Skip to main content
PMC home page
Brain and Behavior logoLink to Brain and Behavior
. 2017 Jun 21;7(8):e00752. doi: 10.1002/brb3.752

Human Urinary kallidinogenase promotes good recovery in ischemic stroke patients with level 3 hypertension

Danhong Wu 1,†, Yi Lyu 2,†, Ping Zhong 3, Fengdi Liu 2, Xueyuan Liu 4,✉
PMCID: PMC5561313  PMID: 28828213

Abstract

Aim

To evaluate the clinical efficacy of Human Urinary kallidinogenase (HUK) in the treatment of acute ischemic stroke (AIS) patients with level 3 hypertension.

Methods

In this retrospective study, from January 2015 to June 2016, 150 consecutive AIS patients were registered in our database. Among them, 47 with level 3 hypertension received either HUK treatment (HUK group, 22 cases) or basic treatment (control group, 25 cases). Basic treatment was administrated on all patients. 0.15 PNA unit of HUK injection plus 100 ml saline in intravenous infusion was performed in the HUK group, with once a day for 14 consecutive days. The modified Rankin Scale (mRS) scores in two groups were analyzed 3 months after the treatment.

Results

No difference was found in the NIHSS scores, age, gender, and comorbidities between two groups before treatment (p > .05). While after treatment, 3‐month mRS score was significantly lower in the HUK group (2.1 ± 1.4 vs. 3.1 ± 1.3, p = .012) and good recovery rate (3‐month mRS score ≤2) in the HUK group was significantly higher than that in the control group (p < .05).

Conclusion

HUK is able to promote long‐term recovery for AIS patients with level 3 hypertension remarkably.

Keywords: acute ischemic stroke, human urinary kallidinogenase, hypertension

1. INTRODUCTION

Stroke is the leading cause of death and disability in China (Bazzano et al., 2007) and the second most common cause of death worldwide after coronary heart disease (Reed, 1990). The epidemiological data show that from 1984 to 2004 the incidence of acute ischemic stroke (AIS) as the most common subtype, representing about 80% of all strokes, has increased by 8.7% per year in China (Jia, Liu, & Wang, 2010). Survivors often have severely diminished quality of life and require long‐term care. In the past 50 years, several important risk factors for AIS have been identified, including hypertension, diabetes, smoking, and dyslipidemia (Sever et al., 2003; Wong et al., 2001). However, blood pressure control in acute phase of AIS has been challenging because it can reduce brain perfusion and aggravate infarct volume.

The kallikrein–kinin system consisting of kinins, kallikreins, and kininogens have been shown to protect against ischemic stroke in patients (Zhang et al., 2012) and animal studies (Chen et al., 2010). Kallikrein, a glycoprotein of the serine proteinase superfamily, can cleave a kininogen substrate to produce the potent vasodilator kinin peptide. Then, kinin mediates a complex series of physiological actions through its receptor signaling pathway (Chao & Chao, 2006; Emanuelia & Madeddu, 2003). Recently, kallikrein has been reported to have a number of functions, including selectively dilating arterioles in the ischemic area, enhancing angiogenesis and neurogenesis, increasing regional cerebral blood flow, inhibiting apoptosis and inflammation, promoting glial cell migration, and improving neurological deficits after AIS (Ling et al., 2008; Lu et al., 2008; Nagano, Suzuki, Hayashi, & Asano, 1992; Stone et al., 2009; Xia et al., 2006). As kallikrein can regulate the dilation of arterioles, whether Human Urinary kallidinogenase (HUK), a commercially available kallikrein–kinin system regulating medicine, is efficient in AIS patient with hypertension has not been reported yet. Recent studies have revealed that elevated blood pressure at the early stage is associated with unfavorable outcome in AIS patients (Tien, Chang, Lee, Liaw, & Chen, 2016). Therefore, we conducted a retrospective, registration‐based study to assess the effects of HUK on prognosis in AIS patients with level 3 hypertension.

2. METHODS

2.1. Patients

From January 2015 to June 2016, 150 consecutive AIS patients, who were admitted in the neurology department of our hospital, were registered in our database. Among them, 47 patients with level 3 hypertension were taken as study subjects. They were in accordance with the diagnostic criteria of cerebral infarction approved by the fourth national cerebrovascular academic conference (1995) (Chinese Neuroscience Society, Chinese Neurosurgical Society, 1996), and confirmed by head CT or MRI. Inclusion criteria for cases: (1) ages ranging from 18 to 90 years; (2) patients with the first onset; (3) onset time less than 48 hr; (4) patients without bleeding disorder or bleeding trends in latest 1 month; (5) patients without incomplete hepatic and renal function; and (6) patients without the medical history of peptic ulcer, hemorrhagic stroke, brain tumor, and brain trauma.

2.2. Therapeutic methods

Basic treatment was performed among patients in both two groups according to disease condition, with antiplatelet therapy, statins preparation, neuroprotective agents, dehydrating agents, blood pressure, and blood glucose controlling agents. On that basis, 0.15 PNA unit of HUK injection (Trade name: Kailikang, Guangdong Techpool Bio‐Pharma Co., Ltd. With approved medicine of H20052065) plus100 mL saline in intravenous infusion was taken in the HUK group, with once a day for 14 consecutive days. In the HUK group, during 24 hr before medication and in the treatment period, angiotensin‐converting enzyme inhibitor, steroid drugs, and other therapeutic drugs on cerebral infarction were forbidden.

2.3. Study design

This was a single‐center, registry‐based, retrospective study. Patients’ data were obtained from our database system, and patients were divided into two groups according to the treatment they received: 22 cases in the HUK group and 25 cases in the control group. Baseline characteristics included gender, age, comorbidities, and National Institute of Health stroke scale (NIHSS) score before treatment. mRS scores at 3 months were obtained by telephone follow‐up. Patients’ baseline characteristics, 3‐month mRS scores, 3‐month good recovery rate (3‐month mRS score ≤2), and adverse consequences were compared.

2.4. Statistical analysis

Categorical variables were reported as number or percentage; continuous variables fitting the normal distribution were expressed as mean ± standard deviation (SD). Patients’ baseline characteristics were compared by the Chi‐squared test or Fisher's exact test as appropriate for categorical variables, and Student's t test for continuous variables. p values were two tailed and considered statistically significant if <.05. Data analyses were performed using IBM SPSS Statistics v.19 (SPSS Inc., Chicago, IL, USA).

3. RESULTS

3.1. Baseline characteristics of all the patients

There were 11 males and 11 females in the HUK group, with an average age at 71.7 ± 11.3 years old. Among them, 13 patients had diabetes mellitus and most of them (92.3%) controlled their blood glucose well. The NIHSS score before treatment in the HUK group was 3.7 ± 1.9. In the control group there were 15 males and 10 females with an average age at 72.0 ± 9.4 years old. Eight cases together with diabetes mellitus and the NIHSS score before treatment was 4.3 ± 1.9. No statistically significant difference in baseline characteristics was found between the two groups (Table 1, p > .05).

Table 1.

Basic characteristics of all level 3 hypertension patients

HUK group (n = 22) Control group (n = 25) p value
Age (year, x¯±s) 71.7 ± 11.3 72.0 ± 9.4 .928
Gender (Male) [Case (%)] 11 (50.0%) 15 (60.0%) .564
Smoking [Case (%)] 3 (13.6%) 7 (28.0%) .297
Diabetes [Case (%)] 13 (59.1%) 8 (32.0%) .082
Good control of blood glucose [Case (%)] 12/13 (92.3%) 7/8 (87.5%) 1.000
Hyperlipoidemia [Case (%)] 12 (54.5%) 14 (56.0%) .920
NIHSS score before treatment (x¯±s) 3.7 ± 1.9 4.3 ± 1.9 .288
Open in a new tab

3.2. Efficacy and safety of HUK

Three‐month mRS scores of the HUK group and the control group were 2.1 ± 1.4 and 3.1 ± 1.3, respectively (p = .012). Eleven patients in the HUK group (50.0%) and five patients in the control group (20.0%) got good recovery (3‐month mRS score ≤2, Table 2, p = .030). No adverse consequence was reported in the HUK group.

Table 2.

Outcomes of all level 3 hypertension patients

HUK group (n = 22) Control group (n = 25) p value
3‐month mRS score (x¯ ± s) 2.1 ± 1.4 3.1 ± 1.3 .012
Good recovery rate [3‐month mRS score ≤ 2, case (%)] 11 (50.0%) 5 (20.0%) .030
Open in a new tab

4. DISCUSSION

HUK is a state category I new drug approved by China's State Food and Drug Administration (SFDA), and it is widely used for AIS in China. Clinical results have shown that HUK effectively and safely improves neurological deficits induced by AIS (Ding et al., 2007). A systematic review in 2010 on the efficacy and safety of HUK in stroke studied 2,433 patients (24 trials) and demonstrated that 2117 patients (22 trials) benefited from HUK treatment, eliciting 87% efficacy rate (Zhang et al., 2012). However, the authors failed to perform subgroup analysis because of insufficient available data. So it is not yet clear whether the routine use of HUK would be effective and safe enough in AIS patients with hypertension. In this study, HUK promoted favorable recovery in level 3 hypertension AIS patients, suggesting that HUK had the potential of regulating blood pressure in AIS patients.

Pulse pressure is a strong cardiovascular diseases’ risk factor. According to a systematic review, 10 mmHg increase in pulse pressure was associated with 1.046‐fold increased risk of stroke occurrence, including systolic blood pressure (pooled HR 1.053, 95% CI: 1.033–1.073, p < .001) and diastolic blood pressure (pooled HR 1.056, 95 % CI: 1.038–1.074, p < .001) (Liu et al., 2016). Moreover, Tziomalos et al. (2015) reported that elevated diastolic but not systolic blood pressure increased mortality risk in hypertensive patients with AIS, but no such relation was found in normotensive AIS patients.

Experimental and clinical evidence implicated an imbalance between endogenous vasoconstrictor and vasodilator systems in the development and maintenance of hypertension (Madeddu, Emanueli, & El‐Dahr, 2007). Tissue kallikrein levels were reduced in humans and in animal models with hypertension. Transgenic mice or rats overexpressing human tissue kallikrein or kinin B2 receptor were permanently hypotensive (Chao, Bledsoe, Yin, & Chao, 2006). Kinins, including bradykinin and lys‐bradykinin, are endogenous vasodilators and natriuretic peptides known best for their ability to antagonize angiotensin‐induced vasoconstriction and sodium retention. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal, and neurological function through selectively dilating arterioles, thus without blood pressure reduction (Chao et al., 2006).

Researches showed that the B1 kinin receptor contributed to vascular hypertrophy in angiotensin‐II‐induced hypertension, through a mechanism involving reactive oxygen species generation and extracellular signal‐regulated kinase (ERK1/2) activation (Ceravolo et al., 2014). In myocardial infarction produced by ischemia/reperfusion, kinins help reduce infarct size following preconditioning or treatment with angiotensin‐converting enzyme (ACE) inhibitors (Rhaleb, Yang, & Carretero, 2011). Kinins act via nitric oxide (NO) contribute to the vascular protective effect of ACE inhibitors during neointima formation, and kallikrein/kinin leads to increased levels and Akt activation, and reduces reactive oxygen species formation, TGF‐beta1 expression, MAPK, and nuclear factor‐kappa B activation (Chao & Chao, 2005).

HUK can activate kallikrein–kinin system (Sahan et al., 2013), transfer kininogen hydrolysis into kinin and kallidin and combine with BI receptor produced under induction of ischemic brain tissue to release NO and relax vascular smooth muscle (Ariturk et al., 2012; Perilli et al., 2012). So it can expand blood vessels in the ischemic area, improve cerebral blood supply of penumbra, and restore the neurological deficit as soon as possible. Furthermore, kinins could induce the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2), which then transactivates endothelial NO synthase and promotes new blood vessels formation (Ke & Jing, 2016; Li et al., 2008).

In this study, there is no side effect of hypotension, the most common adverse event of HUK, on the patients using HUK treatment, which provides the evidence on the safety of HUK in the application of AIS patients with level 3 hypertension.

Taken together, this study at first confirmed that HUK could improve favorable recovery in level 3 hypertension AIS patients with great safety because of its property of selectively dilating arterioles in the ischemic area and enhancing angiogenesis. Due to the limitation of the small sample size and short follow‐up period, further investigation is needed in future.

5. CONCLUSION

In conclusion, HUK successfully promoted good recovery in AIS patients with level 3 hypertension. Therapeutic strategy of the supplement of kallikreins to increase cerebral blood flow and modulating vascular protection might prevent the development and progression of ischemic cerebral injury.

CONFLICT OF INTEREST

None declared.

Wu D, Lyu Y, Zhong P, Liu F, Liu X. Human Urinary kallidinogenase promotes good recovery in ischemic stroke patients with level 3 hypertension. Brain Behav. 2017;7:e00752 https://doi.org/10.1002/brb3.752

REFERENCES

  1. Ariturk, Z. , Islamoglu, Y. , Gündüz, E. , Yavuz, C. , Cil, H. , Tekbas, E. , … Elbey, M. A. (2012). Effect of hypoglycemic drugs on aspirin resistance in patients with diabetes mellitus. European Review for Medical and Pharmacological Sciences, 16, 617–621. [PubMed] [Google Scholar]
  2. Bazzano, L. A. , Gu, D. , Reynolds, K. , Wu, X. , Chen, C. S. , Duan, X. , & He, J. (2007). Alcohol consumption and risk for stroke among Chinese men. Annals of Neurology, 62, 569–578. [DOI] [PubMed] [Google Scholar]
  3. Ceravolo, G. S. , Montezano, A. C. , Jordão, M. T. , Akamine, E. H. , Costa, T. J. , Takano, A. P ., … Carvalho, M. H. C. (2014). An interaction of renin‐angiotensin and kallikrein‐kinin systems contributes to vascular hypertrophy in angiotensin II‐induced hypertension: In vivo and in vitro studies. PLoS ONE, 9, e111117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chao, J. , Bledsoe, G. , Yin, H. , & Chao, L. (2006). The tissue kallikrein‐kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction. Biological Chemistry, 387, 665–675. [DOI] [PubMed] [Google Scholar]
  5. Chao, J. , & Chao, L. (2005). Kallikrein‐kinin in stroke, cardiovascular and renal disease. Experimental Physiology, 90, 291–298. [DOI] [PubMed] [Google Scholar]
  6. Chao, J. , & Chao, L. (2006). Experimental therapy with tissue kallikrein against cerebral ischemia. Frontiers in Bioscience, 11, 1323–1327. [DOI] [PubMed] [Google Scholar]
  7. Chen, Z. B. , Huang, D. Q. , Niu, F. N. , Zhang, X. , Li, E. G. , & Xu, Y. (2010). Human urinary kallidinogenase suppresses cerebral inflammation in experimental stroke and downregulates nuclear factor‐kappaB. Journal of Cerebral Blood Flow and Metabolism, 30, 1356–1365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ding, D. Y. , Lv, C. Z. , Ding, M. P. , Su, B. H. , & Chen, F. A. (2007). A multicenter, randomized, double‐blinded and placebo‐controlled study of acute brain infarction treated by human urinary kallidinogenase. Zhonghua Shenjingke Zazhi, 40, 306–310. [Google Scholar]
  9. Emanuelia, C. , & Madeddu, P. (2003). Human tissue kallikrein: A new bullet for the treatment of ischemia. Current Pharmaceutical Design, 9, 589–597. [DOI] [PubMed] [Google Scholar]
  10. Jia, Q. , Liu, L. P. , & Wang, Y. J. (2010). Stroke in china. Clinical and Experimental Pharmacology and Physiology, 37, 259–264. [DOI] [PubMed] [Google Scholar]
  11. Ke, J. , & Jing, M. (2016). Analysis of treatment effect of urinary kallidinogenase combined with edaravone on massive cerebral infarction. Biomedical Reports, 5, 155–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Li, P. , Kondo, T. , Numaguchi, Y. , Kobayashi, K. , Aoki, M. , Inoue, N. , … Murohara, T. (2008). Role of bradykinin, nitric oxide, and angiotensin II type 2 receptor in imidaprilinduced angiogenesis. Hypertension, 51, 252–258. [DOI] [PubMed] [Google Scholar]
  13. Ling, L. , Hou, Q. , Xing, S. , Yu, J. , Pei, Z. , & Zeng, J. (2008). Exogenous kallikrein enhances neurogenesis and angiogenesis in the subventricular zone and the peri‐infarction region and improves neurological function after focal cortical infarction in hypertensive rats. Brain Research, 1206, 89–97. [DOI] [PubMed] [Google Scholar]
  14. Liu, F. D. , Shen, X. L. , Zhao, R. , Tao, X. X. , Wang, S. , Zhou, J. J. , … Liu, J. R . (2016). Pulse pressure as an independent predictor of stroke: A systematic review and a meta‐analysis. Clinical Research in Cardiology, 105, 677–686. [DOI] [PubMed] [Google Scholar]
  15. Lu, R. , Shen, Q. , Yang, L. , Li, M. , Wang, Y. , & Peng, Y. (2008). Effects of kallikrein gene transfer on penumbral microvascular proliferation and regionalcerebral blood flow following cerebral ischemia/reperfusion injury. Neural Regeneration Research, 3, 1045–1050. [Google Scholar]
  16. Madeddu, P. , Emanueli, C. , & El‐Dahr, S. (2007). Mechanisms of disease: The tissue kallikrein‐kinin system in hypertension and vascular remodeling. Nature Clinical Practice Nephrology, 3, 208–221. [DOI] [PubMed] [Google Scholar]
  17. Nagano, H. , Suzuki, T. , Hayashi, M. , & Asano, M. (1992). Effect of a human urinary kininogenase (SK‐827) on cerebral microcirculation after glass bead‐induced cerebral embolism in rabbits. In Vivo, 6, 497–502. [PubMed] [Google Scholar]
  18. Perilli, V. , Aceto, P. , Modesti, C. , Ciocchetti, P. , Sacco, T. , Vitale, F. , … Sollazzi, L . (2012). Low values of left ventricular ejection time in the post‐anhepatic phase may be associated with the occurrence of primary graft dysfunction after orthotopic liver transplantation: Results of a singlecentre case‐control study. European Review for Medical and Pharmacological Sciences, 16, 1433–1440. [PubMed] [Google Scholar]
  19. Reed, D. M. (1990). The paradox of high risk of stroke in populations with low risk of coronary heart disease. American Journal of Epidemiology, 131, 579–588. [DOI] [PubMed] [Google Scholar]
  20. Rhaleb, N. E. , Yang, X. P. , & Carretero, O. A. (2011). The kallikrein‐kinin system as a regulator of cardiovascular and renal function. Comprehensive Physiology, 1, 971–993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sahan, M. , Sebe, A. , Acikalin, A. , Akpinar, O. , Koc, F. , Ay, M. O. , Satar, S . (2013). Acute‐phase reactants and cytokines in ischemic stroke: Do they have any relationship with short‐term mortality? European Review for Medical and Pharmacological Sciences, 17, 2773–2777. [PubMed] [Google Scholar]
  22. Sever, P. S. , Dahlof, B. , Poulter, N. R. , Wedel, H. , Beevers, G. , Caulfield, M. , … Östergren, J . (2003). Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower‐than‐average cholesterol concentrations, in the Anglo‐Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT‐LLA): A multicentre randomised controlled trial. Lancet, 361, 1149–1158. [DOI] [PubMed] [Google Scholar]
  23. Stone, O. A. , Richer, C. , Emanueli, C. , et al. (2009). Critical role of tissue kallikrein in vessel formation and maturation: Implications for therapeutic revascularization. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 657–664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tien, Y. T. , Chang, M. H. , Lee, Y. S. , Liaw, Y. F. , & Chen, P. L . (2016). Pulse blood pressure correlates with late outcome in acute ischemic stroke without significant culprit artery stenosis. Journal of Stroke and Cerebrovascular Diseases: The Official Journal of National Stroke Association,25, 1229–1234. [DOI] [PubMed] [Google Scholar]
  25. Tziomalos, K. , Giampatzis, V. , Bouziana, S. D. , Spanou, M. , Papadopoulou., M. , Kostaki, S. , … Hatzitolios, A. I . (2015). Elevated diastolic but not systolic blood pressure increases mortality risk in hypertensive but not normotensive patients with acute ischemic stroke. American Journal of Hypertension, 28, 765–771. [DOI] [PubMed] [Google Scholar]
  26. Wong, T. Y. , Klein, R. , Couper, D. J. , Cooper, L. S. , Shahar, E. , Hubbard, L. D. , … Sharrett, A. R . (2001). Retinal microvascular abnormalities and incident stroke: The Atherosclerosis Risk in Communities Study. Lancet, 358, 1134–1140. [DOI] [PubMed] [Google Scholar]
  27. Xia, C. F. , Yin, H. , Yao, Y. Y. , Borlongan, C. V. , Chao, L. , & Chao, J. (2006). Kallikrein protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. Human Gene Therapy, 17, 206–219. [DOI] [PubMed] [Google Scholar]
  28. Zhang, C. , Tao, W. , Liu, M. , & Wang, D . (2012). Efficacy and safety of human urinary kallidinogenase injection for acute ischemic stroke: A systematic review. Journal of Evidence‐Based Medicine, 5, 31–39. [DOI] [PubMed] [Google Scholar]

Articles from Brain and Behavior are provided here courtesy of Wiley

RESOURCES