1. Acute tubulointerstitial nephritis & TINU syndrome
Nephrology R4 김양균

2. Acute tubulointerstitial nephritis (ATIN)
Primary tubulointerstitial disease
Characterized by histologic and functional abnormalities that involve the tubules and interstitium to a greater degree than the glomeruli and renal vasculature
Secondary tubulointerstitial disease
Occurs as a consequence of progressive glomerular or vascular injury
Pathogenesis
Expression of endogenous nephritogenic antigens or exogenous antigens processed by tubular cells
Cell-mediated immunity (major)
Drug-induced (m/c)  immunologic basis
Hypersensitivity, dose-independent, recurrence of AIN after re-exposure to the offending drug
Nonspecific nature of the histology  biopsy specimens rarely provide a specific diagnosis
Urine sediment is also unlikely to be diagnostic, except in allergic forms of acute tubulointerstitial disease in which eosinophils may predominate in the urinary sediment.

3. Secretion↓
Hydrogen  Acidemia, Urine pH > 5.9
Potassium  Hyperkalemia
Reabsorption ↓
Sodium  Natriuresis
Reabsorption ↓
Sodium  Natriuresis
Bicarbonate  Acidemia
Urate  Hypouricemia
Glucose  Glucosuria
Phosphate  Phosphaturia
Amino Acids  Fanconi syndrome
Reabsorption ↓
Sodium Natriuresis
Chloride Urine concentration ↓
Response to ADH↓
Urine concentration ↓

4. Etiology H2 blocker (Cimetidine, ranitidine..)
- Start within 2wks of f initiation (1d~11mon)
d/t Hypersensitivity, good prognosis
PPI
Omeprazole > Pantoprazole > Esomeprazole > Lansoprazole, Rabeprazole
Direct toxic effect?
Average 9.9 wk of initiation, good prognosis

6. Clinical manifestations
Nonspecific
Symptoms and sings of acute renal dysfunction (nausea, vomiting..)
Drug-induced
Mean delay (drug ~ Sx) : 10 days
3-5 days with a second exposure ~ several weeks to many months with a first exposure (rifampin : 1 d, NASAID : 18 months)
Specifically, allergic-type reaction
Rash
fever
eosinophilia
Triad of rash, fever and eosinophilia (10%)
Arthralgia

7. Defects in urinary acidification and concentrating ability often represent the most troublesome of the tubule dysfunctions encountered in patients with tubulointerstitial disease. Hyperchloremic metabolic acidosis often develops at a relatively early stage in the course. Patients with this finding generally elaborate urine of maximal acidity (pH 5.3). In such patients the defect in acid excretion is usually caused by a reduced capacity to generate and excrete ammonia due to the reduction in renal mass. Preferential damage to the collecting ducts, as in amyloidosis or chronic obstructive uropathy, may also predispose to distal or type I RTA, characterized by high urine pH ( 5.5) during spontaneous or NH4Cl-induced metabolic acidosis. Patients with tubulointerstitial diseases affecting predominantly medullary and papillary structures (such as analgesic nephropathy and sickle cell disease) may also exhibit concentrating defects, with resultant nocturia and polyuria.
Harrison 17 th

8. Laboratory findings
1. eGFR ↑ 2. Tubular abnormalities Maximal urinary concentrating ability↓ (polyuria, nocturia) RTA (hyperchloremic metabolic acidosis) Fanconi’s syndrome (phosphaturia, uricosuria, bicarbonaturia, glycosuria, aminoaciduria) 3. Renal endocrine deficiencies Hyporeninemic hypoaldosteronism (hyperkalemia, metabolic acidosis) Calcitriol defeciency (renal osteodystrophy) Erythropoietin deficiency (anemia) 4. Urinalysis May be normal, usually contains cellular elements Proteinuria (< 3g/d) : low molecular weight “tubular”proteins (lysozyme, B2 microglobulin)
Eosinophiluria (DDx with RPGN, renal atheroemboli)
Granular, epithelial cell casts
CF) White cell cast, red cell cast  acute GN
Proteinuria
Old patients - larger amount (3g/d) could be
NSAIDs, amipicillin, rifampin, interferon,interferon, ranitidine 
- concurrent NS (MCD, MGN) (> 3.5 g/d)
Unerlying disease (DN, GN) have to be considered
FENa > 1%
Renal biopsy from a patient who developed acute renal failure and the nephrotic syndrome following therapy with a cephalosporin. Left panel: Evidence of interstitial nephritis characterized by an interstitial infiltrate and separation of the tubules due to interstitial edema: Middle panel: Light microscopy shows a normal glomerulus. Right panel: Electron microscopy reveals diffuse foot process fusion consistent with minimal change disease. Courtesy of Helmut Rennke, MD.

9. Histopathologic findings
Acute forms
Interstitial edema
Marked interstitial infiltrate of inflammatory cells
T lymphocytes primarily
Eosinophils, plasma cells, neutrophils
The classic lesion "tubulitis"
Granuloma formation – rare (Tb, sarcoidosis)
IF (-), EM – nonspecific
Chronic forms
Interstitial fibrosis predominates
Start within 7-10 days of initiation of inflammatory process
Inflammatory cells – mononuclear
Abnormalities of the tubules more widespread
Atrophy, luminal dilatation, thickening of tubule basement membranes

10. Low power view of severe acute interstitial nephritis showing diffuse interstitial inflammatory infiltrate. One normal glomerulus is present at the top of the slide.
High power light micrograph of acute interstitial nephritis showing diffuse interstitial infiltrate of inflammatory cells on the right and an uninvolved glomerulus on the left.
Light micrograph with hematoxylin and eosin stain of acute interstitial nephritis showing diffuse interstitial infiltrate with many red-staining eosinophils. An uninvolved glomerulus is on the left.
High power light micrograph of interstitial nephritis showing diffuse interstitial infiltrate of mononuclear cells, many of which are actively invading the tubules leading to disruption of the tubular basement membranes (arrows). A white cell cast is present in the tubule in the upper right corner.
Light micrograph shows granulomatous change in acute interstitial nephritis. The interstitial infiltrate is seen on the left, while the granuloma is on the right. The granuloma consists of both giant cells (arrows) and epithelioid cells with abundant cytoplasm which has an amorphous red appearance. Although these findings are characteristic of sarcoid involvement in the kidney, they can be seen with any cause (drug or infection) of acute interstitial nephritis.

11. Diagnosis History and laboratory findings
Indications of renal biopsy
1. Uncertainty to the Dx
2. Advanced renal failure
3. Lack of spontaneous recovery from cessation of drug
Diagnosis
History and laboratory findings
Offending drug
Characteristic laboratory findings (ARF, eosinophilia, urine sediment, eosinophiluria)
Gallium scan  the role incompletely defined
Diffuse, intense, bilateral uptake (consistent with interstitial inflammatory infiltrate)
Negative in ATN (acute tubular necrosis)
(+) scan  suggestive AIN, (-) scan  not preclude Dx (FN)
Renal biopsy or empiric therapy
Diagnosis can be confirmed only by renal biopsy
In mild cases, discontinuation of the suspected drug ± steroid

12. Treatments 1. Corticosteroid 2. Other agents (steroid resistant pts)
* Cessation of causative drug !!
 After 3-7 days, if not have improvement of serum creatinine,
Renal biopsy
Confirm AIN, exclude other diseases, significant chronic damage (eg, marked interstitial fibrosis, tubular atrophy)
If biopsy is not feasible & highly suspected AIN  empirical steroid Tx
1. Corticosteroid
optimal dose and duration of therapy are unclear
PDL 1mg/kg/d (max 40-60mg) x 1-2 weeks  tapering  total duration of 2-3 months
Most patients will improve in the first one to two weeks.
2. Other agents (steroid resistant pts)
Mycophenolate mofetil (MMF), cyclosporine, cyclophosphamide

13. Prognosis Diverse depending on causes
Up to 40% :persistent elevation of the serum creatinine concentration
The final serum Cr - not correlate with the maximum value during AIN
Clinical indicators of prolonged renal failure (> 3 weeks)
AIN associated with NSAID use
Pathology - Interstitial granulomas, interstitial fibrosis, tubular atrophy
1,068 renal Bx
AIN 6.5% < infection 10%, idiopathic 4%, drug 85%
Reversible 69%, permanent 31% (12% partially reversible, 19% irreversible)
Infection induced AIN : always reversible
Drug induced AIN : permanent 36% (in NSAIDs 56%)

14. TINU syndrome TINU (TubuloInterstitial Nephritis + Uveitis)
First described in 1975, by Dobrin
More than 150 cases were reported
Pathogenesis
Unknown!
Renal tubular & ciliary body epithelia : electrolyte transporters sensitive to carbonic anhydrase inhibitors  share common autoantibody?
Cell-mediated immunity, delayed-type hypersensitivity ?
Risk factors
No identifiable risk factors have been found
Infection (Chlamydia , EBV), drugs (antibiotics, NSAIDs), "goreisan,"
Autoimmune diseases (hypoparathyroidism, hyperthyroidism , IgG4-related autoimmune disease, RA)

16. Clinical manifestations
Epidemiology
Median age 15 yrs
F:M = 3:1
HLA-DQA1*01, HLA-DQB1*05, HLA-DQB1*01
Clinical manifestations
Ocular  systemic (~20%) / systemic  ocular (65%, ~14months)
Uveitis  good prognosis
Sx : Eye pain, redness, photophobia, decreased visual acuity
Typically bilateral (77%), unilateral, alternating
Anterior (80%): conjunctival injection, keratic precipitates, dry eyes
Posterior : chorioretinitis, intraretinal h/rr, retinal vascular sheathing, cotton wool spots, dilated retinal vessels, retinal edema, arteriovenous nicking
Kidney involve
Tends to resolve either spontaneously or with corticosteroids

18. Laboratory findings Treatments No specific serum markers
For the exclusion of other correspondent disease, serologic markers (ANA, ANCA, RF, hypocomplementemia)
Beta-2 microglobluin, Krebs Von Den Lung-6 (KL-6) ↑
Treatments
Renal
Usually self controlled
Progressive renal insufficiency : PDL 1 mg/kg per day , MMF
Uveitis
Topical & systemic corticosteroids
Recurrences and relapses common; steroid-sparing immunosuppressive agents (cyclosporine, methotrexate, MMF)
Early referral to and management by an ophthalmologist