Acute Kidney Injury

DefinitionSudden impairment of kidney function resulting in retention of Nitrogenous & other waste by the kidney i.e. increased BUN& serum Cr + often reduced urine output

Laboratory definition:A rise in SCr of >= 0.3mg/dL or 50% higher than baseline, within a 24-48 hr period OR

A reduction in urine output to 0.5ml/kg/hr for > 6 hrs

This is important to differentiate AKI from CKI however, it is difficult when there is no recent baseline SCr reading available. If so radiological studies (small shrunken kidneys + cortical thinning on US, or renal osteodystrophy) or lab tests (Normocytic anaemia, 2 Hyperparathyroidism with hyperphosphatemia and hypocalcemia) can help identify CKD

No set of tests, however, can rule out AKI superimposed on CKD since AKI is a frequent complication in patients with CKD, further complicating the distinction

EpidemiologyAKI complicates 30% admissions in the ICU & is associated with a markedly increased risk of death in hospitalized individuals

It is a major medical complication in the developing world owing to specific etiologies such as snakes, bees, malaria, leptospirosis, crush injuries from earthquakes (and resultant rhabdomyolysis)

EtiologyPre-renal Azotemia

Intrinsic Renal Parenchymal disease

Postrenal obstruction

Pre-renal Azotemia

Definition: A rise in SCr or BUN (f) inadequate renal plasma flow & intraglomerular hydrostatic pressure to support normal glomerular filtration.

It involves no parenchymal damage to the kidney + is rapidly reversible once intraglomerular hemodynamics are restored.

Causes:Hypovolemia

Decreased effective circulating volume CCF

Liver failure i.e. Hepatorenal Syndrome in advnaced cirrhosis There is prerenal azotemia despite total body volume overload

Arterial vasodilation in the splanchnic circulation activation of vasoconstrictor responses seen in hypovolemia AKI

Type 1 Hepatorenal syndrome: AKI persists despite volume administration and withholding of diuretics

Type 2 Hepatorenal syndrome: Less severe form characterized by refractory ascites

Decreased CO

NSAIDs/ ACE Inhibitors/ Ang II inhibitors/ Cyclosporine Inhibit renal autoregulation

Physiology of normal renal GFR autoregulation: Maintained by relative resistances of afferent & efferent renal arterioles determines glomerular plasma flow and transcapillary hydraulic pressure gradient drives glomerular ultrafiltration

Mild hypovolemia/CO reductions compensatory renal physiologic changes:Renal efferent vasoconstriction Ang II mediated, in response to reduced renal blood flow

Renal afferent vasodilation Myogenic Reflex within afferent arteriole: Low perfusion pressure afferent arteriole dilation

Increased intrarenal synthesis of vasodilator molecules in response to low perfusion pressure e.g. PGs, Kallikrein, Kinins, NO

Tubuloglomerular feedback: Decreased solute delivery to macula densa dilation of juxtaposed afferent arteriole mediated by NO

N.B: There is a limit to this autoregulation it fails once systolic BP falls below 80 mmHg

The robustness of the autoregulatory response can be reduced due to:I) Hyalinosis and myointimal hyperplasia (leading to structural narrowing and impaired capacity for afferent vasodilation) caused by:Atherosclerosis

Long standing HTN

Old age

N.B: Diabetes can cause hyalinosis in both afferent and efferent vessels??

II) Drugs NSAIDs inhibit renal PG production limits renal afferent vasodilation

ACEInh/ARBs limit renal efferent vasoconstriction

Combined use of NSAIDs and ACEInh/ARBs high risk for developing prerenal azotemia

Intrinsic AKI

Most common causes:Sepsis

Ischaemia

Nephrotoxins

Pre-renal azotemia advancing to tubular injury e.g. ATN

Sepsis-associated AKIAKI complicates 50% of severe sepsis & markedly increases risk of death

Pathophysiology:Inflammation and interstitial edema

Tubular injury tubular debris and casts in injury

GFR reduction arises from generalised arterial vasodilation (efferent > afferent) Cytokines that upregulate iNOS

Ischaemia-associated AKIDespite receiving 10% of resting O2 consumption (and 20% of CO), the kidneys are also the site of one of the most hypoxic regions in the body i.e. the renal medulla (esp. outer medulla).

AKI associated with ischaemia tends to occur not when ischemia occurs alone, but when ischaemeia occurs in the context of:Limited renal reserve e.g. CKD or Older age

Sepsis

Nephrotoxic drugs

Rhabdomyolysis

Systemic Inflammatory states e.g. burns/pancreatitis

Post-operative period esp. after major operations involving significant blood loss and intraoperative hypotension Examples of surgeries:Cardiac surgery with cardiopulmonary bypass

Vascular procedures with aortic cross clamping

Intraperitoneal procedures

RFs:CKD

Older age

DM

CCF

Emergency procedures

Mechanism:Persistent preglomerular vasoconstriction (f):Tubuloglomerular feedback activation (f) enhanced solute delivery to macula densa after proximal tubule injury

Increased basal vascular tone

Decreased vasodilatory responsiveness

Backleak of filtrate across ischemic and denuded tubular epithelium

Mechanical obstruction of tubules from necrotic debris

Burns & Acute pancreatitisMechanisms:Extensive fluid loss into extravascular body compartments severe hypovolemia and decreased CO increased neurohormonal activation

Dysregulated inflammation

Increased risk of sepsis and ALI

Abdominal compartment syndrome massive fluid resuscitation can lead to elevated intraabdominal pressures renal vein compression and reduced GFR

Microvascular AKI ischaemiaCauses:Thrombotic microangiopathiesAPLS

Radiation nephritis

Malignant nephrosclerosis

TTP/HUS

Scleroderma

Atheroembolic disease

Large vessel disease causing AKIRenal artery dissection

Renal artery thrombosis

Renal vein compression/thrombosis

Nephrotoxic-associated AKIThe kidney has high susceptibility to nephrotoxicity (f):Extremely high BP & concentration of circulating substances along the nephron where water is reabsorbed & medullary interstitium high-concentration exposure of toxins to tubules, interstitium and EC

RFs:CKD

Pre-renal azotemia

Old age

Hypoalbuminemia

Contrast AgentsIodinated contrast agents (e.g. used for CT imaging) are the LEADING cause of AKI

The risk increases markedly in:CKD

Diabetic nephropathy

Multiple myeloma

Clinical course:Rise in SCr begins 24-48 hrs after exposure

SCr peaks 3-5 days

Resolves wtihin 1 week

Mechanisms:

Antibiotics Aminoglycosides Tubular necrosis

Can result in Non-oliguric AKI (10-30% of times)

Typically manifests after 5-7d of therapy & can present after drug is discontinued

Hypomagnesemia is a common finding

Amphotericin B Causes renal vasoconstriction from an increase in tubuloglomerular feedback

Tubular necrosis mediated by ROS + binds to tubular membrane cholesterol and introduces pores

Leads to: Polyuria, hypomagnesemia, hypocalcemia, metabolic acidosis (non anion gap)

VancomycinCauses AKI when trough levels are high

Acyclovir Causes AKI by tubular obstruction

Foscarnet

Pentamidine

Cidofovir

Secondary to acute interstitial nephritis (f) ABs such as penicillins, cephalosporins, quinolones, sulfonamides, rifampin

Chemotherapeutic agents Cisplatin

Carboplatin

Ifosfamide

Bevacizumab

Toxic ingestionsEthylene gylcol Present in car antifreeze

Metabolites can cause direct tubular injury

Diethylene glycol Industrial agent

Melamine May contaminate foodstuffs

Can cause nephrolithiasis and AKI

Balkan nephropahty

Endogenous toxins Myoglobin Can be released by injured muscle cells e.g. Rhabdomyolysis

Causes of Rhabdomyolysis include:Traumatic crush injuries

Muscle ischemia during vascular/orthopedic surgery

Compression during coma/immobilisation

Prolonged seizure activity

Excessive exercise

Heat stroke/Malignant hyperthermia

Infections

Metabolic disorders e.g. hypophosphatemia, severe hypothyroidism

Myopathies e.g. durg-induced, metabolic, inflammatory

Mechanisms:Intrarenal vasoconstriction

Direct proximal tubular toxicity

Mechanical obstruction of distal nephron when myoglobin/hemoglobin precipitates with Tamm-Horsfall protein (favoured by acidic urine)

Hemoglobin

Uric acid Tumour lysis syndrome after initiation of cytotoxic therapy in patients with high-grade lymphomas and ALL massive release of uric acid precipitation of uric acid in renal tubules AKI

TLS also causes hyperkalemia and hyperphosphatemia

Myeloma light chains Mechanisms:Direct tubular toxicity

Binds to Tamm-Horsfall protien obstructing intratubular casts

Hypercalcemia intense vasoconstriction and volume depletion

Tumour lysis syndrome following initiation of treatment

Allergic acute tubulointerstitial disease Allergic response to drugs characterised by an inflammatory infiltrate + peripheral & urinary eosinophilia

Post-renal AKI

Unidirectional flow of urine is acutely blocked partially or totally retrograde hydrostatic pressure reduced GFR

N.B: Normal urinary flow rates DO NOT rule out presence of partial obstruction as GFR is normally 2X magnitude higher than the urinary flow rate

In healthy individuals, obstruction must affect both kidneys to cause AKI

In those with significant underlying CKD, unilateral obstruction can result in AKI

Causes:Bladder neck obstruction e.g. BPH, Prostate Ca

Neurogenic bladder

Anticholinergic drugs

Obstructed Foley catheters

Calculi

Urethral strictures

Blood clots

Neoplasia

External compression e.g. retroperitoneal fibrosis, neoplasia, abscess, inadvertent surgical damage

Pathophysiology:Abrupt increase in intratubular pressures hyperemia from afferent arteriolar dilation intrarenal vasoconstriction (f) Ang II, TXA2, Vasopressin, Reduction in NO Reduced GFR (f) underperfusion of glomeruli

Complications of AKI

Uremia

Elevated BUN is a hallmark of AKI

Only when levels > 100 mg/dL does it cause problems such as mental status changes and bleeding complications = Uremia????

The correlation of BUN and SCr concentrations with uremic symptoms is extremely variable, due in part to differences in urea and creatinine generation rates across individuals.

Hypervolemia and Hypovolemia

Oliguric/anuric AKI ECF volume expansion (Hypervolemia) weight gain, dependent edema, raised JVP, Pulm edema, Acute lung injury characterised by increased vascular permabiity and inflammatory cell infiltration (rare)

AKI recovery involves polyuria (due to osmotic diuresis from retained urea + delayed recovery of tubular reabsorptive functions) hypovolemia

Hyponatremia

Following administration of excessive hypotonic crystalloids or isotonic dextrose solutions

Hyperkalemia

The most concerning complication of AKI

Especially marked if underlying etiology is:Rhabdomyolysis

Hemolysis

Tumour lysis syndrome

Can lead to: Muscle weakness, arrhythmias (can be fatal)

Acidosis

Raised anion gap metabolic acidosis

Hyperphosphatemia & Hypocalcemia

Hyperphosphatemia is more likely to occur in AKI arising due to:Rhabdomyolysis

Hemolysis

Tumour lysis syndrome

Hypocalcemia can occur due to:Hyperphosphatemia metastatic deposition of Calcium phosphate

Deranged Vit D-parathyroid axis

Hypocalcemia is often asymptomatic if mild; but if excessive can lead to:Peri-oral parasthesias

Muscle cramps

Seizures

Carpopedal spasms

Prolonged QT interval

Hematological complicaitons

Anaemia (f) decreased erythropoieisis

Bleeding (f) platelet dysfunction

Infections

Infections are a common precipitant of AKI and also a dreaded complication of AKI.

There is impaired host immunity in end-stage renal disease

Cardiac complciations e.g. arrhythmias, pericarditis, pericardial efflusion

Malnutrition due to the severely hypercatabolic state of AKI