Etiopathogenesis of Acute Kidney Injury

Etiopathogenesis of Acute Kidney Injury

ETIOPATHOGENESIS OF ACUTE KIDNEY INJURY Dr Dwijen Das, MD, FACP (USA) Silchar Medical College, Silchar Assam, India. Governing body member, ACP India Chapter. Immediate past Hon Gen Secretary, API Assam Chapter. Co-editor Assam Journal of Internal Medicine. Peer reviewer of 2 nationl journals. Introduction:

Function of the kidneys Excretion of waste materials..ingested or produced Control volume and composition of body fluids and Maintenance of electrolytes in the body Guyton, Arthur C.; Hall, John E. (2006). Textbook of Medical Physiology. Introduction: Each human kidney contains 1M nephrons. It decreases gradually with aging, renal injury and diseases.

After age 40, the number decreases about 10% every 10 years. Definition: AKI is defined by an abrupt decrease in kidney Broad clinical syndrome function that includes, but is not limited to, ARF. Specific kidney Nonspecific diseases:

AIN AGN VRD conditions: - Ischaemic Toxic Extr-arenal: -Prerenal

-Post Renal Definition: (cont..) Minor acute reduction in KF has an adverse prognosis. Early detection and treatment of AKI may improve outcomes. Two similar definitions based on SCr and urine output (RIFLE and AKIN) have been proposed and validated. There is a need for a single definition for practice, research, and public health.

Definition: (cont) AKI is defined as any of the following: Increase in SCr by 0.3 mg/dl (26.5 lmol/l) within 48 hours; or Increase in SCr to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or Urine volume of <0.5 ml/kg/hr for 6 hours. STAGING OF AKI (KDIGO) Staging: (cont) Staging of AKI is appropriate because, with

increased stage of AKI, the risk for death and need for RRT increases. Lancet 2005; 365 (9457): 41730 Staging: (cont) There is long-term risk of subsequent development of CVD or CKD and mortality, even after apparent resolution of AKI. Lancet 2005; 365 (9457): 41730 Renal failure:

Kidney failure is defined as a GFR of 15 ml/min per 1.73 m2 BSA, or requirement for RRT. - GFR is the most useful overall index of kidney function in health and disease - Changes in SCr and urine output are surrogates for changes in GFR. - In clinical practice, an abrupt decline in GFR is assessed from an increase in SCr or oliguria. EPIDEMIOLOGY OF AKI: AKI complicates 5-7 % of acute care hospital admissions

~ 30 % of admissions to the ICU [AGE, Infection, Disasters], Mortality due to AKI may exceed 50% in ICU AKI increases the risk of development or worsening CKD. AKI Community acquired: Volume depletion Drugs and Toxins Obstructive uropathy

Hospital acquired: -sepsis, -surgical procedures, -heart and liver failure, -IV iodinated contrast -Nephrotoxic medication Classification of AKI: PATHOPHYSIOLOGY OF AKI: Azotemia is defined as a higher blood level of urea or other nitrogen-containing compounds.

There are three pathophysiologic states in azotemia, as follows: Usually caused by inability of the kidneys to Prerenal azotemia excrete these compounds. Intrarenal azotemia Postrenal azotemia PRE-RENAL AZOTEMIA: Most common cause of AKI Renal

hypoperfusion. - 60-70% are community acquired and 40% hospital acquired. Hypovolemia, Decreased CO, Advanced cirrhosis and Medications. Pathogenesis: Pre-renal AKI No parenchymal damage Intra glomerular

pre-renal Prolonged hemodynamics azotemia may cause are restored ischemia Reversible ATN Intensive Care Med. 2010 Mar;36(3):392-411. Renal

AKI hypoperfusion Very common IV Volume reduction Very common Vasodilation (Splanchic) Vasodilation

AG II Triggered byPG volume depletion & SBP image8-4.jpg Sympathetic Renin release activity Cirrhosis of Liver

Maintain coronary Vasoconstriction Increase & cerebral & cerebral Hepato-renal syndromecirculation Aldosterone Maintain GFR

Na+ & Water retension Maintain IV Volume INTRARENAL AZOTEMIA: Ischemia associated AKI: Tubules, interstitium, vasculature and glomerulus. Causes: Tubular cell injury

ATN Ischemia Sepsis Toxins (Endo/Exo) Intensive Care Medicine. 42 (4): 521530 Ischemic ATN: Detachment of live & necrotic cells of PCT Loss epithelial cell barrier and cell tight

junctions Solute reach fluid to Macula densa Enters into lumen Leakage into interstitium Cast

formation Lumen blockade GFR afferent arteriolar vasoconstrictio nnn JAMA 2008; 299 (7): 793805. Phases of Ischemic ATN: Four distinct clinical and cellular phases: -Initiation,

-Extension, -Maintenance and -Recovery. Cellular stages in ischemic ATN: Post operative ATN: Intra-operative blood loss or hypotension Cardiac & intraperitonea

l surgery Decreased renal perfusion ATN JAMA 2008;. 299 (7): 793805. Burns and pancreatitis: AKI seen in 25% cases Hypovolemia Immune

dysregulation Sepsis ALI Fluid resuscitation Abdominal compartment al syndrome ATN

GFR Sepsis associated AKI: AKI complicates > 50% of the cases of severe sepsis Increases the risk of death. GFR in sepsis can occur in absence of hypotension Tubular injury/ interstitial edema/ mitochondrial damage, must be considered in the pathophysiology of sepsis induced AKI. Mechanism of AKI in Sepsis: Sepsis RAAS activation

Renal vasoconstriction Microvascular thrombosis Oxidative stress Leukocyte adhesion Tubular cell damage

NO Endothelin Vasopressin Efferent arteriolar dilatation GFR JAMA 2008; 299 (7): 793805. Nephrotoxin induced AKI: High susceptibility to nephrotoxicity due to extremely high blood perfusion.

Risk factors include CKD, old age, and DM. Contrast induced nephrotoxicity: Iodinated contrast agent used for the cardiovascular and CT imaging are the leading causes of AKI. It occurs due to the combination of factors including Hypoxia due to perturbations in microcirculation and occlusion of small vessels. Cytotoxic injury to tubule and oxidative free radicals Transient tubule obstruction due to precipitous contrast Risk is high in diabetics

Antibiotics induced AKI: Aminoglycosides and Amphotericin B both causes tubular necrosis. Non-oliguric AKI accompanies 10-30% of courses of aminoglycoside antibiotics. Aminoglycosides freely filtered across glomerulus and accumulate in renal cortex. Intensive Care Medicine 2015; 42 (4): 521530. Amphotericin B causes renal vasoconstriction as well as direct tubular injury mediated by reactive oxygen species.

Cisplatin and Carboplatin accumulated by the PCT causes necrosis and apoptosis. Other drugs which are associated with AKI are ifosphomide, mitomycin C, gemcitabine and bevacizumab. Toxin induced AKI: Exogenous Endogenous Ethylene

glycol Fish Bile Myoglobin/ hemoglobin Metabolite s Metabolite s oxalic acid, and

5glycolaldehyde -Cyprinol sulfate glyoxylate, Direct Tubulo tubulotoxic Toxic Br Med J 1941; 1 (4185): 42732. Rhabdomyolysis Hemolysis Crush injury, seizure,

myopathy etc. -Tubulo toxic -Occlusion -Vasoconstriction AKI in tumor lysis syndrome: TLS: following cytotoxic therapy for high grade lymphomas and ALL; Massive release of uric acid (>15 mg/dl) leads to its accumulation in renal tubules and AKI. Associated with hyperkalemia and hyperphosphatemia Also seen in solid tumors & MM

POST RENAL AZOTEMIA: Caused by obstruction to luminal flow of the glomerular filtrate. Results in transmission of backpressure to Bowman space of the glomerulus. This backpressure would reduce the GFR. However, by dilation of afferent arteriole, the GFR is preserved. Br Med J 1941;1 (4185): 42732. CONCLUSION: AKI is common, harmful and significant

contributors of morbidity and mortality. Pre-renal AKI is the commonest type. Early diagnosis can improve mortality and morbidity. Diagnosis is still based on S Creat and UO. There is a need of early biomarkers to detect AKI early. THANK YOU

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