Detective Nephron, world-renowned for his expert analytic skills, trains budding physician-detectives in the diagnosis and treatment of kidney diseases. Mackenzie Ula Densa, a budding nephrologist, plans to present a new case to the master consultant.
Nephron: It's been a while, Mac. What do you have for me?
Mac: I have a 68-year-old with a kidney transplant and now with chronic diarrhea.
Nephron: (excited) Whoa! Stop right there—that is a GI consult. I am sorry, but I am a nephrologist.
Mac: Trust me, you are going to love this one! You are like a king when it comes to figuring out non-nephrology stuff. Aren't transplant nephrologists the kings and queens of all internists?
Nephron: Well, in that case, we may have to put on my transplant hat or call a friend over for some NY-style coffee. I think I shall invite my friend, Dr. Graft Guardian. He is just a phone call away.
Mac: Hmm…oh well. I can totally relate to that one.
Pause as Dr. Graft Guardian enters.
Guardian: Dear Nephron and Mac, please continue to discuss the case. The “Transplant Guru” has arrived.
Mac: This is a 68-year-old male with a history of deceased donor kidney transplant in 2008 for end stage kidney disease secondary to hypertension (or as some believe). He had a history of bilateral, native kidney nephrectomies for renal cell carcinoma and was on maintenance immunosuppression therapy with mycophenolate sodium 360 mg p.o. b.i.d. [by mouth, two times a day], 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.
Nephron: Stop…nice! What an amazing topic. Nephrologists love and hate hypertension. Didn't we have an editorial in the September issue of Kidney News on who should own hypertension?
Mac: (laughing out loud) Can we move on? The focus is diarrhea.
Guardian: (angry) Oh, come on! Please continue.
Mac: (angry) He presented to the clinic with complaints of fatigue, decreased appetite, chronic diarrhea (two to three loose, watery stools daily), and significant weight loss of approximately 20 kg over the last 1½ years. He denied any fever, sweating, cough, hematemesis, or melena. His blood pressure was low (90/55 mmHg). Laboratory work showed non-anion gap metabolic acidosis (HCO3 13 mEq/L) and AKI with a serum creatinine of 3.5 mg/dL. The tacrolimus level was elevated above goal, at 14 ng/mL, and this was attributed to ongoing, severe diarrhea. The kidney transplant ultrasound showed patent flow in the transplant renal artery and vein without any significant obstruction.
We need to focus on something that all the patients would have been exposed to since they all had the same signs and symptoms.
Nephron: (bored, rolling his eyes) Oh, yes, you just nailed point number 1: This is a boring transplant case.
Guardian: Interesting. Diarrheal illness in transplant patients is a tough one. Medications and infections usually top the list. Malignancy may be a distant third. I assume mycophenolate acid was not the suspect here these many years out, and he was also on the enteric-coated mycophenolate. Enteric-coated MMF [mycophenolate mofetil] has the potential to reduce the incidence of diarrhea by delaying release of MPA [mycophenolic acid] into the small intestine instead of the stomach. In a recent review of the U.S. Renal Data System database of 41,442 renal transplant recipients in the United States, the 3-year cumulative incidence of diarrhea was 22%, with 18% classified as non-infectious. While infections can cause death, non-infectious diarrhea episodes can also lead to graft loss and death. The most common causative agent of diarrhea in solid organ transplant patients is MMF. In some studies of liver-transplant recipients taking 3 gm of MMF daily, the incidence of diarrhea is as high as 51%. Often, non-immunosuppressive agents can be implicated in causing diarrhea, as solid organ transplant patients often receive many medicines, such as other antibiotics. Other, less common causes of diarrhea in transplant recipients include post-transplant lymphoproliferative disorder (PTLD), inflammatory bowel disease, colon cancer, and bacterial overgrowth syndromes.
Nephron: (winking) Dr. Guardian, are we done with your medicine lecture yet?
Mac: Let me tell you more to explain the situation. He was admitted to the hospital for supportive care, and an extensive workup for his symptoms was undertaken. Hydration resolved his AKI. Stool Clostridium difficile toxins A and B were negative. Stool culture was negative for growth of any routine enteric pathogens and Vibrio cholerae, and a qualitative fecal fat test to rule out malabsorption was negative. Serum cytomegalovirus (CMV) polymerase chain reaction (PCR), Epstein Barr virus PCR, and cryptococcal antigen were negative. HIV and tuberculosis T-SPOT testing were negative as well. A cancer antigen 19-9 level was obtained, which was normal. His last colonoscopy done 6 months ago did not detect any concerning lesions. There were no masses on a chest x-ray and on ultrasound imaging, and his nephrectomy beds were negative for any recurrent or remnant disease. Echocardiography showed normal ejection fraction and no valvular vegetation. Now what?
Nephron: (laughing) Pre-renal AKI resolved. Great…done. We can sign off!
Guardian: I am sorry, but I cannot sign off on a transplant patient's case. This is my forte, regardless of what part of medicine it is. This is the best part of being a transplant nephrologist. I think we know more IDs [infectious diseases] than ID docs, more heme-onc [hematology-oncology] than hematologists, and more immunology than immunologists.
Nephron: Talk about modesty! Hmm….
Mac: (trying to remember) As part of the malignancy workup, an esophagogastroduodenoscopy was done, which was unremarkable except for peptic duodenitis. A stool PCR test for Shiga toxin 1 and 2, Cryptosporidium, Giardia, Cyclospora, Campylobacter, Yersinia enterocolitica, adenovirus, and rotavirus was negative as well.
Guardian: (jumping in) I think what you have done is a very good workup. Stool cultures and ova and parasites (O+P) evaluations are important. Conventional stool cultures are also useful, especially in bacterial causes. The yield is low, with acute, watery diarrhea. With bloody stools, the laboratory should be requested to look for Shiga toxin-producing Escherichia coli. With seafood ingestion, the laboratory should be requested to look for Vibrio. A stool can be tested for C. difficile toxin A and B by EIA [enzyme immunoassay] or cytotoxin assay, although some hospitals are moving toward PCR testing. Recent antibiotic use and hospitalization are traditional risk factors, but they are increasingly being seen in outpatients, so there should be a low threshold for diagnostics with diarrhea and leukocytosis. Send stool for O+P exam Giardia antigen testing, especially with chronic diarrhea. You need to request a modified, acid-fast stain for Cryptosporidia, Cyclospora, and Isospora and a trichrome stain for microsporidia. A CMV PCR should be obtained in patients where CMV enterocolitis is considered, especially with other constitutional symptoms in individuals with moderate to high risk. However, they may have negative or low-level viremia and still have active GI disease. Finally, CT scans and endoscopic evaluations, as you did, are excellent next steps.
Mac: Hmm…and then we have the culprit.
Nephron: (shocked) Let me guess, it's SARS-CoV-2?
Mac: (smirking) No, no, it's not COVID-19-induced this time around. Although, adding that to the title of any publication would probably lead to quicker acceptance of a paper on this case.
Guardian: Go on with the real stuff of the harder part of the case, and let's leave SARS-CoV-2 out of this. In all seriousness, we lost many of our patients to the pandemic. Please respect the virus.
Mac: (decisively) Norovirus (NoV) PCR is positive on the stool PCR. The repeat value confirmed this.
Guardian: Hmm…fascinating. NoV infections are the most common cause of acute gastroenteritis worldwide. In the transplant population, NoV infections can result in chronic diarrhea, which has long-standing after-effects on nutrition, quality of life, elevated tacrolimus levels, and resultant toxicity and graft dysfunction. Even though the first cases were reported in 2009, awareness about this infection and approaches to its management leave room for improvement.
NoV binds to antigens on enterocytes, causing edema and severe enterocyte injury resulting in diarrhea. Clinical manifestations of NoV/sapovirus gastroenteritis in patients who are immunocompromised include non-bloody, watery diarrhea; nausea; vomiting; abdominal discomfort; bloating; weight loss; and wasting. Fever is unusual. It spreads mainly via the food-borne, fecal-oral routes but also through person-to-person contact or contaminated surfaces. Both T cell and B cell responses are required to clear NoV infection, and immunosuppressive therapy is a risk factor for prolonged infection. In kidney transplant recipients, because of iatrogenic immunosuppression, NoV symptoms can be prolonged and chronic, with periods of symptom exacerbation and remission. If not treated, kidney graft dysfunction can occur due to severe dehydration. The diarrhea can also disrupt the P-glycoprotein efflux pump, leading to supra-therapeutic tacrolimus levels, further worsening the AKI. Also, patients are at higher risk of rejection due to immunosuppression reduction that is done to allow the host immune response to eliminate the infection.
Nephron: (showing off) Good point. A 2021 study by Gäckler et al. in Transplantation addressed the gaps in our understanding of the clinical characteristics of NoV infections post-kidney transplantation. The study enrolled 60 patients with kidney transplants diagnosed with NoV infection by a positive stool PCR test. It aimed to identify the characteristics of chronic NoV infections in kidney transplant recipients and their effect on allograft function. The study also evaluated the safety and efficacy of using intravenous immunoglobulin (IVIg) as a therapeutic measure in 18 patients with chronic diarrhea. NoV gastroenteritis occurred a median of 52 months after transplant, resulting in a cumulative median hospital length of stay of 8 days for patients admitted with acute gastroenteritis. Thirty-one of the 60 patients were found to have chronic infection. Compared with those with acute infection, patients with chronic infections stayed longer in the hospital (10 vs. 7 days), and they were hospitalized more frequently for their illness (17 patients vs. 1 patient). Multivariate analysis showed that both diabetes mellitus and the administration of lymphocyte-depleting induction therapy were independent prognostic factors for the development of chronic NoV infection among kidney transplant recipients.
Guardian: (jumping in) Nephron, you just stole those lines from the March Kidney News issue, in which it was highlighted as an important topic.
Mac: IVIg? Interesting…. Why not hold MMF and start nitazoxanide?
Guardian: No therapy has shown to be consistently effective, and there are no specific therapies for treating NoV infection. Symptom relief should include intravenous hydration, anti-motility agents to relieve diarrhea, and reduced immunosuppression. Immunosuppression reduction may help reduce clinical symptoms and prevent chronic carriage and recurrent infection. Reduction of immunosuppression in organ transplant recipients should be done carefully due to the risk of precipitating a rejection. Limited case studies have shown nitazoxanide to be effective in treating NoV with a significant reduction in time to resolution of symptoms. Nitazoxanide is a thiolide antimicrobial agent that exerts its effect against parasitic worms, protozoa, bacteria, and viruses. The antiviral effects of nitazoxanide are two-fold, including activation of natural antiviral defenses and inhibition of cellular pathways that lead to viral replication. Nitazoxanide therapy for the treatment of NoV should be continued until stool RNA studies are negative. A systematic review of activity of nitazoxanide on viral gastroenteritis concluded that nitazoxanide may be useful in reducing the disease burden in transplant recipients who are immunocompromised. Now, with IVIg, as Detective Nephron pointed out, a recent study showed some good benefits. In that study, he mentioned that 18 kidney transplant recipients with chronic NoV infection were treated with IVIg based on severity perceived by treating clinicians. Thirteen of these patients had no further clinical signs of NoV infection and did not require further hospitalizations. However, 10 of the 13 patients demonstrated NoV in stool samples even following therapy, so it didn't completely clear the virus.
Mac: (nodding) So, what do we do here?
Nephron: (puzzled) Do all of the above: start nitazoxanide therapy, give a few doses of IVIg, and hold MMF. I doubt he will reject his kidney these many years out with an elevated tacrolimus level.
Mac: You are so dramatic!
Guardian: (laughing out loud) On a serious note, he may be correct. As I had mentioned, currently, there is no single, proven therapy to cure NoV in the kidney transplant population who are immunocompromised. Treatment with medications such as nitazoxanide and Ig has proven effective in limited cases. Reducing immunosuppression for the patient's immune system to clear the infection may lead to renal transplant rejection, so we must be careful.
Nephron: Mac! What are you going to do? The ball is in your court.
Mac: (confidently) We will hold MMF, give the nitazoxanide, and eventually monitor for renal function and graft rejection. IVIg may have a role in the next few weeks if clinically there is no improvement, and symptoms don't resolve.
Guardian: Sometimes, you must make tough decisions in transplant nephrology. No evidence is going to help guide you; it will be your clinical acumen.
Nephron: (jumping in) Yes, of course. Tell the team your plan.
A few days later
Mac: (surprised) Well, we did as we planned. He did clear his virus, and kidney function remained stable at 1.8 mg/dL. We did do a protocol renal biopsy, and no rejection was noted.
Nephron: Fantastic! I assume he stays off MMF?
Mac: For now.
Guardian: Preventive measures for NoV are important given the morbidity associated with the infection. Hand hygiene is of paramount importance.
Nephron: You sound like a joint commission surveyor.
Nephron: (laughing) There you go again! Fascinating diagnosis and treatment, Mac, and special thanks to our transplant nephrologist in helping us with this tough case. I must say, transplant nephrologists are truly the best internists on the planet. Now, let's have some NY-style coffee.
Dr. Graft Guardian takes a bow and winks.