Granulomatous Interstitial Nephritis Induced by Piperacillin-Tazobactam After Renal Allograft

Authors: 
David N. Dado, DO
San Antonio Military Medical Center, Fort Sam Houston, Texas

Michael Babigumira, MD, and Christine Toth, MD
University of Texas Health Sciences Center at San Antonio, Texas

Citation: 
Dado DN, Babigumira M, Toth C. Granulomatous interstitial nephritis induced by piperacillin-tazobactam after renal allograft. Consultant. 2018;58(8):220-223. 

A 56-year-old man with history of end-stage renal disease secondary to diabetic nephropathy had been on hemodialysis since 2012; he also had hypertension and hepatitis C virus (HCV) infection. He underwent HCV-positive deceased-donor kidney transplant and received induction therapy with thymoglobulin. He required 1 hemodialysis treatment postoperatively for hyperkalemia. He subsequently was discharged on postoperative day 7 with a serum creatinine level of 2.6 mg/dL, significantly lower than the 9.6 mg/dL level at the time of transplant. He was discharged on 5 mg of prednisone in addition to tacrolimus and mycophenolate mofetil.

The patient was readmitted 2 days later with epigastric and right upper quadrant (RUQ) pain, dysphagia, and transient dysuria. Laboratory test results were significant for a serum creatinine level of 1.9 mg/dL and a tacrolimus level of 13.1 ng/mL; urinalysis results showed 2+ protein and 3+ blood on dipstick, and 14 white blood cells per high-power field (HPF) and 267 red blood cells/HPF on microscopy (Table). The blood eosinophil count on manual differential was normal. Ultrasonography of the transplanted kidney revealed mildly elevated resistive indices and 2 new small peritransplant fluid collections.

Following admission, he was empirically treated for a urinary tract infection with 1 dose of ceftriaxone and maintained on piperacillin-tazobactam for 5 days. He was started on intravenous pantoprazole on day 4 for persistent dysphagia that was later stopped on day 6. Serum creatinine increased from 1.9 mg/dL on admission to a peak of 3.3 mg/dL on day 5 of admission. Piperacillin-tazobactam was discontinued on day 5 with a subsequent decrease in his serum creatinine concentration over the next few days (Figure 1). Hypertension was well controlled with nifedipine 30 mg per day, a medication he had been taking prior to admission.

Urine and blood cultures were negative for pathogens. RUQ ultrasonography results showed gallbladder sludge but were otherwise unremarkable. Computed tomography of the abdomen and pelvis revealed postsurgical changes of right lower quadrant renal transplant with a high-density peritransplant fluid collection, which was felt to represent postoperative hematoma. Esophagogastroduodenoscopy revealed erosive esophagitis.

Renal biopsy was performed on hospital day 6. Compared with the zero-hour renal biopsy, there were significant changes. Light microscopy revealed normal glomeruli, poorly defined granulomas without giant cells or caseous necrosis, and mild interstitial fibrosis. Results of acid-fast, fungal, Gram, and polyomavirus staining were negative. Immunofluorescent staining was negative for immunoglobulins G and M, C3, C1q, fibrin, κ light chain, λ light chain and C4d. On electron microscopy, the podocyte foot processes were not effaced, and osmophilic dense deposits were not seen in any part of the glomerulus; the glomerular basement membrane was normal.

He was additionally started on tapering doses of prednisone on day 7 (the day after the biopsy). His renal function continued to improve. At outpatient follow-up, his serum creatinine level was 1.1 mg/dL, and the proteinuria had resolved.

NEXT: Discussion

Discussion. Acute kidney injury (AKI) in the immediate posttransplant period is not an unusual occurrence and has been associated with different etiologies.^1,2 Granulomatous interstitial nephritis (GIN) is one of the many causes of AKI, but it is rarely found in renal allografts.³ GIN can be caused by systemic inflammatory conditions, infections, and drugs.⁴ The list of offending medications is extensive, and several penicillins including ampicillin, oxacillin, and methicillin have been linked to GIN.⁵ While piperacillin has been associated with interstitial nephritis, it is not common,⁵ and to the best of our knowledge, piperacillin-tazobactam has not been documented in the literature as a cause of GIN in a renal allograft.

The pathogenesis of GIN is not clearly understood but is thought to be immune-mediated, based on data from experimental studies in animal models.⁵ Disregarding the episode of hyperkalemia requiring a single session of hemodialysis, our patient had been following a typical postoperative renal transplant course until he was readmitted and given, significantly, antibiotics and a proton-pump inhibitor (PPI), among other medications.

As demonstrated in Figure 1, serum creatinine rose in tandem with the administration of piperacillin-tazobactam and declined with cessation of this therapy. While PPIs, particularly omeprazole, have been implicated as a cause of GIN,⁶ our patient was not given a PPI until day 4, by which time serum creatinine already was peaking. In addition, renal function began to improve in spite of continued PPI administration. He also received a single dose of ceftriaxone, which has not been linked to GIN, and creatinine continued to rise beyond administration of this medication. Nifedipine, a known cause of GIN,⁷ had been a part of his medication regimen since transplant and, despite continuing this medication, his renal function continued to improve, indicating that it was not the cause of AKI.

Serum calcium levels remained normal throughout admission, and our patient did not have extra-renal manifestation of sarcoidosis. Tuberculosis had been ruled out as part of his pretransplant workup, and Ziehl-Neelsen staining of the renal biopsy was negative. The patient does have active HCV infection and had been matched with an HCV-positive donor. No cases of GIN had been associated with HCV infection to date, and there was no evidence of HCV-related renal disease on biopsy. Additionally, the patient recovered renal function even in the absence of specific treatment for HCV infection.

Renal biopsy done on day 6 confirmed the diagnosis of GIN by demonstrating noncaseating granulomas with mild-to-moderate interstitial fibrosis (Figures 2-4). Peripheral eosinophilia is quite common in cases of acute interstitial nephritis associated with penicillins, although it was not seen in our patient’s case. The renal allograft biopsy was not suggestive of other potential causes of renal failure such as acute graft rejection, acute tubular necrosis, infection, infiltrative disease, glomerulonephritis, or calcineurin toxicity. Zero-hour biopsy of the renal allograft was grossly normal (Figure 5).

Figure 2: Histological section of renal specimen on day 6 showing diffuse granulomatous interstitial inflammation (hematoxylin-eosin, original magnification ×100).

Figure 3: Histological section of renal specimen on day 6 showing interstitial granuloma composed of epithelioid cells (hematoxylin-eosin, original magnification ×200).

Figure 4: Histological section of renal specimen on day 6 showing tubular destruction due to granulomatous inflammation (periodic acid–Schiff, original magnification ×100).

Figure 5: Histological section of the donor kidney at zero hour showing normal glomeruli, interstitium, tubules, and blood vessels (hematoxylin-eosin, original magnification ×100).

In general, withdrawal of the offending agent should result in resolution of drug-induced GIN. Our patient’s renal function improved after piperacillin-tazobactam was stopped. Even though the role of corticosteroid therapy in the management 

of drug-induced GIN is not clear,⁸ we opted to increase his regular dose of prednisone to 60 mg/d and taper it slowly. We maintained the rest of his renal transplant immunosuppressive medications, with full recovery of his renal graft function.

This patient’s case suggests that piperacillin-tazobactam may lead to GIN in the transplanted kidney. Piperacillin-tazobactam should be recognized as a cause of GIN, and the role of increasing corticosteroids as a treatment strategy of GIN in the posttransplant period should be further explored. 

References: 

1. Panek R, Tennankore KK, Kiberd BA. Incidence, etiology, and significance of acute kidney injury in the early post-kidney transplant period. Clin Transplant. 2016;30(1):66-70.
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Disclaimer:

The views and opinions expressed in this article are those of the authors and do not reflect official policy or the position of the United States Air Force, the Department of Defense, or the United States Government.