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Copyright ª Blackwell Munksgaard 2004
Clin Transplant 2004 DOI: 10.1111/j.1399-0012.2004.00191.x




Risk factors for BK p...
Rocha et al.

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Risk factors for BK nephritis

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Rocha et al.

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Risk factors for BK nephritis

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Rocha et al.

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Risk factors for BK nephritis

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Risk factors for BK polyomavirus nephritis in renal allograft recipients

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Risk factors for BK polyomavirus nephritis in renal allograft recipients

  1. 1. Copyright ª Blackwell Munksgaard 2004 Clin Transplant 2004 DOI: 10.1111/j.1399-0012.2004.00191.x Risk factors for BK polyomavirus nephritis in renal allograft recipients1 Rocha PN, Plumb TJ, Miller SE, Howell DN, Smith SR. Risk factors for Paulo N Rochaa, Troy J Plumba, BK polyomavirus nephritis in renal allograft recipients. Sara E Millerb, David N Howellb Clin Transplant 2004 DOI: 10.1111/j.1399-0012.2004.00191.x and Stephen R Smitha ª Blackwell Munksgaard, 2004 Departments of a Medicine and b Pathology, Duke University Medical Center, Durham, NC, Abstract: Recurrent episodes of acute rejection (AR) and/or the intense USA immunosuppression used for their treatment have been proposed as risk factors for BK nephritis (BKN; BK refers to the initials of the first patient from whom this polyomavirus was isolated). To further examine the rela- tionship between AR and BKN, we analyzed all kidney transplants per- formed at our center between January 1999 and August 2001 (n ¼ 286). After a mean follow-up of 737 ± 22 d, we identified nine cases of BKN (3.1%). The mean time to diagnosis of BKN was 326 ± 56 d. No patient with BKN had a prior history of AR. During the same period, 62 patients were diagnosed with AR (22%). The mean time to diagnosis of AR was 197 ± 40 d (p ¼ 0.01 vs. time to diagnosis of BKN). Despite aggressive Key words: immunosuppression – kidney therapy with methylprednisolone and, in some cases, anti-lymphocyte transplantation – kidney/pancreas antibody, none of these patients with AR developed BKN. We compared transplantation – polyomavirus – rejection the baseline characteristics of patients in both groups and found that BKN patients were more likely to be white people (78 vs. 44%, p ¼ 0.05) and Corresponding author: Stephen R. Smith MD, male (89 vs. 53%, p ¼ 0.04). Moreover, the mean tacrolimus (TAC) levels MHS, Duke University Medical Center, before diagnosis were higher in BKN than in AR patients (11.7 ± 0.5 vs. PO Box 3014, Durham, NC 27710, USA. 6.5 ± 0.6 ng/mL, p < 0.001). In summary, our study shows that BKN Tel.: 919 660 6858; fax: 919 684 4476; often occurs in the absence of prior episodes of AR. In addition, our e-mail: smith060@mc.duke.edu findings suggest that white males exposed to higher TAC levels are at greater risk of developing BKN. Accepted for publication 19 December 2003 Over the last decade, renal transplantation has the more powerful modern immunosuppressants become the treatment of choice for most patients are a predisposing factor (5). with end-stage renal disease. The advent of potent The work of Atencio et al. provided an alter- new immunosuppressants such as tacrolimus native to the traditional view that viral reactivation (TAC) and mycophenolate mofetil (MMF) has results from immunosuppression (6). Because kid- contributed to a reduction in the incidence of acute neys of newborn – but not adult – mice are highly rejection (AR) episodes. However, many centers permissive for polyomavirus infection (7), the have noted a concomitant rise in the incidence of authors proposed that ongoing cellular differenti- opportunistic infections caused by BK virus (1). ation is required for viral reactivation. They Although BK virus was initially described in the showed that chemical or ischemic renal injury early 1970s (2), the first case of BK nephritis promoted high levels of polyomavirus replication (BKN) was only recognized in 1995 (3). Since then, in adult mouse kidneys in the absence of immuno- many cases have been reported, and BKN is suppression (6). currently a growing problem in kidney transplan- As several reported cases of BKN have been tation (4). The precise reasons behind this phe- preceded by recurrent episodes of AR (5, 8–10), nomenon are unknown, but it is well accepted that some authors (11) have united both theories and proposed the following scheme: (a) the cycle of renal 1 This work was presented in a plenary session at the American injury and repair caused by an episode of AR would Transplant Congress, Washington DC, on June 2, 2003. lead to ongoing cellular differentiation; (b) this 1
  2. 2. Rocha et al. would promote replication of latent BK virus in trough TAC level for each patient and averaged the kidney tissue; (c) the intense immunosuppression mean levels for all patients in each group. In the used for the treatment of AR would further facilitate BKN group, 205 levels were measured prior to viral replication, and BKN would ultimately devel- diagnosis (mean ¼ 26 data points/patient) and 87 op; (d) the reduction in immunosuppression em- post-diagnosis (mean ¼ 11 data points/patient). In ployed for the treatment of BKN would, in turn, the AR group, 688 (mean ¼ 13 data points/patient) predispose to further episodes of AR. and 1402 (mean ¼ 27 data points/patient) levels The clinical experience with BKN, however, were measured pre- and post-diagnosis, respectively. shows that the correlation between AR and BKN is very inconsistent. Although in some reports AR Histology preceded all cases of BKN (5, 9, 10), this time course was not observed in many others (12–14). In Renal allograft biopsy specimens were routinely fact, in the largest series to date, AR preceded processed and stained by the hematoxylin and BKN in only 12% of cases (15). To further eosin, periodic acid-Schiff, periodic acid-methen- examine the relationship between AR (and its amine silver, and Masson trichrome methods. treatment) and BKN, we conducted a retrospective Acute cellular rejection was diagnosed and graded analysis of all kidney transplants performed at our according to the Banff 97 working classification of institution between January 1999 and August 2001. renal allograft pathology (16). Acute humoral rejection was diagnosed using a combination of histology, C4d staining, and flow cytometry cross- Materials and methods matching as previously described (17). Immunop- eroxidase staining for BK polyomavirus was Study group performed in all histologic specimens using a We retrospectively reviewed all kidney and kidney– monoclonal primary antibody directed against the pancreas transplants performed at Duke University BK virus large T antigen (Chemicon, Temecula, Medical Center from January 1999 until August CA, USA). The avidin–biotinylated peroxidase 2001. Pertinent patient information was obtained staining technique was used, with diaminobenzi- from electronic medical records. Diagnostic proce- dine as chromogen. dures such as urine electron microscopy (EM) for viruses or allograft biopsies were performed at the EM of urine discretion of the treating nephrologist to evaluate clinically significant graft dysfunction and not as Electron microscopy was performed as previously part of a surveillance protocol. Recipients were described (13). Briefly, cells and debris were first classified into three groups: BKN, AR, or controls. removed from urine by low speed centrifugation, The diagnosis of BKN rested on a combination of and 1.5–3.0 mL of supernatant was ultracentri- urine EM and histology in all but one patient, for fuged at 100 000 · g for 50 min (Beckman whom a positive urine EM in the setting of a TL-Optima; Beckman Instruments, Palo Alto, compatible clinical presentation was considered CA, USA). The pellet was re-suspended in sufficient by the treating nephrologist. Similarly, approximately 20 lL distilled water, placed on a the diagnosis of AR was based on allograft biopsy Formvar- and carbon-coated grid, negatively findings in all but one patient who was empirically stained with uranyl acetate, and examined by EM treated with methylprednisolone within the first at 60 000–80 000· (Philips EM 300, EM 400, or month of transplant for presumed cellular rejection. CM 12; FEI-Philips, Hillsboro, OR, USA). Occa- All other subjects who did not undergo renal biopsy sionally, the pellet had to be re-suspended in or whose biopsy reports revealed conditions other 200 lL water and washed by ultracentrifugation than BKN or AR were included in the control to remove contaminating soluble protein (Beck- group. man Airfuge, Beckman Instruments) prior to uranyl acetate staining. Tacrolimus levels Induction and maintenance immunosuppression We analyzed all trough TAC levels obtained from the day of transplant until the diagnosis of BKN or Patients who were sensitized or considered to be at AR. We also computed all levels from diagnosis high immunologic risk received induction therapy as until last follow-up. A dummy value of zero was per our previously published protocol (17). All other assigned to undetectable levels (<4 ng/mL). We patients received no induction. Maintenance immu- then calculated the mean pre- and post-diagnosis nosuppression consisted of a calcineurin inhibitor, 2
  3. 3. Risk factors for BK nephritis MMF, and prednisone. TAC was the calcineurin All kidney and Kidney–Pancreas transplants inhibitor used in 80% of our patients; the target January 1999 to August 2001 trough level was 10–15 ng/mL during the first (n = 286) month and 5–10 ng/mL afterwards. MMF was started at 1 g twice daily and dose adjusted, if Follow-up needed, for gastrointestinal or bone marrow toxicity. March 2003 Methylprednisolone was given as a 250 mg i.v. bolus mean 737 ± 22 d in the operating room and then tapered to 30 mg oral prednisone by postoperative day 4. The prednisone BKN AR Control dose was tapered by 5 mg every 2 wk until a (n = 9) (n = 62) (n = 215) maintenance dose of 5–10 mg/d was achieved. 3% 22% 75% F/U post diagnosis F/U post diagnosis Treatment of acute rejection 412 ± 57 d 373 ± 37 d The treatment of acute cellular rejection consisted of methylprednisolone pulses; anti-lymphocyte Fig. 1. Study flow-chart. antibody therapy was reserved for severe cases (Banff II or greater) or steroid resistance. One were identified and followed for approximately patient with mild acute cellular rejection received 2 yr (mean ± SEM, 737 ± 22 d) (Fig. 1). Using a no therapy. Acute humoral rejection was treated combination of urine EM and/or histology, we with plasmapheresis and intravenous immunoglob- diagnosed nine cases of BKN for an incidence of ulin as previously described (17). 3.1% of all transplants. None of these cases had a prior history of AR. During the same period, 62 patients were diagnosed with AR for an incidence Treatment of BKN of 22%. Similarly, none of the AR patients Maintenance immunosuppression was reduced in subsequently developed BKN during the follow- all cases. MMF was either reduced or discontinued up period despite aggressive therapy of rejection while TAC doses were typically tapered to achieve with methylprednisolone pulses (61/62) and anti- a serum level around 5 ng/mL. TAC was switched lymphocyte antibody therapy (27/62). Moreover, to cyclosporine in one case and discontinued in BKN and AR did not co-exist in any of the another. biopsies studied. The remaining 215 patients com- prised the control group. Most patients in the control group experienced stable allograft function Statistics throughout the study period and therefore did not We used ANOVA and the two-tailed, unpaired t- undergo diagnostic studies. Among the biopsied test to compare continuous variables and the control patients, the most common histologic chi-square test for comparison of dichotomous findings were calcineurin toxicity and acute tubular variables between groups. All calculations were necrosis. performed using MINITAB for Windows version Compared with AR, the time of presentation of 10.2 (Minitab Ltd, State College, PA, USA). BKN was significantly delayed (326 ± 56 vs. Graphs were created with SigmaPlot 2000 for 197 ± 40 d post-transplant, p ¼ 0.01) (Fig. 2A). Windows version 6.00 (SPSS, Chicago, IL, USA). Furthermore, BKN was associated with less severe Figures and tables were created in MicrosoftÒ graft dysfunction at diagnosis, as evidenced by a PowerPointÒ 2000. Results were expressed as considerably lower mean serum creatinine value mean ± standard error of the mean (SEM) or (3.2 ± 0.4 vs. 6.1 ± 0.5 mg/dL, p ¼ 0.017) median and range. Survival analysis was per- (Fig. 2B). We compared the characteristics of formed with SAS software version 8.2 (SAS Insti- patients who developed BKN with those of tute Inc., Cary, NC, USA) using the Kaplan–Meier patients who developed AR and found that BKN method and comparisons between survival curves patients were more likely to be male (89 vs. 53%, were made with the log-rank test. Statistical p ¼ 0.04) and white people (78 vs. 44%, p ¼ 0.05) significance was defined as p £ 0.05. (Table 1). In addition, BKN patients were less likely to have a positive PRA. In contrast, the highest percentage of females, black people and Results pre-sensitized patients was found in the AR group. Between January 1999 and August 2001, 286 Cold ischemia time and incidence of delayed graft kidney or kidney–pancreas transplant recipients function were similar between groups (data not 3
  4. 4. Rocha et al. A B 1200 18 Days post-transplant 16 Serum Cr. (mg/dL) 1000 p = 0.01 p = 0.017 Fig. 2. Clinical presentation. (A) Time 14 800 12 to diagnosis of BKN and AR. (B) Ser- 600 10 um creatinine at the time of diagnosis 8 of BKN and AR. The 25th percentile 400 6 (boundary of the box closest to zero); 200 median (line within the box); 75th per- 4 0 2 centile (boundary of the box farthest 0 from zero); 90th and 10th percentiles BKN AR BKN AR (whiskers above and below the box). Table 1. Baseline characteristics 16 p = 0.001 p < 0.0001 BKN AR Control 14 BKN Variables (n ¼ 9) (n ¼ 62) (n ¼ 215) p-value 12 p = 0.001 AR Age 44 ± 5 44 ± 2 47 ± 1 0.28 10 Gender Male 89% (8)a 53% (33) 61% (131) 0.11 8 Female 11% (1)a 47% (29) 39% (84) 6 Race b Black people 22% (2) 56% (35) 37% (80) 0.01 4 Non-black people 78% (7)b 44% (27) 63% (135) Transplant type 2 CAD 78% (7) 74% (46) 65% (140) 0.32 0 LD 22% (2) 26% (16) 35% (75) Positive PRA (>10%) 11% (1) 34% (21) 20% (43) 0.05 Tacrolimus 89% (8) 84% (52) 79% (170) 0.576 Cyclosporin A 11% (1) 16% (10) 21% (45) 0.57 Fig. 3. Mean tacrolimus levels. PRE, all levels from transplant Induction therapy 56% (5) 63% (39) 53% (113) 0.35 until diagnosis; POST, all levels from diagnosis until last follow-up. a p ¼ 0.04 vs. AR. b p ¼ 0.05 vs. AR. p-values on the last column represent a comparison between the three groups. immunostaining of a kidney biopsy specimen with We used ANOVA to compare recipient age and the chi-square test for all other an antibody specific for BK virus. The same variables. method was used to confirm the absence of BKN CAD, deceased donor; LD, living donor; PRA, panel reactive antibody. in 17/25 patients with negative urine EM. The treatment of BKN consisted of a decrease in shown). All patients received prednisone and maintenance immunosuppression. Table 2B separ- MMF; TAC use was no different across groups ates BKN patients into two groups according to the (Table 1). degree of reduction in immunosuppression. The We then calculated the mean of all trough TAC first group is composed of seven patients for whom levels obtained since the day of transplant until the MMF was completely discontinued. Most of them day of diagnosis of BKN or AR and found that (five of seven) also experienced a reduction in the BKN patients had been exposed to significantly dose of the calcineurin inhibitor, and one was higher TAC levels (11.7 ± 0.5 vs. 6.5 ± 0.6 ng/mL, switched from TAC to cyclosporin A. In all of these p < 0.001). As part of the treatment of these seven patients, urine EM became negative for virus conditions, trough TAC levels were reduced in the approximately 5 months after diagnosis and none BKN group and increased in the AR group. It is lost their grafts. The other group is composed of important to highlight that these variations in two patients for whom MMF dose was decreased levels occurred within the therapeutic range but not discontinued. Neither of these patients (Fig. 3). cleared the viruria, and one ultimately lost the During the study period, 55 patients had urine allograft to the viral infection (Table 2B). Two-year EM analysis for BK virus as part of the investiga- graft survival in BKN patients was 89%, a rate no tion of renal dysfunction; Table 2A depicts 25 of different than that observed in controls (Fig. 4A). these patients for whom a concomitant kidney However, serum creatinine values obtained at last allograft biopsy was available and could be used as follow-up revealed significantly higher levels of the gold standard. All eight of 25 patients with a graft dysfunction in the BKN group compared with positive urine EM were confirmed to have BKN by AR or control patients (Fig. 4B). 4
  5. 5. Risk factors for BK nephritis Table 2. Performance of urine EM in the diagnosis and follow-up of patients with BKN (A) Urine EM BKN AR Controls Total Positive 8 0 0 8 Negative 0 11 6 17 Total 8 11 6 25 Conversion to Time to negative Graft (B) Groups Additional treatment negative urine EM (%) urine EM (days) loss (%) D/C MMF (n ¼ 7) Decrease Cl (5) 100 147 (29-257) 0 TAC fi CyA (1) fl MMF (n ¼ 2) D/C TAC (1) 0 – 50 Time to negative urine EM is presented as median (range). BKN, BK nephritis; EM, electron microscopy; MMF, mycophenolate mofetil; NEG, negative; D/C, discontinue; fl, decrease; Cl, calcineurin inhibitor; CyA, cyclosporin A. A B 12 † p = 0.05 vs. AR Serum cr. (mg/dL) 10 ‡ p < 0.001 vs. control Graft survival 8 †‡ 6 ‡ 4 2 0 BKN AR Control Months of followup Fig. 4. Outcomes. (A) Kaplan–Meier survival curves. Renal allograft survival data was calculated from the day of transplant. solid line, control group; dashed line, BKN group; dotted line, AR group. Values on top of horizontal axis represent the number of patients at risk. Death with graft function was included as allograft loss. (B) Serum creatinine of patients with graft function at last follow-up. The 25th percentile (boundary of the box closest to zero); median (line within the box); 75th percentile (boundary of the box farthest from zero); 90th and 10th percentiles (whiskers above and below the box). replication of polyomaviruses (6). AR is one cause Discussion of renal injury that is peculiar to allografts and has The main findings of this retrospective analysis been shown by some to predate all cases of BKN were that male gender, white people and exposure (5). The heavy immunosuppression that follows an to higher TAC levels were associated with BKN. In episode of AR may provide an even more condu- addition, AR did not precede BKN in any of the cive environment for viral replication. Herein we cases studied; rather the two complications tended describe nine cases of BKN that were not preceded to occur in distinct patient groups. Compared with by AR. Our findings are in agreement with those of BKN, AR tended to present earlier, with more Ramos et al. who noted a previous episode of AR severe renal impairment, and in a more sensitized in only eight of 68 (12%) cases of BKN (15). We group of patients. also did not find an association between BKN and The apparent predilection of BK virus for the cold ischemia time or delayed graft function. Our kidney allograft over native kidneys of recipients of data suggests that neither overt kidney damage nor non-renal solid organ transplants has been the treatment of AR is required for the development of focus of much speculation (18). Transplantation of BKN. kidneys from BK virus seropositive donors into Why are we not seeing more cases of BKN seronegative recipients cannot fully explain this involving the native kidneys of non-renal solid discrepancy as it has been reported that most organ transplant recipients? One possibility is that recipients who ultimately developed BKN were the Ôalloimmune environmentÕ, perhaps in the form seropositive before surgery (10). Atencio et al. have of low-level, subclinical rejection, is indeed neces- shown that the ongoing cellular differentiation that sary to potentiate viral reactivation. Another follows kidney injury (and repair) promotes the theory, however, is that these cases are simply 5
  6. 6. Rocha et al. underdiagnosed. In this regard, Haririan et al. Mancinelli et al. (21), we postulate that the recently described a case of BKN involving the increased incidence of BKN among white people native kidneys of a solitary pancreas transplant maybe related to higher drug (TAC) exposure in recipient (19). The same group has detected BK this group. To our knowledge, this is the first virus in the urine of four of 38 pancreas alone report to correlate trough TAC levels and BKN. recipients (20). In their study, higher TAC levels Although we found significant differences constituted a risk factor for BK viruria. We between BKN and AR patients regarding gender, speculate that similar cases could be going unde- time to diagnosis, TAC levels, and serum creatinine tected by transplant physicians and written off as at presentation, it is critical to recognize that there Ôcalcineurin nephrotoxicityÕ when renal dysfunction was a significant overlap with respect to all of these develops later. parameters. Moreover, given the low incidence In the present study, BKN and AR tended to of BKN, a white male presenting with allograft affect distinct groups of renal allograft recipients. dysfunction is still more likely to have AR than While we noted a predominance of white males in BKN. Thus, a renal biopsy is often needed to the BKN group, the highest percentage of black reliably distinguish AR from BKN, especially people and females were encountered in the AR because the appropriate treatment of these entities group. In addition, BKN and AR patients were at requires opposite strategies. Several groups have opposite ends of the spectrum regarding pre- demonstrated interest in identifying a less invasive sensitization, as defined by a historic panel reactive means to distinguish between these two conditions antibody (PRA) >10%. The significance of these (9, 10, 14, 22, 23). Our data suggests that the urine findings remains unclear at present. Female gender, EM might be a dependable method to diagnose (or black race and pre-sensitization are known risk exclude) BKN. Because of the retrospective nature factors for AR, while white people and male of our study, diagnostic procedures such as urine gender have not been consistently associated with EM and allograft biopsies were only performed BKN. In a recent study, however, investigators when deemed necessary by the treating clinician. from the University of Maryland found that the Therefore, we do not have concomitant urine EM percentage of males was significantly higher in the and allograft biopsy data for all 286 patients. BKN group than in controls (79 vs. 65%, Nevertheless, when a kidney biopsy was available p ¼ 0.02) (15). Whether this reflects a true pre- to serve as the gold standard, we showed that the dilection of BKN for the male gender or simply a urine EM correctly identified BKN in eight of eight high incidence of females with AR in their control patients. Similarly, the urine EM correctly exclu- group is unclear. ded BKN from 17 patients who were found to have A recent report showed no association between other conditions on allograft biopsy. It is import- the mean doses of immunosuppressants (predni- ant to underscore that we did not use urine EM as sone, MMF, TAC, cyclosporin A) and develop- a screening tool but rather to investigate clinically ment of BKN (15). However, a rigorous significant graft dysfunction. When used in this assessment of medication doses is difficult to setting, the urine EM appears to be highly sensitive accomplish because doses are frequently adjusted, and specific for BKN. However, a large, prospect- and accurate documentation is not always avail- ive study is needed to determine whether the urine able. In addition, the dose of a given immunosup- EM can be used as a non-invasive means to pressant may not correlate with true drug distinguish BKN from AR. exposure. For example, Mancinelli et al. have We also found the urine EM to be a useful tool demonstrated that serum concentration of TAC for following BKN patients after a reduction in after oral administration varies significantly with immunosuppression. In seven of nine cases, race, with the highest levels seen in white people immunosuppression was gradually tapered until and the lowest in black people; the authors clearance of viruria was achieved. All seven hypothesize that these results may be explained patients remained with graft function until last by differences in intestinal CYP3A or P-glycopro- follow-up. Persistence of viruria was associated tein activities (21). We therefore decided to investi- with graft loss in one of the remaining two gate the relationship between trough TAC levels patients. Two-year graft survival in the BKN and BKN as they more closely reflect true drug group was 89% and not different from controls. exposure and are readily accessible from electronic However, BKN patients with surviving allografts medical records. Our data shows that the mean exhibited significant renal dysfunction at last TAC level was significantly higher in patients who follow-up as demonstrated by serum creatinine developed BKN compared with those who devel- values (Fig. 4B). It is probable that the higher oped AR. In light of the aforementioned data by serum creatinine values in the BKN group repre- 6
  7. 7. Risk factors for BK nephritis sents a surrogate marker for a poor outcome and 9. Nickeleit V, Klimkait T, Binet IF et al. Testing for that a longer follow-up will reveal a much lower polyomavirus type BK DNA in plasma to identify renal- allograft recipients with viral nephropathy [see comments]. graft survival in these patients. N Engl J Med 2000: 342: 1309. In summary, our findings show that BKN often 10. Hirsch HH, Knowles W, Dickenmann M et al. occurs in the absence of a prior history of AR. In Prospective study of polyomavirus type BK replication the present study, BKN and AR tended to affect and nephropathy in renal-transplant recipients [see com- distinct populations. The mean TAC levels were ments]. N Engl J Med 2002: 347: 488. 11. Randhawa PS, Demetris AJ. Nephropathy due to highest in the group of patients who developed polyomavirus type BK [comment]. N Engl J Med 2000: BKN, suggesting that the intensity of immunosup- 342: 1361. pression is critical for viral reactivation. Transplant 12. Randhawa PS, Finkelstein S, Scantlebury V et al. nephrologists should be aware of this potential Human polyomavirus-associated interstitial nephritis in relationship between high TAC levels and BKN, the allograft kidney. Transplantation 1999: 67: 103. 13. Howell DN, Smith SR, Butterly DW et al. Diagnosis especially in white males. A substantial reduction and management of BK polyomavirus interstitial nephritis in immunosuppression was associated with 89% in renal transplant recipients. Transplantation 1999: 68: graft survival at 2 yr. However, as other reports 1279. have shown that BKN may ultimately lead to graft 14. Limaye AP, Jerome KR, Kuhr CS et al. Quantitation loss in up to 45% of patients despite reduction in of BK virus load in serum for the diagnosis of BK virus- associated nephropathy in renal transplant recipients [see immunosuppression (15), there is a need for further comments]. J Infect Dis 2001: 183: 1669. studies designed to evaluate the efficacy of new 15. Ramos E, Drachenberg CB, Papadimitriou JC et al. therapies (24, 25) against BKN. Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002: 13: 2145. 16. Racusen LC, Solez K, Colvin RB et al. The Banff 97 Acknowledgements working classification of renal allograft pathology. Kidney Int 1999: 55: 713. The authors would like to thank Dr Thu Le for her 17. Rocha PN, Butterly DB, Greenberg A et al. Beneficial comments and critical review of this manuscript. There was effect of plasmapheresis and intravenous immunoglobulin no external source of funding. on renal allograft survival of patients with acute humoral rejection. Transplantation 2003: 75: 1490. 18. Haririan A, Klassen DK. BK virus infection after References nonrenal transplantation. Graft 2002: 5: S58. 1. Reploeg MD, Storch GA, Clifford DB. BK virus: a 19. Haririan A, Ramos ER, Drachenberg CB, Weir MR, clinical review. Clin Infect Dis 2001: 33: 191. Klassen DK. Polyomavirus nephropathy in native 2. Gardner SD, Field AM, Coleman DV, Hulme B. New kidneys of a solitary pancreas transplant recipient. human papovavirus (B.K.) isolated from urine after renal Transplantation 2002: 73: 1350. transplantation. Lancet 1971: 1: 1253. 20. Haririan A, Hamze O, Drachenberg CB, Ramos E, 3. Purighalla R, Shapiro R, McCauley J, Randhawa P. Weir MR, Klassen DK. Polyomavirus reactivation in BK virus infection in a kidney allograft diagnosed by native kidneys of pancreas alone allograft recipients. needle biopsy. Am J Kidney Dis 1995: 26: 671. Transplantation 2003: 75: 1186. 4. Mylonakis E, Goes N, Rubin RH, Cosimi AB, Colvin 21. Mancinelli LM, Frassetto L, Floren LC et al. The RB, Fishman JA. BK virus in solid organ transplant pharmacokinetics and metabolic disposition of tacrolimus: recipients: an emerging syndrome. Transplantation 2001: a comparison across ethnic groups. Clin Pharmacol Ther 72: 1587. 2001: 69: 24. 5. Binet I, Nickeleit V, Hirsch HH et al. Polyomavirus 22. Ding R, Medeiros M, Dadhania D et al. Noninvasive disease under new immunosuppressive drugs: a cause of diagnosis of BK virus nephritis by measurement of mes- renal graft dysfunction and graft loss. Transplantation senger RNA for BK virus VP1 in urine. Transplantation 1999: 67: 918. 2002: 74: 987. 6. Atencio IA, Shadan FF, Zhou XJ, Vaziri ND, 23. Hirsch HH, Mohaupt M, Klimkait T. Prospective Villarreal LP. Adult mouse kidneys become permissive monitoring of BK virus load after discontinuing sirolimus to acute polyomavirus infection and reactivate persistent treatment in a renal transplant patient with BK virus infections in response to cellular damage and regeneration. nephropathy. J Infect Dis 2001: 184: 1494. J Virol 1993: 67: 1424. 24. Kadambi PV. Treatment of refractory BK virus-associated 7. Rochford R, Moreno JP, Peake ML, Villarreal LP. nephropathy with cidofovir. Am J Transplant 2003: 3: 186. Enhancer dependence of polyomavirus persistence in 25. Vats A, Shapiro R, Singh RP et al. Quantitative viral mouse kidneys. J Virol 1992: 66: 3287. load monitoring and cidofovir therapy for the manage- 8. Nickeleit V, Hirsch HH, Binet IF et al. Polyomavirus ment of BK virus-associated nephropathy in children and infection of renal allograft recipients: from latent infection adults. Transplantation 2003: 75: 105. to manifest disease. J Am Soc Nephrol 1999: 10: 1080. 7

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