Acute Tubulointerstitial Nephritis

Question 1

Acute Tubulointerstitial Nephritis
Epidemiology of Acute Tubulointerstitial Nephritis:

Answer 1

Prevalence of acute tubulointerstitial nephritis (ATIN) is increasing in recent years.

Overall prevalence of biopsy-proven ATIN is 2% to 5%.

Incidence conveys information about the risk of contracting the disease, whereas prevalence indicates how widespread the disease is.

Prevalence of biopsy-proven ATIN in patients with acute kidney injury (AKI) is 10% to 15%.

Question 2

Acute Tubulointerstitial Nephritis
Pathogenesis of ATIN:
(3 suggested mechanisms)

Answer 2

1. The inciting agent (i.e., infection or drug) acts as a hapten. That is, the inciting agent binds to an otherwise nonimmunogenic native kidney protein and renders it immunogenic.
2. Antibodies made against the inciting agent cross-reacts with native kidney antigens.
3. Circulating immune complexes formed against the inciting agent deposit into the kidney interstitium and induce an inflammatory immunologic response.

Question 3

Acute Tubulointerstitial Nephritis
Pathogenesis of ATIN:
Immunologic response:

Answer 3

Predominantly cell mediated: kidney biopsy typically reveals predominant T-cell infiltrates in interstitium.

Hallmark of AIN: Inflammatory interstitial infiltrate of monocytes and lymphocytes (fewer eosinophils, plasma cells, and neutrophils) Interstitial edema Renal tubule separation Tubulitis Absence of glomerular or vascular pathology

Fibrotic changes may be seen as early as within 7-10 days Granuloma patterns can occur and commonly drug-related

Question 4

Acute Tubulointerstitial Nephritis
Pathogenesis of ATIN:
Immunologic response:

Answer 4

Less commonly antibody mediated:

Most biopsies do not reveal immune complex deposits.

In some cases, immune complex deposits may be seen in tubular basement membranes (TBM)

Question 5

Acute Tubulointerstitial Nephritis

Clinical Manifestations of ATIN

Answer 5

Classic triad of skin rash, leukocyturia, and fevers:

Not common; likely seen in <10% of cases

Classic triad is uncommonly seen in NSAIDS-induced ATIN.

More commonly seen with antibiotic-induced ATIN

Question 6

Acute Tubulointerstitial Nephritis

Clinical Manifestations of ATIN

Answer 6

AKI:

Onset of kidney injury typically occurs within 10 to 20 days of exposure to inciting agent.

Kidney injury may occur within 2 to 3 days with re-exposure.

De novo kidney injury from a medication previously tolerated may be observed.

Question 7

Acute Tubulointerstitial Nephritis

Clinical Manifestations of ATIN

Answer 7

Abnormal urinalysis: leukocytouria, microscopic or gross hematuria, eosinophiluria, white blood cell casts, granular casts, proteinuria. Red blood cell casts reported but rare.

Eosinophiluria:

Poor sensitivity (40% to 91%) and specificity (52% to 95%), but improved specificity if eosinophils is >5% of total leukocyturia.

test sensitivity is the ability of a test to correctly identify those with the disease (true positive rate), whereas test specificity is the ability of the test to correctly identify those without the disease (true negative rate).

Eosinophiluria may also be seen in urinary tract infections, prostatitis, bladder malignancy, and rapidly progressive glomerulonephritis.

Hansel stain for eosinophilia is preferred over Wright stain due to Hansel stain’s consistent sensitivity with varying urine pH.

Question 8

Acute Tubulointerstitial Nephritis

Clinical Manifestations of ATIN

Answer 8

Proteinuria:

Typically nonnephrotic range (i.e., <1 g/d, or urine protein to creatinine ratio < 1 g/g)

LMW proteinuria predominance a.k.a. “tubular proteinuria”: albuminuria generally comprises less than 25% of total proteinuria.

May be nephrotic if associated with NSAIDS use.

Question 9

Acute Tubulointerstitial Nephritis

Clinical Manifestations of ATIN

Answer 9

Blood tests:

Elevated serum creatinine (SCr),

leukocytosis with increased eosinophilia,

anemia, elevated erythrocyte sedimentation rate, transaminitis. Anti-neutrophil cytoplasmic antibody (ANCA) may be positive without associated glomerular disease.

Question 10

Acute Tubulointerstitial Nephritis

Histopathology of ATIN

Light microscopy (LM):

Answer 10

Inflammatory infiltrates within the interstitium:

Infiltrative lesions can be diffuse, but often are patchy, predominating in the deep cortex and outer medulla. Inflammatory cells are mostly T-cells and monocytes, macrophages, and also plasma cells, eosinophils, and a few neutrophilic granulocytes

Question 11

Acute Tubulointerstitial Nephritis

Histopathology of ATIN

Light microscopy (LM):

Answer 11

Tubulitis may be seen in ATIN.

Tubulitis refers to leukocytes and lymphocytes infiltration into tubular epithelium.

Question 12

Acute Tubulointerstitial Nephritis

Histopathology of ATIN

Light microscopy (LM):

Answer 12

Granulomas may be seen in ATIN or CTIN associated with sarcoidosis,

Sjogren syndrome, granulomatous polyangiitits, infections (e.g., tuberculosis, leprosy, histoplasmosis, xanthogranulomatous pyelonephritis), crystals/foreign bodies (e.g., urate, oxalosis, recreational drug impurities), medications (e.g., sulfas, synthetic penicillins, NSAIDS, thiazides, levofloxacin).

Question 13

Acute Tubulointerstitial Nephritis

Histopathology of ATIN

Immunofluorescent microscopy (IF) and electron microscopy (EM):

Answer 13

IF and EM are typically negative because most ATIN have no immune complex deposits.

Question 14

Acute Tubulointerstitial Nephritis

Histopathology of ATIN

Immunofluorescent microscopy (IF) and electron microscopy (EM):

Answer 14

In some instances, antibodies may be formed linearly against antigens or drugs bound to tubular basement membrane (TBM) (e.g., methicillin, NSAIDS, phenytoin, allopurinol).

Question 15

Acute Tubulointerstitial Nephritis

Histopathology of ATIN

Immunofluorescent microscopy (IF) and electron microscopy (EM):

Answer 15

Kidney biopsies from patients with AKI from hantavirus infection may reveal granular immune deposits along the TBM and within glomeruli in 50% of cases.

Question 16

Acute Tubulointerstitial Nephritis

Diagnosis of ATIN

Answer 16

Gold standard: kidney biopsy

Urinalysis with abnormalities mentioned earlier

Question 17

Acute Tubulointerstitial Nephritis

Diagnosis of ATIN

Answer 17

Gallium scan:

Gallium binds to lactoferrin on white blood cells and originally thought to identify conditions with high white blood cell count such as ATIN.

Poor sensitivity and specificity and not recommended for the diagnosis of ATIN

May also be positive in association with glomerular diseases, presumably with concurrent interstitial disease, pyelonephritis, atheroembolic disease, etc.

Question 18

Acute Tubulointerstitial Nephritis

Causes of ATIN

Answer 18

85% to 95% of ATIN are either drug- (adults in the United States) or infection induced (children, developing countries).

Drugs (Allergic interstitial nephritis) (70-75%) • Antibiotics: 30-50% • Mean delay between drug start date and AKI is 10 days • Latent period can be as short as 1 day with some antibiotics

Infections (bacterial, viral, parasitic) (5-10%)

Systemic disease (10-20%) • Autoimmune diseases (Sarcoidosis SLE, Sjögren’s, ANCA) • Neoplastic (leukemias, lymphomas) • Acute allograft rejection

Idiopathic (5-10%)

Question 19

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Answer 19

Common drugs associated with ATIN: antibiotics (particularly β-lactams, sulfas), NSAIDS including cyclooxygenase-2 (COX-2) inhibitors, proton pump inhibitors, diuretics, etc.

Question 20

NSAIDS (and COX-2 inhibitors): These agents may induce kidney injury via various mechanisms:

Answer 20

Acute tubular necrosis due to acute afferent arteriolar vasoconstriction and resultant reduction in intraglomerular filtration pressure

Interstitial nephritis which may present as acute, chronic, or granulomatous interstitial nephritis.

Papillary necrosis in patients with underlying ischemic renal disease (e.g., patients with diabetes mellitus and associated arteriosclerosis, sickle cell disease)

Three-fourth of NSAIDS-induced ATIN is associated with nephrotic syndrome and glomerular lesions including minimal change disease, membranous glomerulonephropathy, and less commonly, focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephropathy. Risks include older age, chronic use, and use of fenoprofen.

Question 21

Rifampin: Renal injury pattern may reflect pattern of use:

Answer 21

Intermittent or interrupted use:

Acute tubular necrosis with or without associated interstitial infiltrations, intravascular hemolysis, or thrombocytopenia

Patient may present with flu-like symptoms within hours of drug ingestion.

Continuous use: interstitial nephritis, light chain proteinuria, or even rapidly progressive glomerulonephritis

Question 22

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Allopurinol:

Answer 22

Thought to be due to immunologic reactions between the metabolite oxypurinol with purines, ribonucleoproteins, and nucleic acids. Accumulation of oxypurinol increases with reduced kidney function. Dose reduction in chronic kidney disease (CKD) is recommended.

Question 23

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Allopurinol:

Answer 23

Clinical manifestations:

Male-to-female ratio estimated to be 2:1

Besides ATIN ± granulomas, patients may also develop toxic epidermal necrolysis, exfoliative dermatitis, or diffuse maculopapular rash, hepatic necrosis, and cholangitis.

Question 24

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Cimetidine:

Answer 24

Histamine stimulates a subset of suppressor T-cells via H2 receptors. Blockage of H2 receptors may lead to increased cell-mediated responses.

Question 25

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

5-aminosalicylates:

Answer 25

5-aminosalicylates (sulfasalazine, mesalamine, olsalazine): ATIN typically occurs within the first year of use.

Question 26

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Aristolochic acid nephropathy, a.k.a. Chinese herb nephropathy:

Answer 26

First reported in Belgium, presumed etiology of Balkan nephropathy

Aristolochic acid was mixed in slimming regimens.

Question 27

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Aristolochic acid nephropathy, a.k.a. Chinese herb nephropathy:

Answer 27

Affected patients may develop rapidly progressive interstitial nephritis which can progress to end-stage renal disease (ESRD).

Associated with uroepithelial malignancy.

Question 28

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Oxalate nephropathy presenting as ATIN:

Answer 28

Ascorbic acid (vitamin C), star fruit, orlistat (induces malabsorptive state that promotes gastrointestinal [GI] oxalate absorption), rhubarb leaves

Question 29

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Drug reaction with eosinophilia and systemic symptoms (DRESS):

Answer 29

Clinical manifestations: fevers, facial edema, skin lesions (diffuse macular/papular erythematous lesions with lymphocytic infiltrates, exfoliative dermatitis), lymphadenopathy, multiorgan inflammatory response (e.g., pneumonitis, hepatitis).

Question 30

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Drug reaction with eosinophilia and systemic symptoms (DRESS):

Answer 30

Laboratory findings: eosinophilia, lymphocytosis, elevated aminotransferase (ALT)

Question 31

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Drug reaction with eosinophilia and systemic symptoms (DRESS):

Answer 31

Reported responsible agents: phenytoin, phenobarbital, allopurinol, sulfonamides, dapsone, vancomycin, minocycline, raltegravir, vemurafenib, lenalinomide (used for multiple myeloma), β-lactams

Treatment: drug withdrawal, supportive care, steroids

Question 32

Acute Tubulointerstitial Nephritis

Causes of ATIN
Drug Induced

Other recently reported drug-induced ATIN:

Answer 32

liraglutide, varenicline, rosuvastatin, ipilimumab (monoclonal antibody that activates the immune system via inhibition of CTLA-4, used in treatment of melanoma), kudzu root (Japanese arrowroot) juice ingestion, linezolid, clindamycin.

Question 33

Acute Tubulointerstitial Nephritis

Causes of ATIN

Infection-related:

Answer 33

May involve various bacteria, viruses, parasites, atypical microorganisms, fungi

Granulomatous ATIN may be seen, particularly with fungal, mycobacteria, and parasites.

Question 34

Acute Tubulointerstitial Nephritis

Causes of ATIN

Infection-related:

Answer 34

AKI during treatment of infections may result from infection-related ATIN, and not necessarily antibiotic/treatment-related ATIN.

Question 35

Acute Tubulointerstitial Nephritis

Causes of ATIN

Glomerular disease-associated tubulointerstitial nephritis (TIN):

Answer 35

Nonselective proteinuria of proinflammatory proteins and growth factors may induce peritubular inflammatory response, complement activation, and progressive interstitial fibrosis.

Question 36

Acute Tubulointerstitial Nephritis

Causes of ATIN

Immune mediated:

Answer 36

autoimmune/collagen vascular diseases (e.g., systemic lupus erythematosus (SLE), Sjogren’s, essential cryoglobulinemia, primary biliary cirrhosis, tubulointerstitial nephritis and uveitis (TINU)), sarcoidosis Tubulointerstitial nephritis and uveitis: see next slide

Question 37

Acute Tubulointerstitial Nephritis

Causes of ATIN

Immune mediated:

Answer 37

Inflammatory disease involving dysregulated T-cells that affect both eyes and kidneys

Mechanism of disease not known

Commonly seen in young women

Question 38

Acute Tubulointerstitial Nephritis

Causes of ATIN

Immune mediated:

Answer 38

Clinical manifestations: painful red eyes (uveitis), ATIN, possibly transaminitis

Treatment: prednisone 1 mg/kg/d × 3 to 6 months with slow taper. Addition of cytotoxic agent may be necessary (e.g., mycophenolate, calcineurin inhibitor)

Question 39

Acute Tubulointerstitial Nephritis

Causes of ATIN

Other causes of ATIN:

Answer 39

antineoplastic agents, heavy metals, herbal products, idiopathic

Question 40

Acute Tubulointerstitial Nephritis

Prognosis of ATIN:

Answer 40

Recovery depends on duration of drug exposure, duration of AKI, and severity of interstitial fibrosis and tubular atrophy.

Question 41

Acute Tubulointerstitial Nephritis

Prognosis of ATIN:

Answer 41

Recovery may take several weeks. 50% recover fully, while the other 50% will have elevated serum creatinine.

Question 42

Acute Tubulointerstitial Nephritis

Management of ATIN:

Answer 42

Supportive, dialysis as needed

Removal of offending agent

Question 43

Acute Tubulointerstitial Nephritis

Causes of ATIN

Management of ATIN:

Answer 43

Role of glucocorticoids:

May lead to prompt recovery if given early, but not necessarily overall outcome

Due to the questionable benefit of glucocorticoids, risks must be minimal.

Consider systemic glucocorticoids if severe systemic involvement (e.g., DRESS)

Question 44

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 44

For asymptomatic women, two consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts ≥ 105 cfu/mL defines bacteriuria.

Question 45

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 45

For asymptomatic men, a single clean-catch voided urine specimen with one bacterial species isolated in a quantitative count ≥ 105 cfu/mL defines bacteriuria.

Question 46

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 46

For both asymptomatic women and men, a single catheterized urine specimen with one bacterial species isolated in a quantitative count ≥ 102 cfu/mL defines bacteriuria.

Question 47

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 47

Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial therapy.

Question 48

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Screening for and treatment of asymptomatic bacteriuria are recommended for the following:

Answer 48

Pregnant women should be screened for bacteriuria by urine culture at least once in early pregnancy and be treated if positive results.

• The duration of antimicrobial therapy should be 3 to 7 days.
• Periodic screening for recurrent bacteriuria should be done following therapy.
• No recommendation can be made for or against repeated screening of culture-negative women in later pregnancy.

Question 49

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Screening for and treatment of asymptomatic bacteriuria are recommended for the following:

Answer 49

Before transurethral resection of the prostate: Antimicrobial therapy should not be continued after the procedure, unless a postprocedural indwelling catheter is needed.

and

Before other urologic procedures with anticipated mucosal bleeding

Question 50

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 50

Screening for or treatment of asymptomatic bacteriuria is not recommended for premenopausal, nonpregnant women, diabetic women, older persons living in the community, elderly institutionalized subjects, persons with spinal cord injury, catheterized patients with indwelling catheters.

Question 51

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 51

Antimicrobial treatment should be considered for asymptomatic women with catheter-acquired bacteriuria that persists 48 hours after indwelling catheter removal.

Question 52

Acute Tubulointerstitial Nephritis

Asymptomatic Bacteriuria: Infectious Diseases Society of America Guidelines 2005

Asymptomatic bacteriuria is defined differently for different population and manner of urine collection:

Answer 52

Urinalysis: Positive leukocyte esterase indicates presence of white blood cells; Positive nitrite suggests presence of bacteria that can convert dietary nitrates to nitrite (E. coli, proteus spp., Klebsiella pneumoniae); Nitrite may be absent in presence of bacteria that cannot convert nitrates to nitrite (enterococci, staphylococci, adenovirus)

Question 53

etiologia

Answer 53

Agudas
 Alérgica => indicações relativas para corticóide!
 Sjögren=> infiltrado inflamatório. Síndrome sicca
 Com uveíte (TINU)=dx exclusão. Olhos só em 1/3
 LES=>nefrite intersticial às vezes até pode dominar!
 Granulomatosa=>sarcoidose? Evolução arrastada
 IgG4=>ipo Sjögren com pseudo-tumores
 Idiopática= será fármaco? auto-imune? Ac anti-céls. tubulares
 Associada à infecção

Question 54

drug-induced AIN

Answer 54

drug-induced AIN Drugs: Allergic interstitial nephritis Antibiotics: Beta-lactam (PCN, Cephalosporins): remains a frequent reported cause of AIN Quinolones: most often seen with ciprofloxacin Sulfonamide: Sulfamethoxazole/Trimethoprim (bactrim) Others: rifampin, sulfa, vanco, erythromycin, acyclovir, ethambutol (EMB) Diuretics: thiazides, furosemide, bumetanide, triamterene NSAIDS (including selective COX-2 inhibitor): pure interstitial nephritis (ISN) ± papillary necrosis/ minimal change nephropathy (MCN) + ISN (85%) H2 blockers (cimetidine, ranitidine-rare) PPI (omeprazole and lansoprazole) Allopurinol Indinavir 5-aminosalicylates (5-ASA) ( i.e. mesalamine) Others: phenobarbital, phenytoin, nitrofurantoin, IFN, IL-2, Angiotensin converting enzyme inhibitor (ACEI: i.e.captopril) The drug-induced AIN is not dose dependent, and recurrence or exacerbation can occur with a repetitive exposures to the same or a related drug (Up-To-Date)