2 Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in appendix L of the full guideline.

2.1 Long-term outcomes of acute kidney injury

What are the long-term outcomes of acute kidney injury in adults, children and young people?

Why this is important

Long-term follow-up studies, predominantly from North America, have shown that acute kidney injury is associated with an increased risk of chronic kidney disease or exacerbation of underlying chronic kidney disease. This can lead to end‑stage renal disease (ESRD) and long‑term dialysis. About a quarter to a third of the costs associated with acute kidney injury in adults are due to ESRD. Older adults with comorbidities are at particular risk.

Although acute kidney injury is traditionally regarded as reversible, the psychological effects are not well studied. Some studies of adults who have recovered from acute kidney injury suggest a reduced quality of life, including higher rates of depression. People also often need more social care or discharge to residential care.

The factors associated with the long‑term complications of acute kidney injury are poorly understood. A large, prospective epidemiological or cohort study is needed with a control group (for example, patients admitted to hospital as an emergency with an acute illness, but without acute kidney injury). In adults follow‑up should be for at least 2–3 years, and the study should be adequately powered to detect factors predictive of the two most costly outcomes in adults, new ESRD and new need for residential care or the inability to live independently in the community. In children and young people, longer follow‑up beyond puberty is needed. Important long‑term complications for children and young people include hypertension, proteinuria and reduced renal function.

2.2 Rapid referral to nephrology services for moderate to severe acute kidney injury

What is the clinical and cost effectiveness of rapid referral (within 12 hours) to nephrology services for adults with moderate to severe (stage 2 to 3) acute kidney injury not needing critical care?

Why this is important

There is national variation in referral of patients with moderate to severe acute kidney injury to nephrology services. Evidence is lacking on the effect of rapid referral (within 12 hours) on major outcomes, including the need for renal replacement therapy, mortality, length of hospital stay and health‑related quality of life at 6 months. In most patients acute kidney injury is managed by correcting volume depletion and hypotension and avoiding further renal insults, including nephrotoxic drugs. This does not usually require specialist input from nephrology or critical care services.

In a proportion of patients, renal function may deteriorate further because of primary renal diseases needing specialist treatment (for example, immunosuppressive therapy), progressive organ failure needing treatment with adverse effects on the kidneys (for example, high‑dose diuretics in congestive heart failure) or inadequate correction of volume depletion and hypotension.

The optimal timing for referral to nephrology services is not known. Rapid referral of all patients with stage 2 to 3 acute kidney injury may allow earlier detection of primary renal diseases and avoid delay in starting appropriate therapy. It may also ensure more rapid correction of volume depletion and hypotension and initiation of targeted investigations. Potential benefits also include prevention of progressive acute kidney injury, avoidance of renal replacement therapy, avoidance of a delayed transfer to critical care, improved chances of renal recovery, a shorter hospital stay and better long‑term outcomes.

The challenge would be to provide rapid referral (within 12 hours) out of hours. This would be a particular challenge in hospitals without a renal unit on site. Rapid referral of all patients with stage 2 to 3 acute kidney injury would also mean extra costs associated with referring patients whose renal function would have recovered quickly with basic general management alone.

A randomised controlled trial is needed to evaluate the clinical and cost effectiveness of rapid referral (within 12 hours) to nephrology services for all adult patients with moderate to severe (stage 2 to 3) acute kidney injury compared with referral based on clinical judgement (that is, standard care). Outcomes should include need for renal replacement therapy, mortality, length of hospital stay and health‑related quality of life at 6 months.

2.3 Definition of acute kidney injury – system for staging and detection

Can a simplified definition and staging system, based on Système International (SI) units, be used to predict short- to medium‑term outcomes in acute kidney injury?

Why this is important

Definitions of acute kidney injury have evolved fairly rapidly in recent years, from RIFLE (2004), through AKIN (2007), to KDIGO (2012) (a merger of RIFLE and AKIN, but with less rigorous requirements for detection in those with chronic kidney disease). All three are complex and rely on non‑SI units for creatinine.

Absolute creatinine rises have been shown to be independently associated with mortality, but the evidence comes from US studies that used non‑SI units for creatinine. Stage 1 acute kidney injury is currently defined by a rise in creatinine of 0.3 mg/dl within 48 hours, which translates to 26.4 micromol/litre in SI units (note that laboratories report creatinine as an integer value only). The current definitions are complex and difficult to use for non‑specialists in healthcare systems that use SI units for creatinine measurement (including the UK).

A large, prospective epidemiological or cohort study is needed to investigate whether a simplified system, derived from KDIGO, would be useful for detecting and staging acute kidney injury in the NHS. The study should investigate the relationship of acute kidney injury, as defined by creatinine rise in SI units, with outcomes, adjusted for comorbidity. It also needs to investigate whether the same absolute rise in creatinine equally reflects outcomes among patients with and without chronic kidney disease. The study should include a control group (for example, patients admitted to hospital as an emergency with an acute illness, but without acute kidney injury) and be adequately powered to show the effect of acute kidney injury on mortality, length of stay and dialysis for acute kidney injury at 6 months.

2.4 Introducing renal replacement therapy

What is the clinical and cost effectiveness of early versus later introduction of renal replacement therapy in patients with acute kidney injury stages 2 and 3, when there is no urgent need for therapy?

Why this is important

In some patients renal replacement therapy is a lifesaving intervention (for example, in those with hyperkalaemia). For other patients, there may be no clear indicators of when renal replacement therapy should be started because oliguria, fluid overload and uraemia are common and ill‑defined indications.

An early introduction of renal replacement therapy might reduce the incidence of uraemia or other complications of acute kidney injury, but might also expose the patient to more risks from the therapy itself. Later introduction might increase the incidence of uraemia or other complications of acute kidney injury, but might also reduce the risks associated with renal replacement therapy.

A prospective study is needed of adult inpatients with acute kidney injury AKIN stages 2 and 3, who are likely to need renal replacement therapy within a given timeframe (for example, 72 hours), but have no urgent need for therapy. Units participating in the study should be able to provide early or later dialysis for these patients. Mortality, length of stay, incidence of complications of acute kidney injury, incidence of complications of renal replacement therapy and usage of dialysis should be compared in patients having early therapy and those having later renal replacement therapy. Possible indicators for early renal replacement therapy could be weight gain less than 10%, urea less than 25 mmol/litre and oliguria 0.5 ml/kg/hour or less for at least 24 hours.

2.5 Preventing deterioration

What is the clinical and cost effectiveness of continuing ACE inhibitor or ARB treatment, versus stopping treatment 24 hours before cardiac surgery and resuming 24 hours after, in people with chronic kidney disease and an eGFR of less than 30 ml/min/1.73 m2?

Why this is important

People who need cardiac surgery are often receiving ACE inhibitors or ARBs for their cardiac disease. It is unclear whether these people should stop ACE inhibitors or ARBs around the time of cardiac surgery when their blood pressure will be most unstable. Stopping ACE inhibitors or ARBs might cause deterioration of cardiac disease, which is often a concern for cardiology clinicians, but trials of ACE inhibitors and ARBs in cardiac disease have typically excluded patients undergoing cardiac surgery whose condition is unstable. Stopping ACE inhibitors or ARBs at the time of surgery may prevent exacerbation of acute kidney injury in patients whose condition is unstable.

A randomised controlled trial is needed in patients on ACE inhibitors or ARBs undergoing cardiac surgery to compare continuing treatment with stopping treatment for 48 hours (24 hours before and after surgery). Outcomes should include the incidence of acute kidney injury, cardiovascular events, all‑cause mortality, number of patients needing renal replacement therapy and length of hospital stay.

  • National Institute for Health and Care Excellence (NICE)