Screening for BK virus nephropathy in kidney transplant recipients: comparison of diagnostic tests

Abstract

Urine cytology and qPCR in blood and urine are commonly used to screen renal transplant recipients for polyomavirus-associated nephropathy (PVAN). Few studies, however, have directly compared these two diagnostic tests, in terms of their performance to predict PVAN. This was a systematic review in which adult (≥ 18 years old) renal transplant recipients were studied. A structured Pubmed search was used to identify studies comparing urine cytology and/or qPCR in urine and plasma samples for detecting PVAN with renal biopsy as the gold standard for diagnosis. From 707 potential papers, there were only twelve articles that matched the inclusion criteria and were analyzed in detail. Among 1694 renal transplant recipients that were included in the review, there were 115 (6.8%) patients with presumptive PVAN and 57 (3.4%) PVAN confirmed. In this systematic review, the qPCR in plasma had better performance for PVAN compared to urine cytopathology.

Keywords:
biopsy; BK virus; cell biology; DNA; kidney transplantation

Resumo

A citologia urinária e a reação da cadeia da polimerase em tempo real (qPCR) em amostras de sangue e/ou urina são comumente utilizados para rastrear nefropatia associada ao polyomavirus (PVAN), em pacientes transplantados renais. Entretanto, poucos estudos comparam diretamente esses testes diagnósticos quanto ao desempenho para predizer esta complicação. Aqui realizamos uma revisão sistemática na qual foram estudados pacientes transplantados renais adultos (≥ 18 anos). Uma pesquisa estruturada Pubmed foi utilizada para identificar estudos comparando citologia urinária e/ou qPCR em amostras de urina e plasma para detectar PVAN, utilizando a biópsia renal como padrão-ouro para o diagnóstico. Dentre os 707 artigos em potencial, apenas 12 atendiam aos critérios de inclusão e foram analisados em maior detalhe. Foram incluídos 1694 pacientes transplantados renais, entre os quais 115 (6,8%) classificados com PVAN presuntivo e 57 (3,4%) PVAN confirmado. Nessa revisão sistemática, o qPCR no plasma tive melhor desempenho para PVAN em comparação com citopatologia urinária.

Palavras-chave:
biologia celular; biópsia; DNA; transplante de rim; vírus BK

Introduction

Kidney transplantation is the treatment of choice for many end-stage renal diseases that would otherwise require dialysis and renal replacement therapy.¹ One of the main threats for graft survival is infection caused by the polyomavirus BK (BKV). The prevalence of clinically significant BKV reactivation after kidney transplantation varies, depending on the study, from 1 to 10% and the incidence of allograft loss due to BKV have ranged from as low as 10% to more than 80% of patients with clinically significant BKV infection.² Rapid and sensitive detection of BKV infection, either in urine or plasma, can lead to early management strategy that is critical to prevent irreversible kidney damage and loss.

The diagnosis of BKV nephropathy requires allograft biopsy,³ however, it may be too late to reverse the damage. Studies have shown that cytological abnormalities ('decoy cells') and polyomavirus DNA are detected in the urine several weeks before kidney damage occurs.^2,4 Decoy cells may be observed in the urinary sediment as a result of renal and urothelial cells infected by BKV.⁵ Despite being a relatively inexpensive test, the detection of decoy cells requires considerable expertise and these are not specific for BKV infection.^6,7 Detection and quantitation of BKV DNA can be performed using real time real time polymerase chain reaction (qPCR). While it is comparatively more expensive, in comparison to urine cytopathology, the BKV qPCR has the potential for higher test sensitivity, better linearity and independence from personal expertise for accurate results.

In this systematic review, we searched for studies that directly compared the analytical performance of urine cytopathology and qPCR, for predicting the diagnosis of BKV-associated nephropathy, as proven by histopathology.

Material and Methods

Criteria for considering studies for this review

We selected for inclusion in this review studies involving patients who had undergone kidney transplantation not combined with receipt of other transplanted organs.

Types of studies

Cross section, prevalence and cohort studies were included. Studies involving 10 or less patients were not included.

Types of participants

Adult (≥ 18 years old) renal transplant recipients were considered for study, regardless of sex, race, or nationality.

Types of interventions

Since biopsy is gold standard test for BKV nephropathy, we included only studies that compared biopsies with urine cytology and/or qPCR.

Types of outcome measures

The outcome measure was nephropathy caused by BKV, as confirmed by renal biopsy. Additional information such as BKV viral load in plasma and urine; presence of 'decoy cells' on urine cytopathology; use of SV40 antibody staining on biopsied tissue was investigated and associated with the outcome.

Search strategy

We searched PubMed electronic database using the strategy demonstrated in Table 1. The search was conducted on 14^th February 2014 and included all papers retrieved in the database.

Table 1
Search strategy used in the study (PubMed)

(humans)
AND
(((transplant) OR (graft survival[mh]) OR (“graft survival”) OR (graft rejection[mh]) OR (“graft rejection”))
AND
((kidney[mh]) OR (kidney) OR (“allograft loss”) OR (kidney disease[mh]) OR (“kidney disease”)))
AND
((molecular diagnostic techniques[mh]) OR (“molecular diagnostic techniques”) OR (molecular biology[mh]) OR
(“molecular biology”) OR (“molecular biology”) OR (PCR) OR (“polymerase chain reaction”) OR (“polymerase chain
reaction”) OR (polymerase chain reaction[mh) OR (cytological techniques[mh]) OR (“cytological techniques”) OR
(“decoy cells”) OR (papanicolaou) OR (biopsy) OR (viremia) OR (viruria) OR (“viral load”))
AND
((“BK virus”) OR (polyomavirus infection[mh]) OR (“polyomavirus infection”) OR (polyomavirus) OR (“BK nephropathy”))

Exclusion criteria

Papers that were not written in English and/or not conducted in humans were excluded. Since this study aimed for a comparison of diagnostic tests, we excluded review articles, case reports, studies involving patients younger than 18 years old, studies of patients submitted to transplant procedures other than renal transplantation (even when combined), drug intervention studies, studies in which biopsies were not performed to confirm nephropathy and studies that did not compare biopsies with at least one of the tests under study. Attempts were made to contact corresponding authors when articles were not available on Pubmed or when additional information was required. In the situations when a response was not received, the respective articles were excluded.

Studies included in the review and data synthesis

The flow-chart diagram in Figure 1 shows the total number of papers screened and number of manuscripts that met the inclusion criteria. Additional data were extracted from these studies.

Figure 1
Flow-chart of article screenned.

Ethical aspects

The study was approved by the Institutional Review Board (protocol numbers 3531/11 and 915/12).

Results

The systematic search initially identified 707 potential articles. However, a total of 12 articles were included in the final analyses. A total of 1694 renal transplant recipients were included in this review (Table 2). Using biopsy as gold standard there were 115 cases (6.8%) of presumptive nephropathy without observation of BKV and 57 cases (3.4%) of polyomavirus-associated nephropathy (PVAN). The range of sensitivity, specificity, PPV (positive predictive (PPV) value) and NPV (negative predictive (NPV) value) using qPCR as non-invasive test to detect and predict PVAN in plasma was 60-100%, 33-100%, 7-65% and 72-100% respectively (Table 3). The range of plasma viral load at the time of diagnosis was 2.7 - 7 log. The threshold of ≥ 3.7 log for PVAN provide specificity of 91% and positive predicted value (PPV) of 29%, whereas > 4.2 log enhanced the specificity to 96% and PPV to 50%. Sensitivity and NPV were 100% in both cases.⁸ In those studies where cytology test were performed (n = 506 patients), decoy cells were found in 30.6% (n = 155) of the patients. In comparison with qPCR, decoy cells showed better range on NPV (97-100%), while sensitivity, specificity and PPV were diminished (Table 4). In one study, the BKV replication indicated by decoy cell shedding in urine, BKV viremia (qPCR), and PVAN (histopathology) occurred in 29%, 13%, and 6% respectively, and the median time for detection was 3.7 months, 5.4 months and 6.5 months after transplant, respectively.² In all studies range time for the detection of viruria, decoy cell and viremia were 0.03-12 month, 0.5-16.1 month and 0.9-25 month after transplant respectively. The early (day 5) detection of BKV viruria may predict the occurrence of both BKV viremia and nephropathy.⁹ Also, the finding of two or more consecutively positive urine samples was shown to be a helpful tool to predict BKV viremia (sensitivity 100%; specificity 94%; positive and negative predictive values of 50% and 100%, respectively).¹⁰ It was demonstrated that 20% patients became viremic when BKV copies in the urine achieved 7 log /mL - a percentage that increased to 33%, 50% and 100% at 8 log, 9 log and ≥ 10 log, respectively.¹¹ Such an association has not been demonstrated for decoy cells.

Table 2
Prospective studies that compared qPCR, urine citology and kidney biopsy in the diagnosis of PVAN in kidney transplant receptors

Author	n	Decoy cells a	Viremia (n)	Viral Load (plasma)	Presumptive PVAN(n)b	PVAN + (n)
Hirsch et al. 2	78	23	10	4.4 - 7 log	5	5
Pang et al. 11	183	NA	44	Median 2.84 (0-5.86)	0	8
Thamboo et al. 28	97	15	4	3.3 - 5.4 log	7	3
Viscount et al. 8	204	26	16	> 3.7 log	12	4
Almerás et al. 24	123	NA	13	2.7 - 5.6 log	11	3
Babel et al. 10	233	NA	16	Mean 5.9 (range 4.3-7.5)c	10	6
Helanterä et al. 22	68	NA	0	NA	5	0
Girmanova et al.29	120	NA	6	> 4.5 log	3	3
Pollara et al. 16	75	39	26	2.8 - 6.5 log	19	7
Saundh et al. 9	112	NA	12	Mean 5.5 log(range, 3.6 - 6.5)	10	2
Knight et al. 21	349	NA	57	5.7 log (SD ± 5.9)	17	15
Menter et al. 23	52	52	17	> 7 log	16	1

• ^a
  Number of patients diagnosed with decoy cells on cytopathology;
• ^b
  Number of patients with diagnosis of nephropathy but with no visualization of BKV by SV40 or viral alterations characteristics;
• ^c
  Mean peak of viral load; NA: Not applicable; PVAN: Polyomavirus-associated nephropathy; sd: Standard deviation.

Table 3
Performance of BKV viremia detected by qPCR in the prediction of PVAN

Author	Molecular target	Primer or probe	Sequence (5'-3')	Sensitivity	Specificity	PPV	NPV
		Primer 1,	AGCAGGCAAGGG TTCTATTACTAAAT	100	88	50	100
		Primer 2,	GAAGCAACAGCA GATTCTCAACA
			AAGACCCTAAAGACTTT
Hirsch et al. 2	NI	Probe	CCCTCTGATCTACA CCAGTTT labeled with 6-carboxyfluorescein at the 5` end and
			6-carboxytetramethylrhodamine at the
			3` end
		BKpangF	ATGTGACCA ACACAGC	60	76	65	72
		BKpangR	CTG TGCCATCAAACACC
Pang et al.11	VP1 gene	BKpangP1	AGGAGAACCCAGA GAGTGGA-fluorescein
		BKpangP2	LC-Red 640-GGCAGCCTATGT ATGGTATGGAA-phosphate
			(5`-AGG TAG AAG AGG TTA GGG TGT
			TTG ATG GCA CAG-3`) dual-labeled at
Thamboo et al. 28	VP1 gene	NI	the 5` end with 6-carboxyfluorsecein (FAM) and the 3` end with	67	33	20	80
			6-carboxytetramethylrhodamine
			(TAMRA)
		Primer PoL1s,	CACTTTTGGGGGACCTAGT	100	96	50	100
Viscount et al.8	VP2 gene	Primer PoL2as, Probe 1,	CTCTACAGTAGCA AGGGATGC TCTGAGGCTGCTGCT
		PoLP1,	GCCACAGGATTTT-fluorescein
		Probe 2,	LC-Red 640-AGTAG CTGAAATTGCTG
		PoLP2,	CTGGAGAGGCTGCT-phosphate
		Primer PoL1s,	CACTTTTGGGGGACCTAGT	100	91	15	100
Almerás et al. 24	VP2 gene	Primer PoL2as, Probe 1, PoLP1,	CTCTACAGTAGCAAGGGATGC TCTGAGGCTGC TGCTGCCA CAGGATTTT-fluorescein
		Probe 2, PoLP2,	LC-Red 640-AGTAGCTG AAATTGCTGC TGGAGAGGCTGCT-phosphate
Babel et al. 10	VP1 gene	NI	NI	100	96	43	100
Girmanova et al. 29	Gene that encode large T Ag	Commercial kit	BKV Q-PCR Detection Alert Kit (Chemagen)	100	68	7	100
Pollara et al. 16	Gene that encode large T Ag	Commercial kit	BKV Q.Alert Kit (Nanogen Advanced Diagnostics, Italy)	95	100	NI	NI
Saundh et al. 9	Gene that encode large T Ag	BKV Forward BKV Reverse BKV Probe	TGA CTA AGA AAC TGG TGT AGA TCA YTCC TT TAAT GA AAA ATG GGA FAM AGT GTT GAG AAT CTG CTG TTG CTT C BHQ-1	100	91	17	100
Knight et al. 21	NI	NI	NI	100	87	26	100
		Primer 1,	AGCAGGCAAGGGTTCTATTACTAAAT	100	57	41	100
		Primer 2,	GAAGCAACAGCAGATTCTCAACA
Menter et al. 23	NI	Probe	AAGACCCTAAAGACTTTCCCTCTGAT CTACACCAGTTT labeled with 6-carboxyfluorescein at the 5` end and 6-carboxytetramethylrhodamine at the 3` end

• Ag: Antigen; BKV: BK vírus; NI: Not informed; NPV: Negative Predictive Value; PPV: Positive Predictive Value; PVAN: Polyomavirus-associated nephropathy.

Table 4
Performance of urine cytopathology in the prediction of PVAN

Author	Decoy cell (n)	PVAN (n)	Sensitivity	Specificity	PPV	NPV
Hirsch et al. 2	23	5	100	71	29	100
Thamboo et al. 28	15	3	67	85	20	98
Viscount et al. 8	26	4	25	85	5	97
Pollara et al. 16	39	7	100	53	18	100

• NPV: Negative Predictive Value; PPV: Positive Predictive Value; PVAN: Polyomavirus-associated nephropathy.

Discussion

This study shows the paucity of data in the literature regarding the comparison of the performance of qPCR (either blood or urine) and urine cytopathology for the diagnosis of PVAN. It seems clear that viruria (defined as detection of BKV DNA in the urine) precedes the detection of decoy cells on urinary cytology, which antecedes viremia and PVAN.² Detection of decoy cells and BKV viruria are important markers of BKV replication but poor predictors of PVAN.

The cut-off to determine the clinical relevance of BKV viremia remains controversial. The American Society of Transplantation (AST) recommends that in the presence of plasma loads > 4 log for three or more weeks the diagnosis PVAN should be presumed and biopsy should be considered for definitive diagnosis.¹² While the American Society of Transplantation and the Kidney Disease Improving Global Outcomes Group suggest a BK viral load of 4 log copies (10.000 copies) as a cut-off value for PVAN, there is no US Food and Drug Administration approved or standardizes methods for BK viral load evaluation. The diagnosis of BKV is currently based on different qPCR approaches, but since there is no standard method for BKV viral load assessment, it is essential that institutions implement clinical validation studies certifying their own methodology to be used as a guide for clinical treatment.^2,13-19

The definitive PVAN diagnosis is made histopathologically²⁰ in a context in which the viral infection may be difficult to differentiate from organ rejection. In our review, only four articles reported the use of SV40 staining in the histopathological test.^21-24 Therefore, the absence of a confirmatory test may underestimate the actual frequency of PVAN. The SV40 should be performed when clinicians suspect of BKV infection, despite the absence of visible alterations on the examined tissue.²⁵ The AST recommends a minimum of two core biopsies with medullary tissue preferable in an intention to decrease the false negative diagnosis of PVAN, which can be as high as 20-30% (12, 26). Therefore, a negative biopsy does not rule out PVAN.²⁶

Conclusion

This study demonstrates the paucity of data in the literature on the comparison of diagnostic tests for the prediction of PVAN. qPCR has an overall better diagnostic performance than urine cytopathology for the detection of PVAN. However, the cut-off for qPCR tests remain poorly defined. In contrast to cytomegalovirus (CMV), for which the World Health Organization has produced international standards,²⁷ there is a need for standardization for BKV-related tests. Additional prospective studies are ultimately required in order to elucidate the ideal cut-off for viral load in the plasma and urine, for the early diagnosis of PVAN, as well as the moment for occurrence of viremia, and co-factors associated with the transplant recipient.

• Funding: This study was funded by FAPERGS (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul), a Brazilian governmental research agency.

Acknowledgements

The different techniques limit the comparison between qPCR assays included, once there is no international standard for BKV quantification.

References

• ¹
  Hume DM, Merrill JP, Miller BF, Thorn GW. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest 1955;34:327-82. DOI: http://dx.doi.org/10.1172/JCI103085
  » http://dx.doi.org/10.1172/JCI103085
• ²
  Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002;347:488-96. PMID: 12181403 DOI: http://dx.doi.org/10.1056/NEJMoa020439
  » http://dx.doi.org/10.1056/NEJMoa020439
• ³
  Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79:1277-86. PMID: 15912088 DOI: http://dx.doi.org/10.1097/01.TP.0000156165.83160.09
  » http://dx.doi.org/10.1097/01.TP.0000156165.83160.09
• ⁴
  Brennan DC, Agha I, Bohl DL, Schnitzler MA, Hardinger KL, Lockwood M, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 2005;5:582-94. DOI: http://dx.doi.org/10.1111/j.1600-6143.2005.00742.x
  » http://dx.doi.org/10.1111/j.1600-6143.2005.00742.x
• ⁵
  Poloni JA, Pinto GG, Pasqualotto AC, Rotta LN. Decoy cells due to polyomavirus BK infection in the urine sediment of a patient with lupus nephritis. Lupus 2013;22:1547-8. DOI: http://dx.doi.org/10.1177/0961203313504635
  » http://dx.doi.org/10.1177/0961203313504635
• ⁶
  Kahan AV, Coleman DV, Koss LG. Activation of human polyomavirus infection-detection by cytologic technics. Am J Clin Pathol 1980;74:326-32. PMID: 6251715 DOI: http://dx.doi.org/10.1093/ajcp/74.3.326
  » http://dx.doi.org/10.1093/ajcp/74.3.326
• ⁷
  Traystman MD, Gupta PK, Shah KV, Reissig M, Cowles LT, Hillis WD, et al. Identification of viruses in the urine of renal transplant recipients by cytomorphology. Acta Cytol 1980;24:501-10.
• ⁸
  Viscount HB, Eid AJ, Espy MJ, Griffin MD, Thomsen KM, Harmsen WS, Razonable RR, et al. Polyomavirus polymerase chain reaction as a surrogate marker of polyomavirus-associated nephropathy. Transplantation 2007;84:340-5. PMID: 17700158 DOI: http://dx.doi.org/10.1097/01.tp.0000275205.41078.51
  » http://dx.doi.org/10.1097/01.tp.0000275205.41078.51
• ⁹
  Saundh BK, Baker R, Harris M, Welberry Smith MP, Cherukuri A, Hale A. Early BK polyomavirus (BKV) reactivation in donor kidney is a risk factor for development of BKV-associated nephropathy. J Infect Dis 2013;207:137-41. DOI: http://dx.doi.org/10.1093/infdis/jis642
  » http://dx.doi.org/10.1093/infdis/jis642
• ¹⁰
  Babel N, Fendt J, Karaivanov S, Bold G, Arnold S, Sefrin A, et al. Sustained BK viruria as an early marker for the development of BKV-associated nephropathy: analysis of 4128 urine and serum samples. Transplantation 2009;88:89-95. PMID: 19584686 DOI: http://dx.doi.org/10.1097/TP.0b013e3181aa8f62
  » http://dx.doi.org/10.1097/TP.0b013e3181aa8f62
• ¹¹
  Pang XL, Doucette K, LeBlanc B, Cockfield SM, Preiksaitis JK. Monitoring of polyomavirus BK virus viruria and viremia in renal allograft recipients by use of a quantitative real-time PCR assay: one-year prospective study. J Clin Microbiol 2007;45:3568-73. PMID: 17855578 DOI: http://dx.doi.org/10.1128/JCM.00655-07
  » http://dx.doi.org/10.1128/JCM.00655-07
• ¹²
  Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK virus in solid organ transplant recipients. Am J Transplant 2009:S136-46. PMID: 20070673 DOI: http://dx.doi.org/10.1111/j.1600-6143.2009.02904.x
  » http://dx.doi.org/10.1111/j.1600-6143.2009.02904.x
• ¹³
  Randhawa P, Kant J, Shapiro R, Tan H, Basu A, Luo C. Impact of genomic sequence variability on quantitative PCR assays for diagnosis of polyomavirus BK infection. J Clin Microbiol 2011;49:4072-6. DOI: http://dx.doi.org/10.1128/JCM.01230-11
  » http://dx.doi.org/10.1128/JCM.01230-11
• ¹⁴
  Hirsch HH, Drachenberg CB, Steiger J, Ramos E. Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management. Adv Exp Med Biol 2006;577:160-73. PMID: 16626034
• ¹⁵
  Bechert CJ, Schnadig VJ, Payne DA, Dong J. Monitoring of BK viral load in renal allograft recipients by real-time PCR assays. Am J Clin Pathol 2010;133:242-50. PMID: 20093233 DOI: http://dx.doi.org/10.1309/AJCP63VDFCKCRUUL
  » http://dx.doi.org/10.1309/AJCP63VDFCKCRUUL
• ¹⁶
  Pollara CP, Corbellini S, Chiappini S, Sandrini S, De Tomasi D, Bonfanti C, et al. Quantitative viral load measurement for BKV infection in renal transplant recipients as a predictive tool for BKVAN. New Microbiol 2011;34:165-71.
• ¹⁷
  Hassan S, Mittal C, Amer S, Khalid F, Patel A, Delbusto R, et al. Currently recommended BK virus (BKV) plasma viral load cutoff of = 4 log10/mL underestimates the diagnosis of BKV-associated nephropathy: a single transplant center experience. Transpl Infect Dis 2014;16:55-60. DOI: http://dx.doi.org/10.1111/tid.12164
  » http://dx.doi.org/10.1111/tid.12164
• ¹⁸
  Kudose S, Dong J. Clinical validation study of quantitative real-time PCR assay for detection and monitoring of BK virus nephropathy. Ann Clin Lab Sci 2014;44:455-60. PMID: 25361932
• ¹⁹
  Mitui M, Leos NK, Lacey D, Doern C, Rogers BB, Park JY. Development and validation of a quantitative real time PCR assay for BK virus. Mol Cell Probes 2013;27:230-6. DOI: http://dx.doi.org/10.1016/j.mcp.2013.08.001
  » http://dx.doi.org/10.1016/j.mcp.2013.08.001
• ²⁰
  Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8:753-60. DOI: http://dx.doi.org/10.1111/j.1600-6143.2008.02159.x
  » http://dx.doi.org/10.1111/j.1600-6143.2008.02159.x
• ²¹
  Knight RJ, Gaber LW, Patel SJ, DeVos JM, Moore LW, Gaber AO. Screening for BK viremia reduces but does not eliminate the risk of BK nephropathy: a single-center retrospective analysis. Transplantation 2013;95:949-54. DOI: http://dx.doi.org/10.1097/TP.0b013e31828423cd
  » http://dx.doi.org/10.1097/TP.0b013e31828423cd
• ²²
  Helanterä I, Ortiz F, Auvinen E, Räisänen-Sokolowski A, Lappalainen M, Lautenschlager I, et al. Polyomavirus BK and JC infections in well matched Finnish kidney transplant recipients. Transpl Int 2009;22:688-93. DOI: http://dx.doi.org/10.1111/j.1432-2277.2009.00847.x
  » http://dx.doi.org/10.1111/j.1432-2277.2009.00847.x
• ²³
  Menter T, Mayr M, Schaub S, Mihatsch MJ, Hirsch HH, Hopfer H. Pathology of resolving polyomavirus-associated nephropathy. Am J Transplant 2013;13:1474-83. DOI: http://dx.doi.org/10.1111/ajt.12218
  » http://dx.doi.org/10.1111/ajt.12218
• ²⁴
  Alméras C, Foulongne V, Garrigue V, Szwarc I, Vetromile F, Segondy M, et al. Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study. Transplantation 2008;85:1099-104. PMID: 18431228 DOI: http://dx.doi.org/10.1097/TP.0b013e31816a33d4
  » http://dx.doi.org/10.1097/TP.0b013e31816a33d4
• ²⁵
  Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2007;2:S36-46. DOI: http://dx.doi.org/10.2215/CJN.00920207
  » http://dx.doi.org/10.2215/CJN.00920207
• ²⁶
  Drachenberg CB, Papadimitriou JC, Hirsch HH, Wali R, Crowder C, Nogueira J, et al. Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transplant 2004;4:2082-92. DOI: http://dx.doi.org/10.1046/j.1600-6143.2004.00603.x
  » http://dx.doi.org/10.1046/j.1600-6143.2004.00603.x
• ²⁷
  NIBSC/Medicines and Healthcare Products Regulatory Agency/World Health Organization. WHO International Standard - 1st WHO International Standard for Human Cytomegalovirus for Nucleic Acid Amplification Techniques - NIBSC code: 09/162 - Instructions for use (Version 6.0, Dated 09/10/2014). [Cited 2014 Nov 11]. Available from: https://www.nibsc.org/documents/ifu/09-162.pdf https://www.nibsc.org/documents/ifu/09-162.pdf
  » https://www.nibsc.org/documents/ifu/09-162.pdf
• ²⁸
  Thamboo TP, Jeffery KJ, Friend PJ, Turner GD, Roberts IS. Urine cytology screening for polyoma virus infection following renal transplantation: the Oxford experience. J Clin Pathol 2007;60:927-30. DOI: http://dx.doi.org/10.1136/jcp.2006.042507
  » http://dx.doi.org/10.1136/jcp.2006.042507
• ²⁹
  Girmanova E, Brabcova I, Bandur S, Hribova P, Skibova J, Viklicky O. A prospective longitudinal study of BK virus infection in 120 Czech renal transplant recipients. J Med Virol 2011;83:1395-400. PMID: 21618550 DOI: http://dx.doi.org/10.1002/jmv.22106
  » http://dx.doi.org/10.1002/jmv.22106

Publication Dates

• Publication in this collection
  Jul-Sep 2016

History

• Received
  20 Sept 2015
• Accepted
  11 Apr 2016