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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2013  |  Volume : 24  |  Issue : 1  |  Page : 80-85
Cytomegalovirus disease in a renal transplant recipient: the importance of pre-transplant screening of the donor and recipient


1 Nephrology Division, Department of Medicine, Medical School, King Saud University, Riyadh, Saudi Arabia
2 Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia

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Date of Web Publication22-Jan-2013
 

   Abstract 

A 16-year-old female patient who was born with a single kidney developed chronic kidney disease during her early childhood due to reflux nephropathy and recurrent urinary tract infection. She progressed to end-stage renal disease (ESRD) and was commenced on renal replacement therapy in the form of peritoneal dialysis in May 2011. Subsequently, she underwent living unrelated donor kidney transplantation in China. She was hospitalized soon after returning to Saudi Arabia for management of high-grade fever, shortness of breath, and deterioration of renal function, which was found to be due to cytomegalovirus (CMV) disease, proved by kidney biopsy and presence of high level of anti-CMV immunoglobulins. Allograft biopsy showed mature viral particles sized between 120 and 149 nm in the nuclei of the glomerular endothelial cells. The patient was treated with valgancyclovir and specific CMV immunoglobulin, as well as by reducing and even stopping the dose of tacrolimus and mycophenolate. Despite all these measures, her condition continued to deteriorate and she finally died. Our study emphasizes that unrelated renal transplantation, especially if unplanned and improperly prepared, is a very risky procedure that might transfer dangerous diseases and increase the morbidity and mortality of the patients. We strongly stress the need for mandatory and proper screening for CMV carrier status among donors as well as recipients prior to transplantation. Also, a recommendation is made to reject CMV-positive donors.

How to cite this article:
Mitwalli AH, Nazmi A, Al Ghonaim M, Shaheen F, Kfoury H. Cytomegalovirus disease in a renal transplant recipient: the importance of pre-transplant screening of the donor and recipient. Saudi J Kidney Dis Transpl 2013;24:80-5

How to cite this URL:
Mitwalli AH, Nazmi A, Al Ghonaim M, Shaheen F, Kfoury H. Cytomegalovirus disease in a renal transplant recipient: the importance of pre-transplant screening of the donor and recipient. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Jun 5];24:80-5. Available from: http://www.sjkdt.org/text.asp?2013/24/1/80/106250

   Introduction Top


Viral infections remain a major problem in the management of renal transplant recipients. [1],[2] Of them, cytomegalovirus (CMV) is a significant cause of morbidity and mortality. Detection of the virus defines CMV infection, while presence of signs and symptoms indicates CMV disease. [3] CMV can be transmitted from the donor to the recipient through the transplanted kidney, and immunosuppressive drugs increase the risk of CMV disease. [4],[5] Initial infection results in features such as fever, pneumonitis, enterocolitis, nephritis, and hepatitis, [6],[7] as well as acute and chronic rejection and even death. [8] The diagnosis of CMV is confirmed on allograft biopsy by the presence of viral inclusion bodies. Infection with CMV adversely affects the outcome of renal transplantation, [9] and valganciclovir and ganciclovir as well as hyperimmune globulin are used for the prevention and treatment of CMV infection. [10] Immunosuppressive drugs may have to be stopped so as to help eradicate the virus.

Here we report a patient who developed severe and fatal CMV disease after renal transplantation even though she was put on prophylaxis with valganciclovir. An attempt is made to highlight the mode(s) of transmission of the infection.


   Case Report Top


A 16-year-old female patient was born with a single kidney and had delayed speech and walking. She was diagnosed to have chronic kidney disease early in her childhood secondary to reflux nephropathy and recurrent urinary tract infections. She progressed to end-stage kidney disease and was commenced on renal replacement therapy in the form of peritoneal dialysis in May 2011.

Six months later, she underwent living unrelated donor kidney transplantation in China. No details were available about the surgery, donor status, laboratory work-up, cytomegalovirus (CMV) antibodies, human immunodeficiency virus (HIV) status, or human leukocyte antigen (HLA) match. The native kidney of the patient was not removed during the surgery. After transplantation, she was started on tacrolimus 3 mg every 12 h, mycophenolate mofetil (MMF) 1000 mg every 12 h, prednisolone 30 mg daily, prophylactic trimethoprim-sulfamethoxazole (TMP-SMX), and valgancyclovir. Her serum creatinine (SCr) level soon after transplantation was around 90 umol/L.

Four weeks later, she developed urinary tract infection which was treated with ciprofloxacin. Urine culture grew gram-negative bacilli, which were identified later as Pseudomonas species. Three weeks after this episode, she presented with fever and upper respiratory tract infection. Physical examination was normal except for congested throat. Laboratory investigations including complete blood count (CBC) and cultures from blood, urine, and sputum were done, apart from a chest X-ray (CXR). Investigations revealed elevated SCr of 180 umol/L, but all the other investigations were within acceptable limits. CXR was also normal. A graft biopsy was not performed as the patient and her parents refused the procedure. She was started on pulse methylprednisolone 250 mg intravenously (i.v.) for three days, along with broad-spectrum antibiotics, pending the availability of the culture results. A technetium-99m diethylene-triamine-penta-acetic acid (DTPA) scan was performed and was reported as suggestive of acute tubular necrosis; there was no evidence of rejection. After the completion of five days of i.v. antibiotics, she was placed on oral antibiotics and sent home. The SCr at discharge had come down to140 umol/L and she was not febrile.

However, on 20/02/2012, within 24 hours of discharge, she developed high fever and was readmitted to the hospital, and blood and urine samples were again sent for culture. Additionally, quantitative CMV assay by polymerase chain reaction (PCR) test, HIV, and other viral workup were done, following which she was started on another course of antibiotics in the form of meropenem, and single daily dose of i.v. amikacin (for three days), i.v. ganciclovir, and i.v. fluconazole, along with nystatin swish and swallow. All antimicrobials were dosed according to her estimated glomerular filtration rate (GFR). Cultures grew multi-drug resistant  Escherichia More Details coli from blood and urine, which was sensitive only to meropenem. The dose of tacrolimus and MMF was decreased gradually over three days. The dose of prednisolone was decreased to 10 mg per day.

An allograft biopsy was performed the following day which showed, on a preliminary report, no evidence of rejection but incidentally showed intra-cytoplasmic inclusion bodies suggestive of viral tissue invasion. Four days later, a full report showed the following: the sample had 53 glomeruli and five arteries. Sixteen glomeruli were globally sclerosed and six were segmentally sclerosed (NOS lesion). There was mild mesangial matrix expansion in few glomeruli. Enlarged endothelial cells were seen in the glomerular capillary loops, having eosinophilic nuclear inclusions with surrounding halo and red or amphophilic granular inclusions in the cytoplasm. Few enlarged cells showed smudged nuclei and hyperchromasia [Figure 1]. A Cowdry type A intranuclear inclusion body was also seen. These changes were observed in approximately 10% of the glomerular capillaries. There was no evidence of mononuclear leukocyte glomerular infiltrate (g-0) or double contour formation (cg-0). Viral changes were noted only in few tubular cells. There was no evidence of significant tubulitis (t-0) or interstitial inflammatory infiltrate (i-0) (ti-0). Occasional tubules showed few intraluminal inflammatory cells. Focal interstitial micro-calcifications were also noted. Approximately 15% of the tissue showed interstitial fibrosis and tubular atrophy (ct-1, ci-1) as evident on the trichrome stain. Mild intimal fibrosis of the arteries was noted (cv-1); however, there was no PAS-positive arteriolar hyaline thickening (ah-0). Also, no evidence of arteritis was noted (v-0). Peritubular capillaritis was not seen (ptc-0). The Congo red stain was negative as well. The CMV immunostaining highlighted the infected cells in the glomerular tufts [Figure 2]. The C4d immunostaining was negative (C4d-0). Immunostaining for polyoma virus was also negative.
Figure 1: Light microscopy showing glomerular endothelial cells with enlarged cytoplasm and intracytoplasmic inclusions. No interstitial inflammation was noted.

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Figure 2: Immunostaining highlighting the cytomegalovirus in the glomerular endothelial cells.

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Immunofluorescence microscopy showed four glomeruli. One glomerulus was globally sclerosed. There was diffuse mesangial positivity for IgA (2+), kappa (1+), and lambda (2+), and focal mesangial positivity for IgM (1+). Tubules contained reabsorbed proteins (albumin, IgG, C3) in the form of reabsorbed droplets. The interstitium revealed scattered fibrin deposition. Arterioles showed focal C3 reactivity.

Electron microscopy showed 10 glomeruli. None of the glomeruli showed sclerosis. There was focal fusion of the epithelial cell foot process with increased intracytoplasmic vacuolations. Glomerular endothelial cells showed focal loss of fenestrations. A number of electron-dense deposits were seen in the mesangial and para-mesangial areas. Mature viral particles sized approximately 120-149 nm were found in the nuclei of the glomerular endothelial cells, consistent with CMV [Figure 3].
Figure 3: Electron photomicrograph showing the intranuclear virions of 140 nm (uranyl acetate, lead citrate ×8000).

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Once the biopsy report was available, the dose of ganciclovir was adjusted according to her estimated GFR. A computed tomography (CT) of the chest was done which showed bilateral symmetrical ground glass haziness with mild septal thickening. No features of Pneumocystis jiroveci (carinii) pneumonia (PCP) were found. No pleural effusion or lymphadenopathy was seen.

At this time, the white blood cell (WBC) count was 1900/mm 3 , hemoglobin (Hb) 7.1 gm/dL, platelet count 96,000/mm 3 , blood urea 13 mmol/L, SCr 161 umol/L, sodium 139 mmol/L, potassium 5.4 mmol/L, chloride 108 mmol/L, and bicarbonate was 18 mmol/L. She was started on granulocyte colony stimulating factor (G-CSF) and MMF was stopped.

Despite the treatment, the patient's condition progressively worsened and she remained febrile. She continued to feel unwell with lethargy, poor appetite, and abdominal pain. A repeat CT scan of the chest, abdomen, and pelvis was performed without contrast, which showed no evidence of intra-abdominal or pelvic collection, as well as normal chest findings. No stent was seen in the transplanted kidney. The other organs were normal. The WBC count was 9600/mm 3 , Hb 7 gm/dL, platelet count 77,000/mm 3 , lactate dehydrogenase (LDH) 1178 IU, prothrombin time (PT) 15 sec, activated partial thromboplastin time (APTT) 30 sec, and the INR was 1.1. The peripheral blood film showed normal red blood cells and there were no schistocytes.

She continued to feel unwell and complained of mild abdominal pain. Ultrasonography (US) of the transplanted kidney was performed which showed no evidence of collection or obstruction. She also had mild shortness of breath along with cough, and a CXR showed small areas of airspace disease bilaterally. Her oxygen saturation was maintained at 93% with 2 L/min oxygen delivered through a nasal cannula.

The CMV PCR report became available on 25/02/2012 and was reported as 1,000,000 copies per mL. Tissue-invasive CMV infection was considered and her immunosuppression was tapered down to minimum. The dose of tacrolimus was decreased to 0.5 mg daily, along with prednisone (5 mg daily). The dose of TMP-SMX was increased. Despite this, she continued to have shortness of breath and cough. She was started on azithromycin to cover the possibility of mycoplasma pneumonia. Her kidney function worsened with SCr rising to 235 umol/L. Her platelets dropped further to 55,000/mm 3 .

She was started on furosemide i.v. The first dose of i.v. immunoglobulin (IVIG) was given on 25/02/2012. However, the response was not satisfactory. She was then transferred to the intensive care unit for observation. High flow oxygen was provided with non-rebreather mask. Two units of packed red blood cells (RBCs) were transfused and the dose of furosemide was increased. The tacrolimus was stopped completely on 26/02/2012.

She received three doses of CMV-specific immunoglobulin infusions starting on 27/02/2012. The SCr had risen to 304 umol/L, platelet count had dropped further to 41,000/mm 3 , LDH was 2563, and peripheral blood film showed schistocytes. In view of these laboratory findings, on 28/02/2012, the patient was administered four sessions of 1.8 L plasma exchange with fresh frozen plasma for the possibility of thrombotic thrombocytopenic purpura (TTP). The IVIG infusions were continued.

Despite all these, her condition progressively worsened and she was started on mechanical ventilation after elective intubation using a 6-French endotracheal tube. Her blood pressure dropped to 74/48 mmHg and dopamine infusion was started, but with no significant improvement. On 05/03/2012, she had a cardiac arrest from which she could not be resuscitated and was declared dead.


   Discussion Top


Symptomatic CMV infections typically occur one to four months after transplantation. Symptoms include fever, malaise, myalgia, and arthralgia, and are usually associated with leukopenia and mild atypical lymphocytosis. A mild elevation in serum aminotransferase concentrations also may be seen. Some of the patients with CMV disease can develop marked leukopenia.

Our case highlights the rapid deterioration associated with CMV disease in renal transplant recipients. These patients are often refractory to treatment and can have a fatal outcome. The point of interest in our patient is that CMV disease was seen within three months of undergoing living unrelated donor transplantation abroad even though she was on prophylaxis with valganciclovir. This highlights two major points: firstly, since the patient underwent unrelated donor transplantation abroad, details regarding the donor including the laboratory investigations were not available, a situation seen commonly in patients who have unrelated transplants outside Saudi Arabia. It is eminently possible that the donor might have been a carrier of CMV and the same was transmitted to the recipient through the transplanted kidney. Proper evaluation of the donor is mandatory to avoid such unfortunate occurrences. Thus, apart from the ethical issues, even medical factors, as seen in our patient, indicate that transplants at such centers should be strongly discouraged. Secondly, pre-transplant records of the patient also were not available, and thus it is not known whether screening for CMV carrier status was carried out in the donor as well as in the patient. This serves as another reminder that proper screening before transplantation is of utmost importance. Also, we suggest that renal transplantation with a CMV-positive donor must be discouraged in order to improve the outcome of renal transplantation.

Once diagnosed, the therapy of CMV disease varies with the severity of the clinical manifestations and often involves a reduction in the overall level of immunotherapy with or without antiviral therapy. We usually do not discontinue cyclosporine or tacrolimus unless there is evidence of life-threatening infection. The discontinuation of the anti-metabolites, azathioprine, or MMF is helpful for virus eradication when valganciclovir is used for treatment of CMV disease.

Patients with invasive disease should be treated with i.v. ganciclovir. Weekly quantitative PCRs should be obtained during treatment to determine an adequate response. If the quantitative PCR level does not decrease by 50% in two weeks, viral resistance or recipient immune incompetence should be suspected. In this setting, the dose of valganciclovir should be increased or if they are on oral therapy, the patient has to be switched to i.v. ganciclovir to overcome relative resistance.

In conclusion, our case reinforces the need for banning commercial donor transplantations. Before transplantation, proper screening of the donor and recipient for all transmittable diseases should be made mandatory.

 
   References Top

1.Smith SR, Butterfly DW, Alexander BD, Greenberg A. Viral infections after renal transplantation. Am J Kidney Dis 2001;37:659-76.  Back to cited text no. 1
    
2.Kotton CN, Fishman JA. Viral Infection in the renal transplant recipient. J Am Soc Nephrol 2005;16:1758-74.  Back to cited text no. 2
    
3.Brennan DC. Cytomegalovirus in renal transplantation. J Am Soc Nephrol 2001;12: 848-55.  Back to cited text no. 3
    
4.Song AT, Abdala E, Bonazzi PR, Bacchella T, Machado MC. Does mycophenolate mofetil increase the risks of cytomegalovirus infection in solid organ transplant recipients? -A mini-review. Braz J Infect Dis 2006;10:2.  Back to cited text no. 4
    
5.Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. AM J Transplant 2005;5:218-27.  Back to cited text no. 5
    
6.Fishman JA, Rubin RH, Infection in organ transplant recipients. N Engl J Med 1998;338:1741-51.   Back to cited text no. 6
    
7.Schnitzler MA, Lowell JA, Hardinger KL, Boxerman SB, Bailey TC, Brennan DC. The association of cytomegalovirus sero-pairing with outcomes and costs following cadaveric renal transplantation prior to the introduction of oral ganciclovir CMV prophylaxis. Am J Transplant 2003;3:445-51.  Back to cited text no. 7
    
8.Kletzmayr J, Kotzmann H, Popow-Kraupp T, Kovarik J, Klauser R. Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (CMV) disease in CMV high-risk renal transplant recipients. J Am Soc Nephrol 1996;7: 325-30.  Back to cited text no. 8
    
9.Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004;66:329-37.  Back to cited text no. 9
    
10.Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalo-virus disease and early death in recipients of solid-organ transplants: A systematic review of randomized controlled trials. Lancet 2005;365: 2105-15.  Back to cited text no. 10
    

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Correspondence Address:
Ahmed H Mitwalli
Consultant Nephrologist, Nephrology Unit, Department of Medicine (38), King Saud University, P. O. Box 2455, Riyadh 11451
Saudi Arabia
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DOI: 10.4103/1319-2442.106250

PMID: 23354197

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