1. Tubulointerstitial Diseases Dr. Raid Jastania

2. Objectives By the end of this session the student should be able to Describe the types of Acute tubular necrosis and its clinical importance Know the features of Acute and Chronic pyelonephritis, and the risk factors Understand the special issues in Drug- induced interstitial nephritis

3. Tubulointerstitial Diseases Acute tubular necrosis Acute pyelonephritis Chronic Pyelonephritis Drug-induced interstitial nephritis

4. Acute Tubular Necrosis The most common cause of acute renal failure Clinicopathological entity Reversible lesion Destruction of tubular epithelium Acute suppression of renal function (urine >400ml/day)

5. Causes of acute renal failure Pre renal, renal, post renal Acute tubular necrosis Glomerular disease. RPGN Vascular disease. Polyarteritis nodosa Acute papillary necrosis Diffuse cortical necrosis

6. Types of Acute Tubular Necrosis 1. Ischemic 2. Nephrotoxic

7. Types of Acute Tubular Necrosis 1. Ischemic –State of hypoperfusion –Eg. Trauma, septicemia, acute pancreatitis, hypotension, shock

8. Types of Acute Tubular Necrosis 2. Nephrotoxic: –Heavy metals: mercury –CaCl4 –Antibiotics. Gentamicin

9. Pathogenesis 1. Tubular injury 2. Blood flow disturbance (persistent, severe), (Endothelial cell injury)

10. Pathogenesis 1. Tubular injury –Sensitive to ischemia and toxins –Injury –Functional defect: increase Na delivery to distal tubules – vasoconstriction –Cytokines – vasoconstriction –Tubular debris – block urine outflow – increase the pressure –Fluid leak in interstitium – collapse of tubules

11. Pathogenesis 1. Tubular injury 2. Blood flow disturbance (persistent, severe), (Endothelial cell injury)

12. Pathogenesis 2. Blood flow disturbance (persistent, severe), (Endothelial cell injury) –Vasoconstriction –Endothelial injury: release of endothelin, decrease in nitric oxide –Others: renin-angiotensin, norepinephrine)

13. Pathogenesis

15. Morphology Subtle findings, similar in ischemic and toxic Interstitium- edema, mild acute inflammation Proximal tubules Necrosis Rupture of basement membrane Proteinaceous cast in distal and collecting tubules Tamm-Horsfall protein Epithelial regeneration

16. 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

18. Tubulointerstitial nephritis Causes –Infectious: Bacterial, viral, fungal, parasitic –Non-infectious: Physical (radiation) Chemical (toxins, drugs), metabolic, Ischemic, Immune –Acute pyelonephritis –Chronic pylelonephritis

19. Acute Pyelonephritis UTI Commonly bacterial –Gram negative: E.coli, Proteus, Klebsiella, Pseudomonas, Enterobacter Risk factors –Anomalies, Instrumentation, –Obstruction, bladder dysfunction, reflux –Pregnancy –DM. Immunosuppression

20. Acute Pyelonephritis Routes of infections –Hematogenous –Ascending infection: Adhesion to mucosa – colonization of urethra – ascending of infection Female>male

23. Acute Pyelonephritis Morphology: –One or both kidneys –Sharp yellow abscess on the surface –Necrosis, pus (neutrophils) –WBC casts –Pyonephrosis –Papillary necrosis (DM, obstruction, Analgesic) Sharp yellow necrosis at the apex of the pyramid –Cystitis: hypertrophy, trabeculation

24. Acute Pyelonephritis Symptoms –Pain at the costovertebral angle, fever, chills, malaise –Urine: pyuria, bacteria –Dysuria, frequencey, urgency Natural history –Self-limiting –Recurrent –chronic

25. Chronic Pyelonephritis Interstitial inflammation and scarring with deformity of the pelvicalyceal system 1. Chronic obstructive pyelonephritis –Recurrent infections 2. Reflux nephropathy –Vesico-ureteral reflux –infections

28. Chronic Pyelonephritis Morphology: –One or both kidneys –Uneven scarring/inflammation (lymphocytes, plasma cells) –Papillary blunting and calyceal deformities –Dilation/atrophy of tubules, colloid casts (thyoidization) –Vascular changes –Secondary focal segmental glomerulosclerosis

29. Chronic Pyelonephritis Clinical –Late presentation: renal insufficiency, hypertension –Contracted kidneys –Tubular dysfunction: polyruia/nocturia

30. Drug-induced interstitial nephritis Acute drug-induced interstitial nephritis: –Antibiotics –NSAIDs –Diuretics –Begin 15 days after exposure –Fever, eosinophilia, rash –acute renal failure, hematuria, proteinuria

31. Drug-induced interstitial nephritis Acute drug-induced interstitial nephritis: –Pathogenesis Immune mechanism, hypersensitivity Drug is trapped in the kidney during secretion Results in injury ? Type I, high IgE ? Type IV, granuloma

33. Drug-induced interstitial nephritis Acute drug-induced interstitial nephritis: –Morphology: Edema Inflammatory infiltrate: lymphocytes, macrophages, eosinophils Sometimes: granulomas NSAIDs may cause minimal change disease

34. Drug-induced interstitial nephritis Analgesic Nephropathy: –Chronic users –Chronic interstitial nephritis –Renal papillary necrosis –Aspirin, acetaminophen, caffeine, codeine

35. Drug-induced interstitial nephritis Analgesic Nephropathy: –Pathogenesis Unclear, papillary necrosis, inflammation Oxidative damage Aspirin inhibits prostaglandin synthesis (vasoconstriction)

36. Drug-induced interstitial nephritis Analgesic Nephropathy: –Morphology: Papillae: yellow brown, lipofuscin pigment inflammation Coagulative necrosis Clacification Scarring Vessels: basement membrane thickening (analgesic microangiopathy)

37. Drug-induced interstitial nephritis Analgesic Nephropathy: –Clinical Chronic renal failure Hypertension Anemia Increase risk of transitional cell carcinoma

38. Case presentation

39. A twelve-year-old boy presents to his family physician with a history of a sore throat and fever. The sore throat began about 3 days previously; a fever of 39°C developed in the last day. Physical examination reveals a well- developed, well-nourished boy of appropriate size for age in mild distress. His temperature is 39.5°C, pulse 90 (nl 60-100/min), blood pressure 100/75, and respirations 20 (nl 8-16/min). Examination of the oropharynx reveals a red, inflamed throat and tonsils with exudate. Otherwise, the exam is unremarkable.

40. A swab from his throat is used to test for the presence of streptococcal antigens (streptozyme test), and it is positive. When the physician suggests an injection of penicillin, the child throws a wall-eyed fit, and the physician relents, prescribing a ten- day course of ampicillin.

41. After two or three days of treatment, the boy begins to feel better, and has less throat pain. However, his mother notes a red, macular rash over his chest and back, and the boy complains of itching. Calamine lotion is applied for a day or two without relief, and the fever recurs, this time with the complaint of joint aches. When the child becomes listless and loses his appetite, his mother returns him to the doctor, who performs further lab tests

42. Urinalysis: pH 7, yellow-brown protein - 2+ blood - 1+ glucose - neg leukocyte esterase - 3+

43. Micro: 5-10 RBCs/HPF 10-20 WBCs/HPF no bacteria few hyaline casts (nl 0-2 RBCs or WBCs/HPF)

44. WBC 12,000/mm 3 52% neutrophils 5% bands 28% lymphocytes 15% eosinophils

45. Creatinine: 2.1 mg/dL BUN: 40 mg/dL ASO: 350 U/mL Liver function tests: normal 24-hour urine protein: 500 mg/24 hr

46. The child is hospitalized, and a renal biopsy is performed. The ampicillin is discontinued, a course of tapering steroids is begun, and the patient is discharged.

48. Objectives By the end of this session the student should be able to Describe the types of Acute tubular necrosis and its clinical importance Know the features of Acute and Chronic pyelonephritis, and the risk factors Understand the special issues in Drug- induced interstitial nephritis