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Is it time to reconsider blood pressure guidelines?Anna Burgner and Julia B. Lewis

The KDIGO recommendation for blood pressure management in patients with chronic kidney disease and proteinuria is based partly on underpowered subgroup and post hoc analyses. New observational data, however, demonstrate that lower blood pressure goals may be harmful in this group of patients.Burgner, A. & Lewis, J. B. Nat. Rev. Nephrol. advance online publication 23 September 2014; doi:10.1038/nrneph.2014.174

Hypertension is not only a frequent cause of chronic kidney disease (CKD), but also often complicates its management. Hypertension is also associated with an increased risk of stroke and heart disease. The optimal systolic blood pressure (SBP) target in both the general population and in those with CKD is a topic of much debate. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the management of blood pressure in CKD cur­rently recom mends targeting a goal blood pressure of ≤140/90 mmHg in patients without albumin uria and ≤130/90 mmHg in patients with albuminuria.1 However, findings from a new, large, observational study of a historical cohort of US veter­ans with CKD with and without protein­uria do not fully support these guidelines; lower SBP goals were associ ated with an increase in all­cause mortality in all patients with CKD.2

The KDIGO guideline that recommends a lower blood pressure target for patients with CKD and proteinuria is based partly on an underpowered subgroup analy­sis of the Modification of Diet in Renal Disease (MDRD) trial. This analysis dem­onstrated a benefit of randomly allocat­ing 158 patients with proteinuria >1 g per 24 h at study entry to a lower blood pres­sure goal, despite no overall benefit seen in the 840 individuals enrolled in the trial as a whole.3 The KDIGO recommendations are also partly based on follow­up studies of the MDRD and African American Study of Kidney Disease and Hypertension (AASK) trials. These studies identified

benefits in participants who had originally been assigned to the lower mean arterial blood pressure target groups (≤92 mmHg), approximately 7 years after cessation of the trials.4,5 Importantly, neither the AASK nor MDRD trials showed a benefit of lower blood pressure in their well­powered, intention­ to­treat analysis of CKD popula­tions during the course of the trials.3,6 Of note, increasing evidence now suggests that lower blood pressure goals are associ­ated with an increased risk of adverse out­comes in patients with CKD, including risk of stroke.

The study by Kovesdy et al.2 provides additional evidence to further suggest potential increased harm with lower blood pressure goals. The researchers studied a historical cohort of 77,765 US veterans with CKD—defined as having an esti­mated glomer ular filtration rate <60 ml/min/1.73 m2 on at least two occasions, or a spot urine microalbumin–creatinine ratio of at least 30 mg/g on at least one occasion—and uncontrolled hypertension. Participants who received an increased number of anti­hypertensive medications during follow­up were categorized to one of two groups on the basis of their subsequent achieved SBPs on at least 50% of follow­up visits: 120–139 mmHg or <120 mmHg. Analyses were performed on the overall cohort and on a propensity­matched cohort over a median follow­up of 6 years. A statistically significant increase in the risk of death was demonstrated in the lower blood pressure group in both the overall cohort and the propensity­matched cohort.

This study has major strengths due to its large sample size and long follow­up period, which exceeds that of most clinical trials. It also has the unarguably clinically meaning­ful outcome of death. In addition, this study did not exclude patients with proteinuria at any level, including >1 g per 24 h. Although the study population consisted largely of white males, previous studies, such as the VA Cooperative Study on Antihypertensive Agents, which examined blood pressure goals in white male veterans, yielded results that were then confirmed in other popula­tions across race, gender and age groups.7 The authors state perhaps too strongly the correlation between findings from observa­tional studies and randomized clinical trials. This study by virtue of its size, length of follow­up and use of a p ropensity­matched cohort analysis increases the likelihood of a correlation. However, the literature contains many examples of observational study results that were not confirmed in large, well­designed randomized clinical trials, such as the benefit of low­protein diets or the benefit of increased doses of erythropoiesis­ stimulating agents to achieve higher haemoglobin levels.

The study by Kovesdy et  al. is not with out limitations. Participants could enter the cohort with one elevated spot microalbumin– creatinine ratio. Thus, some patients without CKD, who had merely

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transient microalbuminuria (as seen in settings such as fever and congestive heart failure [CHF]), were likely enrolled. More participants had cardiovascular disease, dia­betes and CHF in the low blood pressure group at baseline. Although the propen­sity­matched cohort controls for this base­line discrepancy, no control exists for the develop ment of these conditions over the course of the observation period. The devel­opment of CHF, for example, could have led to a participant developing lower blood pressure as a result of receiving additional antihypertensive agents for CHF treat­ment. Their increased risk of death could therefore be related to CHF rather than to their lower blood pressure. Rarely are clinic blood pressure measurement techniques in accordance with guidelines for measuring blood pressure in clinical trials; correlating the blood pressures achieved in this study with clinical trial data is therefore diffi­cult.8 Participants in the two groups were on the same number of medications at the end of the study. This finding could be due to many factors intrinsic to the individu­als, dosing of medications, or confound­ing diagnoses such as heart or liver failure. Lastly, unfortunately no attempt was made to assess if the increased risk of death in the lower blood pressure group remained sig­nificant if the participants were further sub­divided based upon the presence or absence of proteinuria.

An argument could certainly be made that this properly conducted, well analyzed, observational study, which was performed with statistical rigor, provides stronger evi­dence than that on which current guidelines are based, namely a sub­group analysis of clinical trials in which the intention­to­treat population as a whole received no benefit and post hoc analyses of study populations in which no benefit could be discerned until years after the close of the trial. The ongoing Systolic Blood Pressure INTervention (SPRINT) trial should provide further data in this area.9 For now, the question is, should the findings from this well­done, large observational study trump the afore­mentioned clinical trial results in creating guidelines? With the mounting associ ation of harm with lower blood pressure goals and the lack of hard evidence to show benefit with the lower goals, it might be time to reconsider blood pressure goals in patients with CKD, at least until further evidence is obtained.

Division of Nephrology and Hypertension, Vanderbilt University Medical Center, 1161 21st Avenue South, S‑3223 Medical Center North, Nashville, TN 37232, USA (A.B., J.B.L.). Correspondence to: J.B.L. julia.b.lewis@vanderbilt.edu

Competing interestsA.B. and J.B.L. have received research support from the NIH/NHLBI Systolic Blood Pressure INTervention Trial (SPRINT) HHSN268200900046C.

1. KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. Suppl. 2, 337–414 (2012).

2. Kovesdy, C. P. et al. Observational modeling of strict vs conventional blood pressure control in patients with chronic kidney disease. JAMA Intern. Med. http://dx.doi.org/10.1001/jamainternmed.2014.3279.

3. Klahr, S. et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N. Engl. J. Med. 330, 877–884 (1994).

4. Sarnak, M. J. et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann. Intern. Med. 142, 342–351 (2005).

5. Appel, L. J. et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N. Engl. J. Med. 363, 918–929 (2010).

6. Wright, J. T. Jr et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 288, 2421–2431 (2002).

7. [No authors listed] Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mmHg. JAMA 202, 1028–1034 (1967).

8. Umanath, K., Burgner, A., Lewis, J. B. & Dwyer, J. P. Guidelines and straitjackets: blood pressure targets in the era of the eighth Joint National Committee. Am. J. Kidney Dis. 63, 895–899 (2014).

9. Ambrosius, W. T. et al. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: The Systolic Blood Pressure Intervention Trial (SPRINT). Clin. Trials http://dx.doi.org/10.1177/1740774514537404.

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