Diagnosis of persistent renal dysfunction as an outcome of AKI can be confounded by many factors hampering our ability to define its nature, extent and significance (Table 3.1). The reciprocal relationship between creatinine and GFR implies that, quite large declines in renal function from a normal baseline can occur with only small rises in steady state creatinine, so that GFR can fall by almost half before creatinine becomes clearly abnormal. This is particularly important when assessing renal outcomes because even if the reduction in total nephron mass is relatively small, this can still trigger slow, progressive decline in renal function. Furthermore, in critical illness, acute falls in creatinine generation rate are observed both in clinical settings [24] and animal models [25]. Such reduced creatinine generation, in turn, decreases both the rate of rise and the absolute creatinine increment after a fall in GFR [26]. Importantly, the largest falls in creatinine generation are associated with greatest illness severity [24]. The decreased ability of serum creatinine to reflect the magnitude of decrease in GFR suggests that some patients may develop ‘sub-clinical’ AKI and then CKD. Neutrophil gelatinase–associated lipocalin (NGAL) a biomarker of renal tubular injury is associated with risk of death and other adverse outcomes even in the absence AKI diagnosis based on serum creatinine [27], suggesting that sub-clinical AKI could be common and clinically relevant. It is uncertain whether sub-clinical AKI is a risk factor for CKD. However, as subtle chronic kidney damage can predispose to progressive renal dysfunction, it is possible that some survivors of major illness could be at increased risk of CKD even in the absence of a formal AKI diagnosis during their illness.

Even when the AKI is diagnosed, assessing renal function during recovery can be confounded by pre-existing or acquired alteration in muscle mass, liver function [28] and diet. Steady-state serum creatinine is determined by the equilibrium between creatinine production and creatinine excretion. Many critically ill patients have pre-morbid chronic disease and are likely to have reduced creatinine generation at baseline. The use of creatinine-based eGFR in the general population has recently been the subject of a meta-analysis [29]. The prevalence of CKD rose significantly when cystatin-c, a renal filtration marker less dependent on muscle mass, was used for eGFR estimation, with better prediction of all-cause mortality and cardiovascular death. These results suggest that variations in creatinine generation might confound CKD diagnosis in the general population and that these missed diagnoses are clinically significant. Critical illness is then associated with further profound and progressive loss of skeletal muscle protein [30–32] and muscle thickness [32–34], with a strong inverse correlation between muscle thickness and duration of critical illness [33, 34]. Thus, estimates of renal function after critical illness based on ICU or hospital discharge creatinine can fail to detect significant loss of GFR, and will not be directly comparable to a baseline creatinine.

Even when GFR is accurately assessed, measurements may not represent the extent of chronic kidney damage after AKI. Many patients who have developed chronic renal scarring can have relatively normal GFR for an extended period until overt CKD eventually occurs. It has been speculated that loss of renal functional reserve [35] occurs in early CKD as the kidney lacks capacity to augment GFR in response to demand despite preserved baseline GFR [36]. This may occur when the nephron number is reduced, but total GFR is persevered by glomerular hyperfiltration [37]. Such patients have no capacity to increase GFR as their renal reserve is maximally recruited at baseline. Hyperfiltration may be triggered by neuroendocrine responses to renal damage, including local and systemic generation of angiotensin II, and is associated with glomerulosclerosis and eventual deterioration in renal function. These processes are strongly associated with the development of proteinuria. Irrespective of GFR, microalbuminuria (urinary albumin: creatinine ratio >3.5 mg/mmol) is associated with increased all cause mortality, cardiovascular mortality, progressive CKD, end stage renal disease and risk of new AKI, with increasing risk with more severe levels of proteinuria [38, 39]. Thus, proteinuria is a key prognostic indicator for progression of CKD after AKI at all levels of GFR including apparently normal renal function.

There has been considerable recent research into the development of novel renal biomarkers to accelerate and refine the diagnosis of AKI. However, less is known on how these markers relate to chronic renal outcomes after AKI. Plasma NGAL concentrations at AKI diagnosis do correlate with degree of renal recovery [40] and prediction of renal recovery may be refined by combining markers and clinical risk factors [41]. This suggests that those measures that correlate with renal tubular injury may provide an early prognosis for renal recovery after critical illness. However, existing studies have examined renal recovery as freedom from renal replacement therapy and further research is needed to refine the use novel diagnostics to discriminate severity of CKD in patients who come off, or never need, renal replacement therapy. In addition specific markers of renal recovery or fibrosis may be developed to improve prediction of long-term renal outcomes [41]. Finally, serial measurement of AKI biomarkers may be useful to screen for new AKI during recovery from critical illness allowing measures to minimise subsequent recurrent renal injury, which may have a strong impact on recovery of renal function.

In the treatment of AKI, avoidance of recurrent renal injury is crucial to achieving maximal renal recovery, thus the treatment of AKI merges into the prevention of CKD. Use of intermittent haemodialysis for RRT in AKI has been associated with poorer renal recovery than continuous modalities of RRT [42], possibly related to intra-dialytic falls in cardiac output with rapid ultrafiltration, causing renal hypoperfusion and recurrent ischaemic injury [43]. This concern has led to recommendations for the preferred use of CRRT in the treatment of haemodynamically unstable patients with AKI [44]. More controversially, it has been recently suggested that the kidney might be best protected in AKI by pharmacological intervention (ACE-inhibition or Angiotensin II blockade) to reduce glomerular filtration and decreasing renal vascular resistance, thus reducing oxygen demand while increasing renal oxygen delivery, even if this were at the expense of acute need for renal support [45]. While this strategy cannot currently be recommended for clinical use it is a provocative suggestion that warrants experimental investigation.

Given the diagnostic difficulties outlined above, it seems appropriate to consider all survivors of critical illness at risk of CKD. In particular, in patients who had clinically overt AKI, follow-up for development of CKD should be considered, irrespective of apparent degree of renal recovery. CKD in general has well-developed clinical guidelines [7] for monitoring and treatment and in the absence of evidence to the contrary, we should apply these principles to the management of AKI survivors with or at risk of CKD. Follow-up will involve measurement of serum creatinine, blood pressure, urinalysis and cardiovascular risk factors; in some patients formal measurement of GFR may be helpful. AKI survivors should be regarded, as having a long-term risk factor for CKD and continued screening should be considered. Patients with more severe renal dysfunction or other specific risk factors may benefit from specialist follow-up with a nephrologist [46] while others could be followed-up in primary care and be referred back to renal services if required. Treatment of hypertension and modification of cardiovascular risk factors are central to management of patients with or at risk of CKD. In particular, in patients with diabetes or hypertension and proteinuria, ACE inhibitors or A2 receptor blocking agents should be considered, as these may reduce proteinuria and the rate of progression of CKD [47]. Finally, recurrent episodes of AKI are a particular concern resulting in a step-wise loss of renal function, and any follow-up programme should address the prevention and early detection of new episodes of AKI.