Infection and Drug Associated Tubulointerstitial Nephritis and Acute Tubular Necrosis in a Presentation Similar to That of Post-Streptococcal Glomerulonephritis: A Case Report

Abstract

Tubulointerstitial nephritis (TIN) is an inflammatory infiltrate of interstitial kidney most commonly caused by infections, drugs, allergies, and a number of autoimmune conditions. In this case, we have a 40-year-old male who was thought to have post-streptococcal glomerulonephritis given his symptoms of sore throat and pharyngitis before having renal involvement; however, after further evaluation was found to have biopsy proven interstitial nephritis without glomerular involvement. We note that TIN has multiple etiologies, and in our patient, we believe the combination of sore throat and pharyngitis attributed to Streptococcus pyogenes and the concomitant nonsteroidal anti-inflammatory drug use and eventual bacterial translocation into the bloodstream, led to all the atypical manifestations described in this study. Although TIN is diagnosed definitively through biopsy, it is not able to reveal the specific causes especially when there are multiple causes suspected simultaneously. Such situations may be challenging to pinpoint a cause therefore it is of utmost importance to keep a broad differential for unexplained acute kidney injury.

Introduction

Tubulointerstitial nephritis (TIN) is an inflammatory infiltrate of kidney interstitium most commonly caused by drugs, autoimmune conditions, allergies, and infections. Drug-induced TIN is currently the most common etiology of TIN (70%-75%), with the offending agents most commonly being antimicrobials and nonsteroidal anti-inflammatory drugs (NSAIDs). Infections are also a very common cause of TIN (the second most-common cause in developed countries, and the most common in undeveloped countries), and all microbes from bacteria, viruses, fungi, and parasites have been implicated. Notably, acute kidney injury (AKI) is not a common presenting symptom in infectious TIN.^{1 -3} We report a case involving an atypical presentation in which the clinical scenario portended a diagnosis of post-streptococcal glomerulonephritis (PSGN) due to presentation with sore throat, elevation in anti-streptolysin O antibody (Ab), and Streptococcus pyogenes bacteremia. However, kidney biopsy revealed inflammatory infiltrates in the interstitium and tubular necrosis, consistent with TIN and acute tubular necrosis (ATN), respectively, as opposed to showing a glomerular disease.

Case Discussion

A 40-year-old male with no significant past medical history presented to the emergency room for lower extremity edema, bilateral flank pain, and decreased urinary output. Eight days prior to arrival the patient had a sore throat that self-resolved without pharmacological intervention and also had 2 days of diarrhea and subjective fevers that self-resolved 2 days prior to arrival. The patient denied any eye and visual complaints. Sometime later, the patient experienced severe bilateral lower extremity leg swelling with erythematous rash, bilateral flank pain, and reduced urine output with visible blood in the urine which prompted him to come to the emergency room.

Per his recollection, the patient had “Gram-positive bacteremia and urinary tract infection” and was treated with intravenous cephalexin for 2 days at another hospital 2 days prior to arrival to our emergency room. Notably, the patient also mentioned he took 5 to 6 ibuprofen 600 mg tablets daily for 5 days before presenting to the emergency room. Vitals taken at the time showed temperature 36.6 °C, heart rate 58 beats/minute (sinus bradycardia), blood pressure 129/77 mmHg respiratory rate 18 breaths/minute, and SpO₂ 92% on room air.

Labs (Table 1) revealed elevated white blood cell count of 12.4 K/µL, creatinine of 7.1 mg/dL, urinalysis revealing 3+ blood, 500 leukocyte esterase, >900 RBC/high-power field, and 516 WBC/high-power field with 1+ bacteria which appeared to suggest likely urosepsis with AKI, elevated C-reactive protein of 18.6 mg/dL, and elevated sedimentation rate of 67 mm/hour. The patient did not have any prior labs as this was his first presentation to the hospital and no outside records were available, so baseline creatinine is unknown; however, the patient denied any prior chronic kidney disease. Computed tomography of the abdomen without contrast found moderate splenomegaly of 17 cm without renal cysts, masses, or obstructive changes. Documentation from the previous hospital revealed blood cultures positive for Group A Streptococcus. Throughout the hospital stay, the patient remained hemodynamically stable and repeated blood cultures and urine cultures remained unremarkable as the patient was on antibiotics.

Table 1.

Laboratory Findings Over the 7-Day Hospital Course.

Laboratory value	Reference range	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
Sodium	136-145 mmol/L	138	139	139	139	136	141	140
Potassium	3.5-5.1 mmol/L	3.7	3.7	3.6	3.9	3.8	3.8	4.0
Protein/creatinine ratio	<3.5 mg/mg						2.2
CO2	23-29 mmol/L	20.3	23.5	26.8	26.4	24.5	28.5	29.6
Anion gap	3-11 mmol/L	12	11	9	10	10	10	7
BUN	7-25 mg/dL	57	53	54	53	52	54	50
Creatinine	0.7-1.3 mg/dL	7.1	6.5	6.8	6.4	6.6	6.5	6.5

Abbreviation: BUN, blood urea nitrogen.

Further extensive serology was obtained and autoimmune workup including HIV, hepatitis B and C, glomerular basement membrane antibody, anti-dsDNA antibody, IgA, and anti-neutrophil cytoplasmic antibody were all normal with the exception of elevated anti-streptolysin O Ab elevated at 263 IU/mL (reference range <200 IU/mL). Serum complement levels were ordered showing normal C3 of 109 mg/dL and low C4 at 9.1 mg/dL. Due to the fear adult-onset PSGN with confirmed Group A Streptococcus bacteremia, a transthoracic echocardiography was performed to search for valvular vegetations and was unremarkable from both cardiac structure, function, and endocarditis standpoints.

At this time, the diagnosis of PSGN was still somewhat questionable due to his atypical presentation with oliguria, hematuria, low C4 complement, lower extremity swelling with rash and bilateral flank pain, and so the treating team decided to perform a kidney biopsy. The kidney biopsy revealed inflammation and plasma cell invasion of the interstitium, active tubular inflammation suggestive of tubulitis with tubular atrophy and the presence of leukocyte casts, and early changes of ATN including focal tubular epithelial necrosis and dilation of the proximal tubules. In conclusion, due to biopsy findings, this patient’s TIN was most likely multifactorial in that it was drug induced by NSAIDs and by infection. During the first 2 days of hospitalization, the patient was treated with daptomycin IV 4 mg/kg daily for the lower extremity rash and empiric treatment with cefepime IV 1 g every 8 hours. After the infectious diseases team was consulted, the patient was placed on ceftriaxone IV 2 g daily for the remainder of his hospitalization (4 days). In the days prior to discharge, the patient remained hemodynamically stable and kidney function continued to normalize as well as improvement in lower extremity swelling and erythema. Of note, the urinary protein/creatinine ratio did not exceed 3.5 mg/mg, so nephrotic-range proteinuria was not suggested. The patient was sent home with midline IV access and was to complete a total 14-day course of ceftriaxone IV 2 g daily and is doing well to this day with moderately reduced kidney function. Creatinine upon discharge was at 6.5, and unfortunately the patient was lost to follow–up; therefore, we are unable to confirm if creatinine levels returned to appropriate levels.

Discussion

The first known report of infection-associated TIN was actually described in an extensive article on TIN by Councilman in 1898; in this article, Councilman describes 42 cases of interstitial nephritis in which the kidneys were cultured for bacteria, and 5 of those cultures grew S. pyogenes. ² Thus, while indeed rare, and kidney cultures not being routine standard of care nowadays, one cannot exclude Streptococcus as an implicating organism and cause of TIN. This brings us to our discussion of our patient found to have S. pyogenes bacteremia and associated renal pathology. We note that TIN has multiple etiologies, and in our patient, we believe the combination of sore throat and pharyngitis attributed to S. pyogenes and the patient’s associated NSAID use presumably for pain control and eventual bacterial translocation into the bloodstream, led to all the renal manifestations as described earlier. TIN should be considered in the differential for unexplained AKI. Initial management should include conservative therapy by withdrawing any suspected causative agent. Renal biopsy is needed for confirmation in cases where kidney function fails to improve within 5 to 7 days on conservative therapy. ⁴

Typically for PSGN diagnosis, a biopsy is not warranted, ¹ but given the atypical features of PSGN with low C4 complement instead of low C3 complement and no signs of proteinuria we felt that a biopsy is appropriate. TIN does not typically involve complement activation since AIN is an inflammatory condition of the interstitium triggered by primarily drugs and infections. Lower complement levels usually will indicate a glomerular disease, lupus nephritis, or certain ANCA positive vasculitis. ⁵ Although TIN is diagnosed definitively through biopsy, it is not able to reveal the specific causes especially when there are multiple causes suspected simultaneously. Such situations may be challenging to pinpoint a cause when a patient such as ours presents with a recent infection and is using offending antibiotics or anti-inflammatories. There is 1 case that describes the first instance biopsy-proven TIN associated with Streptococcus-species bacteria in a patient who also had acute renal failure. ⁶ Thus, the decision to proceed with relatively prompt renal biopsy was useful here, allowing us to establish a diagnosis of TIN, and confidently treat the patient with antimicrobials and prevent further rapid decline in kidney function. The primary treatment for AIN is identifying the possible causative drug. If there is no improvement in renal function after 5 to 7 days of withdrawing the causative agent, it is appropriate to initiate corticosteroids to reduce inflammation and recover renal function.^{1 -3}

In conclusion, TIN is an important cause of AKI. The causes are usually and more commonly drug-induced and less commonly from infection or autoimmune causes. The symptoms can be nonspecific and vague, but usually present with fever, malaise, rash with renal manifestations such as nonoliguric AKI and nonnephrotic range proteinuria some of which were present in our patient. PSGN is a glomerular disease mediated by an immune response typically after group A streptococcal infection. Immune complexes are then formed and deposited in the glomeruli leading to complement activation. Clinically, PSGN presents with edema, nephritic syndrome, hypertension, oliguria, and edema. Laboratory findings usually include low C3 levels and presence of anti-streptolysin O Ab. This case is especially interesting due to its atypical presentation of both AIN and PSGN and its overlapping symptoms of rash, edema, sore throat, streptolysin O Ab, and oliguria. It is crucial to obtain a thorough history and review clinical and laboratory findings to manage your patient properly and to determine if renal biopsy is appropriate. To manage AIN, you must withdraw the offending agent. If there is no improvement in renal function within 5 to 7 days, corticosteroids may be appropriate in which early initiation is preferred to prevent worsening kidney injury. ¹ For PSGN, the treatment is usually supportive with antihypertensives, diuretics, and antibiotics such as penicillin to reduce antigenic load of the streptococcal infection.