Acute kidney injury increases the risk of end-stage renal disease after cardiac surgery in an Asian population: a prospective cohort study

Several epidemiological studies have reported an association between AKI and ESRD [16, 17]. In a cohort of patients who underwent coronary angiography and developed AKI, the risk of ESRD was more than 4-fold higher in patients with AKIN stage 1 and almost 12-fold higher in patients with AKIN stage 2–3 compared to patients without AKI; and the incidence of ESRD was 0.6% for that study population [16]. In another cohort of patients who underwent CABG during a 9-year period, 0.4% of the cohort developed ESRD during a mean follow-up of 4.3 ± 2.4 years [17]. In contrast, during a mean follow-up of 4.4 ± 2.8 years in our population, a total of 24 patients (0.9%) developed ESRD, which is twice as high.

It was previously thought that there is no long-term sequelae of an episode of AKI with expectant recovery of renal function. However, recent evidence from multiple observational studies demonstrated a strong reproducible association between AKI, subsequent CKD and ESRD [8, 9, 11, 16]. In some cases, this decline in renal function after AKI follows a rapid trajectory with the patient developing accelerated ESRD requiring long-term renal replacement therapy [17, 18]. We have previously reported that up to 10% of patients who developed AKI in the post-operative period after cardiac surgery have elevated serum creatinine at the point of hospital discharge [19]. It is clear that some of these patients develop accelerated ESRD within 5 years as shown in this study.

AKI is directly associated with the progression of CKD but it is also postulated that it directly causes CKD [20]. Our study confirmed a dose-dependent relationship between the increased severity of AKI and increased incidence of ESRD. Other studies have shown that multiple episodes of AKI predict the development of CKD [21]; and CKD has also been reported in children who had AKI but had no other risk factors such as hypertension, diabetes or cardiovascular disease [22]. The evidence for primary pathogenic links between AKI and CKD remains to be elucidated, but there is some suggestion that in acute tubular necrosis there is rapid progression to ESRD even in patients without pre-existing CKD [20].

These findings suggest that an episode of AKI is particularly detrimental in a cohort of cardiac surgical patients who have pre-existing risk factors for CKD. An episode of AKI in itself can cause CKD as well as worsen pre-existing CKD. Animal studies have outlined a number of causal pathways in the progression of renal dysfunction following AKI [23]. These include maladaptive repair, disordered regeneration or both [23]. However, relatively little is known about the long-term course of AKI in the setting of cardiac surgery with its attendant ischemic injuries and inflammation and these need to be addressed.

The patients who developed ESRD after AKI are mainly males with an average age of 57.3 ± 9.4 years. This is relatively young as compared to the age of initiation of dialysis in other populations, such as that in the United States where the average age of patients starting on dialysis is 64.7 ± 14.5 years [24]. This also reflects the overall younger age of presentation of heart disease in the Asian population, but the early age of presentation of ESRD is particularly alarming given the long-term morbidity and health burden of this chronic disease.

Diabetes mellitus is especially prevalent in the Asian population and diabetics who developed AKI are particularly at risk of developing ESRD. Numerous studies have shown that South Asians have decreased sensitivity to insulin when compared with other ethnic groups which may be related to increased levels of truncal fat and dysfunctional adipose tissue resulting in a blunted response to insulin [25]. It is well known that diabetes mellitus is the leading cause of ESRD worldwide [26] and the common consensus is an expected, linear, progressive and time-dependent decline of CKD to ESRD in the diabetic patient [17, 18]. Perhaps less known is that after an episode of AKI, the trajectory of accelerated ESRD is rapid, and we showed that in our population the rate of decline is as short as 5 years following cardiac surgery. This corroborates with recent publications [17, 18] and has tremendous implications on ESRD care planning as it affects mainly males of a relatively younger age group compared to their Western counterpart.

Equally important is the modification of risk factors that will retard the risk of AKI and subsequent ESRD. Patients who developed AKI and subsequent ESRD have a lower perioperative haemoglobin and higher rates of transfusion. We have shown previously that pre-operative anaemia increased the risk of AKI by 23% and Asians with a smaller body size are particularly vulnerable to the haemodilution associated with cardiopulmonary bypass and need for subsequent blood transfusion – a dual insult that exacerbates the hypoxic insult of low haemoglobin and aggravated by initiation of the systemic inflammatory response associated with blood transfusion [1]. There is debate on the optimal haemoglobin to maintain during cardiopulmonary bypass and it may well differ between diabetic and non-diabetic patients and warrants further investigation.

Pre-operative CKD is a major determinant of post-operative AKI [7]. The transient loss of renal function (i.e., AKI) in patients with pre-existing CKD can occur via a few pathways, such as the failure of renal autoregulation, abnormal vasodilatation of the renal vasculature, increased susceptibility to side effects of anti-hypertensive agents [20]. However, it is apparent that even though 29% of our cohort developed AKI, 62.9% of patients with pre-existing renal impairment had non-recovery of acute-on-chronic kidney injury with a steep downhill trajectory and accelerated ESRD [17, 18].

Overall, patients who developed ESRD within the follow-up period have a 5-fold increased risk of mortality compared with those without ESRD.

It is known that patients who survive an episode of AKI are at risk for major adverse cardiovascular events as well as progression to CKD, regardless of whether there is underlying cardiovascular disease [16]. In this cardiac surgical population with underlying cardiac disease, the added insult of AKI and CKD will further aggravate cardiac disease despite successful revascularization. Studies suggest that “organ crosstalk” may be active long after the initial injury and the acute cardiorenal injury induces a vicious cycle that persists long after the acute event [27]. Pre-clinical models demonstrate that AKI can result in distant organ effects including cardiac cell apoptosis and cardiac leucocyte infiltration [28‐30].

This is a prospective study of a cohort of cardiac surgical patients with clearly defined data points. The patient population is relatively homogenous with easy access to healthcare. The present study was protocol driven with uniform practice among the various anaesthetists, perfusionists and surgeons ensuring reliability of data.

The Singapore Renal Registry is a well-defined nationwide cohort with extensive baseline information. The data capture for ESRD is estimated to be 95% complete [15] as the National Registry of Diseases Act in 2009 mandates all physicians to notify, within 3 months from the data of diagnosis, all ESRD cases to the Singapore Renal Registry of the National Registry of Diseases Office [31].

One of the limitations is that pre-operative renal screening was done using serum creatinine which is the standard of care in Singapore and many parts of the world. Proteinuria is currently not routinely screened in patients undergoing cardiac surgery and this would be part of future prospective studies to enable better renal risk stratification and counselling.

Also, as AKI was previously believed to be self-limiting, patients were not routinely followed up at regular intervals by renal physicians for progression of renal disease.