| Abstract|| |
Tuberculosis (TB) in renal transplant recipients presents important diagnostic difficulties because of the greater incidence of extra-pulmonary involvement, negative sputum smear results despite active disease and its atypical presentation, specifically reactivation of the latent form. BKV nephropathy was first reported in 1995, coinciding with the widespread use of immunosuppressive drugs, which can complicate the cores of 1-10% of renal transplant recipients. It is also not uncommon to find the existence of bacterial or fungal infections in the presence of an immuno-modulating virus like cytomegalovirus infection. Herewith, we describe a 67-year-old Saudi male who presented with deterioration of renal function and fever of unknown origin and was documented to have polyoma virus nephropathy and disseminated TB. To the best of our knowledge, this is the first report of such an association in the literature.
|How to cite this article:|
Al-Warthan S, Al-Hwiesh A. Co-existence of BKV nephropathy and disseminated tuberculosis ain transplant recipient. Saudi J Kidney Dis Transpl 2014;25:1046-50
|How to cite this URL:|
Al-Warthan S, Al-Hwiesh A. Co-existence of BKV nephropathy and disseminated tuberculosis ain transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 May 31];25:1046-50. Available from: http://www.sjkdt.org/text.asp?2014/25/5/1046/139936
| Introduction|| |
Despite the success of solid organ transplantation, particularly renal transplantation, the incidence of infections has markedly increased over years.  These infections can vary from simple bacterial urinary tract infection to deep-seated complicated fungal infections with poor outcome. Sometimes, the transplant patient may develop multiple infections with various organisms.  It is also not uncommon to find the existence of bacterial or fungal infections in the presence of immunomodulating viruses, like cytomegalovirus (CMV) infection.  Such combined infections have been documented to be co-existing with polyoma virus (BKV) as well.  We describe herewith a 67-year-old Saudi male who presented with deterioration of renal function and fever of unknown origin and was documented to have polyoma virus nephropathy and disseminated tuberculosis (TB). To the best of our knowledge, this is the first report of such an association in the literature.
| Case Report|| |
This 67-year-old Saudi male, known to have end-stage renal failure secondary to diabetes mellitus and hypertension of six years duration, was maintained on hemodialysis three times weekly through a left arterio-venous fistula (AVF). He underwent a living unrelated donor kidney transplantation in the Philippines nine months prior to the current presentation. The post-renal transplant course was uneventful. He received induction with anti-lymphocyte globulin for five days and was started on triple-drug immunosuppressive therapy including cyclosporine (CsA) 200 mg every 12 h, mycophenolate mofetil (MMF) 1 g every 12 h and pulse steroids. He was discharged on the following medication: MMF 1 g every 12 h, CsA 150 mg every 12 h, prednisolone 40 mg once daily, amlodipine 10 mg once daily, lipitor 10 mg once daily, septran double strength one tablet thrice weekly and valgancyclovir 900 mg once daily. At discharge, his condition was stable with baseline serum creatinine of 1 mg/dL and blood urea nitrogen of 22 mg/dL. Allograft biopsy was not performed. The patient's CMV status and his HLA matching with donor were not known.
Two months following the transplantation, he presented with fever and tender subcutaneous nodules involving both thighs and deltoid muscles. Blood cultures as well as cultures from the aspirate from the subcutaneous nodules revealed Salmonella enteritidis for which he received intravenous (i.v.) ceftria-xone for two weeks with complete recovery. Three months later, he presented with fever of unknown origin of three weeks duration. Complete blood count, renal function tests, liver function tests, repeated blood cultures, urina-lysis and culture were all negative. Chest X-ray, abdominal ultrasound and computerized tomography (CT) scan of the chest and abdomen were within normal limits. Salmonella antibody titers (Vi, H and O) were negative; Brucella and amoeba titers as well as malaria smear were all negative. He received ceftrioxone 1 g every 12 h and levofloxacin 500 mg every 24 h in addition to ganciclovir i.v., given empirically, for two weeks. Viral studies that included hepatitis A, B, C and human immunodeficiency virus (HIV) were all negative. CMV IgG and EBV IgG were both positive. After being in the hospital for four weeks, he was discharged on CsA, MMF, prednisolone, valganciclovir and septran DS.
Four weeks after discharge, he was again admitted with high-grade fever up to 39.5°C with chills and rigors. On general examination, he looked ill with blood pressure of 110/60 mm Hg, pulse rate of 110/min and respiratory rate of 24/min. There was no lymphadenopathy. Systemic examination revealed a few fine crepitations in both lung bases with no tenderness or bruit in the renal allograft.
Initial investigations showed the following: Hemoglobin (Hb) level of 9 g/dL, white blood cell (WBC) count of 14 × 10/L with predominant neutrophils and platelet count of 150,000/mm 3 . The erythrocyte sedimentation rate (ESR) was 120 mm/h. Routine urinalysis and culture was negative. Early morning urine samples performed on three consecutive days were negative for AFB smear and culture. Serum electrolytes were normal and the anion gap was 13 mmol/L. Blood urea nitrogen was 44 mg/dL, serum creatinine was 2.5 mg/dL, phosphate was 3 mg/dL, calcium was 8.7 mg/ dL and fasting serum glucose was 250 mg/dL. Serum alkaline phosphatase was 350 U/L, serum glutamate pyruvate transaminase (SGPT) was 100 U/L (normal, 7-40), serum glutamate oxaloacetate transaminase (SGOT) was 90 U/L (normal, 5-35), gamma glutamate transpeptidase (GGTP) was 600 U/L (normal, 5-85) and lactate dehydrogenase (LDH) was 400 U/L (normal, 100-200). Serum and urine protein electrophoresis were within the normal range. Chest X-ray showed bilateral infiltration in the lower lung zones. Sputum AFB stain and cultures were positive. Liver biopsy showed epithelioid granulomatous hepatitis consistent with TB [Figure 1]. The patient was started on four-drug anti-TB therapy. In view of persistent renal dysfunction, an allograft biopsy was performed and histopathological examination was consistent with polyomavirus tubulo-interstitial nephritis superimposed on chronic allograft rejection [Figure 2]a and b. Serum and urine polymerase chain reaction (PCR) for polyoma was positive. Urine cytology showed urothelial cells, some containing intranuclear inclusion bodies (decoy cells) [Figure 3].
|Figure 1: Photomicrograph showing epitheloid granuloma and Langerhans giant cell (arrow) in the liver parenchyma (H&E ×100).|
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|Figure 2: Photomicrograph showing (a) intranuclear inclusions within the renal tubular epithelial cells (arrow) with dense interstitial lymphomononuclear infiltrate (H&E ×200). (b) Intranuclear inclusions surrounded by dense chromatin material (H&E ×400).|
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|Figure 3: Urine cytology showing (a) nuclear nomogenization and (b) intranuclear inclusions (Decoy cell) (H&E ×400).|
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Immunosuppressive therapy was modified with discontinuation of MMF and tapering of dosage and subsequent discontinuation of CsA and prednisolone. The patient's allograft function gradually deteriorated and he was stared on hemodialysis. Because he repeatedly developed blood-line-induced sepsis, he was shifted to automated peritoneal dialysis (PD). Upon PD catheter insertion, analysis of the peritoneal fluid was consistent with TB and the fluid cultures grew AFB. He was continued on anti-tuberculous therapy with a low dose of steroids. His overall condition improved and he was discharged in a stable state; he was readmitted six weeks later with extensive antero-lateral wall myocardial infarction and acute pulmonary edema. Ten days later, he succumbed to cardiac complications. No autopsy was performed.
| Discussion|| |
Our patient, a 67-year-old Saudi male, who had undergone unrelated renal transplantation, presented with recurrent prolonged fever posing a diagnostic problem each time. He had multiple infections including non-typhoid salmonella infection, TB and polyoma virus.
BK polyoma virus (BKV) belongs to the Papovaviridae virus family, which are ubiquitous small DNA viruses and which, along with the JC virus (corresponding to initials of infected patients), share homology with murine virus SV40, first reported by Kilham in 1952.  BKV nephropathy (BKVN) was first reported in 1995, coinciding with the widespread use of immunosuppressive drugs, and can complicate the cores of 1-10% of renal transplant reci-pients.  Historically, up to 50% of patients who develop BKVN have lost their renal allo-graft, like what happened in our case. Nephropathy occurs without any overt signs or symptoms except increasing serum creatinine concentrations. Sometimes, BKV infection may only manifest with asymptomatic hematuria associated with hemorrhagic cystis or ureteral stenosis due to tropism of this virus for the genitourinary epithelium. 
In cases of BKVN, active replication of the virus in the transplanted kidney leads to viruria and viremia, particularly in the presence of risk factors including old age, male gender, ureteral trauma, diabetes mellitus, white ethnicity and HLA-mismatch with the donor and/or absence of human leukocyte antigen C7 in the donor.  Immunosuppression plays an important role in the increased incidence of BKVN. It has been suggested that tacrolimus alone, or in combination with MMF, is more often associated with BKVN,  although this observation has not been proven in other studies. 
Early diagnosis of BKV infection is very important. Demonstration of "decoy cells" in the urine, as was seen in our case, is very sensitive but is non-specific, with a low positive-predictive value.  A number of non-invasive diagnostic techniques have been employed for detecting BK viremia, including viral cultures, serum BK IgG titers, quantitative PCR for BKV DNA in blood and, less often, in urine and other molecular tests.  Prognostication of renal allograft function after BKVN diagnosis is now feasible by measurement of transcripts for BKV viral capsid protein 1 (VP-1), GB and PI-9 in urine, as described recently.  The gold standard for diagnosing BKVN is renal biopsy, which shows cytopathic effect and viral inclusions with positive immunohistochemical staining directed against a cross-reactive SV40 large T antigen, as seen in our patient. ,,
Therapeutic recommendations for BK-induced nephropathy are largely based upon anecdotal cases and small series. Because specific antiviral therapy does not currently exist, the cornerstone of therapy is to decrease immuno-suppressive medications. However, antiviral therapy should be considered in those with progressive allograft dysfunction despite a decrease in immunosuppressive therapy.
A pre-emptive strategy based upon the idea that periodic monitoring of BKV-PCR allows the detection of early systemic infection has been recommended. All renal transplant patients should undergo screening every three months, for up to two years post-transplant and/or when renal allograft dysfunction occurs.  Re-transplantation in a patient who lost the graft due to BKVN is possible provided there is no evidence of BKV replication; the post-transplantation immunosuppression and graft outcome are same as in primary graft recipients. 
The second coexisting infection in this patient was disseminated TB. The prevalence of TB among renal transplant recipients in the Indian subcontinent (India and Pakistan) is 13.0%, in the Far East (China, Thailand, and Taiwan) it is 2.0% and among western European and North American populations it ranges from 0.07-1.7%.  TB remains a leading cause of death in endemic countries, and is 20-70-times more common in renal transplant recipients. The major risk factors for TB in a large prospective analysis in an Indian study were chronic liver disease (two-times increased risk), age, other co-existing infections, particularly deep mycoses, pneumocystis pneumonia and nocardia (1.6-times), OKT3 usage (1.8-times) and CMV infections (2.25-times).  Disseminated disease, seen in our patient, may also be more common with the use of OKT3 and in the presence of CMV infection.
The diagnosis of latent TB infection is problematic. Also, the treatment of TB in transplant recipients has its own challenges, which include pharmacokinetic interactions between immunosuppressive and antituberculous medications, allograft-related drug toxicities and inadequate immune responses to Mycobacte-rium tuberculosis due to exogenous immuno-suppression. 
Although a case of BKVN has been reported earlier from Saudi Arabia,  its occurrence with disseminated TB, as seen in our patient, is first of its kind. No such association was found on a Medline search, although the authors did come across other associations with BKV infection such as CMV infection  and histoplasmosis.  It is a matter of conjecture whether there is a cause and effect relationship between these two infections or whether it is a chance association. Because this patient had the transplantation performed outside the country, we cannot be sure whether the unrelated donor was having TB and transmitted this infection through the donor kidney.
Interestingly, our patient presented initially with recurring prolonged fever, which, in the beginning, was likely to be due to infection with Salmonella enteritidis. This organism can also have varied presentations in renal transplant recipients.  These could include fever, leukopenia, pneumonia, diarrhea, abscesses, venous thrombosis, pleural effusion, pyelonephritis and even acute renal failure. Salmonella infections require vigorous treatment, often with a long-term, low-dose regimen. Fortunately, our patient responded to two-week therapy with broad-spectrum antibiotics.
| Conclusions|| |
- Multiple infections can complicate the course of renal transplant recipients.
- BKVN presents with tubulo-interstitial nephritis and is a common cause of graft failure in these patients.
- Reduction of immunosuppression is the main treatment of BKVN, but care should be taken to distinguish it from acute rejection.
- TB is not uncommon after renal transplantation in developing countries. Cooccurrence of BKVN and disseminated TB is interesting, and is the first such report from Saudi Arabia.
- Salmonella enteritidis infection can also rarely occur in renal transplant recipients, and presents with sepsis and other complications.
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Dr. Abdullah Al-Hwiesh
Department of Internal Medicine, King Fahd Hospital of the University, Al-Khobar
[Figure 1], [Figure 2], [Figure 3]