Epidemiology, Classification, Diagnosis, Pathomechanism, Treatment and prognosis

Definition
Acute Kidney Injury Complex disorder Comprises multiple causative factors Occurs in a variety of settings with varied clinical manifestations Minimal but sustained elevation in serum creatinine to anuric renal failure

Prerenal azotemia and other fully reversible causes of acute renal insufficiency are specifically excluded
Devarajan P. J Am Soc Nephrol 17: 1503-1520, 2006

Epidemiology Incidence of AKI not requiring dialysis

Incidence rates (per 100,000 person years)

Year

Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM, Go AS. Kidney Int 72: 208212, 2007

Epidemiology Incidence of AKI requiring Dialysis

Incidence rates (per 100,000 person years)

Year

Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM, Go AS. Kidney Int 72: 208212, 2007

Epidemiology Ward (tertiary hospital)

Liano and Pascual (1996) 748 episodes of AKI* (0.4% of admissions, 21 per 100,000 population) Acute tubular necrosis (45%, diverse causes) Prerenal azotemia (21%, defined) Acute onset chronic renal failure (12.7%, not defined), and Urinary tract obstruction (10%). Crude in hospital mortality was 45% overall, and as high as 65.9% in patients requiring dialysis (36% of all cases of AKI)
*AKI definition: increase in SCr to at least 2.0 mg/dl(baseline 1.5 mg/dl)
Liano F, Pascual J. Kidney Int 50: 811818, 1996

Epidemiology - ICU
No. of Participating Centers (N = 54) No. of Period Patients Prevalence (N = 1738) (95% CI), % Predicted Hospital Mortality, % Mortality (95% CI), %

Indonesia
Japan China Singapore United States

1
4 2 2 6

25
90 77 31 194

4.4 (2.7-6.1)
5.5 (4.4-6.6) 8.8 (6.9-10.7) 6.3 (4.2-8.4) 8.0 (6.8-9.3)

41.4
40.8 48.5 59.3 44.2

72.0 (54.4-89.6)
64.0 (54.1-74.0) 61.0 (50.1-71.9) 74.2 (58.8-89.6) 52.1 (45.0-59.2)

Overall

5.7 (5.5-6.0)

45.6

60.3 (58.0-62.6)

Calculated with Simplified Acute Physiology Score II. *ARF criteria oliguria defined as urine output of less than 200 mL in 12 hours and/or marked azotemia defined as a blood urea nitrogen level higher than 84 mg/dL (30 mmol/L).

Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C. JAMA 294: 813818, 2005

Epidemiology aki as predictors of mortality

Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. J Am Soc Nephrol 16: 33653370, 2005

Classification and diagnosis

1 2 3

Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Crit Care 2007; 11:R31. Cruz D, Ricci Z, Ronco C.Critical Care 2009, 13:211

*setting a 48- hour window *failure if treated with RRT

Classification - Severity Staging of Patients with AKI

RIFLE - Risk / AKIN Stage 1 the most important group, due to the potential of reversibility of this stage* RIFLE - Injury / AKIN Stage 2 the likelihood that the are purely functional (i.e. prerenal) becomes smaller one third (36.8%) of the patients proceeded to stage 3** urine osmolality and FE Na discriminate between prerenal physiology and renal injury RIFLE - Failure / AKIN Stage 3 RRT becomes an important consideration expanded to providing supporting therapy** Loss and End-Stage Kidney Disease 13.8% of AKI patients remained dialysis dependent*** full recovery was achieved in less than 50% of survivors of AKI requiring RRT

* Srisawat N, Hoste EAE, Kellum JA. Blood Purif 2010;29:300307. ** Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, et al. Crit Care 2006; 10:R73. *** Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C. JAMA 294: 813818, 2005

Diagnosis etiology of AKI

Hilton R. Acute renal failure. BMJ 2006;333:78690

Diagnosis Etiology of aki

Hypovolemia
Haemorrhage Volume depletion

Hypotension
Cardiogenic shock Distributive shock (for example, sepsis, anaphylaxis)

Renal hypoperfusion

Oedematous states NSAID Cardiac failure ACE-I/ARB Hepatic cirrhosis Abdominal aortic aneurysm Nephrotic syndrome Renal artery stenosis/occlusion Hepatorenal syndrome

Hilton R. Acute renal failure. BMJ 2006;333:78690

Diagnosis etiology of aki

Post renal causes
Intrinsic
Intra-luminalstone, blood clot, papillary necrosis Intra-muralurethral stricture, prostatic hypertrophy or malignancy, bladder tumour, radiation fibrosis

Extrinsic
Pelvic malignancy Retroperitoneal fibrosis

Hilton R. Acute renal failure. BMJ 2006;333:78690

Pathomechanism ischemic aki

N Engl J Med 332:647655, 1995

Autoregulation of the GFR during Reduction of MAP

In normal autoregulation, the glomerular filtration rate (GFR) is maintained until the mean arterial pressure falls below 80 mm Hg. However, in patients with impaired autoregulation, the GFR falls below normal values while the mean arterial pressure remains within the normal range, resulting in normotensive ischemic acute renal failure.
N Engl J Med 2007;357:797-805.

pathomechanism

Rosen S, Stillman IE. J Am Soc Nephrol 19: 871875, 2008.

Pathophysiology of ischemic and toxic acute renal failure (ARF).

The severe reduction in glomerular filtration rate (GFR) associated with established ischemic or toxic renal injury is due to the combined effects of alterations in intrarenal hemodynamics and tubular injury. The hemodynamic alterations associated with ARF include afferent arteriolar constriction and mesangial contraction, both of which directly reduce GFR. Tubular injury reduces GFR by causing tubular obstruction and by allowing backleak of glomerular filtrate. Abnormalities in tubular reabsorption of solute may contribute to intrarenal vasoconstriction by activating the tubuloglomerular (TG) feedback system. GPFglomerular plasmaflow; Pglomerular pressure; Kfglomerular ultrafiltration coefficient.

Pathomechanism

Alterations in tubule cell metabolism after ischemic acute kidney injury (AKI). The initiation phase is typified by profound ATP depletion, which primes the cell by activating a number of oxidative and cell death mechanisms. During the extension phase, prolonged ischemia followed by reperfusion propels these pathways to completion, resulting primarily in apoptosis and oxidant injury. Inhibition of these pathways may provide novel therapeutic approaches, as recently demonstrated with caspase inhibitors, iron chelators, and antioxidants.

Pathophysiology of Ischemic ARF MICROVASCULAR Glomerular Medullary

O2
Inflammatory and vasoactive mediators

TUBULAR
Cytoskeletal breakdown Loss of polarity Apoptosis and necrosis Desquamation of viable and necrotic cells Tubular obstruction Backleak

Vasoconstriction in response to :
endothelin, adenosine, angiotensin II, thromboxane A2, leukotrienes, sympathetic nerve activity

Vasodilation in response to : Endothelial and vascular

nitric oxide, PGE2, acetylcholine bradykinine

smooth muscle cell structural damage Leucocyte-Endothelial adhesion

vascular obstruction, leucocyte activation and inflammation

J am Soc Nephrol 14: 2199-2210, 2003

Cellular basis of Ischemic acute renal failure (ARF).

Kevin T Bush. Atlas of Kidney disease

Flow chart illustrates the cellular basis of ischemic ARF. As described above, renal tubule epithelial cells undergo a variety of biochemical and structural changes in response to ischemic insult. If the duration of the insult is sufficiently short, these alterations are readily reversible, but if the insult continues it ultimately leads to cell detachment and/or cell death. Interestingly, unlike other organs in which ischemic injury often leads to permanent cell loss, a kidney severely damaged by ischemia can regenerate and replace lost epithelial cells to restore renal tubular function virtually completely, although it remains unclear how this happens.

Diagnosis Biomarker in diagnosis of aki

SCr imperfect tubular secretion, steady-state determination and confounding (muscle mass and volume distribution). Cystatin C (LMW protein produced by all nucleated cells) Freely filtered then reabsorbed and metabolized by the proximal tubule Cystatin C may be superior to SCr for the earlier detection of reduced GFR
Srisawat N, Hoste EAE, Kellum JA. Blood Purif 2010;29:300307.

Diagnosis biomarkers of aki

Biologic response to ischemic or nephrotoxic injury early indicators of AKI. Urine >>> serum or plasma to identify the earliest markers of kidney injury. Urinary injury markers may be present in the urine because of: Impaired tubular reabsorption and catabolism of filtered molecules, Release of enzymes or exosomes from tubular cells, and As a response of tubular cells to ischemic or nephrotoxic injury.
Srisawat N, Hoste EAE, Kellum JA. Blood Purif 2010;29:300307.

Soni SS. Blood Purif 2009;28:165174

Soni SS. Blood Purif 2009;28:165174

Six biomarkers have been tested for their ability to diagnose AKI (defined as a 50% increase in the serum creatinine concentration) in patients who underwent cardiac surgery. This graph depicts the changes in area under the curve (AUC) for the different biomarkers after cardiac surgery. Biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and liver fatty acidbinding protein (L-FABP) have higher accuracy early, and then the accuracy diminishes after 46 hours after surgery (the AUC for L-FABP at 12 hours is estimated). Biomarkers such as interleukin-18 (IL18) and KIM-1 have lower accuracy at 24 hours after surgery, but the accuracy increases at 1224 hours after surgery. The solid bar demonstrates that serum creatinine increases by 50% in these studies at a much later time (2472 hours) after surgery.

Summary of biomarkers
Serum cystatin C, plasma and urine NGAL and urine IL-18 perform best for early diagnosis of AKI. Serum cystatin C, urine IL-18, and urine KIM-1 perform best for the differential diagnosis of established AKI. Urine NGAL, KIM-1, and IL-18 perform best for mortality risk prediction after AKI.

Coca SG. et al. Kidney Int. 2007

Treatment - approach

Hilton R. Acute renal failure. BMJ 2006;333:78690

Urinalysis in Acute Kidney Injury

Normal/bland Abnormal sediment

Hematuria RBC casts proteinuria Prerenal Postrenal Oncotic AKI Glomerulopat hy Vasculitis Thrombotic

WBC WBC casts

Eosinophils

RTE cells Crystalluria NonPigmented albumin casts proteinuria ATN Myoglobin Hemoglobi n Uric acid Toxins Drugs Plasma cell dyscrasia

Pyelonephri tis Interstitial nephritis

AIN Atheroembolic AKI

MA

Hilton R. Acute renal failure. BMJ 2006;333:78690

Urine diagnostic indices in pre-renal vs intrinsic renal ARF

Fry AC. Postgrad Med J 2006;82:106116

Phases of ischemic acute renal failure.

Sutton TA, Fisher CJ, Molitoris BA: Kidney Int 62: 15391549, 2002

Treatment - principles
Identify and correct pre-renal and post-renal factors Optimise cardiac output and renal blood flow Review drugs Accurately monitor fluid balance and daily body weight Identify and treat acute complications Optimise nutritional support Identify and aggressively treat infection Identify and treat bleeding tendency Initiate dialysis before uraemic complications emerge

Hilton R. Acute renal failure. BMJ 2006;333:78690

Treatment nutritional support in AKI

Fiaccadori E. JNEPHROL 2008; 21: 645-656

Acute kidney injury (AKI), at least in critically ill patients, seldom occurs as isolated organ failure. Much more often it emerges as a component of the multiple organ failure syndrome, within the framework of the severe and prolonged catabolic phase determined by critical illness, and intensified by specific derangements in substrate utilization due to the acute loss of kidney function. On these bases, patients with AKI often have proteinenergy wasting (preexisting and/or hospital acquired), which represents a major negative prognostic factor. Thus, nutritional support is frequently required, under the form of parenteral and/or enteral nutrition, even though no formal demonstration exists for its favorable effect on major outcomes. The primary goals of nutritional support in AKI are basically the same as those suggested for critically ill patients with normal renal function: i.e., to ensure the delivery of adequate amounts of nutrients, to prevent protein-energy wasting with the attendant metabolic complications, to promote wound healing and tissue reparation, to support immune system function and to reduce mortality. Due to the loss of the kidneys homeostatic function, and the frequent need of RRT, patients with AKI are especially prone to complications of nutritional support, such as hyperglycemia, hypertriglyceridemia, fluid retention, electrolyte and acid-base derangements

Treatment Renal replacement therapy in AKI

Conventional indications for RRT initiation in AKI Refractory hyperkalemia, Severe metabolic acidosis, Hypervolemia, and Uremic end-organ complications. Early vs. Late initiation of RRT Data inconclusive on specific benefit. One retrospective trial Early (BUN<60mg/dL) vs. Late (BUN >60mg/dL) survival better on early RRT group (39% vs. 20%).* One RCT trial early dialysis (7 hours of UO <30 mL/h) vs. Late (42 hours of UO <30mL/h) did not affect mortality or dialysis dependence in survivors.** One prospective trial RRT with blood urea nitrogen levels of 76 mg/dL (27 mmol/L) or less (adjusted hazard ratio, 0.54; 95% CI, 0.34-0.86).***

Treatment renal replacement therapy in AKI

Fieghen H. Nephron Clin Pract 2009;112:c222c229

Treatment renal replacement therapy in aki

Intermittent hemodialysis
Alternate days 4 or more hours Blood flows of 250 mL/min or greater Sufficient with or without concomitant critical illness.

CRRT
Target dose should be 35 mL/kg per hour (3 L/h in a 70-kg person)

Pannu N. JAMA. 2008;299(7):793-805

Treatment update on Renal tubule assist device

Improved survival

Improved prognosis

Aki in specific setting - Sepsis

Ronco C. Clin J Am Soc Nephrol 3: 531-544, 2008

Aki in specific setting - Sepsis

Ronco C. Clin J Am Soc Nephrol 3: 531-544, 2008

 Peaks of mediators characteristic of systemic inflammatory response syndrome (SIRS) and compensated anti-inflammatory response syndrome (CARS) may be seen in sequence or in parallel. Broad-based control of peaks with continuous renal replacement therapy (CRRT) is hypothesized to lessen the degree of imbalance and restore immunohomeostasis. IL-1, interleukin-1; IL-10, interleukin 10; PAF, platelet-activating factor; TNF, tumor necrosis factor.

Aki in specific setting - Sepsis

Specific measures
Address the surviving sepsis campaign protocol Tight blood glucose control with insulin Low tidal volume ventilation Avoid HES for resuscitation

Ronco C. Clin J Am Soc Nephrol 3: 531-544, 2008

Aki in specific settings contrast induced

Efforts come with little success 12% prevalence of CIN today remains unchanged. Low osmotic vs. iso osmotic agents conflicting data, tends to favor iso osmotic agents.* Volume expansion seems to be beneficial.
NaCl i.v. (0.9%), 1 mL/kg per hour, 12 hours before and after CM administration.*

Sodium bicarbonate infusion proved beneficial.**

154 mEq/L sodium bicarbonate in dextrose and H2O.

IV 3 mL/kg/h for 1 hour immediately before contrast injection. Then, the same fluid at a rate of 1 mL/kg/h during contrast exposure and for 6 hours after the procedure. NAC contrasting evidence, others no benefit.*

*Reddan D. JNEPHROL 2009; 22: 333-351 **Briguori C. Circulation 2007;115;1211-1217

Aki in specific settings cardiorenal syndrome

Cardio-Renal Axis blunted in ADHF In ADHF
Release of vasoconstricting and sodium-retaining neurohormones (Ang II, NE, endothelin, adenosine, and arginine vasopressin ) Release of vasodilatory and natriuretic hormones (natriuretic peptides, prostaglandins, bradykinin, and nitric oxide)

Renal failure in ADHF hemodynamic and neurohormonal dysregulation Important management issues
Use of continuous loop diuretic is recommended Use of anti-aldosterone if there is diuretic resistance, caution for hyperkalemia Nesiritide associated with worsening of renal function, especially in combination with diuretics
Sarraf M. Clin J Am Soc Nephrol 4: 20132026, 2009

Aki in specific settings hepatorenal syndrome

Three main causes of AKI in chronic liver disease:
Volume responsive pre-renal failure (68%), Volume unresponsive pre-renal failure with tubular dysfunction and ATN (33%), and Hepatorenal syndrome type 1 (25%)

Hepatorenal syndrome
Liver transplantation the best therapeutic option. Survival improved with vasoconstrictors (ie.terlipressin) with albumin, or Transjugular intrahepatic portosystemic shunt (TIPS).

RRT is usually only started if liver transplantation is considered a viable option

Slack et al. Critical Care 2010, 14:214 Fry AC. Postgrad Med J 2006;82:106116

Aki in specific settings aki in lung dysfunction

Renal failure increasing pulmonary vascular permeability and promoting pulmonary hemorrhage.
Loss of the normal balance of immune, inflammatory, and soluble mediator metabolism. AKI downregulate pulmonary epithelial Na, K ATPase, EnaC, and aquaporin 5. AKI increase ADMA decrease eNOs increase free radicals lung injury AKI increase IL-1, TNF-a, ICAM-1 cardiac dysfunction lung injury

Stresses the importance of low tidal volume ventilation in AKI

Microvasc Res. 2009 January ; 77(1): 812.

Aki in specific settings - elderly

Anatomic
Aging kidne y Physiologi c
Loss of renal mass Glomerular drop out and glomerulosclerosis Diminished glomerular filtering surface area Decreased tubular size and number Increased tubulointerstitial fibrosis Thickened glomerular and tubular basement membranes Decreased afferent arteriolar luminal area Increased arteriosclerosis

Decreased renal blood flow Decreased glomerular filtration rate Diminished urinary concentrating and diluting capacity Diminished capacity for sodium conservation Decreased plasma renin and aldosterone levels Decreased prostaglandin production Increased vasoconstrictive response to stimuli (e.g., volume depletion)

Abdel Kader K. Clin Geriatr Med. 2009 August ; 25(3): 331358.

Aki in specific settings hiv nephropathy

Incidence of AKI were higher than HIV negative (6% vs. 2.7%) Risk factors for AKI in HIV: Older age Diabetes mellitus Chronic kidney disease Liver disease/ Hepatitis C Low CD4 count High HIV RNA History of AIDS-defining illness History of antiretroviral exposure Etiology of AKI in HIV Intrinsic AKI (ATN and nephrotoxic drugs) 46% Nephrotoxic drugs pentamidine, amphotericin B, acyclovir, streptomycin, ARV (indinavir, atazanavir, didanosine). Prerenal (38%) Overall, 52% associated with infection HIV-associated nephropathy (HIVAN), rare but relevant
Kalim S. Semin Nephrol. 2008 November ; 28(6): 556562

prognosis
Incidence rate of mortality 8.9 vs. 4.3 per 100 person-years in survivors of AKI vs. without AKI (RR 2.59, 95% CI 1.97-3.42). AKI was Associated independently with mortality risk adjusted RR 1.6-3.9 Associated with myocardial infarction RR 2.05, 95% CI 1.612.61 The incidence rate of CKD after AKI 7.8 per 100 patient years. Rate of ESRD was 4.9 per 100 patient-years.
Coca SG. Am J Kidney Dis. 2009 June ; 53(6): 961973.

conclusion
Acute kidney injury is increasingly found, especially because of the aging population and the availability of better medical care. Acute kidney injury carry a grave prognosis, whether from increased morbidity and also mortality. Recognition of early renal insult is the focus of future intervention. Recognition of the crosstalk between kidney and other organs will maximize the treatment outcome in AKI. Up until now there are no effective medical therapy for AKI. Utilization of RRT still confounded by lack of consistent evidence in dose, time of initialization and mode of dialysis.