Mednotes

L12 Renal Acute kidney injury (AKI)

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tagsrenal, lecture
aliasesL12 Renal Acute kidney injury (AKI)

31 min read

Overview

Acute kidney injury is an abrupt fall in kidney function, and the lecture builds it in three parts: the physiology that normally holds glomerular filtration steady (autoregulation, tubuloglomerular feedback, myogenic tone, the vasoconstrictor/vasodilator balance) and how its failure produces hypoperfusion AKI and then acute tubular necrosis; a logical bedside approach worked through three cases (volume depletion via a high-output ileostomy, bladder outlet obstruction, and cardiorenal syndrome in decompensated heart failure); and the assessment, investigation, management, recovery phase and long-term outcomes, including the link from AKI to chronic kidney disease.

Definition of AKI

An abrupt reduction in kidney function (within 48 hours), defined by any one of:

  • absolute rise in serum creatinine of more than 27 µmol/L (if previous function normal)
  • percentage rise in serum creatinine of more than 50% over 7 days
  • oliguria of less than 0.5 mL/kg/hr (less than 35 mL/hour) for more than 6 hours

Decreased urine output is an important component of AKI, not an afterthought. Source: Acute Kidney Injury Network, Mehta et al., Critical Care 2007;11:R31. The take-home slide calls this the “rule of 3” for identifying AKI.

Classification by cause: the LION mnemonic

Causes are classified by phenotype, that is by the initiating mechanism. The first letters spell LION.

  • L, Low perfusion AKI (haemodynamic AKI)
    • Vascular, dilation: local (hepatorenal syndrome, sepsis) or systemic (shock)
    • Vascular, constriction: eclampsia, hypertension, rhabdomyolysis, contrast
    • Raised abdominal pressure (decreased arterial and venous flow)
    • Ventricular: left (LVF), right (RVF, congestive cardiac failure)
    • Volume: decreased (dehydration) or increased (congestive states, hypoalbuminaemia)
  • I, Inflammatory/immune: sepsis; nephritis (including glomerulonephritis and interstitial nephritis); vasculitis (systemic or kidney specific)
  • O, Obstructive: multiple possible locations
  • N, Nephrotoxic and envenomation: direct (toxin-specific, giving acute tubular injury) or indirect (acute interstitial nephritis)

The recurring lecture diagram reduces this to three pathways: low perfusion (which, if prolonged, becomes acute tubular necrosis), inflammation or nephrotoxins, and obstruction, mapped onto the vessel, the glomerulus/tubule and the ureter respectively.

Glomerular filtration and the pressures that drive it

Filtration is driven by a small net pressure, so minor changes in perfusion pressure can reduce GFR. The lecture’s glomerular pressure values:

  • Mean glomerular capillary pressure 45 mmHg
  • Intracapsular (Bowman’s) pressure 10 mmHg
  • Mean hydrostatic pressure gradient 35 mmHg
  • Mean colloid osmotic pressure 25 mmHg
  • Mean pressure driving ultrafiltration 10 mmHg

Perfusion pressures are closely regulated despite changes in systemic pressure: this is autoregulation. Renal blood flow and GFR both plateau across roughly 80 to 180 mmHg mean arterial pressure.

Renal autoregulation

Normal preservation of kidney function rests on:

  • vascular changes in the glomerular arterioles (vasoconstriction and vasodilation) giving fine control of filtration pressure, via myogenic mechanisms and juxtaglomerular cells
  • tubuloglomerular feedback, in which changes in Na+ delivery are sensed by the macula densa
  • changes in renin and angiotensin II and the sympathetic nervous system (short term), and aldosterone (long term)

These mechanisms link directly to clinically observed changes: oliguria, blood pressure, urinary sodium excretion.

On the autoregulation curve (intraglomerular pressure against MAP), the normal line plateaus early and stays flat roughly between 80 and 160 mmHg. In chronic hypertension with normal renal function the plateau is shifted to the right. In chronic hypertension with chronic renal disease the line rises steeply and reaches high pressure without a clear plateau, so protection is lost.

Juxtaglomerular apparatus

A vascular system that regulates peripheral vascular resistance, blood pressure and glomerular filtration while responding to the tubular load and reabsorption rate of NaCl. In evolutionary terms, kidney homeostasis equals blood pressure homeostasis equals salt and water homeostasis, mediated by tubuloglomerular feedback. Single-nephron GFR falls as luminal [NaCl] at the macula densa rises. JG cells act as a pressure-sensing area, analogous to aortic baroreceptors: a change of pressure in the afferent arteriole drives renin release and angiotensin II. Signalling between macula densa and JG cells involves Ca2+ and ATP; renin activity can be imaged along the afferent arteriole near the glomerulus.

Tubuloglomerular feedback: luminal NaCl at the macula densa acts via NKCC2

Low NaCl (a tendency for BP and renal perfusion to fall). Ordered steps:

  1. Low Na+ sensed at the macula densa
  2. Renin release from JG cells
  3. Afferent arteriolar vasodilation
  4. Renin, so increased angiotensin II, so efferent arteriolar vasoconstriction
  5. Increased glomerular capillary pressure and GFR
  6. Increased proximal tubular NaCl reabsorption
  7. Raised systemic BP, restored to normal

Efferent constriction maintains intraglomerular pressure and GFR; angiotensin II also acts on tubular sodium reabsorption to correct the imbalance.

High NaCl (a tendency for BP to rise). Ordered steps:

  1. High Na+ sensed at the macula densa
  2. Renin suppressed
  3. Afferent arteriolar vasoconstriction (via adenosine), reducing transmission of pressure to the glomerulus
  4. Efferent arteriolar vasodilation
  5. Decreased GFR (net effect a small reduction)
  6. Decreased proximal tubular NaCl reabsorption, because angiotensin II is reduced
  7. Systemic BP returned to normal

Both responses restore GFR: autoregulation as a balancing act.

Myogenic constriction

Vasoconstriction to increase or maintain perfusion pressure. The contribution of pre-glomerular vessels is an important protective mechanism preventing transmission of systemic pressures to the glomeruli. Myogenic oscillations can be imaged in afferent arterioles and glomerulus.

The vasoconstrictor/vasodilator balance

Vasoconstricting and vasodilating hormones are continuously released at low doses in tonic fashion to maintain vascular tone.

  • Vasoconstrictors: angiotensin II, noradrenaline and adrenaline (catecholamines, SNS), AVP, endothelin
  • Vasodilators: prostaglandins, nitric oxide

Final control of GFR is the balance of these actions, not independent effects:

  • GFR up = afferent dilation plus efferent constriction, driven by prostaglandins, kinins, low-dose dopamine, ANP, NO and low-dose angiotensin II
  • GFR down = afferent constriction plus efferent dilation, driven by high-dose angiotensin II, noradrenaline (SNS), endothelin, adenosine, vasopressin, and by prostaglandin blockade or angiotensin II blockade

Stress response and angiotensin II

  • A fall in afferent arteriolar pressure triggers renin release in under 1 second
  • Angiotensin II directly constricts pre-glomerular and post-glomerular vessels
  • Pressure-dependent changes in the renin-angiotensin system are the major cause behind hypotensive resetting of renal blood flow autoregulation
  • Beyond a point this becomes a pathophysiological response causing marked reduction of renal perfusion: decreased GFR and decreased blood flow in the vasa recta
  • Angiotensin II and SNS increase NaCl reabsorption in the proximal tubule and modify distal Na+/H+ channels, an attempt to expand blood volume
  • A low distal NaCl load further increases renin-angiotensin release via tubuloglomerular feedback
  • They increase metabolism and decrease tissue oxygen tension; Na+/ATPase action has an obligatory requirement for O2

Altered perfusion and the limits of autoregulation

  • In the normal kidney, renal perfusion is tightly regulated to keep glomerular pressure constant despite variation in systemic BP
  • Any form of cardiovascular instability compromises autoregulation: ischaemic heart disease, atherosclerosis and hypertension, renal impairment, sepsis, and probably age
  • Older age, chronic kidney disease, cardiovascular and peripheral vascular disease (including hypertensive or diabetic vasculopathy) and sepsis impair the reactivity of afferent arterioles to homeostatic stimuli. In these patients even transient, mild hypotension may exhaust the arterioles’ ability to compensate, producing hypoperfusion-associated AKI
  • Maximal arteriolar vasodilation occurs at a MAP of 80 mmHg. Below this, afferent arterioles cannot dilate further and renal perfusion begins to fall
  • Clinically relevant hypotension requiring intervention is often defined as MAP below 65 mmHg (anaesthetics, ICU), so renal perfusion at that pressure may already be significantly compromised

Important

Clinical problem with using MAP: . A 70-year-old man with BP 160/90 has a MAP of 113 mmHg. Acutely unwell at BP 110/70 his MAP is 83 mmHg, apparently “normal” but a large fall from his own baseline into the range where his autoregulation is compromised. Does he need BP support? In normotensive renal failure the GFR curve does not plateau until higher pressures, and diverges from normal around MAP 80 to 85 mmHg.

Haemodynamic insults and drugs

A hypotensive-vasodilatory insult causes decreased renal blood flow, so decreased GFR; and reduces the role of the vasa recta, so increased medullary ischaemia, so acute tubular necrosis. NSAIDs produce the same picture by inhibiting prostaglandin formation in the vasculature and at the macula densa.

Triple whammy myth. ACE inhibitors or ARBs plus diuretics plus NSAIDs are NOT nephrotoxic. They reduce the kidneys’ ability to compensate for acute changes in renal perfusion in the setting of low perfusion. They do not specifically cause direct tubular injury; they potentiate hypoperfusion of the vasa recta, which can then lead to ischaemic injury and acute tubular necrosis. It is safe to restart an ARB or ACEI as the AKI recovers.

Acute tubular necrosis: why the medulla, and what happens

Target area for early ischaemic injury (hypoxic injury):

  1. Tubules: late proximal tubules and the medullary thick ascending limb, rich in mitochondria and active in transport
  2. Vascular endothelium

Injured cells undergo necrosis, apoptosis or sublethal injury.

Oxygen gradient. Cortex is oxygenated at pO2 50 mmHg; medulla is hypoxic at pO2 10 to 20 mmHg. There is a cortex-to-medulla oxygen gradient, and medullary hypoxia is due to countercurrent exchange of O2 in the vasa recta. Basolateral Na+/ATPase in tubular epithelial cells has an obligatory O2 requirement.

Self-reinforcing cascade. Ischaemia leads to endothelial cell activation, dysfunction, injury and/or detachment; then impaired vasodilation, coagulopathy and leukocyte adhesion; then capillary obstruction and continued ischaemia; then inflammation; then extension of acute renal failure, with the later steps feeding back into the loop.

Mechanisms of ischaemic ATN. Endothelial injury: increased adhesion molecules, backleak of fluid, increased vasoconstrictors, decreased vasodilators, congestion and hypoperfusion, all reducing renal function. Tubular injury from oxygen and ATP depletion and metabolic changes: proinflammatory and chemotactic cytokines, leukocyte infiltration, release of cytokines, enzymes and reactive oxygen species, denuded tubular walls, cytoskeletal disruption, loss of microvilli, necrosis, mislocation of integrins, apoptosis, mislocation of Na+/K+-ATPase. Cast obstruction: increased intraluminal sodium and polymerising Tamm-Horsfall protein form casts that obstruct the lumen. Tubular obstruction leads to oliguria. Histology shows necrotic tubular epithelial cells alongside a preserved normal glomerulus.

Continuum of tubular injury (Perazella and Coca, Nat Rev Nephrol 2013): at-risk kidney (ischaemia and/or nephrotoxin), to incipient AKI, to clinical AKI, to dialysis-requiring AKI. Early recognition covers the first two stages and allows rapid renal recovery; late recognition means progression to more severe AKI. Morphologically this is progressive brush border loss, cell detachment and luminal debris.

Injury and repair cycle (Devarajan, JASN 2006): normal epithelium, then ischaemia-reperfusion, then loss of brush border and cell polarity, then necrosis and apoptosis, then sloughing of viable and dead cells with luminal obstruction, then dedifferentiation of viable cells, then proliferation, then differentiation and re-establishment of polarity, then recovery back to normal epithelium. Na/K-ATPase redistributes from basolateral to apical/diffuse locations during injury and returns basolaterally with recovery.

Case 1: volume depletion after ileostomy

A 79-year-old with large bowel obstruction due to adenocarcinoma of colon, background hypertension (pre-op BP 156/88), had total colectomy and end ileostomy and was discharged 7 days after surgery, advised to seek medical attention if unwell or with fevers, severe pain, shortness of breath, nausea or vomiting. Gut physiology matters here: the ileum and colon differ in water and electrolyte handling.

Readmitted 14 days later after 3 episodes of collapse with prior presyncopal symptoms. On examination: tachypnoeic, tachycardic, afebrile, very dehydrated; BP 76/40 sitting; JVP 0 cm lying flat; 4 kg weight loss. Admitted to ICU. More correct to state low intravascular volume than “dehydration”.

Biochemistry on admission (07 Jan): Na 131, K 9.0, urea 53.8, creatinine 1562, eGFR 3, random glucose 6.4, blood gas pH 7.12. Baseline a month earlier (10 Dec): Na 137, K 3.7, urea 7.6, creatinine 109, eGFR 60, CRP 44.

Hyperkalaemia produces progressive ECG change (peaked T waves, widened QRS at K 6.5, 7.0, 8.0, 9.0), and can degenerate into ventricular fibrillation and death. The autoregulation curve again explains the injury: his admission BP of 110/70 sits near MAP 80 mmHg, far below his pre-surgery baseline of 160/90.

Treatment: intravenous fluids including NaCl and NaHCO3 to correct intravascular volume depletion and metabolic acidosis, calcium gluconate to stabilise cardiac rhythm, and insulin and dextrose (which caused a transient glucose of 3.4). Serial biochemistry shows K falling 9.0, 7.6, 7.2, 6.4, 6.8, 6.6, 5.2 over about 36 hours, and creatinine falling 1562, 1520, 1412, 1222, 1226, 1050, then 524, 343, 258, 172, 131 by 27 Jan, with eGFR rising 3 to 48. Bicarbonate was 8 then 12 then 21; chloride 115 to 119; phosphate 3.3 falling to 1.1.

Outcome: rapid resolution of AKI (filtration failure) and acidosis, but note the delay in the fall in creatinine. The half-life of creatinine is prolonged, plus there is tubular injury.

Hyperkalaemia, contributing factors:

  • Metabolic acidosis causes intracellular extrusion of K+; a fall in pH of 0.1 raises K+ by 0.3 mmol/L
  • Role of the kidney in K+ elimination and HCO3- regeneration
  • Loss of HCO3- (here from high stomal output)
  • Reduced tissue perfusion drives anaerobic metabolism and acidosis, producing lactate plus 2 H+ ions. This is the major mechanism; kidney injury is a late component

Case summary: a 79-year-old with an ileostomy who developed life-threatening AKI with severe acidosis and hyperkalaemia; events secondary to profound volume depletion, low intravascular volume hypoperfusion being the major aetiology; the acute component reversed with IV fluids, and the slow return to baseline reflects acute tubular necrosis (acute tubular ischaemia); stomal output was reduced from 3 L/day to about 1 L/day with loperamide. This was a preventable AKI, with good communication and monitoring.

Case 2: obstruction

A 74-year-old man with poor urine output, radiation and surgery for rectal carcinoma 6 months previously, euvolaemic, BP 160/80. Bloods (12 Jan): Na 141, K 4.4, urea 27.4, creatinine 920; Hb 107, MCV 93, platelets 205, WCC 4.6.

AKI: principles of investigation as applied here:

  • Identify low perfusion AKI and distinguish it from renal AKI: assess intravascular volume (BP 160/80, JVP 3 cm, so not hypovolaemic)
  • Identify renal toxic and immunologic causes: urinary dipstick and microscopy
  • Exclude postrenal obstruction: from the history (surgery, previous urinary catheter), a percussable bladder, and ultrasound

Ultrasound showed bilateral hydronephrosis with normal-sized kidneys and a large-volume bladder (dilated collecting systems measuring about 12 cm on each side, compared with a normal kidney of about 10 cm).

Mechanism: obstruction raises tubular back-pressure, which raises intracapsular (Bowman’s) pressure, reduces the net pressure driving ultrafiltration and so produces a progressive reduction in GFR.

Catheterisation drained 1200 mL, urine output continued, and IV normal saline was given. Creatinine fell 920, 490, 220, 111, 80 over about 28 hours (baseline 80 in July); urea fell 27.4 to 3.6.

Imaging: CT pelvis showed no pelvic mass suggesting recurrence; MR pelvis showed a fluid-filled space in the left lobe of the prostate, probably an abscess.

Case summary: a 74-year-old man with AKI secondary to bladder outlet obstruction due to prostatic abscess, corrected by bladder catheterisation, with post-obstructive diuresis (6 L per day) plus IV fluid therapy giving rapid reversal of the elevated creatinine.

Recovery phase of AKI

  • Important: 25 to 50% of mortality occurs in this period
  • Polyuria up to 5 L per 24 hours, especially post-obstruction; watch intravascular volume (JVP and BP)
  • Electrolyte abnormalities: hypokalaemia, hyponatraemia
  • Polyuria arises from loss of the medullary concentration gradient, lack of response to AVP, and osmotic diuresis
  • Recovery can take up to 28 days

Case 3: cardiorenal syndrome

A 65-year-old man presents with acute decompensated congestive heart failure; plasma creatinine has risen from 136 to 198 µmol/L. Why?

In untreated congestive heart failure, compensatory changes maintain a normal arterial BP: cardiac output falls, renal blood flow and GFR fall, total body water and total body sodium rise slightly, extracellular volume and plasma volume rise, right atrial pressure rises about 200% and left atrial pressure about 220%, while blood pressure shows near-zero net change (Anand, CJASN 2013).

Dual haemodynamic pathways for acute cardiorenal syndrome (House, CJASN 2013):

  • Arterial underfilling: decreased cardiac output, decreased effective circulating volume, decreased renal blood flow and plasma flow, activation of RAAS and SNS, inflammatory pathways
  • Venous congestion: venous congestion and venous hypertension with raised intra-abdominal pressure, decreased arteriovenous perfusion gradient, kidney interstitial oedema, activation of RAAS and SNS, inflammatory pathways

Both converge on decreased GFR, Na and H2O retention, increased oedema and preload, and increased afterload.

Sequence leading to salt and water retention. Heart failure gives low cardiac output states; sepsis gives high cardiac output vasodilated states; both threaten or lower blood pressure, unloading high-pressure baroreceptors in the aortic arch and carotid bodies. This raises AVP, sympathetic output and renin-angiotensin. AVP and aldosterone (via renin-angiotensin) increase distal nephron Na reabsorption; sympathetic output reduces renal blood flow and GFR; reduced renal blood flow increases proximal tubular reabsorption. The result is Na and water reabsorption, increased extracellular volume and oedema, and increased venous and intracardiac pressures, which stimulate natriuretic peptide and atrial receptor discharge as counter-regulation.

Schrier (NEJM 1999) frames the same sequence: decreased cardiac output or primary peripheral arterial vasodilatation causes renal vasoconstriction (lowering GFR), decreased renal perfusion pressure, increased alpha-adrenergic activity and increased angiotensin II activity, which together increase proximal tubular sodium and water reabsorption, reduce distal sodium and water delivery, and impair escape from the actions of aldosterone with resistance to natriuretic peptides.

Venous congestion acts locally too: an elevated venous pressure reduces the arteriovenous gradient and so renal perfusion pressure, raises Bowman’s hydrostatic and intratubular pressure, and lowers net filtration pressure and GFR, producing renal venous congestion and sodium avidity, with lymphatic congestion, impaired gut barrier and bowel oedema, and vasoconstriction with endothelial dysfunction reinforcing the loop.

Broader cardio-renal interactions (Schefold, Nat Rev Nephrol 2016) fall into haemodynamic mechanisms (fluid overload and salt and water retention, renal and cardiac congestion with renal venous hypertension, limited organ perfusion from forward failure, end-organ vasoconstriction), (neuro)hormonal mechanisms (RAAS and SNS activation), and cardiovascular disease-associated mechanisms (chronic inflammation and cellular immunity, malnutrition, cachexia and wasting, bone-mineral disorder, acid-base disorder, anaemia and cardio-renal anaemia).

Cardio-renal syndromes are “disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other”.

  • Progressive LVF: decreased cardiac output, reduced systemic perfusion, decreased renal function (mitral regurgitation is a consequence, not a cause)
  • Progressive RVF: back pressure, kidney interstitial oedema with peripheral oedema
  • Failing heart: activation of RAAS, SNS and AVP giving vasoconstriction, salt and water retention and expansion of intravascular volume; by Starling’s law, peripheral oedema; high cardiac afterload, dilated cardiomyopathy and increased left atrial pressure giving pulmonary oedema

Management of congestive heart failure:

  • ACEI or ARB, used despite low blood pressure: they decrease afterload, improve cardiac output which in turn improves blood pressure, improve renal perfusion, and promote natriuresis. On Frank-Starling curves, the failing heart’s flat low curve is shifted toward the normal curve
  • Diuretics: furosemide at increased dose with continuous blockade twice daily (that is, properly spaced, not morning and lunchtime); SGLT2 inhibitors such as empagliflozin
  • ACEI or ARB changed for sacubitril/valsartan (angiotensin receptor blocker neprilysin inhibitor, ARNI)
  • Mineralocorticoid receptor antagonist: spironolactone

Clinical assessment and investigation of AKI

Clinical examination relevant to AKI is covered in Talley and O’Connor, Clinical Examination, 5th edition.

Low perfusion state. Assessment of intravascular volume status, perfusion pressure and cardiac output is critical.

  • BP, including postural hypotension: lying and standing BP
  • Intravascular volume: JVP (emphasised as the key sign)
  • Body weight: in volume depletion the amount of weight lost equates to the fluid deficit
  • Urine biochemistry: low sodium, high osmolality

JVP technique. At 45 degrees the JVP is measured from the sternal angle, which approximates the height of the right atrium (about 3 cm below the sternal angle). The measurement is the vertical height, a column of water in cm. If the patient is lying flat, the right atrium is in the centre of the chest, so the new reference is the centre of the chest (mid-axillary line); the vertical height of the JVP is unchanged. This matters when intravascular volume is low: the JVP is not visible at 45 degrees and may only be visible below the clavicle when lying flat, giving a measurement of 0 cm.

Urine osmolality.

  • Hypovolaemia and stress stimulate ADH release, so concentrated urine represents a normal tubular response
  • Urine osmolality above 500 mosmol/kg is highly suggestive of low perfusion AKI
  • Loss of concentrating ability is an early and frequent finding in AKI
  • Urine osmolality below 450 mosmol/kg indicates ATN, usually below 350 mosmol/kg

Urinary sodium excretion.

  • Low in low perfusion AKI, as sodium is conserved via RAAS (be aware this may be a pathological response, as in congestive heart failure)
  • High in ATN, above 40 mmol/L, due to tubular cell injury
  • There may be overlap because of variations in water reabsorption

Post-renal. Anuria is obstruction until proven otherwise. Site of obstruction:

  • Extrinsic: tumour (pelvic malignancies, para-aortic lymph nodes), prostatic hypertrophy, renal calculi (in a single kidney)
  • Intrinsic: tumour lysis with uric acid precipitation, excess oxalate (vitamin C)
  • Examination: abdomen, PR and PV examination
  • Investigations: ultrasound, urine microscopy

Renal. Remember the contribution of a low perfusion state as well. Sources of injury: drugs (aminoglycosides, cisplatin), toxins (ethylene glycol), sepsis, immunologic (glomerulonephritis, vasculitis). Investigations: urinalysis, biochemistry, renal biopsy. Radiological contrast is NOT a cause of AKI.

Management of AKI

Kidney hypoperfusion, the “3 V’s”. Correct the underlying cause of hypotension by asking which V it is:

  • Volume depletion: restore intravascular volume
  • Vasodilation (sepsis): restore pressure
  • Ventricular, poor cardiac output: correct cardiac output

Do NOT give IV saline for heart failure. Maximise cardiac output. If intravascular volume is restored (JVP normal) but BP remains low, the patient is vasodilated for other reasons such as sepsis and needs a vasopressor agent (noradrenaline). Do not give diuretics simply to create urine output. Correct electrolyte and acid-base abnormalities.

Fluid overload is not harmless. Raised interstitial pressure and renal oedema arise from local inflammation, venous congestion and tubular leakage, plus extrinsic pressure (intra-abdominal hypertension), increased venous pressure and increased renal vascular resistance. This raises tubular pressure and reduces the ultrafiltration gradient, forming a self-reinforcing cycle that maintains AKI (Prowle, Nat Rev Nephrol 2013).

Post-renal AKI. Relief of obstruction: catheter, percutaneous nephrostomy, ureteric stents, removal of stones or tumour. Post-obstructive diuresis gives high urine output of 5 to 10 L per 24 hours, with major risk of volume depletion and electrolyte abnormalities.

Renal AKI. Remove or treat the source of injury (sepsis, drugs, toxins). Acute glomerulonephritis depends on the diagnosis and may need immunosuppressive therapy in consultation with a nephrologist.

General management.

  • Maintain volume and cardiac output. Fluids: previous 24-hour output equals input, plus insensible losses of 800 mL
  • Avoid sepsis: the immune response is impaired. A catheter is not required unless obstructed
  • Adequate and early nutritional intervention
  • Kidney support: haemodialysis or haemofiltration

Indications for dialysis.

  • Electrolytes: severe hyperkalaemia (risk of cardiac arrhythmia); metabolic acidosis (potentiates hyperkalaemia and cardiac dysfunction, frequently severe with sepsis). Treat the cause, not the numbers
  • Fluid overload with pulmonary oedema
  • Catabolic state
  • Mortality associated with AKI is approximately 30%, unchanged over the past few decades, and higher in at-risk individuals with more predisposing factors
  • Survival is critically related to associated organ involvement: AKI alone 5 to 8%; one other organ 25%; multiple organ failure (more than 3) 80 to 100%
  • AKI in ICU carries a 3 to 4 fold higher risk of death in the first 12 months
  • 3 to 5 fold higher risk of chronic kidney disease (Kellum et al., Nat Rev Dis Primers 2021;7:52)

Structural outcome by severity (Kellum 2021):

  • Mild AKI: some tubular epithelial cells injured, then recovery. Full recovery of nephron function and structure, single-nephron GFR normal, increased risk of cardiovascular disease
  • Moderate AKI: necrotic tubular epithelial cells and damaged progenitor cells. GFR partially recovered, some nephrons lost, some regenerated by progenitor clones, remnant single-nephron GFR increased, increased risk of CKD, CVD and possibly kidney cancer
  • Severe AKI: extensive necrotic tubular epithelial cells and granular casts, more immune cell activation and fibroblasts. Large reduction in total GFR, many nephrons lost, no or few nephrons regenerated, remnant nephron hypertrophy via tubular epithelial cell polyploidization, remnant single-nephron GFR greatly increased, increased risk of CKD, CVD and possibly kidney cancer

Lifetime trajectory. AKI accelerates the age-related decline in GFR and can bring kidney failure forward relative to average lifespan, with the effect depending on age at the AKI episode; some trajectories recover toward the normal decline band, others fall to zero GFR before average lifespan.

Absolute risks in the year after hospitalization with AKI in high-income countries (James et al., Nat Rev Nephrol 2020;16:193-205): AKI hospitalization about 34%, all-cause mortality about 27 to 28%, any hospitalization about 25%, chronic kidney disease about 20%, any cardiovascular event about 14%, cardiovascular mortality about 7 to 8%, cancer-specific mortality about 7 to 8%, atherosclerotic events about 5%, heart failure about 4%, end-stage kidney disease under 1%.

Proposed mechanism linking AKI and CKD to cardiovascular disease: AKI or CKD leads to reduced GFR, sympathetic nervous system activation, RAAS activation, coagulation and endothelial dysfunction, and inflammation; these produce neurohormonal activation, volume expansion, hypertension, and electrolyte and acid-base imbalance; which produce cardiac remodelling, left ventricular hypertrophy, heart failure, coronary atherosclerosis, arteriosclerosis, calcification and ischaemia, and arrhythmias.

Take-home points

  • Rule of 3 to identify AKI (the three definition criteria)
  • Low perfusion: kidney hypoperfusion is a major cause in most cases
  • Management is correcting the pathophysiology
  • AKI is associated with increased risk of CKD

Self-test

  1. State the three criteria by which AKI is defined, with the numerical thresholds and time frames.
  2. List the four causal categories of the LION classification, giving one specific cause under each.
  3. Give the five glomerular pressure values from the lecture and state which one is the net pressure driving ultrafiltration.
  4. Describe the ordered steps of tubuloglomerular feedback when luminal NaCl at the macula densa is LOW.
  5. Describe the ordered steps of tubuloglomerular feedback when luminal NaCl at the macula densa is HIGH.
  6. Distinguish the mediators that raise GFR from those that lower it, and state the arteriolar changes each set produces.
  7. Explain the purpose of myogenic constriction in pre-glomerular vessels.
  8. At what MAP does maximal afferent arteriolar vasodilation occur, and why does the common ICU hypotension threshold of MAP below 65 mmHg matter for the kidney?
  9. Calculate the MAP for BP 160/90 and for BP 110/70, and explain why the second value may still represent a dangerous fall for a chronically hypertensive patient.
  10. Explain why ACEI/ARB plus diuretic plus NSAID is called a myth as a nephrotoxic “triple whammy”, and what the combination actually does.
  11. Name the two tissue targets of early ischaemic injury and explain why the medulla is the vulnerable region, quoting the cortical and medullary pO2 values.
  12. Describe the self-reinforcing cascade from ischaemia to extension of acute renal failure.
  13. Explain how casts contribute to ATN and what clinical feature tubular obstruction produces.
  14. Describe the sequence of tubular cell changes from ischaemia-reperfusion through to recovery, including what happens to Na/K-ATPase.
  15. A patient with a high-output ileostomy presents collapsed with BP 76/40, JVP 0 cm lying flat, 4 kg weight loss, K 9.0, creatinine 1562 and pH 7.12. Explain the mechanism of the hyperkalaemia and state which factor the lecture identifies as the major one.
  16. In that case, creatinine fell only slowly despite rapid clinical and biochemical improvement. Give the two reasons offered.
  17. Explain the mechanism by which urinary tract obstruction reduces GFR, in terms of the filtration pressures.
  18. List the features of the recovery phase of AKI and state why it is a dangerous period.
  19. Distinguish low perfusion AKI from ATN using urine osmolality and urine sodium, with the cut-offs.
  20. Describe how the JVP is measured at 45 degrees and lying flat, and what a measurement of 0 cm signifies.
  21. Name the “3 V’s” of kidney hypoperfusion and the corrective action for each, and state the fluid rule that must not be broken.
  22. List the indications for dialysis in AKI.
  23. Explain the two haemodynamic pathways of acute cardiorenal syndrome and why venous congestion alone can reduce GFR.
  24. Why are ACEI or ARB used in decompensated heart failure despite a low blood pressure? Give the chain of effects.
  25. State the mortality figures for AKI alone, AKI with one other organ involved, and AKI with multiple organ failure.
  26. Predict how the long-term nephron outcome differs between mild, moderate and severe AKI.
  27. Integrative: a 79-year-old with treated hypertension and a recent ileostomy is admitted with BP 110/70 and is prescribed an NSAID for pain. Explain, linking autoregulation, tubuloglomerular feedback and the prostaglandin contribution, why he is at high risk of ATN, and what the long-term consequence of that episode may be.

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