Journal of Human Hypertension (2014) 28, 427–431 & 2014 Macmillan Publishers Limited All rights reserved 0950-9240/14 www.nature.com/jhh
ORIGINAL ARTICLE
Decreased renal function in hypertensive emergencies U Derhaschnig1,2, C Testori1, E Riedmueller1, EL Hobl2, FB Mayr2 and B Jilma2 Data about acute renal function in hypertensive crises are scarce. We hypothesised that acute kidney damage could result from hypertensive emergency (HE), as indicated by the earliest biomarker of kidney injury, neutrophil gelatinase-associated lipocalin (NGAL). Thus, we compared renal function between patients with HE, patients with urgencies and normotensive controls. Sixty emergency department patients were enroled in a prospective, cross-sectional study. Creatinine, blood urea nitrogen (BUN), NGAL and cystatin C were measured and estimated glomerular filtration rate was calculated (eGFR). Creatinine and BUN were significantly higher and eGFR was significantly lower in HE as compared with urgencies or controls (Po0.01). Similarly, cystatin C and NGAL levels were significantly higher in emergencies compared with the other groups (Po0.001). All renal function parameters were similar between urgencies and controls. Among HE, NGAL was significantly higher (61%) in patients with pulmonary oedema than in those with cerebral events (P ¼ 0.008), whereas the other parameters were not significantly different. In conclusion, this crosssectional investigation showed that markers of acute and chronic kidney injury were higher in patients with HE than in urgencies or controls. These results should encourage further studies to better characterise the role of acute kidney damage in hypertensive pulmonary oedema, and HE in general. Journal of Human Hypertension (2014) 28, 427–431; doi:10.1038/jhh.2013.132; published online 16 January 2014 Keywords: acute kidney injury; cystatin C; hypertensive emergency; neutrophil gelatinase-associated lipocalin; renal
INTRODUCTION Hypertensive crisis is an acute life-threatening condition. It is currently estimated that 1–2% of patients with hypertension will suffer a hypertensive crisis at some time in their life.1 However, the pathogenesis of hypertensive crisis is poorly understood. It is thought that hypertensive crisis is initiated by an abrupt increase in vascular resistance likely related to humoral vasoconstrictors.2,3 The activation of the renin–angiotensin–aldosterone system seems to be important in this respect.3–5 At the end, the initial vasodilator response of the pre-damaged endothelium is overwhelmed and endothelial decompensation occurs, which in turn leads to a further rise in blood pressure (BP) and endothelial damage.6,7 The result of this vicious cycle can be end-organ hypoperfusion, ischaemia and dysfunction that manifests as hypertensive emergency (HE).1 The kidney plays a central role in BP regulation, not only as an endocrine organ but also as an organ affected by hypertension, and renal function is a predictor of cardiovascular risk in essential hypertension.8 In patients with malignant hypertension, renal dysfunction is commonly observed9 and blood urea nitrogen (BUN) was found to predict mortality.10 Recently, a retrospective study has shown that acute kidney injury is a frequent form of organ damage in severe hypertension.11 A rise in creatinine was particularly seen in patients with pre-existing advanced kidney disease. We hypothesised that subtle acute kidney damage, as indicated by higher levels of the earliest biomarker of kidney injury, neutrophil gelatinase-associated lipocalin (NGAL),12–14 could occur in patients with HE irrespective of the type of end-organ damage. We therefore prospectively compared renal function parameters between patients with HE and hypertensive urgencies (HU) and controls attending a non-surgical emergency department in a cross-sectional study.
MATERIALS AND METHODS Study population The study was conducted at the intensive care unit of the non-surgical emergency department of the Medical University of Vienna, a tertiary care facility. It was approved by the local ethics committee and all participants gave written informed consent. The study population was recently described:15 Sixty patients were enrolled over a period of 1 year: 20 consecutive patients with HE and two different control groups comprising 20 consecutive patients with HU and 20 normotensive patients, who attended the emergency department for other reasons: gastritis (n ¼ 2), back pain (n ¼ 8), needlestick injury (n ¼ 1), follow-up after needlestick injury (n ¼ 8), electric shock (n ¼ 1). The BP of patients was measured within the scope of intermediate or intensive care with an automated device (Hewlett-Packard, Palo Alto, CA USA). HE was defined as critical elevation of BP (systolic BP 4179 mm Hg and/ or diastolic BP4109 mm Hg) with target organ dysfunction (that is, acute pulmonary oedema, coronary ischaemia, hypertensive encephalopathy, cerebral infarction, intracerebral haemorrhage, aortic dissection or acute renal failure, defined by the RIFLE criteria).16,17 HU was defined as severe elevation in BP (s. above) without evidence of target organ deterioration.17 Twenty normotensives (that is, no history of hypertension or intake of antihypertensive drugs, a BP o130/85 mm Hg measured twice with standard equipment by a physician or trained nurse after 5 min of resting in sitting position, who had no history of severe chronic disease, diabetes mellitus, pre-existent cardiovascular disease, cancer, acute infectious disease or other relevant medical illness and a normal physical examination) served as controls. Exclusion criteria were refusal or inability to give informed consent, preeclampsia and eclampsia,17 clinical pattern and additional laboratory signs of acute inflammatory disease (that is, initial elevation of C-reactive protein 410 mg l 1 or fibrinogen 44.5 g l 1) and known, either by selfreport or medical records, chronic kidney disease (CKD) stage 3B or higher. Blood was sampled directly after admission at the emergency department before any relevant intervention. All routine laboratory and
1 Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria and 2Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Correspondence: Professor B Jilma, Department of Clinical Pharmacology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, Vienna A-1090, Austria. E-mail: [email protected] Received 19 April 2013; revised 31 October 2013; accepted 15 November 2013; published online 16 January 2014
Renal function in hypertensive emergencies U Derhaschnig et al
428 diagnostic/therapeutic interventions were performed as appropriate and under the discretion of the attending physician. The final diagnosis of HE/ HU was confirmed by a second independent physician, blinded to the initial clinical diagnosis, after discharge of the patient on the basis of chart review.
Laboratory analyses Blood samples were drawn into sterile evacuated tubes (Vacutainer, BD, NJ, USA) containing EDTA or citrate. Analyses of creatinine and BUN were carried out by routine laboratory examinations (Beckman Coulter, Krefeld, FRG). Samples for cystatin C and NGAL measurements were immediately centrifuged at 3000 g for 15 min and then stored as 0.5 ml aliquots at 80 1C until batch analysis. Cystatin C and NGAL were measured by enzyme-linked immunosorbent assays (ELISA) according to the manufacturer’s instructions. For the cystatin C ELISA (R&D Systems, MN, USA) the limit of detection was 0.102 ng ml 1, intra-assay precision was 3.1–6.6% and inter-assay precision was 5–7%. For the NGAL ELISA (BioPorto, Gentofte, Denmark), the limit of detection was 1.6 pg ml 1, intra-assay variation was 2.8–4.5% and inter-assay variation was 4.4–4.6%. Estimated glomerular filtration rate (eGFR) was calculated using the CKD epidemiology collaboration equations.18
Statistical analysis As data on NGAL levels in hypertensive patients are scarce, a sample size calculation was based on a previous publication presenting creatinine levels in hypertensive patients.19 Assuming a common s.d. of 0.3 mg dl 1 a sample size of 19 was adequate to detect a 32% higher creatinine level (primary outcome variable) in HE as compared with controls or HU ((1-b) of 0.8 for Po0.05). Continuous data are given as median and quartile range and categorical data as frequencies and percentages. Testing for normal distribution is difficult in sample sizes o25. Thus, in order to obtain conservative results, nonparametric tests were used. The Kruskal–Wallis ANOVA and the Mann– Whitney U-test were applied for the comparison of continuous variables between groups. Dichotomous variables were compared with the w2-test or Fisher’s exact test as appropriate. The Spearman rank correlation test was used to correlate renal function parameters in patients with HE (SPSS 16.0, SPSS Inc., Chicago, IL, USA). Although the measured renal function parameters are interdependent, we applied the Bonferroni–Holm procedure to account for multiple comparisons of the four biomarkers.20
RESULTS Nineteen patients with HE, 20 with HU and 20 normotensive controls were finally analysed (1 HE patient had to be excluded
Table 1.
from analysis because of incorrectly processed blood samples). Demographic data are shown in Table 1. There were no significant differences in age, body mass index, smoking habits or sex distribution between groups (Table 1). However, normotensives showed a tendency to have lower body mass index and to be younger. This simply reflects the risk factors for hypertension in our patient population. Thus, the main comparison was made between patients with HU and HE. Clinical characteristics of HU and HE are depicted in Table 2. History of cardiovascular disease, duration of hypertension, number of previous hypertensive crises and type of antihypertensive therapy were equally distributed between patients with HU and HE (PX0.3 for all comparisons). There were significantly more patients with diabetes in the emergency group as compared with the urgency group (Po0.05). Initial systolic and diastolic BP were significantly higher in HE than in HU (Po0.009 for both parameters, Table 1). The average reduction in systolic BP was 32% in HE and 18% in HU, and the average diastolic BP reduction was 34 and 7%, respectively. Pulmonary oedema was the most frequent end-organ damage seen in HE (53%), followed by hypertensive intracerebral haemorrhage (26%). No patient was diagnosed as having HE with acute renal failure according to the RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria. Conventional renal function tests Creatinine levels in the emergency group were 37% higher than in the control group and 28% higher than in the HU group (Po0.001 and P ¼ 0.002, resp.). Likewise, BUN was 42% higher in HE patients than in controls and 58% higher than in the HU group (Po0.02 for both comparisons, Figure 1). eGFR values were 28 and 22% lower in HE as compared with controls or HU, respectively (Pp0.002 for all parameters; Figure 1). In contrast, there were no significant differences in creatinine, BUN and eGFR between normotensives and patients with urgencies (P ¼ 0.68, 0.28 and 0.95, respectively, Figure 1). Novel renal markers Cystatin C was 64% higher in HE than in normotensives and 47% higher than in HU (Po0.001 for both comparisons, Figure 1). NGAL levels were 57% higher in HE as compared with controls or HU (P ¼ 0.003 and Po0.001, respectively, Figure 1).
Demographics and medical history Normotensives (n ¼ 20)
Hypertensive urgencies (n ¼ 20)
Hypertensive emergencies (n ¼ 19)
P-value
55 (15) 11/8 125 (11) 72 (15) 24.5 (5.6) 12 0 0 0 0
57 (15) 10/10 190 (11) 95 (31) 28.7 (7) 7 4 0 36 (131) 10
61 (29) 7/12 200 (40) 105 (20) 29.4 (7.2) 6 5 4 36 (120) 11
X0.4a,b; 0.1c X0.3a,b,c o0.001a,b; 0.002c o0.001a,b; 0.008c X0.08a,b; 0.4c 40.1a,b,c 0.1a; 0.02b; 0.7c 1.0a; 0.04b; 0.04c o0.001a,b; 0.8c o0.001a,b; 0.8c
0 0 0
12 5 3
14 6 4
o0.001a,b; 0.5c 0.04a; 0.008b; 0.7c 0.2a; 0.04b; 0.7
Age (years) Sex (F/M) SBP (mm Hg) DBP (mm Hg) BMI (kg m 2) Smoker (n) CVD (n) DM (n) Duration of hypertension (months) History of previous crisis (n) Cardiovascular medication before admission (n) Antihypertensives (n) Antiplatelet drugs (n) Statins (n)
Abbreviations: BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; DM, diabetes mellitus; SBP, systolic blood pressure. Data are given as median and quartile range. aNormotensives vs hypertensive urgencies. bNormotensives vs hypertensive emergencies. cHypertensive urgencies vs hypertensive emergencies.
Journal of Human Hypertension (2014) 427 – 431
& 2014 Macmillan Publishers Limited
Renal function in hypertensive emergencies U Derhaschnig et al
429 Similar to creatinine, BUN and eGFR, there were no statistically significant differences in cystatin C and NGAL levels between normotensive controls and patients with HU (P ¼ 0.3 and 0.8, respectively, Figure 1).
Table 2. Clinical characteristics of hypertensive urgencies and emergencies Hypertensive urgencies (n ¼ 20) Antihypertensive medication before admission (n, %) No antihypertensive medication 8 (40) ACE-Inhibitor 6 (30) AT II receptor blocker 3 (15) Diuretics 3 (15) -Blocker 7 (35) a-Blocker 2 (10) Calcium channel antagonists 1 (5) Combination of antihypertensive 7 (35) medication 2 Antihypertensives 2 (10) 3 Antihypertensives 5 (25) 43 Antihypertensives 0 Clinical presentation SBP reduction (mm Hg; %) DBP reduction (mm Hg; %) End-organ damage (on admission) Cardiac (n; %) Pulmonary oedema (n) Angina (n) Cerebral (n; %) Hypertensive intracerebral haemorrhage (n) Subarachnoidal haemorrhage (n) Transient ischaemic attack (n) Acute renal failure (n)
40 (34) (17.6) 22 (3) (7)
Hypertensive emergencies (n ¼ 19) 5 6 3 4 5 4
(26) (32) (16) (21) (26) (21) 0 7 (37)
2 (10.5) 4 (21) 1 (5) 70 (39) (31.5)* 40 (25) (34) 12 (63) 11 1 7 (37) 5 1 1 0
Abbreviations: ACE, angiotensin converting enzyme; ATII, angiotensin II; DBP, diastolic blood pressure; SBP, systolic blood pressure. Data are given as median and quartile range; *Po0.05.
Renal function in patients with pulmonary oedema and cerebral events NGAL was significantly higher (61%) in HE patients with pulmonary oedema (n ¼ 11) than in HE patients with cerebral events (n ¼ 7; P ¼ 0.008), whereas the other renal function parameters were not significantly different (Table 3; P40.1 for all parameters). Similarly, no significant difference was found for age, body mass index, duration of hypertension and BP on admission (Table 3). We performed a sensitivity analysis to describe a possible influence of history of diabetes on renal parameters in hypertensive crises. Even after exclusion of patients with diabetes, all renal function parameters remained significantly different between HE and controls or HU patients (Po0.05 for all parameters). Correlations were calculated between renal function tests in patients with HE. Levels of determination ranged from r2 ¼ 0.36 for creatinine vs NGAL to r2 ¼ 0.53 between eGFR and cystatin C (Po0.01 for all parameters except for BUN, which was only borderline significant). DISCUSSION To our knowledge this is the first prospective cross-sectional investigation of renal function in HE. These data extend a retrospective analysis that showed a 425% decrement in renal function in approximately 1/3 of patients with acute severe hypertension.11 Renal function, measured by conventional and novel biomarkers, was decreased in our patients with HE as compared with urgencies or controls (Figure 1). In contrast, renal function parameters were not different between patients with HU and normotensive controls (Figure 1). However, inclusion of both of these groups makes the study design more robust. Although hypertensive crisis is a common event in emergency medicine,7 little is known about its pathogenesis, and most experimental models relate rather to malignant hypertension and nephrosclerosis than to hypertensive crisis encountered in the clinical scenario.21,22 The rapidity of BP elevation suggests a triggering factor superimposed on pre-existing hypertension1 and is thought to be initiated by an increase in vascular resistance due to humoral vasoconstrictors.2,3
Figure 1. Patients with hypertensive emergencies have renal dysfunction as compared to hypertensive urgencies or controls. BUN, blood urea nitrogen, eGFR, estimated glomerular filtration rate, NGAL, neutrophil gelatinase-associated lipocalin; Data are presented as mean±95% CI; ** indicates Po0.01 vs controls and urgenices. Note: blood urea nitrogen in mg dl 1 to mmol l 1, 0.347. & 2014 Macmillan Publishers Limited
Journal of Human Hypertension (2014) 427 – 431
Renal function in hypertensive emergencies U Derhaschnig et al
430 Table 3.
Renal function in hypertensive emergency patients with cerebral events or pulmonary oedema Cerebral event (n ¼ 7) Age (years) Duration of hypertension (mo) SBP (mm Hg) DBP (mm Hg) Creatinine (mg dl 1) BUN (mg dl 1) Cystatin C (ng ml 1) NGAL (ng ml 1)
Pulmonary oedema (n ¼ 11)
50 (20) 36 (60) 200 105 1.06 21 983 109
(35) (30) (0.4) (6) (654) (79)
65 (22) 36 (120) 210 105 1.18 20 1254 194
(50) (20) (0.4) (14) (401) (78)
P-value 0.2 0.9 1.0 0.9 0.2 0.5 0.1 0.008
Abbreviations: BUN, blood urea nitrogen; DBP, diastolic blood pressure; NGAL, neutrophil gelatinase-associated lipocalin; SBP, systolic blood pressure. Data are given as median and quartile range. Conversion factors for units: creatinine in mg dl 1 to mol l 1, 88.4 , blood urea nitrogen in mg dl 1 to mmol l 1, 0.347.
There are two not mutually exclusive explanations for impaired renal function in HE. First, compromised renal function may facilitate the development of HE. Second, a hypertensive crisis may acutely damage the kidney. Interestingly, patients with hypertensive pulmonary oedema had significantly higher NGAL levels as compared with patients with hypertensive intracerebral haemorrhage. NGAL is produced by renal tubular cells in response to different types of injury14 and is considered to be an excellent marker of acute kidney injury.12,23 Serum levels of NGAL have recently been identified as a sensitive marker to predict acute kidney injury after cardiac surgery24 and are able to differentiate between CKD and acute kidney injury.25 Thus, the elevated NGAL levels support the concept that acutely compromised renal function may contribute to the pathogenesis of hypertensive pulmonary oedema. However, the duration of severe hypertension in patients with hypertensive intracerebral haemorrhage is possibly shorter lived than that of patients with pulmonary oedema. It cannot be excluded that differences in NGAL levels are attributable to possible differences in the duration of acute severe hypertension before admission to the hospital. Yet, NGAL is considered the earliest marker of acute renal injury,12 and rises 2 h after contrast media-induced renal damage.26 Alternatively, elevated levels of NGAL may be an expression of impending worsening of renal function during acute heart failure, as described in the literature.27 However, acute hypertensive pulmonary oedema is characterised by preserved left ventricular systolic function and cardiac output.28,29 Pressure elevations, as occuring in acute hypertensive pulmonary oedema, require an increase in either vascular resistance or vascular volume.29 A retrospective analysis of patients with acute hypertensive heart failure revealed that they more commonly had a history of CKD (49% with an average creatinine level of 1.9 mg dl 1 (168 mmol l 1)) as compared with those without heart failure.30 In contrast, none of our patients had a history of advanced CKD, although increased levels of creatinine (on average 1.18 mg dl 1 (104.3 mmol l 1)), BUN and cystatin C may also reflect subtle chronic renal damage.31 NGAL is considered to be a biomarker of the cardio-renal axis31,32 and 10–20% higher levels of NGAL are found in chronic and acute heart failure.33 Thus, this limited increase in NGAL in acute heart failure unlikely explains the 61% increased NGAL levels in our patients with acute pulmonary oedema. There were more patients with a history of diabetes in the HE group (Table 1). However, even after exclusion of patients with diabetes, all renal function parameters remained significantly different between HE and controls or HU patients. Journal of Human Hypertension (2014) 427 – 431
Limitations of the study include the cross-sectional design, which does not allow conclusions on cause-effect relationships. Obviously, it is unethical to demonstrate in humans that an experimental severe increase in BP to levels found in HE causes renal damage. However, animal trials clearly showed that experimental severe hypertension can cause renal damage within a few days.34,35 Within a time frame of one additional day, mean arterial BP even increased from 132 to 156 mm Hg, and hypertensive crisis including renal failure developed in the dog study.35 A second limitation is the limited sample size, which was driven by a sample size calculation but does not allow for any regression analysis. Further, the limited sample size may prevent achievement of a (otherwise possible) statistical difference in age between HE and HU. Finally, we excluded patients with CKD only by medical history and who had no previous data on renal function and proteinuria/ albuminuria. Hence, we cannot entirely exclude the probability of having missed patients with undiagnosed CKD. In conclusion, this is the first prospective cross-sectional investigation of renal function in hypertensive crisis. It demonstrated that markers of acute and chronic kidney injury are higher in HE patients even without a history of CKD than in patients presenting with HU or normotensive controls. The results from this study should encourage further investigations to better characterise the role of acute kidney damage in the pathogenesis of hypertensive pulmonary oedema and HE in general.
What is known about the topic? The kidney has a central role in BP regulation. Acute kidney injury is a frequent form of organ damage in severe hypertension. Prospective data of acute renal function in HE and HU are scarce. What this study adds? Patients with HE have decreased renal function as compared with patients with HU. Among HE the earliest marker of acute kidney injury, NGAL, was highest in patients with pulmonary oedema.
CONFLICT OF INTEREST The authors declare no conflict of interest
ACKNOWLEDGEMENTS We want to thank Karin Petroczi and Astrid Fabry for their valuable laboratory work. This project was supported in part by a research grant (no. 701) of the Austrian heart fund dedicated to UD.
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431 9 van den Born BJ, Koopmans RP, van Montfrans GA. The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension. Am J Hypertens 2007; 20: 900–906. 10 Lip GY, Beevers M, Beevers DG. Complications and survival of 315 patients with malignant-phase hypertension. J Hypertens 1995; 13: 915–924. 11 Szczech LA, Granger CB, Dasta JF, Amin A, Peacock WF, McCullough PA et al. Acute kidney injury and cardiovascular outcomes in acute severe hypertension. Circulation 2010; 121: 2183–2191. 12 Haase M, Bellomo R, Haase-Fielitz A. Neutrophil gelatinase-associated lipocalin. Curr Opin Crit Care 2010; 16: 526–532. 13 Parikh CR, Devarajan P. New biomarkers of acute kidney injury. Crit Care Med 2008; 36: S159–S165. 14 Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A et al. Neutrophil gelatinase- associated lipocalin (NGAL) as marker of kidney damage. Am J Kidney Dis 2008; 52: 595–605. 15 Derhaschnig U, Testori C, Riedmueller E, Aschauer S, Wolzt M, Jilma B. Hypertensive emergencies are associated with elevated markers of inflammation, coagulation, platelet activation and fibrinolysis. J Hum Hypertens 2012; 27: 368–373. 16 Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–R212. 17 The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153: 154–183. 18 Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF, Feldman HI et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604–612. 19 Malyszko J, Bachorzewska-Gajewska H, Malyszko JS, Pawlak K, Dobrzycki S. Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in hypertensive and normotensive patients with coronary artery disease. Nephrol 2008; 13: 153–156. 20 Holm S. A simple sequential rejective multiple test procedure. Scand J Stat 1979; 6: 65–70. 21 Houston M. Hypertensive emergencies and urgencies: pathophysiology and clinical aspects. Am Heart J 1986; 111: 205–210. 22 Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med 1990; 323: 1177–1183.
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23 Coca SG, Yalavarthy R, Concato J, Parikh CR. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008; 73: 1008–1016. 24 Haase-Fielitz A, Bellomo R, Devarajan P, Story D, Matalanis G, Dragun D et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery-A prospective cohort study. Crit Care Med 2009; 37: 553–560. 25 Nickolas TL, O’Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Int Med 2008; 148: 810–819. 26 Malyszko J, Bachorzewska-Gajewska H, Poniatowski B, Malyszko LS. Urinary and serum biomarkers after cardiac catheterization in diabetic patients with stable angina and without severe chronic kidney disease. Ren Fail 2009; 31: 910–919. 27 Aghel A, Shrestha K, Mullens W, Borowski A, Tang WH. Serum neutrophil gelatinase-associated lipocalin (NGAL) in predicting worsening renal function in acute decompensated heart failure. J Card Failure 2010; 16: 49–54. 28 Ford LE. Acute hypertensive pulmonary edema: a new paradigm. Can J Physiol Pharmacol 2010; 88: 9–13. 29 Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin KM. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344: 17–22. 30 Peacock F, Amin A, Granger CB, Granger CB, Pollack CV, Jr., Levy P et al. Stat Investigators. Hypertensive heart failure: patient characteristics, treatment, and outcomes. Am J Emerg Med 2010; 29: 855–862. 31 Peralta CA, Whooley MA, Ix JH, Shlipak MG. Kidney function and systolic blood pressure new insights from cystatin C: data from the heart and soul study. Am J Hypertens 2006; 19: 939–946. 32 Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM et al. Acute Dialysis Quality Initiative (ADQI) consensus group. Cardio-renal syndromes report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010; 31: 703–711. 33 Yndestad A, Landro L, Ueland T, Dahl CP, Flo TH, Vinge LE et al. Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure. Eur Heart J 2009; 30: 1229–1236. 34 Boesen EI, Pollock JS, Pollock DM. Contrasting effects of intervention with TEA and ETB receptor antagonists in hypertension induced by angiotensin II and high-salt diet. Can J Physiol Pharmacol 2010; 88: 802–807. 35 Lohmeier TE, Tillman LJ, Carroll RG, Brown AJ, Guyton AC. Malignant hypertensive crisis induced by chronic intrarenal norepinephrin infusion. Hypertension 1984; 6: 177–182.
Journal of Human Hypertension (2014) 427 – 431
ORIGINAL ARTICLE
Decreased renal function in hypertensive emergencies U Derhaschnig1,2, C Testori1, E Riedmueller1, EL Hobl2, FB Mayr2 and B Jilma2 Data about acute renal function in hypertensive crises are scarce. We hypothesised that acute kidney damage could result from hypertensive emergency (HE), as indicated by the earliest biomarker of kidney injury, neutrophil gelatinase-associated lipocalin (NGAL). Thus, we compared renal function between patients with HE, patients with urgencies and normotensive controls. Sixty emergency department patients were enroled in a prospective, cross-sectional study. Creatinine, blood urea nitrogen (BUN), NGAL and cystatin C were measured and estimated glomerular filtration rate was calculated (eGFR). Creatinine and BUN were significantly higher and eGFR was significantly lower in HE as compared with urgencies or controls (Po0.01). Similarly, cystatin C and NGAL levels were significantly higher in emergencies compared with the other groups (Po0.001). All renal function parameters were similar between urgencies and controls. Among HE, NGAL was significantly higher (61%) in patients with pulmonary oedema than in those with cerebral events (P ¼ 0.008), whereas the other parameters were not significantly different. In conclusion, this crosssectional investigation showed that markers of acute and chronic kidney injury were higher in patients with HE than in urgencies or controls. These results should encourage further studies to better characterise the role of acute kidney damage in hypertensive pulmonary oedema, and HE in general. Journal of Human Hypertension (2014) 28, 427–431; doi:10.1038/jhh.2013.132; published online 16 January 2014 Keywords: acute kidney injury; cystatin C; hypertensive emergency; neutrophil gelatinase-associated lipocalin; renal
INTRODUCTION Hypertensive crisis is an acute life-threatening condition. It is currently estimated that 1–2% of patients with hypertension will suffer a hypertensive crisis at some time in their life.1 However, the pathogenesis of hypertensive crisis is poorly understood. It is thought that hypertensive crisis is initiated by an abrupt increase in vascular resistance likely related to humoral vasoconstrictors.2,3 The activation of the renin–angiotensin–aldosterone system seems to be important in this respect.3–5 At the end, the initial vasodilator response of the pre-damaged endothelium is overwhelmed and endothelial decompensation occurs, which in turn leads to a further rise in blood pressure (BP) and endothelial damage.6,7 The result of this vicious cycle can be end-organ hypoperfusion, ischaemia and dysfunction that manifests as hypertensive emergency (HE).1 The kidney plays a central role in BP regulation, not only as an endocrine organ but also as an organ affected by hypertension, and renal function is a predictor of cardiovascular risk in essential hypertension.8 In patients with malignant hypertension, renal dysfunction is commonly observed9 and blood urea nitrogen (BUN) was found to predict mortality.10 Recently, a retrospective study has shown that acute kidney injury is a frequent form of organ damage in severe hypertension.11 A rise in creatinine was particularly seen in patients with pre-existing advanced kidney disease. We hypothesised that subtle acute kidney damage, as indicated by higher levels of the earliest biomarker of kidney injury, neutrophil gelatinase-associated lipocalin (NGAL),12–14 could occur in patients with HE irrespective of the type of end-organ damage. We therefore prospectively compared renal function parameters between patients with HE and hypertensive urgencies (HU) and controls attending a non-surgical emergency department in a cross-sectional study.
MATERIALS AND METHODS Study population The study was conducted at the intensive care unit of the non-surgical emergency department of the Medical University of Vienna, a tertiary care facility. It was approved by the local ethics committee and all participants gave written informed consent. The study population was recently described:15 Sixty patients were enrolled over a period of 1 year: 20 consecutive patients with HE and two different control groups comprising 20 consecutive patients with HU and 20 normotensive patients, who attended the emergency department for other reasons: gastritis (n ¼ 2), back pain (n ¼ 8), needlestick injury (n ¼ 1), follow-up after needlestick injury (n ¼ 8), electric shock (n ¼ 1). The BP of patients was measured within the scope of intermediate or intensive care with an automated device (Hewlett-Packard, Palo Alto, CA USA). HE was defined as critical elevation of BP (systolic BP 4179 mm Hg and/ or diastolic BP4109 mm Hg) with target organ dysfunction (that is, acute pulmonary oedema, coronary ischaemia, hypertensive encephalopathy, cerebral infarction, intracerebral haemorrhage, aortic dissection or acute renal failure, defined by the RIFLE criteria).16,17 HU was defined as severe elevation in BP (s. above) without evidence of target organ deterioration.17 Twenty normotensives (that is, no history of hypertension or intake of antihypertensive drugs, a BP o130/85 mm Hg measured twice with standard equipment by a physician or trained nurse after 5 min of resting in sitting position, who had no history of severe chronic disease, diabetes mellitus, pre-existent cardiovascular disease, cancer, acute infectious disease or other relevant medical illness and a normal physical examination) served as controls. Exclusion criteria were refusal or inability to give informed consent, preeclampsia and eclampsia,17 clinical pattern and additional laboratory signs of acute inflammatory disease (that is, initial elevation of C-reactive protein 410 mg l 1 or fibrinogen 44.5 g l 1) and known, either by selfreport or medical records, chronic kidney disease (CKD) stage 3B or higher. Blood was sampled directly after admission at the emergency department before any relevant intervention. All routine laboratory and
1 Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria and 2Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Correspondence: Professor B Jilma, Department of Clinical Pharmacology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, Vienna A-1090, Austria. E-mail: [email protected] Received 19 April 2013; revised 31 October 2013; accepted 15 November 2013; published online 16 January 2014
Renal function in hypertensive emergencies U Derhaschnig et al
428 diagnostic/therapeutic interventions were performed as appropriate and under the discretion of the attending physician. The final diagnosis of HE/ HU was confirmed by a second independent physician, blinded to the initial clinical diagnosis, after discharge of the patient on the basis of chart review.
Laboratory analyses Blood samples were drawn into sterile evacuated tubes (Vacutainer, BD, NJ, USA) containing EDTA or citrate. Analyses of creatinine and BUN were carried out by routine laboratory examinations (Beckman Coulter, Krefeld, FRG). Samples for cystatin C and NGAL measurements were immediately centrifuged at 3000 g for 15 min and then stored as 0.5 ml aliquots at 80 1C until batch analysis. Cystatin C and NGAL were measured by enzyme-linked immunosorbent assays (ELISA) according to the manufacturer’s instructions. For the cystatin C ELISA (R&D Systems, MN, USA) the limit of detection was 0.102 ng ml 1, intra-assay precision was 3.1–6.6% and inter-assay precision was 5–7%. For the NGAL ELISA (BioPorto, Gentofte, Denmark), the limit of detection was 1.6 pg ml 1, intra-assay variation was 2.8–4.5% and inter-assay variation was 4.4–4.6%. Estimated glomerular filtration rate (eGFR) was calculated using the CKD epidemiology collaboration equations.18
Statistical analysis As data on NGAL levels in hypertensive patients are scarce, a sample size calculation was based on a previous publication presenting creatinine levels in hypertensive patients.19 Assuming a common s.d. of 0.3 mg dl 1 a sample size of 19 was adequate to detect a 32% higher creatinine level (primary outcome variable) in HE as compared with controls or HU ((1-b) of 0.8 for Po0.05). Continuous data are given as median and quartile range and categorical data as frequencies and percentages. Testing for normal distribution is difficult in sample sizes o25. Thus, in order to obtain conservative results, nonparametric tests were used. The Kruskal–Wallis ANOVA and the Mann– Whitney U-test were applied for the comparison of continuous variables between groups. Dichotomous variables were compared with the w2-test or Fisher’s exact test as appropriate. The Spearman rank correlation test was used to correlate renal function parameters in patients with HE (SPSS 16.0, SPSS Inc., Chicago, IL, USA). Although the measured renal function parameters are interdependent, we applied the Bonferroni–Holm procedure to account for multiple comparisons of the four biomarkers.20
RESULTS Nineteen patients with HE, 20 with HU and 20 normotensive controls were finally analysed (1 HE patient had to be excluded
Table 1.
from analysis because of incorrectly processed blood samples). Demographic data are shown in Table 1. There were no significant differences in age, body mass index, smoking habits or sex distribution between groups (Table 1). However, normotensives showed a tendency to have lower body mass index and to be younger. This simply reflects the risk factors for hypertension in our patient population. Thus, the main comparison was made between patients with HU and HE. Clinical characteristics of HU and HE are depicted in Table 2. History of cardiovascular disease, duration of hypertension, number of previous hypertensive crises and type of antihypertensive therapy were equally distributed between patients with HU and HE (PX0.3 for all comparisons). There were significantly more patients with diabetes in the emergency group as compared with the urgency group (Po0.05). Initial systolic and diastolic BP were significantly higher in HE than in HU (Po0.009 for both parameters, Table 1). The average reduction in systolic BP was 32% in HE and 18% in HU, and the average diastolic BP reduction was 34 and 7%, respectively. Pulmonary oedema was the most frequent end-organ damage seen in HE (53%), followed by hypertensive intracerebral haemorrhage (26%). No patient was diagnosed as having HE with acute renal failure according to the RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria. Conventional renal function tests Creatinine levels in the emergency group were 37% higher than in the control group and 28% higher than in the HU group (Po0.001 and P ¼ 0.002, resp.). Likewise, BUN was 42% higher in HE patients than in controls and 58% higher than in the HU group (Po0.02 for both comparisons, Figure 1). eGFR values were 28 and 22% lower in HE as compared with controls or HU, respectively (Pp0.002 for all parameters; Figure 1). In contrast, there were no significant differences in creatinine, BUN and eGFR between normotensives and patients with urgencies (P ¼ 0.68, 0.28 and 0.95, respectively, Figure 1). Novel renal markers Cystatin C was 64% higher in HE than in normotensives and 47% higher than in HU (Po0.001 for both comparisons, Figure 1). NGAL levels were 57% higher in HE as compared with controls or HU (P ¼ 0.003 and Po0.001, respectively, Figure 1).
Demographics and medical history Normotensives (n ¼ 20)
Hypertensive urgencies (n ¼ 20)
Hypertensive emergencies (n ¼ 19)
P-value
55 (15) 11/8 125 (11) 72 (15) 24.5 (5.6) 12 0 0 0 0
57 (15) 10/10 190 (11) 95 (31) 28.7 (7) 7 4 0 36 (131) 10
61 (29) 7/12 200 (40) 105 (20) 29.4 (7.2) 6 5 4 36 (120) 11
X0.4a,b; 0.1c X0.3a,b,c o0.001a,b; 0.002c o0.001a,b; 0.008c X0.08a,b; 0.4c 40.1a,b,c 0.1a; 0.02b; 0.7c 1.0a; 0.04b; 0.04c o0.001a,b; 0.8c o0.001a,b; 0.8c
0 0 0
12 5 3
14 6 4
o0.001a,b; 0.5c 0.04a; 0.008b; 0.7c 0.2a; 0.04b; 0.7
Age (years) Sex (F/M) SBP (mm Hg) DBP (mm Hg) BMI (kg m 2) Smoker (n) CVD (n) DM (n) Duration of hypertension (months) History of previous crisis (n) Cardiovascular medication before admission (n) Antihypertensives (n) Antiplatelet drugs (n) Statins (n)
Abbreviations: BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; DM, diabetes mellitus; SBP, systolic blood pressure. Data are given as median and quartile range. aNormotensives vs hypertensive urgencies. bNormotensives vs hypertensive emergencies. cHypertensive urgencies vs hypertensive emergencies.
Journal of Human Hypertension (2014) 427 – 431
& 2014 Macmillan Publishers Limited
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429 Similar to creatinine, BUN and eGFR, there were no statistically significant differences in cystatin C and NGAL levels between normotensive controls and patients with HU (P ¼ 0.3 and 0.8, respectively, Figure 1).
Table 2. Clinical characteristics of hypertensive urgencies and emergencies Hypertensive urgencies (n ¼ 20) Antihypertensive medication before admission (n, %) No antihypertensive medication 8 (40) ACE-Inhibitor 6 (30) AT II receptor blocker 3 (15) Diuretics 3 (15) -Blocker 7 (35) a-Blocker 2 (10) Calcium channel antagonists 1 (5) Combination of antihypertensive 7 (35) medication 2 Antihypertensives 2 (10) 3 Antihypertensives 5 (25) 43 Antihypertensives 0 Clinical presentation SBP reduction (mm Hg; %) DBP reduction (mm Hg; %) End-organ damage (on admission) Cardiac (n; %) Pulmonary oedema (n) Angina (n) Cerebral (n; %) Hypertensive intracerebral haemorrhage (n) Subarachnoidal haemorrhage (n) Transient ischaemic attack (n) Acute renal failure (n)
40 (34) (17.6) 22 (3) (7)
Hypertensive emergencies (n ¼ 19) 5 6 3 4 5 4
(26) (32) (16) (21) (26) (21) 0 7 (37)
2 (10.5) 4 (21) 1 (5) 70 (39) (31.5)* 40 (25) (34) 12 (63) 11 1 7 (37) 5 1 1 0
Abbreviations: ACE, angiotensin converting enzyme; ATII, angiotensin II; DBP, diastolic blood pressure; SBP, systolic blood pressure. Data are given as median and quartile range; *Po0.05.
Renal function in patients with pulmonary oedema and cerebral events NGAL was significantly higher (61%) in HE patients with pulmonary oedema (n ¼ 11) than in HE patients with cerebral events (n ¼ 7; P ¼ 0.008), whereas the other renal function parameters were not significantly different (Table 3; P40.1 for all parameters). Similarly, no significant difference was found for age, body mass index, duration of hypertension and BP on admission (Table 3). We performed a sensitivity analysis to describe a possible influence of history of diabetes on renal parameters in hypertensive crises. Even after exclusion of patients with diabetes, all renal function parameters remained significantly different between HE and controls or HU patients (Po0.05 for all parameters). Correlations were calculated between renal function tests in patients with HE. Levels of determination ranged from r2 ¼ 0.36 for creatinine vs NGAL to r2 ¼ 0.53 between eGFR and cystatin C (Po0.01 for all parameters except for BUN, which was only borderline significant). DISCUSSION To our knowledge this is the first prospective cross-sectional investigation of renal function in HE. These data extend a retrospective analysis that showed a 425% decrement in renal function in approximately 1/3 of patients with acute severe hypertension.11 Renal function, measured by conventional and novel biomarkers, was decreased in our patients with HE as compared with urgencies or controls (Figure 1). In contrast, renal function parameters were not different between patients with HU and normotensive controls (Figure 1). However, inclusion of both of these groups makes the study design more robust. Although hypertensive crisis is a common event in emergency medicine,7 little is known about its pathogenesis, and most experimental models relate rather to malignant hypertension and nephrosclerosis than to hypertensive crisis encountered in the clinical scenario.21,22 The rapidity of BP elevation suggests a triggering factor superimposed on pre-existing hypertension1 and is thought to be initiated by an increase in vascular resistance due to humoral vasoconstrictors.2,3
Figure 1. Patients with hypertensive emergencies have renal dysfunction as compared to hypertensive urgencies or controls. BUN, blood urea nitrogen, eGFR, estimated glomerular filtration rate, NGAL, neutrophil gelatinase-associated lipocalin; Data are presented as mean±95% CI; ** indicates Po0.01 vs controls and urgenices. Note: blood urea nitrogen in mg dl 1 to mmol l 1, 0.347. & 2014 Macmillan Publishers Limited
Journal of Human Hypertension (2014) 427 – 431
Renal function in hypertensive emergencies U Derhaschnig et al
430 Table 3.
Renal function in hypertensive emergency patients with cerebral events or pulmonary oedema Cerebral event (n ¼ 7) Age (years) Duration of hypertension (mo) SBP (mm Hg) DBP (mm Hg) Creatinine (mg dl 1) BUN (mg dl 1) Cystatin C (ng ml 1) NGAL (ng ml 1)
Pulmonary oedema (n ¼ 11)
50 (20) 36 (60) 200 105 1.06 21 983 109
(35) (30) (0.4) (6) (654) (79)
65 (22) 36 (120) 210 105 1.18 20 1254 194
(50) (20) (0.4) (14) (401) (78)
P-value 0.2 0.9 1.0 0.9 0.2 0.5 0.1 0.008
Abbreviations: BUN, blood urea nitrogen; DBP, diastolic blood pressure; NGAL, neutrophil gelatinase-associated lipocalin; SBP, systolic blood pressure. Data are given as median and quartile range. Conversion factors for units: creatinine in mg dl 1 to mol l 1, 88.4 , blood urea nitrogen in mg dl 1 to mmol l 1, 0.347.
There are two not mutually exclusive explanations for impaired renal function in HE. First, compromised renal function may facilitate the development of HE. Second, a hypertensive crisis may acutely damage the kidney. Interestingly, patients with hypertensive pulmonary oedema had significantly higher NGAL levels as compared with patients with hypertensive intracerebral haemorrhage. NGAL is produced by renal tubular cells in response to different types of injury14 and is considered to be an excellent marker of acute kidney injury.12,23 Serum levels of NGAL have recently been identified as a sensitive marker to predict acute kidney injury after cardiac surgery24 and are able to differentiate between CKD and acute kidney injury.25 Thus, the elevated NGAL levels support the concept that acutely compromised renal function may contribute to the pathogenesis of hypertensive pulmonary oedema. However, the duration of severe hypertension in patients with hypertensive intracerebral haemorrhage is possibly shorter lived than that of patients with pulmonary oedema. It cannot be excluded that differences in NGAL levels are attributable to possible differences in the duration of acute severe hypertension before admission to the hospital. Yet, NGAL is considered the earliest marker of acute renal injury,12 and rises 2 h after contrast media-induced renal damage.26 Alternatively, elevated levels of NGAL may be an expression of impending worsening of renal function during acute heart failure, as described in the literature.27 However, acute hypertensive pulmonary oedema is characterised by preserved left ventricular systolic function and cardiac output.28,29 Pressure elevations, as occuring in acute hypertensive pulmonary oedema, require an increase in either vascular resistance or vascular volume.29 A retrospective analysis of patients with acute hypertensive heart failure revealed that they more commonly had a history of CKD (49% with an average creatinine level of 1.9 mg dl 1 (168 mmol l 1)) as compared with those without heart failure.30 In contrast, none of our patients had a history of advanced CKD, although increased levels of creatinine (on average 1.18 mg dl 1 (104.3 mmol l 1)), BUN and cystatin C may also reflect subtle chronic renal damage.31 NGAL is considered to be a biomarker of the cardio-renal axis31,32 and 10–20% higher levels of NGAL are found in chronic and acute heart failure.33 Thus, this limited increase in NGAL in acute heart failure unlikely explains the 61% increased NGAL levels in our patients with acute pulmonary oedema. There were more patients with a history of diabetes in the HE group (Table 1). However, even after exclusion of patients with diabetes, all renal function parameters remained significantly different between HE and controls or HU patients. Journal of Human Hypertension (2014) 427 – 431
Limitations of the study include the cross-sectional design, which does not allow conclusions on cause-effect relationships. Obviously, it is unethical to demonstrate in humans that an experimental severe increase in BP to levels found in HE causes renal damage. However, animal trials clearly showed that experimental severe hypertension can cause renal damage within a few days.34,35 Within a time frame of one additional day, mean arterial BP even increased from 132 to 156 mm Hg, and hypertensive crisis including renal failure developed in the dog study.35 A second limitation is the limited sample size, which was driven by a sample size calculation but does not allow for any regression analysis. Further, the limited sample size may prevent achievement of a (otherwise possible) statistical difference in age between HE and HU. Finally, we excluded patients with CKD only by medical history and who had no previous data on renal function and proteinuria/ albuminuria. Hence, we cannot entirely exclude the probability of having missed patients with undiagnosed CKD. In conclusion, this is the first prospective cross-sectional investigation of renal function in hypertensive crisis. It demonstrated that markers of acute and chronic kidney injury are higher in HE patients even without a history of CKD than in patients presenting with HU or normotensive controls. The results from this study should encourage further investigations to better characterise the role of acute kidney damage in the pathogenesis of hypertensive pulmonary oedema and HE in general.
What is known about the topic? The kidney has a central role in BP regulation. Acute kidney injury is a frequent form of organ damage in severe hypertension. Prospective data of acute renal function in HE and HU are scarce. What this study adds? Patients with HE have decreased renal function as compared with patients with HU. Among HE the earliest marker of acute kidney injury, NGAL, was highest in patients with pulmonary oedema.
CONFLICT OF INTEREST The authors declare no conflict of interest
ACKNOWLEDGEMENTS We want to thank Karin Petroczi and Astrid Fabry for their valuable laboratory work. This project was supported in part by a research grant (no. 701) of the Austrian heart fund dedicated to UD.
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