)6,31,32).

Nevertheless, mounting evidence appears to support the efficacy of intensive BP control in reducing adverse CV events and all-cause mortality rates, in patients with CKD with and without diabetes. In previous studies, a BP target of >140 mmHg in patients with CKD with diabetes was regarded as suboptimal33-36). The UKPDS also noted favorable outcomes with tighter BP control (mean BP, 144/82 mmHg vs. mean BP, 154/87 mmHg) in terms of diabetes-related outcomes, mortality, stroke, and microvascular complications33). Additionally, two studies that conducted posthoc analyses, the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study and the Irbesartan Diabetic Nephropathy Trial (IDNT), showed an association between lower BP levels and improved renal outcomes37,38). In a meta-analysis of 123 trials that included 613,815 participants, the risks of major CV events and all-cause mortality were notably lower with every 10 mmHg reduction in SBP39). A pooled analysis of four multicenter RCTs including 4,983 patients with CKD also reported that an SBP target of <130 mmHg was associated with decreased all-cause mortality and CV outcomes compared with the standard BP target of <140 mmHg, excluding patients with an eGFR of ≥60 mL/min/1.73 m2 and who had undergone intensive glycemic control40)

Table 1. Guideline comparisons of goal BP for diabetic patients with hypertension

Several studies have demonstrated the efficacy of intensive BP control. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial involving 11,140 patients with type 2 diabetes confirmed that the risk of significant renal events was reduced with a lower BP level (mean SBP, 134.7 vs. 140.3 mmHg), which was driven by the reduced risks of developing both micro- and macroalbuminuria41). In this study, progressively lower numbers of renal events were observed in patients with increasingly lower SBP levels (<110 mmHg). In the SPRINT, which is the most important clinical study investigating the effectiveness of intensive BP control, intensive BP control had beneficial effects on patients with a risk of experiencing serious adverse effects, such as hypotension, syncope, electrolyte abnormalities, and kidney injury.

However, results on the evaluation of the efficacy and safety of intensive SBP reduction to <120 mmHg were contradicting. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials involving patients with type 2 diabetes, strict SBP control to <120 mmHg (mean BP, 119.3 mmHg) had no association with CV and renal protection compared with the standard SBP target of <140 mmHg (mean BP, 133.5 mmHg), except for the risk of stroke6) . Furthermore, interventions that substantially lowered the SBP level to <120 mmHg were associated with an increased risk of adverse kidney events, such as higher serum creatinine levels or an eGFR of <30 mL/min/1.73 m2 6). The corresponding SBP intervention in the SPRINT also demonstrated a higher incidence of adverse renal outcomes in those without diabetes). Beddhu et al. compared the intensive and standard SBP groups in both SPRINT and ACCORD trials); the intensive intervention group showed an increased risk of incident CKD regardless of the status of type 2 diabetes. Interestingly, the absolute risk was higher in patients with diabetes than in those without diabetes. 

The Appropriate Blood Control in Diabetes study also examined the effect of maintaining a lower BP target of <130/80 mmHg (mean, 128 mmHg) for 5 years on the preservation of renal function compared with that of achieving the standard target of <140/90 mmHg (mean: 137 mmHg) in patients who are normotensive with type 2 diabetes; however, no evidence was found to support the efficacy of intensive BP control43).

In addition to safety issues, some studies have shown a U-shaped association between SBP and the risk of mortality. An observational subgroup analysis in the International Verapamil SR-Trandolapril study showed that an SBP level of <110 mmHg showed a significantly increased risk of all-cause mortality compared with SBP levels of 125-130 mmHg44). Several cohort studies have also suggested the risks associated with a considerable BP reduction). In a previous meta-analysis, BP-lowering treatments reduced the incidence of CV events, particularly in high-risk patients with various comorbidities, but they had no proportional effects in patients with a lower baseline SBP of <130 mmHg 39). According to these results, the international guidelines that defined the optimal BP values have recently been revised, with recommendations including an SBP target of <130 mmHg for high-risk patients, such as those with diabetes or CKD25,48-50)

A few limitations exist in the current RCTs. These involve diverse groups of patients but largely exclude patients with CKD or those with diabetes and advanced CKD. Notably, the SPRINT reported a mean eGFR of 48 mL/min/1.73 m2 , mostly involving patients with CKD stage G3a; however, the study only included those in the prediabetes stage, which was present in 36.5% of the patients7). Another important study, the ACCORD trial, excluded patients with a serum creatinine level of >1.5 mg/dL. Meanwhile, the BP measurements in the SPRINT were performed under ideal conditions; that is, the patients were resting in a quiet room for 5 minutes without an observer, which may have induced a reduction in BP levels compared with that performed in other clinical trials. However, these conditions may not be applicable in a real clinical setting. The KDIGO guidelines suggest that an SBP target of <120 mmHg obtained using non-standardized BP measurement methods may be potentially harmful. Therefore, caution should be taken when applying the updated guidelines of intensive BP control in patients with DKD.

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