Week 4: tubulointerstitial nephritis and drug nephrotoxicity

Question 1

What are the main causes of Acute interstitial nephritis (AIN).

Answer 1

1. Drugs: penicillins, cephalosporins, NSAIDs, sulfonamides, rifampin, indinavir, allopurrinol, PPIs
2. Infections: streptococci, typhoid fever, legionella, leptospirosis, cytomegalovirus
3. Immunological diseases: SLE, Sjogren’s syndrome, sarcoidosis
4. Idiopathic with uveitis

Question 2

Define Acute tubulointerstitial nephritis.

Answer 2

-acute renal failure form immune-mediated tubulointerstitial injury, initiated by medications, infection, and other causes
AS OPPOSED TO
ATN: which is acute tubular cell injury/dysfxn. Commonly caused by ischemia and toxic drugs

Question 3

Pathogenesis of AIN

Answer 3

• may be cell mediated or humoral hypersensitivity reactions
• drug/metabolite may act as hapten to form hapten-protein complex that initiate hypersensitive reaction
• others have circulating autoantibodies to tubular antigens and deposition of these antibodies in tubular BM, e.g. SLE patients

Question 4

Clinical features of classic AIN

Answer 4

• asymptomatic with abnormal urinalysis (nephrotic range proteinuria), e.g. NSAIDS
• symptomatic with (hypersensitivity reaction): maculopapular rash, fever, eosinophilia (triad of rash, fever, eosinophila), oliguria possible
• symptomatic e.g. beta lactam antibiotics

Question 5

What are lab findings in AIN?

Answer 5

• Lab studies: elevated Cr, peripheral Eosinophilia
• urinalysis: rbcs, wbcs, leukocyte casts, low grade proteinuria
• urine microscopy: urine eosinophils
• FeNa>1% usually

Question 6

Pathological findings in Drug-induced AIN

Answer 6

• interstitial edema and infilatrate consisting of primarily T lymphocytes and monoctytes
• eosinophils and histiocytes with granuloma formation in 30%, especially after antibiotics

Question 7

Treatment and prognosis of drug induced AIN

Answer 7

• most forms are self limited and resolve upon stopping the drug
• Advanced prognostic features: prolonged renal failure >3 weeks, NSAIDs, certain findings: granulomas, tubular atrophy, fibrosis

Question 8

Mechanisms of NSAID induced AIN

Answer 8

• hemodynamic: blockage of PGl2 and PGE2 (vasodilatory effects) prevent balance of AngII
• allergic
• Na retention by inhibition of COX-2 natriuretic effect
• hyperkalemia (suppressing renin)

Question 9

Pathogenesis of aminoglycoside induced ATN

Answer 9

• filtered and almost entirely excreted in urine

- small amount is taken up and stored by epithelial cells in PT, where they induce acute tubular necrosis

Question 10

Clinical features of aminoglycoside induced ATN

Answer 10

• develops 7-10 days after treatment
• often non-oliguric, urine output>500ml/day
• occasionally occurs several days after drug is discontinued b/c of prolonged storage in PT cells
• supportive treatment, hemodialysis occasionally needed
• risk factors for nephrotoxicity: old age, obesity, preexisting renal insufficiency or liver disease, frequency/duration of drug therapy, concurrent use of other nephrotoxins

Question 11

pathogenesis of radio contrast media-induced ARF

Answer 11

• direct tubular injury, leading to generation of oxygen radicals
• fall in renal perfusion due to contrast induced release of endothelin–>leading to widespread renal vasoconstriction
• histological lesion consistent with ATN

Question 12

Risk factors for contrast nephropathy.

Answer 12

Age (>65)
Cr >1.5
Diabetes 
CHF, nephrotic syndrome, liver cirrhosis
Volume depletion
High total contrast dose or repeated exposure over short period of time 
Multiple myeloma

Question 13

Clinical course of contrast nephropathy.

Answer 13

-dx made from hx of AFR 24-48 hrs after IV contrast administration.
-nonoliguric ARF
FE[Na]<1%
-UA: renal tubular epithlial casts or muddy brown casts or both
-recovery generally in 1 week
-supportive treatment
-isotonic fluid is only proven prevention

Question 14

Clinical manifestations of amphotericin B nephrotoxicity.

Answer 14

1. Acute renal failure: dose dependent decline in GFR with oliguria or anuria
   - -tubular membranes toxicity associated with vasoconstriction from drug–>ATN
2. other tubular dysfunction: precedes ARF–hypokalemia, hypomagnesemia, distal tubular acidosis

Question 15

Describe toxicity from gadolinium containing contrast agents

Answer 15

• used for MRIs
• increased toxicity in patients with prolonged hemodialysis
• nephrogenic systemic fibrosis (NSF): large areas of hardened skin with fibrotic nodes dn plaques. flexion contractors,

Question 16

Describe Analgesic nephropathy and clinical features.

Answer 16

• chronic interstitial disease, associated with long term use of analgesics
• believed to be due to 2 analgesics +codeine/caffeine
• classically seen with phenacetin
• most are females in 40s or 50s who complain of chronic pain
• can lead to development of both CTIN and papillary necrosis.
• renal damage primarily in medulla: NSAIDs and ASA inhibit PG production–>vasoconstriction–>ischemia and papillary necrosis
• increased risk of transitional cell CA