1. 순천향대학교 서울병원 신장내과 R2 이상재 Acute Kidney Injury

2. Introduction Acute kidney injury (AKI) – Sudden impairment of kidney function resulting in the retention of nitrogenous and other waste products normally cleared by the kidneys AKI is not single disease, designation for heterogeneous group of condition that share common diagnostic feature –The presence of AKI is usually inferred by an elevation in the SCr concentration. – AKI is currently defined by a rise of at least 0.3 mg/dL or 50% higher than baseline within a 24–48-hours period or a reduction in urine output to 0.5 mL/kg per hour for longer than 6 hours

3. Epidemiology AKI complicates 5–7% of acute care hospital admissions and up to 30% of admissions to the intensive care unit The incidence of AKI has grown by more than fourfold in the United States since 1988 and is estimated to have a yearly incidence of 500 per 100,000 population AKI is associated with a markedly increased risk of death in hospitalized individuals, particularly in those admitted to the ICU where in-hospital mortality rates may exceed 50%

4. Etiology and Pathophysiology

5. Prerenal Azotemia Prerenal azotemia is the most common form of AKI A rise in SCr or BUN concentration due to inadequate renal plasma flow and intraglomerular hydrostatic pressure to support normal glomerular filtration Prolonged periods of prerenal azotemia may lead to ischemic injury, often termed acute tubular necrosis prerenal azotemia involves no parenchymal damage to the kidney and is rapidly reversible once intraglomerular hemodynamics are restored.

6. Prerenal Azotemia The most common conditions associated with prerenal azotemia – Hypovolemia – Decreased cardiac output – Medications that interfere with renal autoregulatory responses such as NSAIDs and inhibitors of angiotensin II

7. Intrinsic AKI The most common causes of intrinsic AKI are sepsis, ischemia, and nephrotoxins, both endogenous and exogenous

8. Intrinsic AKI Sepsis-Associated AKI AKI complicates more than 50% of cases of severe sepsis, and greatly increases the risk of death Decreases in GFR with sepsis can occur even in the absence of overt hypotension There is clearly tubular injury associated with AKI in sepsis

9. Intrinsic AKI Sepsis-Associated AKI - Mechanism Reduction in GFR – by the hemodynamic effects of sepsis ①Excessive generalized arteriole vasodilation – Mediated in part by cytokine that upregulating NO synthase ②Renal vasoconstriction – from activation of the sympathetic nervous system (RAA system, vasopressin, and endothelin) ③Endothelial damage – which results in microvascular thrombosis, activation of reactive oxygen species, and leukocyte adhesion and migration – all of which may injure renal tubular cells

10. Intrinsic AKI Ischemia-Associated AKI Healthy kidneys receive 20% of the cardiac output and account for 10% of resting oxygen consumption The kidneys are also the site of one of the most hypoxic regions, The outer medulla is particularly vulnerable to ischemic damage because of the architecture of the blood vessels that supply oxygen and nutrients to the tubule Ischemia alone in a normal kidney is usually not sufficient to cause severe AKI Clinically, AKI more commonly develops when ischemia occurs in the context of limited renal reserve (e.g., CKD or older age) or coexisting insults such as sepsis, vasoactive or nephrotoxic drugs, rhabdomyolysis, and the systemic inflammatory states associated with burns and pancreatitis

11. Intrinsic AKI Nephrotoxin-Associated AKI - Overview The kidney has very high susceptibility to nephrotoxicity – due to extremely high blood perfusion and concentration of circulating substances along the nephron – this results in high-concentration exposure of toxins to tubular, interstitial, and endothelial cells All structures of the kidney are vulnerable to toxic injury – including the tubules, interstitium, vasculature, and collecting system Risk factors for nephrotoxicity include older age, chronic kidney disease (CKD), and prerenal azotemia Hypoalbuminemia may increase the risk of some forms of nephrotoxin- associated AKI – due to increased free circulating drug concentrations

12. Intrinsic AKI Nephrotoxin-Associated AKI - Contrast Agents Iodinated contrast agents used for cardiovascular and CT imaging are a leading cause of AKI The risk of contrast nephropathy is negligible in those with normal renal function but increases markedly in the setting of chronic kidney disease, particularly diabetic nephropathy The most common clinical course of contrast nephropathy is characterized by a rise in SCr beginning 24–48 hours following exposure, peaking within 3–5 days, and resolving within 1 week Contrast nephropathy is thought to occur from a combination of factors –hypoxia in the renal outer medulla due to perturbations in renal microcirculation and occlusion of small vessels –cytotoxic damage to the tubules directly –transient tubule obstruction with precipitated contrast material

13. Intrinsic AKI Nephrotoxin-Associated AKI – Antibiotics Aminoglycosides and amphotericin B both cause tubular necrosis –Aminoglycosides are freely filtered across the glomerulus and then accumulate within the renal cortex –Amphotericin B causes renal vasoconstriction from an increase in tubuloglomerular feedback as well as direct tubular toxicity mediated by ROS Vancomycin –causal relationship with AKI has not been definitively established Acyclovir can precipitate in tubules and cause AKI by tubular obstruction AKI secondary to acute interstitial nephritis –penicillins, cephalosporins, quinolones, sulfonamides, and rifampin

14. Intrinsic AKI Nephrotoxin-Associated AKI – Chemotherapeutic Agents Cisplatin and carboplatin – accumulated by proximal tubular cells and cause necrosis and apoptosis – Intensive hydration regimens have reduced the incidence of cisplatin nephrotoxicity Ifosfamide may cause hemorrhagic cystitis and tubular toxicity Bevacizumab (Antiangiogenesis agent) can cause proteinuria and hypertension via injury to the glomerular microvasculature Mitomycin C and gemcitabine may cause thrombotic microangiopathy with resultant AKI

15. Intrinsic AKI Nephrotoxin-Associated AKI – Endogenous Toxins AKI may be caused by a number of endogenous compounds, including myoglobin, hemoglobin, uric acid, and myeloma light chains Rhabdomyolysis – Pathogenic factors for AKI include intrarenal vasoconstriction, direct proximal tubular toxicity, and mechanical obstruction of the distal nephron lumen when myoglobin or hemoglobin precipitates with Tamm-Horsfall protein Tumor lysis syndrome – massive release of uric acid leads to precipitation of uric acid in the renal tubules Multiple myeloma – Myeloma light chains cause AKI by direct tubular toxicity and by binding to Tamm- Horsfall protein to form obstructing intratubular casts – Hypercalcemia may cause AKI by intense renal vasoconstriction and volume depletion

16. Post-renal AKI Postrenal AKI occurs when the unidirectional flow of urine is acutely blocked, leading to increased retrograde hydrostatic pressure and interference with glomerular filtration The pathophysiology of postrenal AKI involves hemodynamic alterations triggered by an abrupt increase in intratubular pressures – An initial period of hyperemia from afferent arteriolar dilation is followed by intrarenal vasoconstriction from the generation of angiotensin II, thromboxane A2, and vasopressin, and a reduction in NO production For AKI to occur in healthy individuals, obstruction must affect both kidneys – Unilateral obstruction may cause AKI in the setting of significant underlying CKD or in rare cases from reflex vasospasm of the contralateral kidney

17. Cause of AKI

18. Interpretation of urinary sediment in AKI

19. Renal Failure Index FeNa is the fraction of the filtered sodium load that is reabsorbed by the tubules – With prerenal azotemia, the FeNa may be below 1%, suggesting avid tubular sodium reabsorption – In ischemic AKI, the FeNa is frequently above 1% because of tubular injury and resultant inability to reabsorb sodium – In patients with CKD, a FeNa significantly above 1% can still be present despite a prerenal state – Low FeNa is suggestive but not synonymous with effective intravascular volume depletion, and should not be used as the sole guide for volume management The response of urine output to crystalloid or colloid fluid administration may be both diagnostic and therapeutic in prerenal azotemia

20. Novel Biomarkers BUN/Cr are functional biomarkers of glomerular filtration rather than tissue injury biomarkers –may be suboptimal for the diagnosis of actual parenchymal kidney damage – BUN/Cr are relatively slow to rise AKI, Several novel kidney injury biomarkers have been investigated and show great promise for the early and accurate diagnosis of AKI Kidney injury molecule-1(KIM-1) is type 1 transmembrane protein that is abundantly expressed in proximal tubular cells injured by ischemia or nephrotoxins such as cisplatin –KIM-1 can be detected shortly after ischemic or nephrotoxic injury in the urine and, therefore, may be an easily tested biomarker in the clinical setting Neutrophil gelatinase associated lipocalin(NGAL) is another leading novel biomarker of AKI –NGAL is highly upregulated after inflammation and kidney injury and can be detected in the plasma and urine within 2 hours of cardiopulmonary bypass– associated AKI

21. Management of AKI Prevention and treatment of prerenal azotemia requires optimization of renal perfusion AKI due to acute glomerulonephritis or vasculitis may respond to immunosuppressive agents and/or plasmapheresis Early and aggressive volume repletion is mandatory in patients with rhabdomyolysis, achieving urinary flow rates of 200–300 mL/h Transurethral or suprapubic bladder catheterization may be all that is needed initially for urethral strictures or functional bladder impairment

22. Reference Harrison’s Principles of Internal Medicine 19 th Up To Date