Acute Tubulointerstitial Nephritis Flashcards
Acute Tubulointerstitial Nephritis
Epidemiology of Acute Tubulointerstitial Nephritis:
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%.
Acute Tubulointerstitial Nephritis
Pathogenesis of ATIN:
(3 suggested mechanisms)
- 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.
- Antibodies made against the inciting agent cross-reacts with native kidney antigens.
- Circulating immune complexes formed against the inciting agent deposit into the kidney interstitium and induce an inflammatory immunologic response.
Acute Tubulointerstitial Nephritis
Pathogenesis of ATIN:
Immunologic response:
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
Acute Tubulointerstitial Nephritis
Pathogenesis of ATIN:
Immunologic response:
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)
Acute Tubulointerstitial Nephritis
Clinical Manifestations of ATIN
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
Acute Tubulointerstitial Nephritis
Clinical Manifestations of ATIN
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.
Acute Tubulointerstitial Nephritis
Clinical Manifestations of ATIN
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.
Acute Tubulointerstitial Nephritis
Clinical Manifestations of ATIN
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.
Acute Tubulointerstitial Nephritis
Clinical Manifestations of ATIN
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.
Acute Tubulointerstitial Nephritis
Histopathology of ATIN
Light microscopy (LM):
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
Acute Tubulointerstitial Nephritis
Histopathology of ATIN
Light microscopy (LM):
Tubulitis may be seen in ATIN.
Tubulitis refers to leukocytes and lymphocytes infiltration into tubular epithelium.
Acute Tubulointerstitial Nephritis
Histopathology of ATIN
Light microscopy (LM):
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).
Acute Tubulointerstitial Nephritis
Histopathology of ATIN
Immunofluorescent microscopy (IF) and electron microscopy (EM):
IF and EM are typically negative because most ATIN have no immune complex deposits.
Acute Tubulointerstitial Nephritis
Histopathology of ATIN
Immunofluorescent microscopy (IF) and electron microscopy (EM):
In some instances, antibodies may be formed linearly against antigens or drugs bound to tubular basement membrane (TBM) (e.g., methicillin, NSAIDS, phenytoin, allopurinol).
Acute Tubulointerstitial Nephritis
Histopathology of ATIN
Immunofluorescent microscopy (IF) and electron microscopy (EM):
Kidney biopsies from patients with AKI from hantavirus infection may reveal granular immune deposits along the TBM and within glomeruli in 50% of cases.
Acute Tubulointerstitial Nephritis
Diagnosis of ATIN
Gold standard: kidney biopsy
Urinalysis with abnormalities mentioned earlier
Acute Tubulointerstitial Nephritis
Diagnosis of ATIN
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.
Acute Tubulointerstitial Nephritis
Causes of ATIN
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%)
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Common drugs associated with ATIN: antibiotics (particularly β-lactams, sulfas), NSAIDS including cyclooxygenase-2 (COX-2) inhibitors, proton pump inhibitors, diuretics, etc.
NSAIDS (and COX-2 inhibitors): These agents may induce kidney injury via various mechanisms:
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.
Rifampin: Renal injury pattern may reflect pattern of use:
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
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Allopurinol:
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.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Allopurinol:
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.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Cimetidine:
Histamine stimulates a subset of suppressor T-cells via H2 receptors. Blockage of H2 receptors may lead to increased cell-mediated responses.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
5-aminosalicylates:
5-aminosalicylates (sulfasalazine, mesalamine, olsalazine): ATIN typically occurs within the first year of use.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Aristolochic acid nephropathy, a.k.a. Chinese herb nephropathy:
First reported in Belgium, presumed etiology of Balkan nephropathy
Aristolochic acid was mixed in slimming regimens.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Aristolochic acid nephropathy, a.k.a. Chinese herb nephropathy:
Affected patients may develop rapidly progressive interstitial nephritis which can progress to end-stage renal disease (ESRD).
Associated with uroepithelial malignancy.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Oxalate nephropathy presenting as ATIN:
Ascorbic acid (vitamin C), star fruit, orlistat (induces malabsorptive state that promotes gastrointestinal [GI] oxalate absorption), rhubarb leaves
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Drug reaction with eosinophilia and systemic symptoms (DRESS):
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).
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Drug reaction with eosinophilia and systemic symptoms (DRESS):
Laboratory findings: eosinophilia, lymphocytosis, elevated aminotransferase (ALT)
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Drug reaction with eosinophilia and systemic symptoms (DRESS):
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
Acute Tubulointerstitial Nephritis
Causes of ATIN
Drug Induced
Other recently reported drug-induced ATIN:
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.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Infection-related:
May involve various bacteria, viruses, parasites, atypical microorganisms, fungi
Granulomatous ATIN may be seen, particularly with fungal, mycobacteria, and parasites.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Infection-related:
AKI during treatment of infections may result from infection-related ATIN, and not necessarily antibiotic/treatment-related ATIN.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Glomerular disease-associated tubulointerstitial nephritis (TIN):
Nonselective proteinuria of proinflammatory proteins and growth factors may induce peritubular inflammatory response, complement activation, and progressive interstitial fibrosis.
Acute Tubulointerstitial Nephritis
Causes of ATIN
Immune mediated:
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
Acute Tubulointerstitial Nephritis
Causes of ATIN
Immune mediated:
Inflammatory disease involving dysregulated T-cells that affect both eyes and kidneys
Mechanism of disease not known
Commonly seen in young women
Acute Tubulointerstitial Nephritis
Causes of ATIN
Immune mediated:
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)
Acute Tubulointerstitial Nephritis
Causes of ATIN
Other causes of ATIN:
antineoplastic agents, heavy metals, herbal products, idiopathic
Acute Tubulointerstitial Nephritis
Prognosis of ATIN:
Recovery depends on duration of drug exposure, duration of AKI, and severity of interstitial fibrosis and tubular atrophy.
Acute Tubulointerstitial Nephritis
Prognosis of ATIN:
Recovery may take several weeks. 50% recover fully, while the other 50% will have elevated serum creatinine.
Acute Tubulointerstitial Nephritis
Management of ATIN:
Supportive, dialysis as needed
Removal of offending agent
Acute Tubulointerstitial Nephritis
Causes of ATIN
Management of ATIN:
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)
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:
For asymptomatic women, two consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts ≥ 105 cfu/mL defines bacteriuria.
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:
For asymptomatic men, a single clean-catch voided urine specimen with one bacterial species isolated in a quantitative count ≥ 105 cfu/mL defines bacteriuria.
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:
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.
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:
Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial therapy.
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:
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.
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:
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
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 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.
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:
Antimicrobial treatment should be considered for asymptomatic women with catheter-acquired bacteriuria that persists 48 hours after indwelling catheter removal.
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:
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)
etiologia
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
drug-induced AIN
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)
