Clinical and Experimental Nephrology

, Volume 16, Issue 2, pp 333–336

Aliskiren-associated acute kidney injury in a patient with pre-existing chronic kidney disease and dilated cardiomyopathy


    • Department of Nephrology and HypertensionSt. Marianna University Hospital
  • Yugo Shibagaki
    • Department of Nephrology and HypertensionSt. Marianna University Hospital
  • Keita Uehara
    • Department of Nephrology and HypertensionSt. Marianna University Hospital
  • Takashi Yasuda
    • Department of Nephrology and HypertensionSt. Marianna University Hospital
  • Kenjiro Kimura
    • Department of Nephrology and HypertensionSt. Marianna University Hospital
Case Report

DOI: 10.1007/s10157-011-0566-2

Cite this article as:
Yamauchi, J., Shibagaki, Y., Uehara, K. et al. Clin Exp Nephrol (2012) 16: 333. doi:10.1007/s10157-011-0566-2


We report a case of acute kidney injury (AKI) caused by a novel direct renin inhibitor, aliskiren. A 43-year-old Japanese man with dilated cardiomyopathy on cardiac resynchronization therapy with defibrillator and chronic kidney disease (CKD) was started on aliskiren in addition to enalapril, carvedilol, furosemide, and spironolactone for worsening cardiac function suggested by the elevation of serum brain natriuretic peptide. After 1 month, he noticed general malaise, loss of appetite and his serum creatinine level increased from 2.0 to 7.24 mg/dL. He had no evidence of exacerbation of hemodynamic instability (heart failure or hypotension) or post-renal cause of AKI. Although a cessation of aliskiren did not ameliorate AKI, renal function returned to baseline after withholding enalapril. Careful monitoring is necessary when aliskiren is used in patients with CKD and/or significant systolic dysfunction since it can cause normotensive ischemic AKI, especially when there is a concomitant use of other renin–angiotensin–aldosterone system inhibitors.


AliskirenNormotensive ischemic acute kidney injuryDilated cardiomyopathyChronic kidney disease


Aliskiren, an oral direct renin inhibitor recently approved for the treatment of hypertension, exerts its blood pressure (BP)-lowering effect by blocking the rate-limiting step of the renin–angiotensin–aldosterone system (RAAS). Because aliskiren suppresses plasma renin activity (PRA) which can be enhanced by angiotensin I-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB), combination therapy of aliskiren with ACEI and/or ARB has a stronger inhibitory effect on the RAAS, and is considered as a potential treatment for hypertension [1], cardiovascular disease (CVD) including congestive heart failure (CHF) [2] and chronic kidney disease (CKD) [3]. On the other hand, RAAS blockade by ACEI and/or ARB is known to cause acute kidney injury (AKI) by dilating the efferent arterioles of the kidney without absolute or relative systemic hypotension especially in patients with severe systolic dysfunction or CKD; this is known as normotensive ischemic acute kidney injury (NT-AKI) [4]. Here we report a patient with severe NT-AKI induced by aliskiren, which was reversed by lessening of the RAAS blockade.

Case report

A 43-year-old Japanese man with dilated cardiomyopathy (DCM) and CKD was admitted to our hospital for AKI. Since being diagnosed with DCM with ventricular tachycardia at the age of 36, he had been taking enalapril 20 mg/day, carvedilol 10 mg/day, furosemide 40 mg/day, and spironolactone 25 mg/day. However, he experienced repeated exacerbations of heart failure, and underwent an implantation of cardiac resynchronization therapy with defibrillator (CRT-D) when he was 42 years old. Afterwards, his cardiac function stabilized with BP around 90/50 mmHg, and serum level of brain natriuretic peptide (BNP) around 200–300 pg/mL. He also suffered from non-proteinuric CKD of unknown origin with serum creatinine approximately 2.0 mg/dL. He did not have diabetes mellitus. One month prior to admission, he was found to have an elevated BNP level at 420.5 pg/mL without symptoms, and aliskiren was started at a dose of 150 mg daily. Several weeks later, he noticed loss of appetite and general malaise and attended the outpatient clinic and was diagnosed as having severe AKI (7.24 mg/dL). Urine volume was non-oliguric. Nephrotoxic agents such as nonsteroidal anti-inflammatory drugs and radiocontrast had not been administered. There had also been no use of any agent known to increase plasma levels of aliskiren, such as cyclosporin A and itraconazole.

On admission, he felt general malaise and loss of appetite, but was alert and was not in acute distress. He gained 2.0 kg weight over 2 months. His BP was 120/50 mmHg which was not lowered from his baseline level with regular heart rate of 50 beats per minute. He was afebrile. Examination of neck, heart, lung, abdomen, extremities and skin was unremarkable. Jugular vein dilatation or collapse was not seen. No sign of hypovolemia or hypervolemia was detected. Laboratory tests are shown in Table 1. Fractional excretion (FE) of sodium was 5.98% and FE of urea nitrogen was 45.2%. PRA or plasma aldosterone concentration (PAC) was not measured. Neither pulmonary edema nor pleural effusion was detected but slight worsening of cardiomegaly was present by chest X-ray. Electrocardiogram showed pacemaker rhythm of 50 beats per minute. Echocardiogram showed reduced left ventricular wall thickness (interventricular septa 6 mm, posterior wall 7 mm), dilated left ventricle (diastolic diameter 64 mm, systolic diameter 54 mm) and diffuse hypokinesis (ejection fraction 34%), which were similar to previous results. Ultrasonography of abdomen revealed normal-sized kidney (right 111 mm, left 104 mm) with smooth surface and high echo intensity of the cortex. Hydronephrosis was not detected. Renal artery stenosis was denied by duplex sonography [right renal artery: peak systolic velocity (PSV) 29.6 cm/s, end-diastolic velocity (EDV) 7.5 cm/s, renal-aortic ratio (RAR) 0.27; left renal artery: PSV 83.0 cm/s, EDV 9.2 cm/s, RAR 0.76].
Table 1

Results of laboratory tests on admission

Complete blood count


 Red blood cells

3.59 × 106/μL

Aspartate aminotransferase

21 IU/L


12.0 g/dL

Alanine aminotransferase

15 IU/L



Lactate dehydrogenase

188 IU/L



Alkaline phosphatase

184 IU/L


24.8 × 104/μL

C-reactive protein

0.13 mg/dL

Serum biochemistry

Creatine phosphokinase

74 IU/L


113 pg/mL

 Total protein

7.2 g/dL

Urinalysis and urinary sediment


4.6 g/dL

 Urea nitrogen

108.6 mg/dL

 Hematuria (dipstick test)


7.24 mg/dL

 Proteinuria (dipstick test)


 Uric acid

9.9 mg/dL

 Red blood cells



134 mEq/L




4.7 mEq/L



99 mEq/L


4.5 U/L


8.6 mg/dL


52.28 mg/dL


5.1 mg/dL

Urea nitrogen

353.4 mg/dL


73 mEq/L

HPF High-power field, NAGN-acetyl-β-d-glucosaminidase

The patient was suspected to have AKI due to aliskiren, and aliskiren was stopped on admission (Fig. 1). Although serum creatinine decreased to 5.0 mg/dL by 5th hospital day (day 5), renal function did not improve further and serum potassium increased to 5.6 mEq/L. The dose of enalapril was then reduced to 10 mg daily on day 7, and the dose of spironolactone was also reduced to 12.5 mg daily on day 7 and eventually stopped on day 9. Subsequently, renal function immediately improved and serum creatinine decreased to 2.0 mg/dL on day 15. Blood pressure was stable at 80–100/40–50 mmHg throughout hospitalization. After 5 months, serum creatinine decreased to 1.3 mg/dL.
Fig. 1

Clinical course


The present case showed that aliskiren can cause severe but reversible AKI in high-risk patients, such as those with CKD and depressed systolic function. Although the definitive cause of AKI in our case is not clear, post-renal cause was excluded by imaging studies and nephrotoxic agents were never administered or exposed before occurrence of AKI. Physical examination and laboratory tests showed no evidence of pre-renal state or infectious cause like sepsis. Therefore, we assume that ischemic renal parenchymal AKI was the most probable cause in our case. Although aliskiren was reported to be safe in previous studies [13], our case was a much higher risk for AKI compared to previously studied patients due to extremely reduced systolic cardiac function, with double blockade of the RAAS in the setting of low sodium intake (loss of appetite) and pre-existing CKD. It is also well known that AKI occurs frequently in the setting of pre-existing CKD, strong RAAS blockade, and systolic dysfunction, which is known as NT-AKI [4]. ACEI and ARB are well known as drugs that induce NT-AKI; aliskiren is also thought to cause NT-AKI.

Although our patient had CKD as a predisposing factor, kidney size was normal and hematuria, proteinuria or pyuria was not detected. Therefore, we assumed that renal diseases such as glomerulonephritis, diabetic nephropathy or amyloidosis were unlikely to be the cause of CKD. Serum creatinine decreased to 1.3 mg/dL 5 months after reducing the RAAS blockade. This evidence suggests that ischemic nephropathy due to low cardiac output and strong RAAS blockade was the most probable cause of CKD in our patient. In addition, the patient’s creatinine level before admission was variable, which suggests that repeated episodes of subtle AKI caused the kidney damage. It is now well known that AKI is a higher risk for progressive CKD or end-stage kidney disease (ESKD) than the natural course of CKD [5]. According to the cardiologist who managed our case, enalapril was titrated carefully up to 20 mg daily because the patient had experienced repeated decompensated heart failure before the CRT-D was implanted. The renoprotective effect of the RAAS blockade is not evidence-based, especially if CKD shows absence of proteinuria [6]. Although cardiologists tend to concentrate on cardioprotective therapy (low BP and strong RAAS blockade), this treatment sometimes increases the risk of AKI or hyperkalemia, and nephrologists should be aware of this.

Aliskiren, an oral direct renin inhibitor, is a new drug that has been available since 2009 in Japan. Although ACEI and ARB are effective in controlling BP, they cannot completely suppress the RAAS because of a reactive rise in PRA. Aliskiren reduces PRA and inhibits the rate-limiting step in the RAAS, resulting in a stronger suppression of the RAAS [7]. Aliskiren combined with losartan was reported to reduce urinary albumin excretion in type 2 diabetic nephropathy [3]. Aliskiren was also shown to reduce the level of plasma BNP and urinary aldosterone in patients with significant CHF (New York Heart Association class II–IV) treated with an ACEI (or ARB) and β blocker [2]. The occurrence of adverse events was rare and similar between the aliskiren group and the placebo group in both studies; however, mean estimated glomerular filtration rate of participants of those clinical studies was 67–70 mL/min/1.73 m2. The renal dysfunction of our patient was more severe. Ito et al. reported a low incidence of AKI by aliskiren in Japanese hypertensive patients with renal dysfunction (serum creatinine between 1.3 and 3.0 mg/dL in males and between 1.2 and 3.0 mg/dL in females) [8].

On the other hand, a case of a 76-year-old woman developing aliskiren-associated AKI with hyperkalemia in which emergency hemodiafiltration was needed was also reported [9]. In the case report, irbesartan (ARB) and spironolactone had already been administered, and switching from irbesartan to aliskiren caused AKI. The patient was old age, and had long-standing hypertension and bilateral atrophic kidney without proteinuria, indicating that ischemic nephropathy or nephrosclerosis was the probable cause of CKD, although it was not mentioned in the report. Renal ischemia and absence of proteinuria, in particular, may be risk factors of AKI induced by excessive suppression of the RAAS. It was not entirely clear why our patient did not have hyperkalemia in spite of an apparent hyperkalemia in the above case.

In our case, since the cessation of aliskiren was not sufficient for an improvement of renal function, enalapril and spironolactone were tapered; it took 15 days for the serum creatinine to return to baseline after cessation of aliskiren. Aliskiren induces a remarkable renal vasodilation and significant residual vasodilation is observed 48 h after a single dose [7]. Aliskiren can be detected in the rat kidney up to 2 weeks after drug withdrawal [10]. This prolonged effect of aliskiren on the kidney might have delayed the improvement of renal function in our case.

The BNP of our patient significantly decreased after administration of aliskiren in spite of a gain of body weight. There was no change in cardiac function measured by echocardiography compared with previous results. In the ALOFT study [2], BNP significantly decreased with the use of aliskiren despite no difference in echocardiographic measurements of ejection fraction or chamber volumes. Aliskiren may reduce cardiac load and BNP independent of volume status.

There are several limitations of this case report. Because PRA or PAC was not measured, we could not show how much the RAAS was suppressed when AKI occurred. Renal function returned to baseline after enalapril and spironolactone were tapered in addition to the cessation of aliskiren; therefore, we cannot determine that aliskiren alone was the cause of AKI in this case.

In summary, we experienced severe but reversible AKI induced by aliskiren. Although the safety of aliskiren was reported in several studies, the caution for AKI is necessary especially when aliskiren is administered to high-risk patients such as those with CKD, CHF and the concomitant use of RAAS inhibitors.

Conflict of interest

We have no conflict of interest.

Copyright information

© Japanese Society of Nephrology 2011