Atn csbrp
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Atn csbrp
- 1. Acute Tubular Necrosis Dr.CSBR.Prasad, MD., June-2015-CSBRP
- 2. Definition of ARF • Acute renal failure (ARF) is defined conceptually as a rapid (over hours to weeks) and usually reversible decline in GFR that may occur either in the setting of preexisting normal renal function (“classic” ARF) or with preexisting renal disease (“acute on chronic” renal failure) • However, a uniform and precise operational definition of ARF still is not available June-2015-CSBRP
- 3. Causes of Acute Renal Failure • Pre-renal • Renal parenchymal (intrinsic) • Post-renal June-2015-CSBRP Synonyms: Acute kidney failure / Acute kidney injury
- 6. Acute Tubular Necrosis (ATN) ATN – Severe/prolonged ischemia with injury to parenchyma which does not resolve immediately with restoration of renal perfusion • Describes the renal parenchymal injury following renal ischemia OR • Exposure to nephrotoxins, which particularly injure the tubular epithelium June-2015-CSBRP
- 7. Acute Renal Failure Nephrotoxic ATN • Endogenous Toxins – Heme pigments (myoglobin, hemoglobin) – Myeloma light chains • Exogenous Toxins – Antibiotics (e.g., aminoglycosides, amphotericin B) – Radiocontrast agents – Heavy metals (e.g., cis-platinum, mercury) – Poisons (e.g., ethylene glycol) June-2015-CSBRP
- 8. Acute Tubular Necrosis (ATN) • What segments of the nephron? Why? • How to recognize – clinical/histological • Pathophysiology • Ischemia/toxins • Clinical course June-2015-CSBRP
- 9. Acute Tubular Necrosis (ATN) • Site of tubular injury • Proximal tubule (S3, pars recta) • Medullary thick ascending limb – Medulla receives 20% of total renal blood flow – Intense metabolic activity – O2 supply/demand balance is delicate – Multiple causes of cell injury June-2015-CSBRP
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- 11. June-2015-CSBRP
- 12. June-2015-CSBRP
- 13. Acute Tubular Necrosis (ATN) • Causes of cell injury – Endothelin/Nitric Oxide balance • Endothelin(ET-1 isoform) potent vasoconstrictor produced in renal endothelium, epithelium, mesangium • Nitric Oxide potent vasodilator produced in endothelium – ATP Depletion – Cell Swelling June-2015-CSBRP
- 14. Acute Tubular Necrosis (ATN) • Causes of cell injury – Intracellular Calcium increases – Intracellular acidosis – Oxidant injury – Inflammatory response from ischemia/reperfusion June-2015-CSBRP
- 15. Acute Tubular Necrosis (ATN) • Gross: Enlarged & swollen kidney • Tubular Injury – Cell swelling, vacuolation, apical blebbing, loss of brush border, loss of cell polarity, necrosis, sloughing – Eosinophilic hyaline casts June-2015-CSBRP
- 16. Acute Tubular Necrosis (ATN) Histopathology June-2015-CSBRP
- 19. Morphology • Subtle findings - similar in ischemic and toxic • Interstitium- Edema, mild acute inflammation • Proximal tubules: – Necrosis – Rupture of basement membrane • Distal and collecting tubules: – Tamm-Horsfall protein – Epithelial regeneration June-2015-CSBRP
- 20. Clinical course • 1. Initiating phase: 36 hours – Hypotension, decrease urine output, rising urea • 2. Maintenance phase: 2-6 days – Low urine output 50-400 ml/day – Ureamia, fluid overload • 3. Recovery – Increase urine output (upto 3L/day) – Electrolyte imbalance – Risk of infections June-2015-CSBRP
- 21. Acute Tubular Necrosis (ATN) • Diagnostics – U Na > 40 meq/dL – U osm < 350 mosm/dL – Renal Ultrasound – normal size – Urine microscopic – “muddy brown cast” June-2015-CSBRP
- 22. Muddy brown casts of ATN June-2015-CSBRP
- 23. Acute Tubular Necrosis (ATN) • Outcomes – Mortality about 50% June-2015-CSBRP
- 24. Acute Tubular Necrosis (ATN) • Treatment – Supportive – maintain fluid balance – Maintain perfusion of kidneys – Treat underlying illness / interrupt insult June-2015-CSBRP
- 26. Renal vascular diseases • Primary hypertension • Secondary hypertension • Thrombotic microangiopathy • Renal infarcts June-2015-CSBRP
- 27. Benign Nephrosclerosis • Above 60 years • Small contracted kidney • Granular surface, V- shaped scars • Micro: – Hyaline arteriosclerosis – Intimal thickening – smooth muscle proliferation – Tubular atrophy, fibrosis June-2015-CSBRP
- 28. Benign Nephrosclerosis Granular Contracted KidneyGranular Contracted Kidney June-2015-CSBRP
- 29. Benign Nephrosclerosis Hyaline arteriolosclerosisHyaline arteriolosclerosis June-2015-CSBRP
- 30. Benign Nephrosclerosis (PAS stainPAS stain) June-2015-CSBRP
- 31. Malignant Nephrosclerosis • Gross: ‘Flea bitten’ kidney • Enlarged, edematous kidney with petechial hemorrhages • Micro: – Necritizing arteriolitis – Onion skin appearance – Ischaemic changes June-2015-CSBRP
- 32. Malignant Nephrosclerosis Flea bitten KidneyFlea bitten Kidney June-2015-CSBRP
- 33. Malignant Nephrosclerosis Flea bitten KidneyFlea bitten Kidney June-2015-CSBRP
- 34. Malignant Nephrosclerosis ‘Onion peel’ appearance of arterioles June-2015-CSBRP
- 35. Flea bitten Kidney - CausesFlea bitten Kidney - Causes • Malignant hypertension • RPGN • Acute post Streptococcal GN • PAN • TTP / HUS • HS purpura June-2015-CSBRP
- 36. Onion peel appearance – seen inOnion peel appearance – seen in • Malignant hypertension (Hyperplastic arteriosclerosis) • Ewing’s sarcoma –X-ray • Histoplasmosis – Lung – Gross • Bile ducts in PSC / PBC - Histopath June-2015-CSBRP
- 37. June-2015-CSBRP
- 39. Peripheral smear in TMA June-2015-CSBRP
- 40. June-2015-CSBRP
- 41. Pathogenesis of idiopathic TTP caused by ADAMTS13 deficiency June-2015-CSBRP
- 42. Thrombotic Microangiopathy (TMA) Diseases that cause TMA Abbreviation 1. Thrombotic Thrombocytopenic Purpura 2. Hemolytic Uremic Syndrome 3. Atypical TTP/HUS 4. Malignant Hypertension 5. Disseminated Intravascular Coagulation 6. HELLP Syndrome (Hemolysis, Elevated Liver Enzymes, and Low Platelets) 7. Scleroderma Renal Crisis TTP HUS (TTP/HUS) --- DIC HELLP SRC June-2015-CSBRP
- 43. June-2015-CSBRP
- 44. TTP, HUS, and the other varieties of TMA have a number of symptoms in common. These are listed below: SYMPTOM REASON SYMPTOM OCCURS Fatigue, Dizziness, Shortness of breath Low red blood cell count Bruises, Gum/nose bleeds, Minor cuts bleed a lot Low platelet count Confusion, Sleepiness, Seizures Damage to blood vessels in the brain Decreased urine, Swollen legs, High blood pressure Damage to blood vessels in the kidney Fever (more common with TTP) June-2015-CSBRP
- 45. TTP and HUS have different treatments • To prevent death and serious organ damage TTP requires immediate treatment with plasma exchange (PLEX) • In contrast, HUS usually improves on its own require hospitalization for fluids and monitoring. – If kidney function declines too much, dialysis may be necessary – As the causative bacterial infection resolves, toxin leaves the body and symptoms of HUS begin to improve • In many of the more atypical TTP/HUS disease patterns the optimal treatment has not yet been standardized • These are often treated (like TTP) with plasma exchange June-2015-CSBRP
- 47. Causes of ARFCauses of ARF Pre-Renal Renal Post-Renal Absolute hypovolemia GLOMERULAR RPGN Pelvi-calyceal obstruction Relative hypovolemia TUBULAR ATN Ureteric obstruction Cardiac Out put INTERSTITIAL AIN VUJ bladder obstruction Renovascular occlusion VASCULAR EMBOLI Bladder neck – urethra obstruction June-2015-CSBRP
Editor's Notes
- Some of the more common nephrotoxins associated with acute tubular necrosis are listed on this slide.
- Relative hypoxia in the outer medulla predisposes to ischemic injury in the S3 segment of the proximal tubule. The thick ascending limb is also located in this hypoxic region of the kidney and, depending on tubular reabsorptive demand, may also undergo ischemic injury. The thick ascending limb may, however, be more protected against ischemic injury, because this nephron segment possesses more glycolytic machinery for ATP synthesis than the S3 segment.
- Vascular factors contributing to the pathogenesis of ischemic ARF. ET, endothelin; PG, prostaglandin. Figure modified with permission from the Journal of Nephrology (15).
- Usual production of endothelin is low, but increases in injury while NO is lowered in injury
- Acute tubular necrosis showing focal loss of tubular epithelial cells (arrows) and partial occlusion of tubular lumens by cellular debris (D) (H&E stain). The histologic findings in ischemic acute tubular necrosis may be disproportionately small in comparison to the magnitude of renal dysfunction. Focal necrosis of single proximal tubular cells and clusters of cells is seen in the majority of cases of ATN. Portions of tubules not involved by necrosis commonly show effacement of the proximal tubule brush border. Other pathologic findings include flattening of the tubular epithelium and dilatation of the tubular lumina. Many of the flattened tubular cells exhibit signs of regeneration – i.e., mitoses and large hyperchromatic nuclei. Regenerative changes and foci of necrosis are often seen in the same biopsy specimen. Distal nephron segments are characteristically occluded by urinary casts of hyaline, granular, and pigmented varieties.
- Tubular epithelial degeneration and hyaline amphophilic casts (positive with immunologic stains for myoglobin) in a patient with rhabdomyolysis and myoglobinuric acute tubular necrosis.
- Leather texture of the surface. Normal kidney: 10x5cms (lengthxwidth)
- PSC = Primary sclerosing cholangiitis.
- Features: Fragmented RBCs, nRBCs, Polychromatic cells and Thrombocytopenia.
- TTP mainly genetically mediated or immunological mediated – effect is low clipping of ADAMTS13 there by reducing the enzyme activity.
- Pathogenesis of idiopathic TTP caused by ADAMTS13 deficiency. Multimeric VWF adheres to endothelial cells or to connective tissue exposed in the vessel wall. Platelets adhere to VWF through platelet membrane GPIb. In flowing blood, VWF in the platelet-rich thrombus is stretched and cleaved by ADAMTS13, limiting thrombus growth. If ADAMTS13 is absent, VWF-dependent platelet accumulation continues, eventually causing microvascular thrombosis and TTP.
- TTP was once fatal in 90% of individuals who developed the disease. Now that plasma exchange is available, survival can be as high as 80%. In many cases the blood vessel damage in the kidneys and brain will reverse with time. HUS has a good prognosis. During the active phase of the disease kidney failure can often be severe enough to require manual blood cleaning with dialysis. Fortunately this is usually temporary. In fact kidney function almost always returns to the normal range within a few months
- TTP and HUS have different treatments. To prevent death and serious organ damage TTP requires immediate treatment with plasma exchange (PLEX) – see Figure. This process allows the abnormal glue (vWF) that causes TTP to be exchanged for normal vWF. Treatments usually last a few hours each and continue every 1-2 days for about 2 weeks. For those with repeated episodes of TTP, a medication called rituximab is being tested to see if its use can prevent recurrences of the disease. In contrast, HUS usually improves on its own. Patients will require hospitalization for fluids and monitoring while the disease is worsening. If kidney function declines too much, manual blood cleaning with dialysis may be necessary. As the causative bacterial infection resolves, toxin leaves the body and symptoms of HUS begin to improve. In many of the more atypical TTP/HUS disease patterns the optimal treatment has not yet been standardized. These are often treated (like TTP) with plasma exchange, but there is currently some debate about this.