A 59-year-old woman with a history of CKD stage 5 due to diabetes underwent preemptive living unrelated kidney transplantation. At the time of transplant, her panel reactive antibody was 0%, and she had no preformed donor-specific antibodies. Cytomegalovirus (CMV) serology was donor positive and recipient negative. She received induction with alemtuzumab with rapid steroid withdrawal. Her maintenance immunosuppression included tacrolimus (target trough 6–8 ng/ml) and mycophenolate sodium 720 mg twice a day. She received valganciclovir prophylaxis for 6 months. One month post-transplant, serum creatinine was 1 mg/dl with an eGFR of 80 ml/min per 1.73 m2. At 13 months post-transplant, she presented to the emergency room with a 2-week history of malaise, low-grade fever, nausea, vomiting, diarrhea, and weight loss. Her physical examination was unremarkable. Initial investigations showed AKI with a serum creatinine of 2.4 mg/dl. She was admitted for further studies and management.
What is the most likely cause of the patient’s presentation?
- CMV disease
- Norovirus infection
- Clostridium difficile infection
- Cryptosporidium infection
Discussion of Question 1
The correct answer is A. The patient was at high risk for CMV disease on the basis of her CMV serologies at the time of transplant (1). CMV disease most commonly occurs in the patients after completion of CMV prophylaxis. It is manifested as evidence of end organ damage and positive CMV viremia. Norovirus usually presents as perfuse diarrhea without malaise and fever. As there was no history of antibiotics exposure, the risk of C. difficile infection is low. Cryptosporidium infection is seen in highly immunocompromised patients, like those with HIV.
CMV PCR was positive at 2.8 million IU/ml. Intravenous ganciclovir was initiated, with aggressive loading dose protocol; mycophenolate mofetil was held; and intravenous γ-globulin (IVIG) was given in tandem for immunomodulatory effects. Despite aggressive fluid resuscitation, serum creatinine continued to rise despite improvement in symptoms. On postadmission day 4, creatinine peaked at 4 mg/dl. Urine output was 2 L/24 h. The patient underwent a kidney transplant biopsy.
What is the most likely diagnosis?
- Diffuse denudation of the kidney tubular cells with loss of brush border from ganciclovir
- Glomerulitis and owls’ eye inclusions in glomerular capillaries
- Significant interstitial inflammation and moderate tubulitis
- Glomerulitis and peritubular capillaritis
Discussion of Question 2
The correct answer is B. Although kidney function needs to be monitored closely for ganciclovir dose adjustment, acute tubular necrosis from ganciclovir is uncommon in the absence of other nephrotoxic agents. In addition, kidney function was already impaired on presentation, suggesting preexisting injury (option A). Characteristic intranuclear glassy-appearing basophilic inclusions with surrounding halo (owls’ eye–type inclusion) and a marked increase in the size of the cell (cytomegaly) in infected glomerular epithelial cells are noted (Figure 1). Specific diagnosis was confirmed by immunohistochemical staining for CMV (option B). T cell–mediated rejection does not have viral cytopathic changes or positive CMV staining, and there was no evidence of tubulitis (option C) (2). Other viruses are diagnosed by specific immunohistochemistry or in situ hybridization. When glomeruli are affected, endothelial cell injury could overlap with that seen in chronic transplant glomerulopathy, but the latter has no viral inclusions or immunohistochemistry positivity for CMV (option D) (2). Although CMV infection is a risk factor for rejection (3), the timeline is more consistent with CMV nephritis. Further, considering no peritubular capillaritis or C4d staining, the chance of antibody-mediated rejection is low on differential.
Additional Clinical Course
With the diagnosis of CMV glomerulitis, the patient continued to receive intravenous ganciclovir with close monitoring of kidney function and electrolytes. Doses were adjusted daily on the basis of fluctuating kidney function. After 2 weeks of intravenous ganciclovir, CMV viral load decreased to 128,000 IU/ml with resolution of clinical symptoms. Her creatinine also improved to 2 mg/dl. Intravenous ganciclovir was changed to oral valganciclovir 900 mg twice daily given the trend of improving eGFR. The patient was discharged home with close outpatient monitoring. On the last follow-up, her creatinine was back to the baseline of 1.1 mg/dl. CMV viral load became nonquantifiable after 6 weeks of oral valganciclovir.
CMV disease is one of the most common opportunistic infections associated with kidney transplantation (4). As per one report, an average of 60% of kidney transplant recipients develop CMV viremia, and 20% develop symptomatic CMV disease (5). Even with antiviral prophylaxis, CMV viremia occurs in 35% of the transplant recipients who were provided with the prophylaxis within 12 months of transplantation (6). The common manifestations of CMV disease are colitis, hepatitis, retinitis, pneumonitis, and pancreatitis. CMV glomerulitis and nephritis are uncommon but important manifestations of the CMV tissue-invasive disease. Our patient highlights the importance of keeping CMV disease in differential diagnosis while investigating the causes of AKI in kidney transplant recipients. It also highlights some of the ongoing unknowns in the treatment of CMV. At our institution, we follow aggressive ganciclovir induction dosing to avoid underdosing in the setting of fluctuating kidney function associated with CMV nephritis. More studies to this effect are needed. Although alternative antiviral agents exist, these are plagued with toxicity (foscarnet and cidofovir) and are overall less efficacious than ganciclovir derivatives (letermovir). We also use IVIG at our institution in the setting of high-level viremia. Although the role of IVIG for treatment of CMV is debated, there is literature to support its immunomodulatory properties, which may prevent rejection in the setting of withholding maintenance immunosuppression during the treatment of CMV disease. More investigations on the role of IVIG in the treatment of CMV are needed. Per international consensus guidelines, the patients with evidence of tissue-invasive CMV should receive at least 4 weeks of antiviral therapy at treatment dose regardless of the viral load. Patients should have viral loads monitored on a weekly basis via molecular diagnostics (PCR) preferably at a single laboratory to be directly comparable. Weekly monitoring is necessary to evaluate replication kinetics and adjust therapy accordingly without rapid progression of disease. Patients should receive at least every 2-week monitoring of serum creatinine and complete blood count to evaluate appropriateness of antiviral dosing and response to therapy/toxicity. There are currently no recommendations on how best to resume and titrate immunosuppression in the setting of recovery from CMV infection (7).
In an early report, Richardson et al. (8) investigated the relationship between CMV viremia and kidney allograft dysfunction in 14 patients. In this patient series, 50% of the patients showed kidney allograft dysfunction with clinical manifestations of CMV. With the reduction in immunosuppression, the two patients recovered their kidney function completely. They concluded that CMV viremia might be associated with glomerular injury, and reduction in CMV viremia by decreasing immunosuppression can improve kidney function (8). In a recent literature review, Morgantetti et al. (9) described 12 cases of CMV nephritis in kidney transplant recipients. All of these patients underwent transplant kidney biopsy, which confirmed the diagnosis of CMV nephritis. Treatment of CMV nephritis was associated with a return of kidney function to baseline in 42% of the patients, partial improvement in 33% of the patients, and no improvement in the remaining 33% of the patients (9).
CMV infection and disease are associated with higher risk of graft loss but not with a higher mortality (10). The above patient and review of the literature suggest that CMV nephritis can be a significant cause of AKI in kidney transplant recipients with CMV viremia. Aggressive treatment of the CMV disease with antiviral medication and appropriate reduction in immunosuppression can improve kidney function. Further, studies are needed to determine the risk factors, management, and long-term outcomes in kidney allograft recipients with CMV nephritis.
F. Aziz reports employment with the University of Wisconsin. A. Djamali reports employment with the University of Wisconsin School of Medicine and Public Health; consultancy agreements with CareDx and CSL; receiving research funding with CareDx and Takeda; receiving honoraria from CareDx and CSL; and serving as a scientific advisor or member of CareDx and CSL.
For most American Society of Nephrology (ASN) Kidney Week attendees, case-based clinical nephrology talks are one of the most exciting venues. The Nephrology Quiz and Questionnaire is the essence of clinical nephrology and represents what drew all of us into the field of nephrology. The expert discussants prepared vignettes of puzzling cases, which illustrated some topical, challenging, or controversial aspect of the diagnosis or management of key clinical areas of nephrology. These cases were presented and eloquently discussed by our four expert ASN faculty. Subsequently, each discussant prepared a manuscript summarizing his or her case discussions, which serves as the main text of this article (Mark A. Perazella and Ashita Tolwani, comoderators).
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