Acute Kidney Injury

Definition

• AKI formerly acute renal failure (ARF) is the syndrome arising from a rapid fall in GFR (over hours to days). It is characterized by retention of both nitrogenous (including Ur and Cr) and non-nitrogenous waste products of metabolism, as well as disordered electrolyte, acid-base, and fluid homeostasis.

• There is evidence that even relatively small acute reductions in kidney function are associated with poorer outcomes, including increased mortality, higher risk of long-term dialysis, and longer hospital stay.
• Despite a relative insensitivity to acute changes in GFR, most definitions of acute renal dysfunction have been based on serum Cr, either as an absolute value or as a change from baseline. Other definitions have incorporated urine output (UO) or the need for dialysis support.

The RIFLE Criteria For AKI

• The Acute Dialysis Quality Initiative established a multilayered definition of AKI called the RIFLE criteria.
• AKI is stratified into 5 stages, based on severity and duration of renal injury: Risk, Injury, Failure, Loss, and End-stage disease (see Table below).
• Many studies (>0.5 million patients) have validated these criteria.
• RIFLE-defined AKI is associated with significantly reduced survival (with increasing RIFLE stage leading to greater risk of death).

Acute Kidney Injury Network (AKIN)

• More recently, AKIN (an international network of AKI experts) modified RIFLE to incorporate small changes in SCRr occurring within a 48h period and to remove changes in GFR as diagnostic criteria.

KDIGO AKI definition (2012)

• AKI, classified by either of the listed criteria, may identify slightly different patients: RIFLE may not detect 10% of AKIN-identified cases, and AKIN may miss ≈25% RIFLE cases.
• KDIGO have recently produced a definition that incorporates the key elements of both.

Key elements of KDIGO AKI definition

• Increase in SCr by ≥26.5umol/L (≥0.3mg/dL) within 48h
• Increase in SCr by ≥1.5x baseline (known or presumed to have occurred within prior 7d)
• Urine volume <0.5ml/kg/h for 6h

Only one criterion needs to be present to fulfill the definition.

• Hospital:
  • 5-10% of general admissions
  • 20-25% of patients with sepsis and 50% with septic shock
  • 50% of all ICU admissions (where it acts as an independent risk factor for mortality of 20-60%, depending on AKI stage)
• Community:
  • KDIGO estimate a worldwide AKI prevalence of 2,100 pmp, the majority of which are community acquired
  • The burden of AKI may be highest in developing countries
  • Incidence of dialysis-dependent AKI: 200 pmp annually.
  • Individuals with CKD are at increased risk of AKI (and AKI is a risk factor for progression of CKD)

• There is increasing evidence for the adverse outcomes associated with AKI (even after apparent resolution), including longer hospital length of stay, significant complication rates (including infection), risk of CKD (including ESRD), development of CV disease, and higher mortality.

• Despite improvement in clinical care (particularly nutrition and renal replacement therapy), overall mortality in AKI requiring RRT remains greater than 50% (reflecting a high incidence in the elderly and those with multi-organ failure).
• The underlying cause will play a role, e.g., lower for nephrotoxin-driven AKI (less than 30%) vs higher for sepsis and trauma-related AKI (60%).
• Prompt improvement (less than 24h) in renal, cardiovascular, or respiratory function is associated with a better chance of survival.
• Outcomes for patients with sepsis in ICU are linked to timely AKI resolution.

AKI mortality by AKIN Stage

Rise in SCr Odds ratio for hospital mortality

Rise in SCr	Odds ratio for hospital mortality
≥27umol/L (0.3mg/dL)	4.1
≥45umol/L (0.5mg/dL)	6.5
≥90umol/L (1.0mg/dL)	9.7
≥180umol/L (2.0 mg/dL)	16.4

Renal Recovery

Recovery of renal function will depend on the underlying diagnosis. For ATN, 50% will have some degree of residual renal impairment. This will be irreversible, dialysis-dependent renal failure in 5% (10% in the elderly). The risk of worsening or de novo CKD and death following an episode of AKI (even if function appears to return to normal) is high.

3 clinical syndromes can be used to categorize AKI and to direct diagnosis and therapy.

Pre-renal AKI

• Decreased Renal blood flow (RBF) leads to decreased GFR.
• Decreased RBF may be secondary to hypovolemia per se or reduced effective RBF (cardiac output, vasodilatation in sepsis), or intrarenal vasomotor changes (e.g. NSAIDs and ACE-I).
• Potentially reversed by restoration of RBF.
• Kidneys remain structurally normal.

Causes of pre-renal AKI

• Hypovolemia and decreased IVV:
  • Inadequate fluid intake: limited access to fluid (children, elderly [patients with poor mobility, endurance sports), NBM, inadequate IV fluids
  • GI losses
  • Diuretic therapy
  • Uncontrolled DM (osmotic diuresis)
  • Salt-losing nephropathy
  • Post-relief of urinary obstruction
  • Diabetes insipidus
  • Skin losses: excessive sweating, febrile patients, burns
  • Haemorrhage: trauma, surgery (and surgical drains), GI bleeding, intestinal obstruction, peritonitis, pancreatitis, major fractures
• Impaired cardiac output:
  • Cardiac pump failure BP – RBF: Ischaemic heart disease – angina or MI, dyshythmias (incl. uncontrolled AF), new or established LV dysfunction (incl. myocarditis and cardiomyopathy of any cause), pericardial disease (tamponade), CCF
• Peripheral vasodilatation:
  • The pathophysiology of septic shock is complex but causes failure of peripheral circulatory control. Interactions between intraglomerular vaso-dilating and – constricting mediators resulting from sepsis also contribute to decreased GFR.
• Intrarenal vasomotor changes:
  • NSAIDS impede prostaglandin-mediated afferent arteriole dilatation. Post-op patient prescribed NSAIDs.
  • ACE-I and ARB oppose angiotensin II-induced efferent arteriole constriction. Dehydrated elderly patient still taking an ACE-I.
  • Contrast administration, renovascular disease

Intrinsic Renal AKI

• The renal parenchyma itself sustains damage through injury to the renal vasculature, glomerular apparatus, or tubulointerstitium.
• The commonest cause (by far) is acute tubular necrosis (ATN), itself the end product of an ischemic or a nephrotoxic injury. The diagnosis of ATN implies:
  • Glomerular, vascular, and other interstitial disease are not responsible for AKI. Be cautious; these disorders often require specific treatment.
  • Recovery of renal function should occur if supportive measures are adequate (so make sure that they are adequate).
  • A potentially reversible phase has passed during which ATN may have been avoided.

Causes of Intrinsic Renal

• Encompasses all causes of AKI in which the renal parenchyma has been damaged.
• ATN accounts for 80-90% of all intrinsic AKI.
• Exclusion or correction of pre-renal ± post-renal factors is an essential part of the diagnosis.

Large Renal Vessels

• Renal artery occlusion due to thrombosis or dissection
• Cholesterol emboli
• Renal vein thrombosis
• ACE-I + bilateral renovascular disease

Diseases Small Renal Vessels and Glomeruli

• Glomerulonephritis
• Vasculitis
• Thrombotic microangiopathies
• Malignant hypertension
• Scleroderma renal crisis

Causes of Intrinsic Renal Diseases of the Tubulointerstitium

• Acute interstitial nephritis
• Cast nephropathy (complicating multiple myeloma)
• Contrast nephrotoxicity
• Tumour lysis or acute urate nephropathy
• Acute tubular necrosis (ATN) may complicate prolonged pre-renal AKI or accompany any of the disorders listed here.

Acute Tubular Necrosis (ATN)

• ATN is the most common cause of intrinsic AKI.
• It is widely seen in hospitalized patients and is predictable in high-risk clinical scenarios (so it is often preventable).
• The diagnosis implies that pre-renal and post-renal factors have been excluded (or corrected) and that other causes of intrinsic AKI, such as vasculitis or TIN, are deemed unlikely.
• Recovery of renal function can be achieved – but only if the causative insult is removed and adequate supportive measures are put in place.

Causes of ATN include:

• Ischemia (including sepsis)
• ANY cause of reduced renal perfusion
• Hypotension
• Shock (Cardiogenic, Septic)
• Haemorrhagic
• Nephrotoxic agents: Myoglobinuria, Haemoglobinuria, Aminoglycosides, Contrast, Amphotericin, Cisplatin

Presentation

• ATN presents as AKI: GFR – Uraemia and disordered salt, water and electrolyte homeostasis.
• ATN may be oliguric or non-oliguric.
• It represents a continuum from pre-renal failure but with progression to:
  • Actual structural injury to the renal parenchyma.
  • Limited (or no) immediate resolution upon restoration of renal perfusion.
• Differentiation between pre-renal AKI and ATN can be difficult. Helpful features include (not uniformly present):
  • Bland urine on dipstick (or minor proteinuria).

Post-renal AKI

• The kidneys produce urine, but there is obstruction to its flow.
• Back pressure affects tubular function.
• Obstruction may occur at any level in the urinary tract.
• AKI results when both kidneys are obstructed or when there is obstruction of a solitary kidney.
• Obstruction eventually causes structural and/or permanent damage.

Who is at Risk?

• Age
• Pre-existing CKD: Scr, eGFR, or proteinuria
• Surgery:
  • Trauma and burns surgery (hypovolemia, sepsis, myoglobinuria)
  • Cardiac surgery (poor LV function, intra-operative hemodynamic instability, cardiopulmonary bypass)
  • Vascular surgery (e.g. suprarenal aortic cross-clamping) and endoluminal intervention. Pre or intra-operative contrast administration. AAA repairs
  • Hepatic and biliary surgery (over 70% of hepatic transplants complicated by AKI): biliary surgery also high risk.
• Diabetes mellitus (esp. diabetic nephropathy with eGFR)
• Volume depletion (NBM, bowel obstruction, vomiting, burns)
• Drugs that cause renal dysfunction and other cardiac disease:
  • Certain medications can cause renal dysfunction and other cardiac diseases.
• Cirrhosis (of decreased effective arterial volume):
  • Vasomotor changes (NSAIDs, ACE-I, ARB).
• Multiple myeloma (may just be that these patients are often dehydrated, with a degree of renal insufficiency to start with). Precipitation of casts with tubular injury is the concern.

Common Nephrotoxins

• The kidneys are particularly susceptible to nephrotoxic injury because of their rich blood supply and a propensity to concentrate toxic substances within the cortex.
• NSAIDs (including COX-2 inhibitors)
• Diuretics, ACE-I, ARB (especially in volume-depleted patients)
• Antimicrobials: aminoglycosides, vancomycin, amphotericin (lipid preparation is only 50% less nephrotoxic and may still cause AKI).
• Immunosuppressants (e.g., ciclosporin, tacrolimus) and chemotherapeutic agents (e.g., cisplatin)
• IV contrast

STOP AKI

• The London AKI network (LAKIN) is a regional collaborative that aims to collate available evidence, clinical standards, and national guidelines into accessible practical advice and well-defined clinical pathways.
• The guidelines are designed for those managing AKI in general ward areas and aim to facilitate the interaction between general wards, local critical care teams, and regional kidney unit service.
• LAKIN advocates the following STOP (Sepsis; Toxicity; Obstruction; Parenchymal disease) checklist to help improve awareness of the causes of AKI.

Sepsis and Hypotension:

• Severe sepsis
• Haemorrhage
• Dehydration
• Cardiac failure
• Liver failure
• Renovascular insult

Toxicity:

• Nephrotoxic drugs
• Iodinated radiological contrast

Obstruction:

• Bladder outflow
• Stones
• Tumours
• Surgical ligation of ureters
• Extrinsic compression (lymph nodes)

Parenchymal Kidney Diseases:

• Glomerulonephritis
• Tubulointerstitial nephritis
• Rhabdomyolysis
• Haemolytic uraemic syndrome
• Myeloma
• Malignant hypertension

Presenting Feature Of AKI

Usually

• Ur and SCr
• UO (UO < 400mlL/d is frequent (50%) but not invariable)

Frequently

• Volume depletion OR Volume overload – pulmonary edema
• Hyperkalemia (arrhythmias or cardiac arrest)

Rarely

• Uraemic symptoms
• Anuria
• Persistent nausea and vomiting, or prolonged
• Drowsiness or impaired conscious level
• Signs of systemic sepsis
• Hypotension, particularly if severe
• Pulmonary ± peripheral edema
• Metabolic acidosis

IN THE MANAGEMENT OF AKI

• Target the risk factors and the causes e.g. sepsis, blood loss
• Fluid imbalance e.g. hypovolemia overload
• Electrolyte e.g. Hyperkalemia
• Uraemic syndromes e.g. encephalopathy (dialysis is the treatment)
• Management of co-morbidities

Treatment of Hyperkalaemia

1. Calcium gluconate
   • If K+ ≥ 6.6mmol/L or ECG changes
   • Ca2+ is cardioprotective – it does not increase K+
   • Antagonizes membrane K+ effects by poorly understood mechanisms.
   • 10mL 10% calcium gluconate (usually 1 ampoule) – calcium gluconate contains 220umol Ca2+/ml, or
   • Give over 5-10min. Repeat if no ECG improvement after 5min (up to 50ml calcium gluconate).
   • Acts within minutes, but protective effect lasts less than 1h.
   • Can induce digoxin toxicity (a pragmatic approach: halve the initial dose, and give more slowly if taking digoxin).
2. Insulin and Glucose
   • Insulin binds to its cellular receptor and Na K-ATPase activity moving K+ into cells. Glucose alone will K+ through endogenous insulin release, but insulin/glucose is effective.
   • 10-15IU of soluble insulin (e.g. Actrapid) in 50mL of 50% glucose IVI over 10min (alternative: 5IU of soluble insulin in 50mL 20% glucose over 15min by syringe pump and repeated).
   • 50% glucose is extremely viscous and irritant. Find a large vein, and flush with saline afterwards.
   • Effect within 15-30min (peak60min), lasts for 2-4h. Expect a decrease of 0.5-1.5mmol/L; can be repeated after 4h.
3. Sodium bicarbonate
   • If K+ in the presence of acidosis (HCO3- < 16) and volume depletion
   • Na+/K+ exchange. Intracellular Na-K-ATPase activity (i.e. K+ in for Na+ out).
   • 1.26% or 1.4% solutions as 200-500ml over 15-60min IVI.
   • In cardiac arrest: 50mL of 8.4% (1 ampoule) IVI.
4. B2 Agonist e.g. nebulized salbutamol
5. Dialysis – Last option when other treatments fail

Diet and Kayexalate use to treat hyperkalemia:

Diet: A low-potassium diet is often recommended for managing hyperkalemia. This involves avoiding high-potassium foods like fish, red meat, and potatoes, and favoring low-potassium foods like poultry and berries.

Kayexalate (Sodium Polystyrene Sulfonate): This is a synthetic cation-bound resin that exchanges sodium cations for potassium in the gastrointestinal (GI) lumen, resulting in increased fecal potassium excretion that in turn leads to decreased serum potassium levels. However, its use has been associated with intestinal necrosis, especially when administered with sorbitol.

ECG Changes in Hyperkalemia:

Hyperkalemia is defined as a serum potassium level of > 5.2 mmol/L. ECG changes generally do not manifest until there is a moderate degree of hyperkalemia (≥ 6.0 mmol/L).

The earliest manifestation of hyperkalemia is an increase in T wave amplitude.

Other ECG features of hyperkalemia include peaked T waves, P wave widening/flattening, PR prolongation, bradyarrhythmias, conduction blocks (bundle branch block, fascicular blocks), QRS widening with bizarre QRS morphology.

With worsening hyperkalemia (> 9.0 mmol/L), there can be development of sine wave appearance (pre-terminal rhythm), ventricular fibrillation, PEA with bizarre, wide complex rhythm, and asystole.

Indication for dialysis in AKI:

Kidney replacement therapy (KRT), including dialysis, is indicated in patients with severe acute kidney injury (AKI).

Accepted urgent indications for KRT in patients with AKI generally include fluid overload refractory to diuretic therapy.

Other indications include severe hyperkalemia, metabolic acidosis due to renal failure (e.g., pH < 7.2), and certain toxins/drugs.

The timing of RRT initiation in critical illness — early or late — remains controversial.