Background
Diagnosis of AKI
Diagnostic criteria for AKI:
| ||
AKI is defined as any of the following: | ||
• Increase in serum creatinine by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 h; or • Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or • Urine volume <0.5 ml/kg/h for 6 h. | ||
AKI staging system:
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AKI stage | Serum creatinine criteria | Urine output criteria |
AKI stage I | Increase of serum creatinine by ≥0.3 mg/dl (≥26.4 μmol/L) | Urine output <0.5 ml/kg/h for 6–12 h |
or | ||
increase to 1.5–1.9 times from baseline | ||
AKI stage II | Increase of serum creatinine to 2.0–2.9 times from baseline | Urine output <0.5 ml/kg/h for ≥12 h |
AKI stage III | Increase of serum creatinine ≥3.0 times from baseline | Urine output <0.3 ml/kg/h for ≥24 h |
or | or | |
serum creatinine ≥4.0 mg/dl (≥354 μmol/L) | anuria for ≥12 h | |
or | ||
treatment with RRT | ||
or | ||
in patients <18 years, decrease in estimated GFR to <35 ml/min per 1.73 m2
|
Clinical scenario | Consequence |
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Administration of drugs which interfere with tubular secretion of creatinine (i.e. cimetidine, trimethoprim) | Misdiagnosis of AKI (rise in serum creatinine without change in renal function) |
Reduced production of creatinine (i.e. muscle wasting, liver disease, sepsis) | Delayed or missed diagnosis of AKI |
Ingestion of substances which lead to increased generation of creatinine independent of renal function (i.e. creatin, cooked meat) | Misdiagnosis of AKI |
Obesity | Overdiagnosis of AKI if using actual weight when applying urine output criteria |
Conditions associated with physiologically increased GFR (i.e. pregnancy) | Delayed diagnosis of AKI |
Interference with analytical measurement of creatinine (i.e. 5-fluorocytosine, cefoxitin, bilirubin) | Misdiagnosis and delayed diagnosis of AKI (depending on the substance) |
Fluid resuscitation and overload | Delayed diagnosis of AKI (dilution of serum creatinine concentration) |
Progressive CKD with gradual rise in serum creatinine | Misdiagnosis of AKI |
Extrinsic creatinine administration as a buffer in medications (i.e. in dexamethasone, azasetron) | Pseudo-AKI |
Oliguria due to acute temporary release of ADH (i.e. post-operatively, nausea, pain) enhanced by maximal sodium reabsorption in the setting of volume/salt depletion | Misdiagnosis of AKI |
Limitations of creatinine-based criteria for AKI
Limitations of urine-based criteria for AKI
Adjunctive diagnostic tools to diagnose AKI
New AKI biomarkers
AKI biomarker | Description | Handling by the kidney | Factors affecting biomarker levels |
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Alanine aminopeptidase (AAP) | Enzymes located on the brush border villi of the proximal tubular cells | Released from tubular brush border after damage to proximal tubular cells | |
Alkaline phosphatase (ALP) | |||
γ-Glutamyl transpeptidase (γ-GT) | |||
Angiopoietin-1 | 57 kDa endothelial growth factor secreted by endothelial cells, including renal endothelial cells | Upregulated in glomerular disease and sepsis | Systemic inflammation |
Angiopoietin-2 | |||
Diabetes | |||
Malignancy | |||
Calprotectin | Cytosolic calcium-binding complex of two proteins of the S100 group (S100A8/S100A9); derived from neutrophils and monocytes; activator of innate immune system | Detectable in urine following intrinsic AKI | Inflammatory bowel disease |
Urinary tract infection | |||
CKD | |||
Chitinase 3-like protein 1 | 39 kDa soluble intracellular protein of glycoside hydrolase family 18 expressed by chrondrocytes, macrophages, endothelial cells, neutrophils, smooth muscle, and cancer cells; | Glomerular filtration of serum concentrations; in addition: some secretion by macrophages within the kidneys upon renal stress or damage | Inflammatory diseases |
Malignancy | |||
COPD | |||
Liver cirrhosis | |||
Connective tissue disease | |||
Cardiovascular disease | |||
Cystatin C | 13 kDa cysteine protease inhibitor produced by all nucleated human cells and released into the plasma at a constant rate | Freely filtered in glomeruli and completely absorbed and catabolized by proximal tubular cells; no tubular resorption or secretion | Systemic inflammation |
Malignancy | |||
Thyroid disorders | |||
Glucocorticoid disorder | |||
Cigarette smoking | |||
Hyperbilirubinaemia | |||
Hypertriglyceridaemia | |||
HIV disease | |||
α Glutathione S-transferase (α GST) | 47–51 kDa cytoplasmic enzyme in proximal tubule | Released into urine following tubular injury | |
п Glutathione S-transferase (п GST) | 47–51 kDa cytoplasmic enzyme in distal tubules | Released into urine following tubular injury | |
Hepatocyte growth factor (HGF) | Antifibrotic cytokine produced by mesenchymal cells and involved in tubular cell regeneration after AKI | Released into urine following tubular injury | Advanced heart failure |
Hypertension | |||
Bowel inflammation | |||
Hepcidin | 2.78 kDa peptide hormone predominantly produced in hepatocytes but also in kidney, brain, and heart; regulator of iron metabolism | Freely filtered followed by tubular uptake and catabolism | Systemic inflammation |
Iron overload | |||
Insulin-like growth factor binding protein-7 (IGFBP-7), tissue metalloproteinase-2 (TIMP-2) | Metalloproteinases involved in cell cycle arrest | Released into urine after tubular cell stress | |
Interleukin-18 (IL-18) | 18 kDa pro-inflammatory cytokine | Released into urine by proximal tubular cells following tubular injury | Inflammation |
Sepsis | |||
Heart failure | |||
Kidney Injury Molecule-1 (KIM-1) | Transmembrane glycoprotein produced by proximal tubular cells after ischaemic or nephrotoxic injury | Released into urine following ischaemic or nephrotoxic tubular damage | Renal cell carcinoma |
Chronic proteinuria | |||
CKD | |||
Sickle cell nephropathy | |||
Liver-type fatty acid-binding protein (L-FABP) | 14 kDa intracellular lipid chaperone produced in proximal tubular cells and hepatocytes | Freely filtered in glomeruli and reabsorbed in proximal tubular cells; increased urinary excretion after tubular cell damage | CKD |
Polycystic kidney disease | |||
Liver disease | |||
Sepsis | |||
α1 Microglobulin | Low molecular weight protein produced in liver | Freely filtered by glomeruli; reabsorbed and catabolised by proximal tubular cells; urinary excretion after tubular dysfunction | Sepsis |
β2 Microglobulin | 12 kDa light chain of major histocompatibility class I expressed on cell surface of every nucleated cell | Freely filtered by glomeruli; reabsorbed and catabolised by proximal tubular cells; urinary excretion after tubular dysfunction | |
MicroRNA | Endogenous single-stranded molecules of non-coding nucleotides | Upregulated following tubular injury and detectable in plasma and urine | Sepsis |
Monocyte chemoattractant peptide-1 (MCP-1) | Peptide expressed in renal mesangial cells and podocytes | Released into urine | Variety of primary renal diseases |
N-acetyl-β-d-glucosaminidase (NAG) | >130 kDa lysosomal enzyme; produced in proximal and distal tubular cells and non-renal cells | Too large to undergo glomerular filtration; released into urine after tubular damage | Diabetic nephropathy |
Neutrophil gelatinase-associated lipocalin (NGAL) | At least three different types: | 25 kDa and 45 kDa NGAL undergo glomerular filtration and reabsorption in healthy tubular cells | Sepsis |
• Monomeric 25 kDa glycoprotein produced by neutrophils and epithelial tissues, including renal tubular cells • Homodimeric 45 kDa protein produced by neutrophils • Heterodimeric 135 kDa protein produced by renal tubular cells | Malignancy | ||
CKD | |||
25 kDa and 135 kDa NGAL are released into urine following tubular damage | Urinary tract infection | ||
Pancreatitis | |||
COPD | |||
Endometrial hyperplasia | |||
Netrin-1 | 50–75 kDa laminin-related molecule, minimally expressed in proximal tubular epithelial cells of normal kidneys | Highly expressed in injured proximal tubules and released into urine | |
Proenkephalin | Endogenous polypeptide hormone in adrenal medulla, nervous system, immune system and renal tissue | Cleared by glomerular filtration | Systemic inflammation |
Pain | |||
Retinol binding protein (RBP) | 21 kDa single-chain glycoprotein; synthesized by liver | Totally filtered by the glomeruli and reabsorbed but not secreted by proximal tubules; released into urine following tubular injury | Diabetes |
Obesity | |||
Acute critical illness | |||
Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) | Member of the immunoglobulin superfamily of receptors expressed on granulocytes and monocytes, also possibly produced by endothelial cells and tubular epithelial cells | Detectable in urine following glomerular filtration and possibly local production | Sepsis |
Systemic inflammation |
Diagnosis of acute kidney disease
Diagnostic work-up
Urine dipstick
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glomerulonephritis (with haematuria and proteinuria)
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acute pyelonephritis (with pyuria/leucocyturia and nitrites in urine)
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interstitial nephritis (occasionally with eosinophiluria)
Urine microscopy (urinary sediment)
Microscopy finding | Example | Significance |
---|---|---|
Epithelial cells | ![]() | Normal |
Renal tubular cells | ![]() | Acute tubular injury |
Non-dysmorphic red cells | ![]() | Non-glomerular bleeding from anywhere in the urinary tract |
Dysmorphic red cells | ![]() | Glomerular disease, but can also be seen if urine sample is not fresh at time of microscopy |
Red cell casts | ![]() | Diagnostic of glomerular disease |
Leukocytes | ![]() | Up to 3 per high-power field = normal; >3 per high-power field = inflammation in urinary tract |
White cell casts | ![]() | Renal infection |
Hyaline casts | ![]() | Any type of renal disease |
Granular casts | ![]() | More significant renal disease |
“Muddy brown cast” | ![]() | Necrotic tubular cells aggregated with tamm horsfall protein indicating acute tubular injury |
Crystals | ![]() | Some crystals can be found in healthy individuals; “abnormal” crystals may indicate metabolic disorders or excreted medications |
Bacteria | ![]() | Urinary tract infection; contamination |
Urinary electrolytes
Renal ultrasound
Measurement of intra-abdominal pressure
Autoimmune profile
Renal biopsy
Other laboratory tests
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serum creatine kinase and myoglobin (in case of suspected rhabdomyolysis)
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lactate dehydrogenase (LDH) (in case of suspected thrombotic thrombocytopenic purpura (TTP))
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fragmentocytes (in case of possible TTP/haemolytic uraemic syndrome (HUS))
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N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin (in case of suspected cardio-renal syndrome)
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serum/urine protein electrophoresis (in case of suspected myeloma kidney)