Acute interstitial nephritis (AIN) should be ruled
out in children with unexplained acute renal failure. We present a 4½
year old girl who presented with oliguric acute renal failure preceded
by a febrile illness. Renal histopathology revealed features of drug
induced AIN. She recovered with dialysis, other supportive treatment and
a course of steroids.
Key words: Acute interstitial nephritis.
Clinical manifestations of acute tubulointerstitial
nephritis (AIN) are variable and consist of systemic manifestation of
hypersensitivity reaction such as fever, rash, arthralgia and features
of renal impairment ranging from mild azotemia to acute renal failure (ARF).
In 30-40% ARF is non-oliguric. AIN is reported to account for 7% of ARF
in some studies(1). After excluding common causes of ARF like acute
glomerulonephritis, acute tubular necrosis (ATN) and obstruction, AIN
should be suspected, especially in a setting of infection and drug
intake. AIN may be under-diagnosed because clinical features are
non-specific and definitive diagnosis is possible only on renal
biopsy(1). Renal biopsy is routinely not done if renal function begins
to improve soon after withholding the offending agent. We report a case
of biopsy proven AIN after a febrile illness.
Case Report
A 4½-year-old girl had received amoxicillin for lower
respiratory tract symptoms for 3 days. On the third day of treatment she
developed high remittent fever with chills and abdominal pain for which
parenteral crystalline penicillin injection was administered. Soon after
the onset of fever she had two episodes of generalized tonic clonic
seizures, each lasting 5 minutes. Following seizures she developed
altered sensorium and became oliguric. She was referred after two days,
with history of anuria of 12 hours, epistaxis and melena. There was no
history of joint swelling or skin rash.
On examination, her weight was 15 kg and blood
pressure 110/70 mm Hg. The patient showed clinical features of metabolic
acidosis; the hydration was adequate and temperature normal. There was
mild icterus, periorbital edema, epistaxis, gum bleeding and ecchymotic
patches over both lower limbs. Abdominal examination showed mild
hepatosplenomegaly. Glasgow coma scale was 6/15 and fundus examination
was normal. There were no focal neurological deficits. Based on history
and examination, a probable diagnosis of systemic bacterial or viral
infection was made.
Urianlysis showed 2+ albumin, 5-8 RBC and 10-15 WBC
per high power field: there were no eosinophils. Fractional excretion of
sodium was 5.7%. Urine culture was negative. The hemoglobin level was
10.3 g/dL, total leukocyte count 28,700/cu mm with 94% neutrophils and
platelet count 95,000/cu mm. Peripheral smear showed normocytic
normochromic red cells. Prothrombin time and partial thromboplastin time
were prolonged. The blood levels of total and direct bilirubin were 3.5
mg/dL and 2.1 mg/dL respectively, ALT and AST were mildly elevated, urea
148 mg/dL, creatinine 3.4 mg/dL, sodium 121 mEq/L, potassium 6.5 mEq/L
and bicarbonate 8.2 mEq/L. CSF examination was normal. The clinical and
laboratory features suggested multiorgan involvement (hepatic, renal and
disseminated intravascular coagulation) secondary to systemic infection.
Blood culture was negative and tests for malarial parasite,
meningococcal antigen by latex agglutination and leptospira IgM
anti-body by ELISA were negative.
In view of renal impairment, the patient was
peritoneally dialyzed for 48 hours along with supportive treatment.
Treatment with ceftriaxone was started for suspected sepsis and
discontinued after seven days. Although her general condition improved
over one week, the patient was oligoanuric with progressive renal
failure. Renal biopsy showed normal glomeruli, tubular dialtation and
focal tubular necrosis with red blood cells inside the tubular lumina.
There was focal interstitial infiltration with mononuclear cells and
many eosinophils. Immunoflurescence examination was negative. The renal
histo-logy was suggestive of AIN.
Following the biopsy, 12 days after the onset of ARF,
the patient was treated with intravenous methylprednisolone 20 mg/kg/day
for 3 days followed by oral prednisolone 2 mg/kg/day for two weeks. Two
weeks later, the urine output progressively improved and renal functions
returned to normal. On follow up after 1½ month, the patient has normal
renal functions and normal urinalysis.
Discussion
AIN is suspected if there is association of rapidly
progressive renal failure, fever, rash, arthralgia and hematuria. The
infections commonly associated with AIN are Strepto-coccus,
pneumococcus, Epstein-Barr virus, cytomegalovirus, hantavirus,
adenovirus, Leptospira and Toxoplasma(2). AIN usually occurs 2-3 weeks
after the onset of infection(3) and resolves with the treatment of
underlying infection(4). Drugs associated with AIN include antibiotics,
anticonvulsants, NSAIDs, and diuretics. Penicillins are the most widely
reported cause of AIN(5). Other antibiotics include ampicillin,
amoxi-cillin, cloxacillin, methicillin, erythromycin, roxithromycin,
cephalosporins, rifampicin, sulphonamide, nitrofurantoin and
fluroquino-lones(6,7). AIN occurs within hours to months after starting
the drug but the usual duration is 2-3 weeks; the effect may not be dose
related. Drug induced AIN is a hypersensitivity reaction mediated
through both humoral and cell mediated mecha-nisms(8). Nimesulide, a
cyclo-oxygenase-2 inhibitor is reported to be nephro-toxic. It causes
sodium retention and in hyper-reninemic states like congestive cardiac
failure, cirrhosis, nephrotic syndrome and chronic renal failure can
cause acute renal failure(9).
Initially in AIN, symptoms due to infections and
those due to renal failure are difficult to differentiate. In AIN
microscopic hematuria is invariable, macroscopic hema-turia is seen in
5% of cases and proteinuria is in the non-nephrotic range except in
NSAID-associated AIN. Eosinophilia and eosino-philuria may be present
but the absence does not exclude the diagnosis(5). The main functional
derangement relates to uremia and acidosis. In severe AIN with
significant tubular damage there is renal fibrogenesis mediated by
cytokines causing progressive disease(2,8,10). Dialysis may be required
in 30% patients(10) and in oliguric ARF requiring dialysis, a trial of
corticosteroid therapy is indicated, since it may shorten the course of
renal failure. Galpin et al.(11) reported that in patients
treated with steroids, serum creatinine returned to baseline levels in
9.3 days compared to 54 days in untreated patients.
Multisystem involvement, in the present case, was
suggestive of underlying sepsis or leptospirosis. However,
microbiological tests for sepsis and leptospirosis were negative.
Infection or drug mediated ATN or AIN was suspected since ARF persisted.
The classical triad of fever, rash and arthralgia, which is seen in
10-40% of cases of AIN(6,11), was not present in this case. Renal biopsy
in ATN shows only tubular changes whereas in this patient preponderance
of interstitial changes with some tubular changes suggests AIN as the
etiology. Presence of eosinophils in the interstitum favors the
diagnosis of drug induced AIN(6). Amoxicillin, which was used to treat
lower respiratory tract infection, may have been the drug responsible
for AIN. The etiology of AIN may be multifactorial related to both drugs
and infection.
The prognosis in AIN is excellent. Most recover renal
function completely within weeks to months of onset of renal failure. As
any drug or infection can produce AIN it should be considered in all
cases of ARF of unknown etiology in presence of infection and drug
intake. Prompt treatment of infection and withdrawal of the drug is
essential. Rechallenge with the drug has led to recrudescence in a
number of cases and beta-lactam antibiotics are best avoided in patients
who have had penicillin related AIN.
