Abstract
Introduction
In patients with chronic kidney disease stages 4 and 5 (CKD stages 4–5) without dialysis and arterial hypertension, it is unknown if the values of systolic blood pressure (SBP) considered in control (<120 mm Hg) are associated with kidney replacement therapy (KRT) and mortality.
Methods
In this retrospective cohort study, hypertensive CKD stages 4–5 patients attending the Renal Health Clinic at the Hospital Civil de Guadalajara were enrolled. We divided them into those that achieved SBP <120 mm Hg (controlled group) and those who did not (>120 mm Hg), the uncontrolled group. Our primary objective was to analyze the association between the controlled group and KRT; the secondary objective was the mortality risk and if there were subgroups of patients that achieved more benefit. Data were analyzed using Stata software, version 15.1.
Results
During 2017–2022, a total of 275 hypertensive CKD stages 4–5 patients met the inclusion criteria for the analysis: 62 in the controlled group and 213 in the uncontrolled group; mean age 61 years; 49.82% were male; SBP was significantly lower in the controlled group (111 mm Hg) compared to the uncontrolled group (140 mm Hg); eGFR was similar between groups (20.41 mL/min/1.73 m2). There was a tendency to increase the mortality risk in the uncontrolled group (HR 6.47 [0.78–53.27]; p = 0.082) and an association by the Kaplan-Meir analysis (Log-rank p = 0.043). The subgroup analysis for risk of KRT in the controlled group revealed that patients ≥61 years had a lower risk of KRT (HR 0.87 [95% CI, 0–76-0.99]; p = 0.03, p of interaction = 0.005), but no differences were found in the subgroup analysis for mortality. In a follow-up of 1.34 years, no association was found in the risk of KRT according to the controlled or uncontrolled groups in a multivariate Cox analysis.
Conclusion
In a retrospective cohort of patients with CKD stages 4–5 and hypertension, SBP >120 mm Hg was not associated with risk of KRT but could be associated with the risk of death. Clinical trials are required in this group of patients to demonstrate the impact of reaching the SBP goals recommended by the KDIGO guidelines.
Keywords: Hypertension, Kidney replacement therapy, Chronic kidney disease, Mortality
Introduction
Approximately 850 million people have chronic kidney disease (CKD) worldwide, and more than 80% of them have hypertension [1]. The incidence of hypertension worsens as renal function decreases, increasing the risk of suffering from hypertension by 3.5 times when the glomerular filtration rate is less than 30 mL/min/1.73 m2 [2]. Hypertension is one of the largest contributors to the development of cardiovascular (CV) complications and worsening renal function. In a 5-year follow-up of patients with CKD stage 4, it was observed that 45% died, mostly due to CV events, with this event being more common than starting dialysis [3]. Hypertension plays a fundamental role in CV death and is one of the largest contributors to mortality in CKD [4], which is why the nephrology community has for decades focused on lowering blood pressure (BP). It is believed that, by eliminating hypertension, we would observe the greatest reduction in CV death, and it would be more relevant than eliminating diabetes, obesity, or smoking [5]. Although the criteria according to which BP is considered to be under control for people with CKD and hypertension have varied in recent decades, the KDIGO guidelines published in 2021 recommended a BP <120/80 mm Hg to consider control [6], justified mainly by the SPRINT clinical trial results [7]. Despite these recommendations, 69.5% of patients with CKD lack BP control [8]. However, major guideline bodies do not agree about BP targets for CKD [9]. Unfortunately, these major guideline discrepancies create an environment of uncertainty and directly affect the care of CKD patients, prompting intense debates and treatment changes that can impair quality of life and outcomes.
However, the appropriate treatment target for BP in advanced CKD populations (stages 4 and 5 without dialysis) remains unclear, and the benefits of intensive BP control are debated [10]. We believe that there is scarce evidence on the appropriate goals for systolic blood pressure (SBP) numbers to be achieved in patients with CKD G4-5 with hypertension, specifically to observe a benefit in outcomes such as kidney replacement therapy (KRT) and mortality. To contribute to shortening the existing gap in this area of interest, we conducted this study, in which we analyzed the association between SBP and the risk of KRT or death in patients with advanced CKD.
Materials and Methods
Study Design and Patient Population
A retrospective cohort study was conducted at the Hospital Civil de Guadalajara Fray Antonio Alcalde, Mexico, between August 2017 and June 2022; the hospital is a tertiary referral academic center with 964 beds. All patients considered were under the care of the nephrology service and attended the Renal Health Clinic, an interdisciplinary health care model that involves the participation of a nephrology nurse, a nutritionist, a psychologist, and a nephrologist. The clinic has the purpose of preventing the risks of renal and CV progression, optimizing the management of comorbidities, educating patients about KRT, and delaying the progression of CKD from a multiparametric and comprehensive perspective. For the purpose of this study, we only included CKD stages 4 and 5 without dialysis in patients with hypertension at baseline. CKD was defined by the KDIGO guidelines using the estimated glomerular filtration rate (eGFR) by the CKD-EPI equation less than 60 mL/min/1.73 m2 or any marker of kidney disease for more than 3 months. CKD stages 4 and 5 were defined as an eGFR of 29–15 mL/min/1.73 m2 and ≤14 mL/min/1.73 m2, respectively [11].
Hypertension under control was defined according to the 2021 KDIGO guidelines, in which controlled BP was defined as “treated with a target SBP of <120 mm Hg, when tolerated, using standardized office BP measurement (2B)” [6], and SBP >120 mm Hg was considered uncontrolled. We decided to focus only on systolic pressure <120 mm Hg because it is the current recommendation considered controlled by KDIGO [6].
We included patients >18 years old, CKD stages 4–5, who were not on dialysis or who had not undergone a kidney transplant, with a diagnosis of arterial hypertension or who were taking antihypertensives since their last visit; they had at least 3 follow-up visits during the study period, had a record of the BP during their visits, and had an eGFR record. Patients who did not meet any of the inclusion criteria were excluded. A nurse performed the BP measurements at the clinic using the OMRON HEM-907XL or HEM-6127 device, following the recommendations for CKD patients [12]. The most appropriate size for the 2 devices was chosen; the patients remained seated for at least 5 min, their arms were uncovered, speaking was not allowed during the measurements, 3 measurements were taken with a difference of 2–3 min between them, and the average of 3 readings obtained with 3 measurements to calculate the mean SBP and DBP for each participant was considered [13]; the results were commented upon and noted. The renal nutritionist focused on suggesting a low sodium diet (<2.4 g/day) in accordance with international recommendations [14], in addition to guiding food intake in accordance with the KDIGO guidelines for the management of CKD and hypertension [6] and increased physical activity [15]. Adherence to treatment was evaluated by asking about the missing pills during the last month by the nurse and again by the nephrologist. We considered adherence to be present when the doses were met on >80% of the days.
Our primary objective was to analyze whether there is an association between SBP considered controlled, compared to uncontrolled, and the start of KRT and all-cause mortality as a secondary objective. Additionally, we considered whether there were subgroups of patients who achieved some benefit from reaching these SBP values. KRT was defined as the initiation of peritoneal dialysis, hemodialysis, or kidney transplantation. All-cause mortality was defined from the date of death in linked death certification records.
No financial compensation was provided. Written informed consent was obtained from participants. The study was approved by the Hospital Civil de Guadalajara Fray Antonio Alcalde Institutional Review Board (HCG/CEI-0550/15). This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [16].
Data Collection
Clinical characteristics, demographic information, and laboratory data were collected using automated retrieval from the institutional electronic medical records system. The main predictors of interest were KRT and all-cause mortality. Demographic and clinical variables were collected, including age, diabetes, BP, hypothyroidism, CKD stage, eGFR, smoking, cerebrovascular disease, ischemic heart disease, nephrotoxic drugs, and prespecified biochemical data, such as hemoglobin, cholesterol, serum albumin, proteinuria, platelets, leukocytes, glucose, urea, creatinine, sodium, potassium, chloride, phosphate, and calcium. Antihypertensives and other drugs were commonly prescribed. KRT consisted of hemodialysis or peritoneal dialysis. Indications for KRT were fluid overload resistant to diuretics, severe hyperkalemia, severe metabolic acidosis, and uremic manifestations, including encephalopathy, pericarditis, and seizures [17–19].
Statistical Analysis
The incidence of KRT and all-cause deaths per 1,000 person-years during follow-up was calculated. The distribution of the continuous variables was examined using the Kolmogorov-Smirnov and Shapiro-Wilk tests, with which their nonnormal distributions were confirmed. As a result, continuous variables were expressed as medians and interquartile ranges, while categorical variables were expressed as counts and proportions. Differences in categorical variables between the controlled and uncontrolled groups were analyzed using the χ2 test or Fisher’s exact test, as appropriate. Continuous variables were compared with Wilcoxon’s rank test. The incidence of each outcome was expressed as the total number of events per 1,000 patient-years at risk.
A Cox proportional hazards regression model was used to analyze the relationship between baseline BP and outcome variables. Initially, a univariate Cox analysis was performed with those variables with a p < 0.20 in the analysis of differences between groups of baseline characteristics. Subsequently, those that had p < 0.20 in the univariate analysis were included in the Cox multivariate model to adjust the comparison for potential confounders. We used Kaplan-Meier plots to compare survival curves between SBP. In addition, Kaplan-Meier curves and log-rank analyses were performed, separated by group (controlled and uncontrolled). Finally, a forest plot of the hazard ratio was performed by predefined subgroups to find those patients who obtained the greatest benefit from controlled SBP against the initiation of KRT and survival. Statistical significance was defined as p < 0.05. Data were analyzed using Stata software, version 15.1 (StataCorp, College Station, TX, USA).
Results
During the period from 2017 to 2022, there were 11,250 consultations at the Renal Health Clinic for a total of 2,167 patients, of whom 1,892 were excluded for not meeting the inclusion criteria (22 for being <18 years old; 1,102 for having CKD stage 1, 2, or 3; 320 because of nonhypertensive; 12 for having a previous kidney transplant; 62 for having fewer than 3 consultations; and 374 for missing available SBP records or having <3 eGFR measurements). For the final analysis, a total of 275 patients were divided into 62 in the controlled group and 213 in the uncontrolled group, as shown in the flow chart of Figure 1.
Fig. 1.
Flow chart of the study.
Table 1 shows the baseline characteristics and the comparison between the patients in the controlled and uncontrolled SBP groups. No differences were found between the groups in age (61 years old) or in male sex (49.82%). As expected, SBP was significantly lower in the controlled group (111 mm Hg) than in the uncontrolled (140 mm Hg) group. In the same way, the DBP was 70 mm Hg compared to 80 mm Hg. The eGFR was similar between both groups, 20.41 mL/min/1.73 m2, categorizing them as having CKD stage 4. In both groups, the presence of diabetes and chronic heart failure was similar, and 50% and 46% had it, respectively. No differences were found between the two groups in the mean concentrations of hemoglobin (11.6 g/dL), glucose (101 mg/dL), urea (104 mg/dL), serum albumin (4.0 g/dL), or electrolytes.
Table 1.
Baseline clinical characteristics according to groups of SBP
| Variable | Controlled SBP <120 mm Hg (n = 62) | Uncontrolled SBP >120 mm Hg (n = 213) | Total (n = 275) | p value |
|---|---|---|---|---|
| Age, years | 62 (42–70) | 61 (49–79) | 61 (49–71) | 0.38 |
| Male sex, n (%) | 33 (53.23) | 104 (48.83) | 137 (49.82) | 0.54 |
| SBP, mm Hg | 111 (108–116) | 140 (130–160) | 131 (124–155) | <0.01* |
| Diastolic blood pressure, mm Hg | 70 (60–78) | 80 (73–88) | 80 (70–86) | <0.01* |
| Creatinine mg/dL | 2.8 (2.4–3.3) | 2.9 (2.4–3.26) | 2.8 (2.4–3.3) | 0.60 |
| eGFR, mL/min | 21.24 (16.13–30.19) | 20.3 (15.5–26.88) | 20.41 (15.56–27.32) | 0.21 |
| CKD stage 4, n (%) | 38 (61.29) | 134 (65.05) | 172 (64.18) | 0.58 |
| CKD stage 5, n (%) | 8 (13.79) | 36 (18) | 44 (17.05) | 0.29 |
| Hemoglobin, g/dL | 11.7 (10.8–12.5) | 11.5 (10.6–12.7) | 11.6 (10.6–12.6) | 0.65 |
| Glucose, mg/dL | 95 (87–114) | 104 (90–126) | 101 (88–120) | 0.07a |
| Urea, mg/dL | 100 (78.5–141) | 105.6 (8–135) | 104 (84–136) | 0.42 |
| Uric acid, mg/dL | 6.7 (5.3–8) | 6.4 (5.3–8) | 6.6 (5.3–8) | 0.79 |
| Cholesterol, mg/dL | 144.5 (129–173) | 155 (131–191) | 154 (131–187) | 0.02* |
| Serum albumin | 4 (3.7–4.4) | 4 (3.6–4.3) | 4 (3.6–4.3) | 0.49 |
| Serum sodium | 139 (138–141.5) | 139 (138–141) | 139 (138–141) | 0.63 |
| Serum potassium | 4.6 (3.9–5.2) | 4.8 (3.9–5.3) | 139 (3.9–5.2) | 0.38 |
| Serum calcium | 9.1 (8.7–9.4) | 9.2 (8.8–9.5) | 9.2 (8.8–9.5) | 0.68 |
| Serum phosphate | 3.81 (3.45–4.55) | 4.1 (3.6–4.6) | 4.1 (3.6–4.6) | 0.11a |
| Proteinuria, g/day | 0 (0–0) | 0 (0–0.71) | 0 (0–0.52) | 0.01* |
| ACEi, n (%) | 28 (45.16) | 61 (28.64) | 89 (32.36) | 0.01* |
| ARB, n (%) | 30 (48.39) | 131 (61.50) | 161 (58.55) | 0.06a |
| β-blockers, n (%) | 7 (11.29) | 56 (26.29) | 63 (22.91) | 0.01* |
| Calcium channel blockers, n (%) | 15 (24.19) | 89 (41.78) | 104 (37.82) | 0.01* |
| Furosemide, n (%) | 34 (54.84) | 129 (60.56) | 163 (59.27) | 0.41 |
| Statins, n (%) | 54 (87.1) | 192 (90.14) | 246 (89.45) | 0.49 |
| Calcium carbonate, n (%) | 4 (6.45) | 12 (5.63) | 16 (5.82) | 0.80 |
| Calcitriol, n (%) | 6 (9.68) | 19 (8.92) | 25 (9.09) | 0.85 |
| Alopurinol, n (%) | 51 (83.61) | 174 (81.69) | 225 (82.12) | 0.73 |
| Vitamin D3, (%) | 7 (11.29) | 35 (16.43) | 42 (15.27) | 0.32 |
| Sodium bicarbonate, n (%) | 9 (14.52) | 30 (14.08) | 39 (14.18) | 0.93 |
| Hypoglycemic treatment, n (%) | 3 (4.84) | 16 (7.51) | 19 (6.91) | 0.46 |
| Insulin treatment, n (%) | 22 (35.48) | 97 (45.75) | 119 (43.43) | 0.15a |
| Vitamin B complex, n (%) | 1 (1.61) | 6 (2.87) | 7 (2.58) | 0.58 |
| Folic acid, n (%) | 3 (4.84) | 4 (1.89) | 7 (2.55) | 0.21 |
| Aspirin, n (%) | 4 (6.45) | 19 (8.96) | 23 (8.39) | 0.53 |
| Iron, n (%) | 10 (16.13) | 23 (10.85) | 33 (12.04) | 0.26 |
| Gabapentin, n (%) | 4 (6.45) | 21 (9.95) | 25 (9.16) | 0.40 |
| Levotiroxin, n (%) | 4 (6.45) | 14 (6.64) | 18 (6.59) | 0.95 |
| Tamsulosin, n (%) | 0 | 9 (4.25) | 9 (3.28) | 0.09a |
| Omeprazol, n (%) | 4 (6.45) | 3 (1.42) | 7 (2.55) | 0.04* |
| Outcomes | ||||
| KRT, n (%) | 8 (12.9) | 28 (13.15) | 36 (13.09) | 0.96 |
| Hemodialysis, n (%) | 5 (8.06) | 10 (4.69) | 15 (5.45) | 0.44 |
| Peritoneal dialysis, n (%) | 3 (4.84) | 18 (8.45) | 21 (7.64) | |
| Dead on follow-up, n | 1 (1.61) | 15 (7.04) | 16 (5.82) | 0.13 |
| Days of follow-up | 641 (434–1,127) | 454 (255–681) | 490 (272–787) | <0.01 |
Continuous data presented as median and interquartile range, compared with the Wilcoxon’s rank test (Mann-Whitney U). Categorical data are presented in number and percentage and compared with χ2 or Fisher’s exact test as appropriate.
ACEi, angiotensin converting enzyme inhibitors; ARB, antagonist receptor blockers; eGFR, estimated glomerular filtration rate.
*Statistical significance; p < 0.05.
aIncluded in the bivariate analysis; p < 0.20.
In the controlled group, cholesterol levels were significantly lower (144.5 vs. 155.0 mg/dL), the patients had higher proteinuria (0 (0–0) versus 0 (0–0.71); p = 0.01), and they used more drugs, such as ACE inhibitors (45.16% vs. 28.64%) and omeprazole (6.45% vs. 1.42%). The controlled group consumed fewer β-blockers (11.29% vs. 26.29%) and calcium antagonists (24.19% vs. 41.78%). Other drugs, such as statins, furosemide, sodium bicarbonate, hypoglycemic agents, and insulin, were similar between the groups (p ≥ 0.05 for all; Table 1).
SBP Groups and the Incidence of KRT and Death
The median follow-up of the total cohort was 1.34 years (IQR 0.74–2.15), corresponding to 406.31 person-years. Regarding KRT, the median follow-up was 1.36 (0.74–2.17) years, corresponding to 388 person-years. There were 8 events in the controlled group and 26 events in the uncontrolled group, 34 in total, corresponding to a KRT incidence rate of 87.59 (IQR 62.58–12.59) per 1,000 patient-years. In patients who died, the median follow-up was 1.36 years (IQR 0.74–2.24). One event was reported in the controlled group, and 14 events were reported in the uncontrolled group, corresponding to a total incidence rate of death of 36.97 (IQR 22.28–61.32) per 1,000 patient-years. Details of the incidence rates of KRT and mortality can be seen in Table 2.
Table 2.
Incidence rate of KRT and death according to SBP groups
| Group | Patient-years | Events | Rate (1,000 patient-years) | LIC | UIC |
|---|---|---|---|---|---|
| KRT | |||||
| Controlled | 92.27 | 8 | 86.69 | 43.35 | 173.35 |
| Uncontrolled | 295.87 | 26 | 87.87 | 59.83 | 129.06 |
| Total | 388.15 | 34 | 87.59 | 62.58 | 122.59 |
| Mortality | |||||
| Controlled | 109.44 | 1 | 9.13 | 1.28 | 64.86 |
| Uncontrolled | 296.27 | 14 | 47.25 | 27.98 | 79.78 |
| Total | 405 | 15 | 36.97 | 22.28 | 61.32 |
Primary Objective of KRT Risk by Controlled or Uncontrolled SPB Groups
Before propensity score matching, we evaluated the risk of KRT by SBP group. The univariate analysis included cholesterol, age, phosphate, eGFR, β-blockers, omeprazole, proteinuria, ACE inhibitors, insulin, tamsulosin, calcium blockers, glucose, and ARB. The multivariate analysis included the uncontrolled group, cholesterol, age, phosphate, eGFR, β-blockers, and omeprazole. We found that each 1-mg/dL increase in the cholesterol value greater than 200 mg/dL was associated with an increased risk of needing KRT (HR 1.01 (95% CI: 1.00–1.02); p = 0.002), each year of age decreased the risk (HR 0.97 (95% CI: 0.94–0.99); p = 0.040), and as expected, each unit of eGFR greater than 20 mL/min/1.73 m2 decreased the risk (HR 0.93 (95% IQ: 0.86–0.99); p = 0.049). When evaluating the risk of KRT according to the SBP controlled or uncontrolled SBP groups in a multivariate Cox analysis, no association was found, nor was any association found in the Kaplan-Meier analysis curves, as shown in Table 3 and online supplemental Figure 1 (for all online suppl. material, see https://doi.org/10.1159/000533438).
Table 3.
Bivariate and multivariate Cox regression analysis of factors related to KRT of CKD patients
| Predictors | Bivariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Uncontrolled group | 0.55 (0.70–3.44) | 0.275 | 0.85 (0.31–2.32) | 0.756 |
| Cholesterol | 1.00 (1.00–1.01) | 0.008 | 1.01 (1.00–1.02) | 0.002 |
| Age | 0.97 (0.96–0.99) | 0.014 | 0.97 (0.94–0.99) | 0.040 |
| Phosphate | 1.47 (0.99–2.17) | 0.055 | 1.07 (0.063–1.81) | 0.787 |
| eGFR | 0.95 (0.91–1.00) | 0.058 | 0.93 (0.86–0.99) | 0.049 |
| β-blockers | 1.80 (0.88–3.69) | 0.104 | 2.44 (0.90–6.60) | 0.077 |
| Omeprazole | 3.07 (0.73–12.93) | 0.125 | 1.49 (0.94–23.58) | 0.776 |
| Proteinuria | 1.00 (0.99–1.00) | 0.234 | ||
| ACEi | 0.63 (0.29–1.35) | 0.238 | ||
| Insulin | 1.41 (0.72–2.78) | 0.313 | ||
| Tamsulosin | 1.75 (0.41–7.36) | 0.440 | ||
| Calcium blockers | 1.30 (0.65–2.58) | 0.444 | ||
| Glucose | 0.99 (0.98–1.00) | 0.498 | ||
| ARB | 1.03 (0.52–2.023) | 0.920 | ||
ACEi, angiotensin converting enzyme inhibitors; ARB, antagonist receptor blockers; eGFR, estimated glomerular filtration rate.
Online Supplemental Table 1 shows the risks, and Figure 2 shows the forest plot of the subgroup analysis for the risk of needing KRT among patients with controlled or uncontrolled SBP. In the controlled group, people ≥61 years of age, compared to those <61, had a lower risk of needing KRT (HR 0.87 (95% CI: 0–76-0.99); p = 0.03, p of interaction = 0.005), and those patients with cholesterol <200 mg/dL presented a higher risk of needing KRT (HR 1.01 (95% CI: 1.00–1.03); p = 0.02), but there was no significant interaction when compared to patients with cholesterol >200 mg/dL. There was no difference in risk in the other predefined subgroups.
Fig. 2.
Forest Plot for KRT by subgroups.
Secondary Objective of Mortality Risk by Controlled or Uncontrolled SPB Groups
Using the same variables for the univariate analysis, cholesterol, uncontrolled group, omeprazole, ACE inhibitors, age and β-blockers, proteinuria, ARB, insulin, eGFR, glucose, calcium blockers, and phosphate were included. No variables were associated with mortality risk. In the multivariate analysis, cholesterol, uncontrolled SBP, omeprazole, and ACEi were included. A tendency to increase the mortality risk was found in the uncontrolled group (HR 6.47 (0.78–53.27); p = 0.082), and an association was found in the Kaplan-Meir analysis and log-rank test (Table 4 and online suppl. Fig. 2). Cholesterol and the use of ACE inhibitors were associated with an increased mortality risk (HR 1.01 (95% CI: 1.00–1.02); p = 0.029 and HR 3.63 (95% CI: 1.12–11.73), p = 0.031, respectively) (Table 4). Table 5 and Figure 3 show the risks and the forest plot analysis of predefined subgroups for survival among patients with controlled or uncontrolled SBP, respectively, and no differences were found.
Table 4.
Bivariate and multivariate Cox regression analysis of factors related to mortality risk among CKD stages 4–5 patients
| Predictors | Bivariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| Cholesterol | 1.01 (0.99–1.02) | 0.050 | 1.01 (1.00–1.02) | 0.029 |
| Uncontrolled group | 6.26 (0.81–47.92) | 0.077 | 6.47 (0.78–53.27) | 0.082 |
| Omeprazole | 5.53 (0.71–42.74) | 0.101 | 10.04 (0.91–110.25) | 0.059 |
| ECAi | 2.42 (0.83–6.98) | 0.102 | 3.63 (1.12–11.73) | 0.031 |
| Age | 1.03 (0.99–1.07) | 0.126 | 1.01 (0.97–1.05) | 0.597 |
| β-blockers | 2.21 (0.77–6.32) | 0.135 | 2.25 (0.68–7.45) | 0.182 |
| Proteinuria | 0.48 (0.11–2.02) | 0.324 | ||
| ARB | 0.59 (0.20–1.70) | 0.333 | ||
| Insulin | 1.56 (0.56–4.33) | 0.391 | ||
| Tamsulosin | 2.27 (0.29–3.65) | 0.428 | ||
| eGFR | 0.97 (0.92–1.03) | 0.494 | ||
| Glucose | 0.99 (0.98–1.00) | 0.613 | ||
| Calcium blockers | 1.22 (0.43–3.45) | 0.702 | ||
| Phosphate | 1.12 (0.55–2.27) | 0.737 | ||
ACEi, angiotensin converting enzyme inhibitors; ARB, antagonist receptor blockers; eGFR, estimated glomerular filtration rate.
Table 5.
Subgroup analysis for mortality risk
| Subgroup | Patients | Events | HR | IC | p interaction |
|---|---|---|---|---|---|
| Age | |||||
| <60 | 129 | 5 | 1.02 (p = 0.62) | 0.93–1.11 | 0.081 |
| ≥61 | 146 | 31 | 1.04 (p = 0.20) | 0.97–1.12 | |
| Hb | |||||
| <10 | 37 | 4 | 1.21 (p = 0.76) | 0.32–4.52 | 0.040 |
| ≥10.1 | 234 | 12 | 0.88 (p = 0.61) | 0.54–1.43 | |
| eGFR | |||||
| <30 | 223 | 14 | 1.06 (p = 0.23) | 0.96–1.18 | 0.521 |
| ≥30.1 | 51 | 2 | 0.04 (p = 0.19) | 0.00–4.90 | |
| Cholesterol | |||||
| <200 | 205 | 10 | 1.00 (p = 0.78) | 0.98–1.02 | 0.260 |
| ≥201 | 41 | 6 | 0.98 (p = 056) | 0.95–1.02 | |
| Albumin | |||||
| <3.5 | 53 | 6 | 1.23 (p = 0.86) | 0.11–13.75 | 0.075 |
| ≥3.6 | 179 | 10 | 0.73 (p = 0.75) | 0.10–5.12 | |
| Phosphate | |||||
| <4.5 | 170 | 11 | 1.18 (p = 0.77) | 0.36–3.84 | 0.483 |
| ≥4.6 | 55 | 4 | 0.18 (p = 0.29) | 0.00–4.36 | |
| Total | 275 | 36 | 0.94 | 0.49–1.39 | |
eGFR, estimated glomerular filtration rate.
Fig. 3.
Forest Plot mortality risk by subgroups.
Discussion
The key finding of the present analysis is that, in patients with CKD stages 4–5 with hypertension, we observed that SBP considered uncontrolled (>120 mm Hg), compared to controlled SBP (<120 mm Hg), was not associated with the risk of needing KRT but could be associated with the risk of dying. Our findings of the lack of benefit regarding KRT in CKD patients who maintain SBP levels considered controlled have been previously described. It is possible that the control of BP in these patients is not entirely beneficial for kidney function in the short- and medium-term follow-up. Three large clinical trials in CKD patients without diabetes, MDRD [20], AASK [21], and REIN-2 [22], have aimed to achieve a BP <130/80 mm Hg, which is considered low compared to <140/90 mm Hg. They failed to demonstrate kidney benefits. Neither reached even lower BP values (<120/80 mm Hg), as occurred in the SPRINT study and in our cohort. The SPRINT study randomized 9,361 patients (∼2,600 with CKD stage 3) to intense control for BP <120 mm Hg compared to <140 mm Hg, and intense control had no difference in the risk of CKD progression [7].
Paradoxically, kidney function worsens in CKD patients randomized to intense BP control. In a post hoc study of the SPRINT trial that analyzed patients without CKD, it was observed that, among those who were randomized to intense control of SBP (<120 mm Hg), no improvement was noted in kidney function; in fact, this group had a greater probability of decreasing eGFR, with only 15.9 patients needing to be treated to cause 1 event of kidney function impairment [23]. In the subgroup of patients with CKD in the SPRINT study, the BP reached at 12 months in the intensive arm was 123.3/66.9 mm Hg, compared to 136.9/73.8 mm Hg; after a follow-up of 3.3 years, a 19% risk reduction in primary composite CV outcome and 28% reduction in risk of all-cause death were observed, but patients with SBP <120 mm Hg lost eGFR at a 47% faster rate [24].
A combined analysis of the AASK and MDRD studies described that, even 14 years after achieving BP control, no decrease in the risk of end-stage renal disease was observed [25]. A meta-analysis of 9 clinical trials and 8,127 patients with CKD did not demonstrate any kidney benefit from BP control [26]. In a Taiwanese cohort of 2,144 CKD stages 3–4 patients with diabetes who maintained an SBP between 96 mm Hg and 110 mm Hg, compared to 111 mm Hg and 120 mm Hg, the patients had a 3–14-fold increased risk of a kidney event [27]. The neutral or negative effect on eGFR in CKD patients who reach BP control is not well clarified. One explanation could be that, once they reach these BP goals, the risk of acute kidney injury increases by 51% [12], and the increased risk of postural hypotension [28]. Hypoperfusion affected the recovery of kidney regional blood flow and aggravated chronic inflammation and vasculopathy, accelerating kidney function loss [29].
The ESC/ESH guidelines in 2018 suggested treating hypertension according to age. In people with CKD and >80 years old, treatment should only be started before BP reaches >160/90 mm Hg [30]. In young people when BP reaches >140/90 mm Hg, regardless of age, those with CKD suggested a goal of <139/79 mm Hg. Recently, in 2021, the ESC proposed starting the management of hypertension in CKD with a goal of 130–139 mm Hg [31].
A tendency to increase the mortality risk was found in the uncontrolled group (>120). It has previously been described that uncontrolled hypertension is associated with a higher risk for CV morbidity and mortality [10], and reducing BP is beneficial.
In the CRIC cohort, 319 young patients (20–40 years old) with CKD stage 3a were observed over an 11-year follow-up, and those with SBP >130 mm Hg had a 2.3-fold increased risk of CV events or death and a 68% increased risk of CKD progression [32]. The SPRINT study was terminated prematurely due to the evident positive results since those assigned to the strict BP group (<120/80 mm Hg) had 19% fewer CV events and an 18% reduction in all causes of death [24]. Mortality benefits over SBP control (<130 mm Hg) in people with advanced CKD, such as stages 3–5, were demonstrated in a meta-analysis of 18 clinical trials with 15,934 patients, in which this control was associated with a 14% decrease in the risk of death [33]. The largest clinical trials that have achieved SBP figures <130 mm Hg have used an average of 3 drugs to achieve this goal [34], so polypharmacy is frequent in these scenarios. The combination of antihypertensive drugs decreases the risk of death by 50% [35].
Achieving BP control in CKD patients is a clinical challenge, and up to 30% of them are classified as resistant [36]. The pathophysiological mechanism of arterial hypertension in CKD is multifactorial and very complex. It is believed that it mainly involves marked endothelial dysfunction, increased renin production, decreased sodium excretion, and sympathetic hyperactivity [10].
Volume overload is a strong contributor to the development of hypertension in CKD G4-5 [38]. In a cohort of patients with CKD stage 3b, it was observed that 43% had volume overload, and 23% of them were classified as having uncontrolled arterial hypertension [15]. It is important to mention that volume overload worsens as eGFR decreases. At the start of peritoneal dialysis, 56% had volume overload [37], had positive relationships with BP, proteinuria, and pulse wave velocity, and had a negative correlation with eGFR [38].
Our findings on the association of high cholesterol values with mortality are similar to those reported in cohorts of patients with CKD stages 3–5. In one study, authors observed that total cholesterol >221 mg/dL was associated with a 2-fold increase in the risk of death over a follow-up of 2.8 years [39]. Advanced CKD patients exhibit lipid disorders that are more common than in the general population [40].
We found an association between the use of ACE inhibitors and mortality. Although it is an unexpected finding, it could have plausible explanations, including risk of hyperkalemia, hemodynamic alterations in kidney function, and poor response to acute kidney injury events that can occur during this vulnerable period. The report of the NKF-KDOQI group in 2018 concluded that evidence for the use of renin angiotensin aldosterone system inhibitors is scarce in patients with advanced CKD [41]. The largest clinical trial on this topic is the STOP-ACEi study, in which patients with CKD stage 4 and an approximate BP of 136/76 mm Hg were randomized to continue with renin angiotensin aldosterone system inhibitors or discontinue them, and no differences were found between the groups in loss of kidney function, initiation of KRT, or death [42]. To date, in these groups of patients, the high-grade evidence is scarce.
SBP >120 mm Hg in patients with CKD stages 4–5 could represent a plausibly modifiable CV risk factor since it could be related to an increased risk of death, consistent with the existing evidence in patients with normal kidney function or mildly reduced eGFR, but this association is not necessarily true for the risk of KRT. By reducing SBP to <120 mm Hg, as suggested in the KDIGO guidelines, we could prolong the lives of patients and allow them to better plan their KRT options, as well as improve how to carry out the transplant protocol [43] or, in the worst of cases, educate patients in a timely manner so that they can decide among PD [44], receiving an arteriovenous fistula for HD [45], or nondialysis treatments.
Our study has important limitations that must be considered when interpreting our results. The retrospective design of the study only allowed for finding associations and generating hypotheses. The lack of multiple variables could have affected the outcomes, albuminuria for example. The follow-up time was relatively short to assess KRT and mortality. Our analysis was based on eGFR using the CKD-EPI equation, which has inherent limitations and might not have been reliable during this critical process. We did not analyze patients who were lost to follow-up or who missed key information, such as not having ambulatory BP monitoring. The study was performed at a single center, which does not allow these results to be extrapolated to other races or ethnicities. The study represents real-world routine clinical practice, and thus, some variables were not routinely analyzed outside nephrology departments. The strengths of our cohort lie in having captured patients with advanced CKD, a group of patients poorly analyzed in previous studies. The patients were divided between SBP values according to the new recommendations of the KDIGO guidelines. Propensity score matching allowed us to homogenize the groups and perform a fairer comparison.
Conclusions
In a retrospective cohort of patients with stage 4–5 CKD and hypertension, SBP >120 mm Hg was not associated with the risk of needing KRT, although it could be associated with risk of death. Clinical trials are required in this group of patients to demonstrate the impact of reaching the SBP goals recommended by the KDIGO guidelines.
Acknowledgments
The author would like to thank all the social service students of medicine who have been in the nephrology service, without whom, this article would have been not possible.
Statement of Ethics
The study was conducted in adherence with the Declaration of Helsinki and was approved by the Hospital Civil de Guadalajara Fray Antonio Alcalde Institutional Review Board (HCG/CEI-0550/15). Written informed consent was obtained from participants consenting to participate.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None of the authors received funding to conduct this study.
Author Contributions
Jonathan S. Chávez-Íñiguez and Jose J. Zaragoza designed the study, analyzed data, made tables and figures, and wrote the manuscript. Ana E. Huerta-Orozco, Jahir R. Camacho-Guerrero, Vanessa Villavicencio-Cerón, Rafael Valdez-Ortiz, Gael Chávez-Alonso, Ana E. Oliva-Martinez, Bladimir Díaz-Villavicencio, Clementina E. Calderón-García, Jose D. González-Barajas, Manuel Arizaga-Nápoles, Frida M. De La Vega-Méndez, Juan A. Gómez-Fregoso, Francisco G. Rodríguez-García, Guillermo Navarro-Blackaller, Ramón Medina-González, and Luz Alcantar-Vallin recollected data and wrote the manuscript. Guillermo García-García wrote the manuscript and supervised all the process.
Funding Statement
None of the authors received funding to conduct this study.
Data Availability Statement
The files and data are in the physical and electronic archives of the Civil Hospital of Guadalajara Fray Antonio Alcalde and can be requested with prior authorization. All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Supplementary Material
Supplementary Material
Supplementary Material
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The files and data are in the physical and electronic archives of the Civil Hospital of Guadalajara Fray Antonio Alcalde and can be requested with prior authorization. All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
