Potential Nephrotoxicity of Lisinopril and Valsartan on Patients with Congestive Heart Failure

Lisinopril (angiotensin converting enzyme inhibitor) and valsartan (angiotensin II receptor blocker) are the first-line treatment for patients with congestive heart failure (CHF). These two drugs potentially cause side effects on renal functions. However, limited information was available regarding the comparison of potential nephrotoxicity of these drugs in Indonesian CHF patients. This research was aimed to compare the potential nephrotoxicity between lisinopril and valsartan in outpatients with CHF at a hospital in Palu, Indonesia. This was an observational study conducted during April-May 2015. Potential nephrotoxicity were assessed by measuring serum creatinin (SCr) and blood urea nitrogen (BUN). Data were obtained from Cardiology Unit from a hospital in Palu, Indonesia. Statistical analysis was conducted using T-test and Mann-Whitney test. The increasing trend of SCr and BUN were observed in lisinopril-treated patients with the mean of increase were 21% and 59%, respectively. Relatively higher increase was observed in valsartan treatment group with 47% and 51% in SCr and BUN, respectively. The analysis showed that there were significant differences in SCr level between lisinopril and valsartan groups (p=0.001), but the opposite results observed in BUN parameter (p=0.697). Therefore, valsartan was potentially more nephrotoxic than lisinopril based on the increase of SCr parameter. Thus, lisinopril is recommended for CHF patients who are particularly at high risks of having renal impairment.


Introduction
Antihypertensive drugs such as diuretics, angiotensin converting enzyme inhibitors (ACEI), beta blockers, and angiotensin II receptor blockers (ARB) could be used for the treatment of congestive heart failure (CHF). 1,2The first-line treatment of CHF are ACEI or ARB drugs class.ACEI drugs can increase cardiac output and decrease left vetricular filling pressure due to vasodilation effects, while ARB is used as a substitute or adjunctive therapy for ACEI in CHF treatment. 3isinopril may induce nephrotoxicity or acute kidney damage if accompanied by other nephrotoxic drugs.ACEI may exacerbate renal function due to the dominant dilatation of efferent arterioles and consequent reduction in glomerular filtration.Valsartan significantly decreases glomerular filtration rate (GFR), renal plasma flow (RPF) and renal vascular resistance (RVR). 4nal dysfunction is common in patients with CHF and is associated with high morbidity and mortality.Heart disease and renal dysfunction can worsen each other through various mechanisms such as fluid overload, increased venous pressure, hypoperfusion, neurohormonal activation and inflammation.The interaction between cardiac and renal dysfunction play a major role in disease progression. 5e incidences of CHF and chronic kidney disease (CKD) continue to increase with the increasing age of the general population.CHF and CKD often coexist, which may be associated with common risk factors, such as hypertension, diabetes, and atherosclerosis.Sympathetic activation of the nervous system, renin angiotensin system, inflammation, and oxidative stress are among the mechanism that may worsen those condition.CKD occurs in 30%-40% of patients with CHF. 6 In Indonesia, the highest prevalence of coronary heart disease was observed in Central Sulawesi (0.8%) followed by North Sulawesi (0.7%), DKI Jakarta (0.7%), and Aceh (0.7%). 7Information regarding comparison of potential nephrotoxicity of lisinopril and valsartan in this population was limited.
Therefore, this research was conducted to assess potential nephrotoxicity between lisinopril and valsartan in CHF patients at one hospital in Palu, Central Sulawesi, Indonesia.

Methods
This was an observational study conducted in two months during April-May 2015.We  Potential nephrotoxicity was assessed by evaluating SCr and BUN levels during initial and the end of study.Baseline characteristics based on sex, age, and level of education of two groups were compared.Statistical analysis was performed using using Mann-Whitney, Spearman, and coefficient correlation test.The data were obtained from cardiology outpatient clinic at Undata Hospital, Palu, Indonesia.

Results and Discussion
The subjects were grouped as follows: 16 lisinopril-treated and 14 valsartan-treated.We found out that there were no significant differences on the baseline of those two groups (p>0.05)(Table 1).Therefore, there were no significant influences from sex, age and level of education on renal functions.
The increasing trend of SCr and BUN were observed in lisinopril-treated patients with the mean of increase were 21% and 59%, respectively.Relatively higher increase was observed in valsartan treatment group with 47% and 51% in SCr and BUN, respectively.The analysis showed that there were significant differences in SCr level between lisinopril and valsartan groups (p=0.001),but the opposite results observed in BUN parameter (p=0.697).Therefore, valsartan was potentially more nephrotoxic than lisinopril based on the increase of SCr parameter (Table 2).
Valsartan causes nephrotoxicity by decreasing glomerular capillary hydrostatic pressure which can ultimately decrease glomerular ultrafiltration.This occurs when the regulation of blood flow is reduced in the glomerular afferent artery and the efferent artery undergoes vasconstriction in maintaining the glomerular capillary hydrostatic pressure for ultrafiltration. 8Lisinopril and valsartan may reduce intrarenal perfusion and decrease intracapillary hydraulic pressure thereby reducing the filtration fraction and finally GFR. 9 According to De Broe et al., inhibition of renin angiotensin aldosteron system (RAAS) by lisinopril and valsartan may also weaken renal fibrosis and decrease excretion of fibrogenic cytokines. 10The ACEI group may increase SCr by reducing 30% of efferent vascular tone to reduce the pressure of glomerular filtration.However, it can lead to diuresis which can Valsartan or lisinopril are often used in combination with other drugs such as other diuretics and non-steroid anti-inflammatory drugs.In this study, selection of subject (normal SCr and BUN value) was based on the presence of valsartan or lisinopril, regardless the concomitant medications used, therefore the possibility of selection bias could be excluded.

Conclusion
Based on the comparison of potential nephrotoxicity between lisinopril and valsartan in CHF patients, valsartan was potentially more nephrotoxic than lisinopril based on the increase of SCr value.Thus, lisinopril is recommended for CHF patients with high risk of renal impairment.
b 0.216 b a) Mann-Whitney test; b) Spearman's testincluded thirty subjects aged ≥18 years with hypertension, CHF, using lisinopril 5 mg or valsartan 80 mg, with normal serum creatinine (SCr) and blood urea nitrogen (BUN) levels (0.6-1.3 mg/dl) at initial period of study.The conduct of this research was approved by ethical committee Universitas Padjadjaran.