The patient was a 68 year old African American male with history of deceased donor kidney transplant in 2008 for end stage renal disease secondary to hypertension. He had a history of bilateral native kidney nephrectomies for renal cell carcinoma and was on maintenance immunosuppression therapy with mycophenolate mofetil 750 mg p.o b.i.d, tacrolimus 1 mg b.i.d (with a goal level of 4-6 ng/mL), and prednisone 5 mg p.o daily. His baseline creatinine was 1.7 mg/dL.
He presented to clinic in October 2018 with complaints of fatigue, decreased appetite, chronic diarrhea (2-3 loose watery stools daily) and significant weight loss of ~ 15 kilograms over last 1 year, denying any fever, sweating, cough, hematemesis, or melena. His blood pressure was low (BP 89/59 mmhg). Laboratory work showed non-anion gap metabolic acidosis (HCO3 13 meq/L) and acute renal failure with a creatinine of 3.5 mg/dL. Tacrolimus level was found to be elevated above goal, at 14 ng/mL and this was attributed to ongoing severe diarrhea. Renal transplant ultrasound showed patent flow in transplant renal artery and vein without any significant obstruction. He was admitted to the hospital for supportive care and an extensive work up for his symptoms was undertaken. Stool Clostridium difficile toxins A and B were negative. Stool culture was negative for growth of any routine enteric pathogens as well as cholera vibrio and a qualitative fecal fat test done to rule out malabsorption was negative. Serum Cytomegalovirus PCR, Epstein Barr Virus PCR, and cryptococcal antigen were negative. HIV and tuberculosis T-Spot testing were negative as well. A CA 19-9 level was obtained the result of which was normal. His last colonoscopy in June 2018 did not detect any concerning lesions. There were no masses on chest x ray and on ultrasound imaging his nephrectomy beds were negative for any recurrent or remnant disease. Echocardiography showed normal ejection fraction and no valvular vegetations.
As part of malignancy work up an esophagogastroduodenoscopy was done which was unremarkable except for peptic duodenitis. Stool PCR test for Shigatoxin 1 and 2, Cryptosporidium, Giardia, Cyclospora, Campylobacter, Yersinia enterocolitica, Adenovirus and Rotavirus was negative but positive for norovirus. Patient was diagnosed with having chronic norovirus gastroenteritis. He received bicarbonate containing intravenous fluids during the hospitalization. Tacrolimus dose adjustments were made to target goal level. His mycophenolaate mofetil was decreased from 750 mg p.o bid to 500 mg p.o bid for immune reconstitution to increase immune response against the norovirus. He was also started on nitazoxanide 500 mg b.i.d for 14 days at discharge. Four days after starting nitazoxanide patient was seen in transplant clinic. Diarrhea had completely resolved. He reported better energy levels and improved appetite. Patient was advised to complete 14 days of nitazoxanide which he did. A repeat sigmoidoscopy/colonoscopy was deferred after the patient was diagnosed with norovirus gastroenteritis.
One month later patient was readmitted to hospital with complaints of feeling weak, short of breath, with loss of appetite and recurrence of diarrhea. Labs showed serum bicarbonate of 8 meq/L and creatinine of 6.7 mg/dL. The patient was also hypokalemic, hypomagnesemic and hypocalcemic. The electrolyte abnormalities were secondary to his worsening diarrhea and decreased oral intake. He received supportive care which lead to improvement in clinical and laboratory parameters. He was found to be positive for norovirus again on stool PCR. He was placed back on nitazoxanide for 6 weeks given relapse of symptoms after stopping nitazoxanide. Serum IgA and IgG levels were checked and were found to be adequate and hence he did not receive any oral or intravenous immunoglobulin (IVIG) infusion.
At 3 weeks follow up the patient had marked clinical improvement and had gained 6 kilograms body weight and the diarrhea had once again completely resolved. However, at this visit he was still positive for norovirus PCR on stool. His mycophenolate mofetil was further decreased to 250 mg p.o bid with the aim to help patient's immune system clear the virus and prevent another recurrence. Given persistently increasing weight, markedly improved general sense of well-being, no reported side effects along with continued norovirus shedding in stool, we extended nitazoxanide treatment beyond 6 weeks. At this point his creatinine was 1.9 mg/dL. A post nephrectomy follow up positron emission tomography (PET) scan obtained at this point showed no recurrent tumor at renal beds and no active tumor lymphadenopathy or distant metastasis.
During routine follow-up clinic visit in February 2019 while on nitazoxanide, stool PCR was negative for norovirus but positive for sapovirus. There was no diarrhea and patient was continuing to gain weight. However, patient was noted to have an increase in serum creatinine of up to 3.3 mg/dL. Ultrasound of transplanted kidney showed preserved vascular flow and mild pelvic caliectasis. There was high suspicious for renal allograft rejection due to recently lowered immunosuppression. A renal transplant biopsy was obtained which showed Banff IA acute cellular rejection (Fig. 2), acute tubular necrosis (ATN), with no arteritis, and no evidence of humoral rejection (C4d negative, no peritubular capillaritis). SV 40 stain (BK Virus) was negative. Donor specific antibodies (DSA) were negative as well. For the treatment of his acute allograft rejection he received methylprednisone 500 mg intravenously daily for 4 days, followed by a prednisone taper. Thymoglobulin was not used. His mycophenolate mofetil dose was increased back to 500 mg p.o b.i.d. The creatinine improved to a new baseline of 2.6 mg/dL after treatment of rejection. Patient was instructed to continue nitazoxanide. A repeat stool sample was again positive for sapovirus and negative for norovirus.
During follow-up visits in the outpatient clinic, patient continued to gain weight with no recurrence of diarrhea. However, repeat stool on April 2019 was again positive for norovirus even on nitazoxanide. In June 2019 patient stopped taking nitazoxanide as diarrhea had completely resolved. In August 2019, patient began to experience diarrhea and weight loss again. Stool PCR was positive for norovirus. Patient was restarted on nitazoxanide 500 mg p.o bid. See Table 1 for sequence of events. Despite initial improvement in creatinine after treatment of cellular rejection with steroids, on outpatient follow up creatinine started increasing progressively with development of uremic symptoms and patient ultimately ended up on dialysis in September 2019.