1. Tubulointristitial Nephritis
Dr. Hamed Shakhatreh
Consultant nephrologest
Head of nephrology department,Al-basher hospital. M.O.H

2. Primary interstitial nephropathies make up a diverse group of diseases that elicit interstitial inflammation associated with renal tubular cell damage.
Traditionally, interstitial nephritis has been
classified morphologically and clinically into:
acute and chronic forms.

6. Acute Interstitial Nephritis
70% Drug hypersensitivity
30% Antibiotics: PCNs (Methicillin), Cephalosporins, Cipro
Sulfa drugs
NSAIDs
Allopurinol...
15% Infection
Strep, Legionella, CMV, other bact/viruses
8% Idiopathic
6% Autoimmune Dz (Sarcoidosis, Tubulointerstitial nephritis/Uveitis)

7. Drug Causes of AIN Antibiotics
Cephalosporins, Ciprofloxacin, Ethambutol, Isoniazid, Macrolides, Penicillins, Rifampin, Sulfonamides, Tetracycline, Vancomycin
NSAIDs
Almost all agents, including selective COX-2 inhibitors
Diuretics
Furosemide, Thiazides, Triamterene
Miscellaneous
Acyclovir, Allopurinol, Amlodipine, Azathioprine, Captopril, Carbamazepine, Clofibrate, Cocaine, Diltiazem, Famotidine, Indinavir, Mesalazine, Omeprazole, Phenteramine, Phenytoin, Pranlukast, Propylthioruacil, Quinine, Ranitidine
Development of drug-induced AIN is not dose-dependent and recurrence or exacerbation can occur with a second exposure to the same or a related drug.

8. AIN from Drugs Renal damage is NOT dose-dependent
May take weeks after initial exposure to drug
More common is seen several months to a year after use
But as early as 1 week after medication is begun
Fever (27%)
Serum Eosinophilia (23%)
Maculopapular rash (15%)
Bland sediment or WBCs, RBCs, non-nephrotic proteinuria
WBC Casts are pathognomonic!
Urine eosinophils on Wright’s or Hansel’s Stain
Also see urine eos in RPGN, renal atheroemboli
Leukocytoclastic vasculitis

9. Interstitial nephritis
Acute allergic IN- presents with fever, maculopapular rash, arthralgia, eosinophilia with use of certain drugs or systemic infection
UA_ microscopic hematuria, pyuria, non nephrotic proteinuria, eosinophiluria
Usually resolves after d/c of offending drug and steroids

10. Clinical Presentation
AIN of any cause
Drug-Induced AIN
Nausea
Vomiting
Malaise
Rash %
Fever %
Eosinophilia %
Triad %
Nonspecific symptoms, signs/symptoms of acute renal dysfunction. When drug-induced, onset of symptoms ranges from 3-5 days with second exposure to several weeks with a first exposure. Classic triad obserrved in methicillin

11. Laboratory Manifestions
Acute rise in plasma creatinine concentration
Eosinophilia and eosinophiluria
Urine sediment: wbcs, rbcs, white cell casts
Proteinuria (< 1 g/day)

12. Infectious Causes of AIN
Bacterial
Corynebacterium diphtheriae, legionella, staphylococci, streptococci, yersinia
Viral
CMV, EBV, HIV, HCV, HSV, hantaviruses, mumps, polyoma virus
Other
Leptospira, mycobacterium, mycoplasma, rickettsia, syphilis, toxoplasmosis
Pathogenesis of AIN related to infectious organisms is not well understoof. One possible mechanism is stimulation of chemokine release by the pathogen, leading to infiltration of leukocytes

13. Acute bilateral pyelonephritis
Flank pain, toxic, febrile
U/A : pyoria, hematuria, proteinuria, bacteriuria
B/C & U/C help to diagnosis

14. Infiltrative/Autoimmne Causes of AIN
Sarcoidosis
Sjogren’s Syndrome
Leukemia
Lymphoma
Systemic lupus erythematosus
TINU SYNDROME
More commonly cause a chronic interstitial nephritis

15. Acute Kidney Injury Prerenal Intrinsic Postrenal Hypovolemia
Decreased cardiac output
Renal vasoconstriction
Intrinsic
Acute Tubular Necrosis
Glomerulonephritis
Vascular disorders
Postrenal
Bladder Neck
Ureteral
Tubular
Pathogenesis of AIN related to infectious organisms is not well understoof. One possible mechanism is stimulation of chemokine release by the pathogen, leading to infiltration of leukocytes

16. Renal biopsy Indications Uncertainty of diagnosis
Advanced renal failure
Lack of spontaneous recovery following removal of offending drug
diffuse interstitial infiltrate with many red-staining eosinophils. An uninvolved glomerulus is on the left. The only way to confirm the diagnosis.

18. Discontinuation of offending agent Corticosteroids
Treatment
Discontinuation of offending agent
Corticosteroids
Prednisone 1 mg/kg to a max of mg x 1-2 weeks
IV Methylprednisolone 0.5 – 1 g/day x 3 days
Optimal therapy unknown because no randomized controlled trials. Corticosteroids in patients who are poor candidates for renal biopsy and who do not have improvement in serum cr within 3 to 7 days after discontinuation of drug. IV methylprednisolone in patient with more severe acute renal failure. NSAID-induced AIN generally does not respond to steroids.

19. AIN PROGNOSIS Most patients recover full kidney function in 1 year
Poor prognostic factors
AKI > 3 weeks
Advanced age at onset

20. Chronic Tubulointerstitial Disease
chronic interstitial nephritis (CIN) follows a more indolent course and is characterized by tubulointerstitial fibrosis and atrophy associated with interstitial mononuclear cell infiltration.
Over time, glomerular and vascular structures are involved, with progressive fibrosis and sclerosis within the kidney

21. Causes of chronic interstitial nephritis
Toxins( analgesic nephropathy, lead nephropathy)
Infection (chronic pyelonephritis)
Autoimmune( Sjogren syndrome, SLE, renal rejection)
Metabolic( hyperuricemia, hypercalcemia)
Radiation
Neoplastic infiltration( leukemia, lymphoma, multiple myeloma)
Hereditary renal diseases(ADPKD,MCD,MSK)

22. Analgesic abuse nephropathy
chronic interstitial nephritis
Result from excessive consumption
(NSAID & Aspirin)
Dose dependent (at least 1 kg)
Being responsible for 1% to 3% of ESRD cases

23. Bacterial infection
bacterial infection of the renal parenchyma causes interstitial nephritis
infection without anatomical abnormality seldom produces permanent damage
obstruction (stones, prostate etc) in combination with infection can cause progressive disease
tuberculosis causes extensive destruction from granulomata, fibrosis and caseation

24. At first, interstitial edema and PMN infiltration, then formation of irregular abscesses and eventually scars
Risk factors:
diabetes mellitus
obstruction
delayed antimicrobial therapy
severe infection with ATN
reflux nephropathy
papillary necrosis

25. Urinary tract obstruction

26. Consequences of urinary tract obstruction
Reduced glomerular filtration rate
Reduced renal blood flow (after initial rise)
Impaired renal concentrating ability
Impaired distal tubular function
Nephrogenic diabetes insipidus
Renal salt wasting
Renal tubular acidosis
Impaired potassium concentration
Reduced RBF leads to renal ischemia tubular atrophy

27. ˜... due to —... due to GFR RBF Intraluminal pressure
h Intratubular pressure
—... due to
Vasodilation
Prostacyclin
Prostraglandin E2
obstruction
h Peristalsis
Phase A
Continuing obstruction
vasoconstriction
Vasoconstriction
Angiotensin II
Thromboxane A2
Disorganised peristalsis dilation of tubules and ureter
Phase B

28. Acute urinary tract obstruction
Functional consequences
Hours
baseline

29. myeloma
Bence-Jones protein (light chains from malignant plasma cell clone) causes interstitial nephritis, tubular obstruction(cast nephropathy) and amyloid deposition
Myeloma kidney :the classic pathologic include THP+LC casts in dilated, atrophic distal tubuls with infiltration monocyte & macrophage & plasma cells that produce giant cells
LCs are nephrotoxic through direct injury of tubular epithelial cells & intrarenal obstruction from cast formation

30. Predisposing factors:
LC concentration
LC isoelectric point
intraluminal PH
tubular flow rate
presence of Tamm-Horsfall Pr

31. Hypercalcemic Nephropathy
Chronic hypercalcemia is seen in
Hyperparathyroidism
Sarcoidosis
Multiple myeloma
Vitamin D toxicity
Metastasis bone disease

32. Hypercalcemia decrease GFR through renal vasoconstriction
Calcium deposition in distal nephron and interstitial that leads to mononeuclear cell infiltration and tubular necrosis
Defective concentration ability, poliuria, nocturia
Nephrocalcinosis & nephrolitiasis

33. WBC Casts Cells in the cast have nuclei (unlike RBC casts)
Pathognomonic for Acute Interstitial Nephritis

34. Match: 1. hyaline casts 2. muddy brown casts 3. RBCs 4. RBC casts
5. Oval fat bodies
6. eosinophils
A. ATN
B. prerenal azotemia
C. glomerulonephritis
D. nephrolithiasis
E. interstitial disease
F. nephrotic syndrome

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