Risk of chronic kidney disease in hypertensive patients with other metabolic conditions

Using a retrospective cohort design and electronic medical records, we examined chronic kidney disease (CKD) risk over a 6-year period among hypertensive patients in relation to the presence of diabetes, hyperlipidaemia and/or high body mass index. After adjusting for age, sex, smoking status and baseline glomerular filtration rate (GFR), hypertensive patients without other metabolic risk factors had a relative risk of CKD (versus normotensive patients) of 2.0 (95% CI 1.8–2.2); hypertensive patients with other metabolic conditions had adjusted relative risks ranging from 2.4 to 2.6 for those without comorbid diabetes, and from 3.3 to 5.5 for those with comorbid diabetes. Our study thus confirms prior research demonstrating elevated CKD risk in hypertensive patients, and suggests that this risk varies substantially in relation to other metabolic conditions, especially diabetes.

Hypertension is a well-established risk factor for CKD.1, 2, 3 Many patients with hypertension also have other metabolic conditions, such as diabetes, hyperlipidaemia and obesity, and accumulating evidence suggests that the presence of multiple metabolic conditions increases CKD risk.2, 3, 4, 5, 6 However, prior research has not clarified the extent to which CKD risk may vary among hypertensive patients based on the specific combination of metabolic conditions that are present. We undertook a retrospective cohort study to examine this issue.

Data were obtained from the electronic medical records system of Kaiser Permanente Northwest—a health maintenance organization covering 480 000 persons in the Portland, OR and Vancouver, WA metropolitan area. Available data included member demographics and eligibility, in-patient and outpatient encounters, pharmacy prescriptions and dispenses, cumulative ‘problem lists’, laboratory tests and clinical measurements; all such data are linkable by member, and can be arrayed chronologically.7

The study population consisted of all Kaiser Permanente Northwest members who, in 1998 (‘index year’), were aged 35 years and free of CKD, defined as no GFR measurement <60 ml per min per 1.73 m2 (based on the Modification of Diet in Renal Disease study equation) and the absence of renal replacement therapy.1, 8 Subjects were first stratified according to whether or not they had hypertension in the index year; those with hypertension were further stratified into one of eight cohorts, based on whether or not they also had diabetes, hyperlipidaemia and/or high body mass index in the index year. The presence of these conditions was ascertained on the basis of diagnoses, clinical measurements, laboratory tests and drug prescriptions; a detailed description of case-ascertainment algorithms may be found elsewhere.9 Patients were excluded from the study population if they did not have 1 serum creatinine value recorded during the index year, were not continuously enrolled in Kaiser Permanente Northwest, or were pregnant.

The study outcome, onset of CKD, was ascertained based on two consecutive GFR measurements <60 ml per min per 1.73 m2, separated by at least 90 days, beginning from 1 January 1999 and ending on the date of disenrollment the health plan, death or the end of the observation period (31 December 2004), whichever occurred first.1 Risks of CKD per 1000 person-years for hypertensive and normotensive patients (and corresponding relative risks) were estimated along with 95% confidence intervals. Kaplan–Meier method was employed to depict (unadjusted) time to onset of CKD. Cox proportional hazard models were used to estimate relative risk of CKD for hypertensive patients—overall and by risk-factor cohort—versus normotensive patients, controlling for age, sex, smoking status and baseline GFR.

Of the 54 836 patients in the study population, 62% had hypertension. Mean (s.d.) age of hypertensive patients was 62 (±12.5) years, versus 55 (±12.1) years for normotensive patients. Baseline GFR averaged 87.3 (±18.5) and 90.3 (±18.8) ml per min per 1.73 m2, respectively. Approximately two-thirds of hypertensive patients had at least one additional metabolic condition (Table 1). A complete description of patient characteristics may be found in the Supplementary Information.

Table 1 Unadjusted and adjusted risks of chronic kidney disease

Over a mean follow-up of 4.5 years, unadjusted risk of CKD was 27.6 (95% CI: 25.9–29.3) per 1000 person-years for hypertensive patients, versus 7.0 (5.9–8.1) for normotensive patients; corresponding relative risk was 3.9 (3.6–4.2). For hypertensive patients without additional metabolic conditions, unadjusted CKD risk was 23.8 (22.5–25.2) per 1000 person-years; for patients with additional metabolic conditions, unadjusted CKD risk ranged from 20.8 (19.3–22.4) to 29.0 (26.6–31.5) per 1000 person-years for those without comorbid diabetes, and from 37.1 (33.8–40.7) to 46.2 (41.8–51.0) per 1000 person-years for those with comorbid diabetes. A figure describing unadjusted CKD risks over time may be found in the Supplementary Information. After adjusting for age, sex, smoking status and baseline GFR, overall relative risk of CKD for hypertensive patients (versus normotensive patients) was 2.7 (2.5–2.9). In stratified analyses, relative risks were lowest for patients without comorbid diabetes, ranging from 2.0 (1.8–2.2) for those with hypertension only to 2.6 (2.2–2.9) for those with hypertension, hyperlipidaemia and high body mass index. For those with comorbid diabetes, relative risks ranged from 3.3 (2.9–3.8) for those with hypertension and diabetes to 5.5 (4.9–6.2) for those with hypertension, diabetes, hyperlipidaemia and high body mass index.

Our study of over 50 000 persons found that those with hypertension had a substantially higher risk of developing CKD than those without it (adjusted relative risk, 2.7). While this estimate of relative risk is somewhat higher than that reported in prior research, differences in study designs and patient populations probably explain most of the discrepancy.2, 3

Our study also found that, among patients with hypertension, risk of CKD varies not only according to how many risk factors are present but, more importantly which ones are present. For hypertensive patients without additional metabolic conditions, adjusted relative risk of CKD (versus normotensive patients) was 2.0. For those with one additional metabolic condition, relative risk ranged from 2.4 to 3.3, with the greatest risk of CKD conferred by diabetes, which is not surprising given that diabetic nephropathy has been reported to develop in 20–40% of patients with diabetes.10 For those with two conditions, it ranged from 2.6 to 4.8, again, with diabetes conferring the greatest risk. For those with all three, relative risk of CKD was 5.5. Taken together, our findings indicate that simply counting the number of conditions present—as done in prior research—is less informative than considering each metabolic condition as a discrete entity—whether present alone or in combination with others—when evaluating the risk of CKD among patients with hypertension.2, 3

Several comments regarding our study are noteworthy. First, although broader definitions of CKD exist, we defined onset of CKD based on a GFR measurement <60 ml per min per 1.73 m2 both for convenience and consistency with other studies.1, 2, 3, 11 Moreover, this threshold is associated with a graded increased risk of major adverse outcomes, and thus is an important marker for clinicians.11 Second, because we required that subjects have a serum creatinine value recorded in the index year, study results may not be generalizable to an unselected population of health plan members.9 Third, although proteinuria and blood glucose are important predictors of CKD risk, our analyses did not adjust for differences in these measures between hypertensive patients and normotensive patients. However, our objective was not to identify predictors of CKD risk, per se, but to describe absolute levels of CKD risk for subgroups of hypertensive patients defined on the basis of information readily available to clinicians. Moreover, blood glucose values were available for only about 40% of subjects, who may not be representative of the entire study population. Finally, our study does not attempt to ascertain the extent to which hypertension causes CKD, as the presence of hypertension (at baseline) in many patients may reflect underlying—but undetected—kidney disease, possibly from another cause. Rather, the objective of our study was to describe the risk of CKD over time in a large cohort of hypertensive patients—on an overall basis and for subgroups defined on the basis of specific combinations of metabolic conditions—and their corresponding relative risks versus normotensive patients.

In conclusion, our results suggest that hypertensive patients are at elevated risk of CKD (versus normotensive patients), especially if they have other metabolic conditions, particularly diabetes. Findings from our study may help clinicians target patients who require close monitoring for the development of CKD.

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Acknowledgements

Funding for this research was provided by Novartis Pharma AG.

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Correspondence to D Weycker.

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Supplementary Information accompanies the paper on the Journal of Human Hypertension website (http://www.nature.com/jhh)

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Weycker, D., Nichols, G., O'Keeffe-Rosetti, M. et al. Risk of chronic kidney disease in hypertensive patients with other metabolic conditions. J Hum Hypertens 22, 132–134 (2008) doi:10.1038/sj.jhh.1002276

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