Survival and renal function after acute kidney injury : epidemiological and biomarker studies

Acute Kidney Injury (AKI) occurs frequently in the critically ill and has an extremely high short-term mortality. The long-term risks of death, Chronic Kidney Disease (CKD) and End Stage Renal Disease (ESRD) have not been fully established and have never been investigated in the Swedish intensive care (ICU) population. Nephrological surveillance and intervention could improve outcome for AKI survivors at particular risk of persistent renal dysfunction; these patients need to be identified and their renal function, reflected in the glomerular filtration rate (GFR) ought to be followed. However, the performance of endogenous biomarkers in estimating GFR in the recovery period has not been evaluated. Sarcopenia during ICU stay confounds creatinine´s use during admission and this effect could persist beyond ICU discharge.

All studies were cohort in design. In studies I and II, we used the Swedish intensive care registry (2005-2011) comprising 130,134 adult patients and applied epidemiological techniques. Studies III and IV were clinical studies with AKI patients recruited from the Karolinska University Hospital´s adult ICU. Study IV was a cohort nested within this local database.

In study I, we found that AKI patients had significantly higher crude mortality at one (48.4% vs 24.6%) and five years (61.8% vs 39.1%) compared to non-AKI patients. CKD and ESRD were significantly more common in AKI survivors at one year (adjusted incidence rate ratio (IRR) 7.6 and 22.5 respectively) than in the non-AKI group. Study II examined the impact of pre-existing renal dysfunction on survival and development of ESRD. Five-year mortality was highest in patients with Acute on Chronic disease (AoC) being 71.3%, for the CKD group it was 68.2%. AoC and CKD were associated with an increased risk of ESRD, adjusted IRR were 259, and 96.4 respectively compared to the no renal disease group. Risk factors independently associated with ESRD in one-year survivors were: AoC, CKD, AKI, congestive cardiac failure and elevated admission serum potassium. Study III investigated the proportion of AKI survivors developing Chronic Kidney Disease according to creatinine, and cystatin C estimated GFR (eGFR) three months after ICU discharge. We found that a quarter of patients fulfilled CKD criteria using creatinine and two-thirds using cystatin C based GFR estimation methods. Age, discharge cystatin C, discharge creatinine and female gender were predictive of creatinine defined CKD at follow-up. Study IV compared the performance of creatinine and cystatin-C eGFR to estimate Iohexol clearance (mGFR) 9 months post ICU discharge. We found that creatinine equations overestimated mGFR, and demonstrated greater accuracy (82.6% versus 60.8% of estimates within 30% of mGFR (p30)) compared to cystatin C; which underestimated mGFR. Combined CKD-EPI-creatinine-cystatin-C formula showed minimal bias, and the greatest precision and accuracy (P30 =87%). Concordance between creatinine and cystatin-C eGFR increased from discharge to nine-month follow-up.

We conclude that patients with AKI are at increased long-term risk of death and renal dysfunction. Patients with pre-existing renal dysfunction have the highest risk of developing ESRD. We recommend implementing systematic follow-up of renal function at three months using combined creatinine and cystatin C eGFR estimation. At risk patients may be identified using our predictive models.

List of scientific papers

I. Evolution of chronic renal impairment and long-term mortality after de novo acute kidney injury in the critically ill; a Swedish multi-centre cohort study. C Rimes-Stigare, P Frumento, M Bottai, J Mårtensson, C-R Martling, S Walther, G Karlström, M Bell. Critical Care. 2015 May 6;19:221.
https://doi.org/10.1186/s13054-015-0920-y

II. Long-term mortality and risk factors for development of end-stage renal disease in critically ill patients with and without chronic kidney disease. C Rimes-Stigare, P Frumento, M Bottai, J Mårtensson, C-R Martling, M Bell. Critical Care. 2015 19:383.
https://doi.org/10.1186/s13054-015-1101-8

III. Using Creatinine and cystatin-C to describe Acute Kidney Disease and Chronic Kidney Disease in AKI survivors. C Rimes-Stigare, B Ravn, A Awad, K Torlén, C-R Martling, M Bottai, J Mårtensson, M Bell. [Submitted]

IV. Evaluating performance of Creatinine and Cystatin C for estimating Iohexol measured GFR in AKI survivors. C Rimes-Stigare, B Ravn, A Awad, K Torlén, C-R Martling, E Löfberg, M Bottai, J Mårtensson, M Bell. [Submitted]