Background: The correct valganciclovir dose for cytomegalovirus (CMV) prophylaxis depends on renal function estimated by the Cockcroft–Gault (CG) estimated creatinine clearance (CG-CrCl) formula. Patients with delayed or rapidly changing graft function after transplantation (tx) will need dose adjustments. Methods: We performed a retrospective investigation of valganciclovir dosing in renal transplant patients receiving CMV prophylaxis between August 2003 and August 2011, and analysed valganciclovir dosing, CG-CrCl, CMV viraemia (CMV- PCR<750 copies/mL), leucopenia (<3500/mL) and neutropenia (<1500/mL) in the ﬁrst year post-transplant. On Days 30 and 60 post-transplant, dosing pattern in relation to estimated creatinine clearance was analysed regarding CMV viraemia, leucopenia and neutropenia. Results: Six hundred and thirty-ﬁve patients received valganciclovir prophylaxis that lasted 1296 68 days with a mean dose of 2486 152 mg/day of whom 112/635 (17.7%) developed CMV viraemia, 166/635 (26.1%) leucopenia and 48/635 (7.6%) neutropenia. CMV resistance within 1 year post-transplant was detected in three patients. Only 137/609 (22.6%) patients received the recommended dose, while n¼ 426 (70.3%) were underdosed and n¼ 43 (7.1%) were overdosed at Day 30 post-tx. Risk factors for CMV viraemia were donor positive D (þ)/receptor negative R () status and short prophylaxis duration, but not low valganciclovir dose. Risk factors for developing leucopenia were Dþ/R status and low renal function. No signiﬁcant differences in dosing frequency were observed in patients developing neutropenia or not (P¼ 0.584). Conclusion: Most patients do not receive the recommended valganciclovir dose. Despite obvious underdosing in a large proportion of patients, effective prophylaxis was maintained and it was not associated as a risk factor for CMV viraemia or leucopenia. Key words: CMV prophylaxis, renal transplantation, retrospective analysis, valganciclovir Received: August 30, 2017. Editorial decision: October 31, 2017 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CMV prophylaxis after renal transplantation | 565 highest possible data quality on medication. This study was Introduction approved by the local ethics committee of the hospital. Cytomegalovirus (CMV) infection and disease continue to be clini- From 2004 on, every patient received Bactrim as universal cally relevant infectious complications for renal allograft recipi- prophylaxis. ents. It can result in CMV syndrome, tissue invasive disease, asymptomatic CMV infection  with neutropenia or leucopenia, or most often in ‘flu-like illness’ with myalgia and fatigue. Dosing frequency of valganciclovir Indirect effects of CMV infections are allograft rejection, At our transplant centre, valganciclovir prophylaxis has been increased risk of opportunistic infections and reduced allograft prescribed since the introduction of valganciclovir in 2003 in and patient survival . Risk factors for developing CMV infection kidney transplant recipients depending on donor/recipient sta- after renal transplantation (tx) are donor positive/receptor nega- tus. Valganciclovir dosing was adjusted to the estimated creati- tive (Dþ/R) serostatus, short prophylaxis duration, higher levels nine clearance based on CG-CrCl. Except for early start of of immunosuppressive therapy and allograft rejection . prophylaxis in the first week post-transplant with once weekly Recent guidelines recommend for CMV prophylaxis for patients dosing for patients with estimated creatinine clearance <10 mL/ with good renal function (>60 mL/min) a daily dose of 900 mg min (for this group of patients no dosing recommendations valganciclovir for 3 months or up to 6 months for high-risk patients exist), there was no formal site-specific dosing guidance given. [1, 3, 4]. Valganciclovir is a valine ester of ganciclovir, with a 66% As recommended by guidelines, official dosing recommenda- higher bioavailability compared with oral ganciclovir capsules. It is a tions were provided to the treating physicians and dose adjust- prodrug, and is rapidly absorbed and metabolized to the active form ments were to be performed according to the renal function. ganciclovir. Valganciclovir prophylaxis with 450 mg daily dose According to the medical records in the transplant database, achieved comparable area under the curve (AUC )valuescom- 0–24 h dosing schema and frequency was analysed according to the pared with 1 g oral ganciclovir every 8 h . Dose adjustments dosing recommendation in the prescribing information. Dosing depending on the glomerular filtration rate (GFR) are needed as the schema was divided into underdosing (lower dose prescribed apparent clearance of ganciclovir is highly correlated with renal func- than recommended), recommended dosing (dose prescribed tion . It is recommended to adjust the valganciclovir dose accord- according to prescribing information) or overdosing (higher ing to the Cockcroft–Gault (CG) estimated creatinine clearance dose prescribed than recommended). Comparisons were made (CG-CrCl) formula [3, 7]. Key issues facing CMV prophylaxis with val- for CG-CrCl on Days 30 and 60. ganciclovir are late-onset CMV disease and higher rates of leucopenia or neutropenia, which are common side-effects of valganciclovir . In order to decrease the risk for haematological side effects CMV viraemia it is discussed whether low-dose prophylaxis (450 mg) may be used instead of standard dose (900 mg) for prophylaxis treatment CMV viraemia was defined as CMV-PCR >750 copies/mL and [6, 9–13]. Kalil et al. compared in a meta-analysis effectiveness CMV infection as positive PCR in combination with clinical of valganciclovir 900 mg versus 450 mg for CMV prophylaxis. symptoms. CMV infection was divided into mild infection There was no significant difference in frequency of CMV disease defined as mild leucopenia and mild general symptoms, and but significantly higher risk for leucopenia for the high dose severe infection defined as severe leucopenia colitis, hepatic or group . However, due to lack of sufficient data especially for other organ involvement. Additionally, we analysed hospital- high-risk patients, currently valganciclovir prophylaxis with ization caused by CMV viraemia and/or CMV infection. 450 mg daily is not recommended. Major concerns are higher risk Leucopenia was defined as mild leucopenia <3500 cells/mLand for ganciclovir resistance and late-onset disease . severe leucopenia <2000/mL. Neutropenia was defined according to NCI Common Terminology Criteria for Adverse Events v3.0 as grade 1 (mild neutropenia) with <1500/mL and grade 4 (severe neu- Materials and methods tropenia) with <500/mL. The main objective of this retrospective study was to evaluate the routine prescribing frequency for all GFR classes in relation to under dosing/recommended dosing or overdosing due to the Statistics prescribing information/current recommendations. Major out- For statistical data analysis, SPSS version 23 (IBM SPSS Inc., come objectives were CMV viraemia and occurrence of CMV Chicago, IL, USA) was used. Continuous variables were shown infection as parameters for the effectiveness and adverse drug either as mean6 standard deviation (SD) or median (range). reactions like leucopenia or neutropenia. Categorical variables were analysed by v test and time to event All adult (18 years) kidney transplant patients receiving val- data by log rang test. Group comparisons were made between ganciclovir prophylaxis in our center, were included who were CMV positive/negative patients, patients developing leucopenia transplanted between August 2003 (¼ the introduction of routine or neutropenia during prophylaxis and patients without leucope- valganciclovir prophylaxis in our center) and August 2011. nia or neutropenia. Additionally, multivariable logistic regression Complete 1-year follow-up was available for all patients, except was performed to identify risk factors for CMV viraemia and side for patients with graft loss or death; at that time patient observa- effects. Risk factors (R/Dþ status, sex, age at transplantation, tion ended. Also, observation ended when CMV viraemia was induction therapy, MPA intake, valganciclovir prophylaxis dura- detected and CMV therapy started. All laboratory data (CMV sta- tion, valganciclovir dosing in relation to renal function, steroid tus, leucocytes, neutrophil granulocytes and renal function), medi- doses at Days 30 and 60 post-transplant, tacrolimus c ,cyclo- cation history and medical records were reviewed from the 0h sporine c , CG-CrCl at Days 30 and 60 post-transplant) were transplant database. All patients are closely followed in our clinic 0h identified by univariate analysis and were included if P< 0.20. A for the first year. At each visit, medication is checked and patients are provided with an actual medication list, which guarantees the type I error rate below 5% (P< 0.05) was considered significant. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 566 | O. Rissling et al. doctors only weekly adhered to the official prescribing recom- Results mendations. Especially in case of improving renal function, Patient characteristics dose adjustments were performed too late or even forgotten in a busy outpatient clinic. Duration of valganciclovir prophylaxis Six hundred and thirty-five patients were included in the analysis ranged from 5 to 365 days (median: 109.0 days), as in some and underwent kidney transplantation at the Charite ´ Hospital patients prophylaxis was stopped early (e.g. in case of graft Mitte, Berlin, from August 2003 to August 2011. All patients loss). In other patients, it was forgotten to stop valganciclovir at received valganciclovir for prevention of CMV disease since the the end of recommended prophylaxis. day of transplantation. Evaluation of CMV serostatus revealed First, we analysed daily valganciclovir doses on Day 30. 103 (16.2%) high-risk recipients (Dþ/R). Most patients received Overall, 70.3% patients (426/606) were underdosed on Day 30 basiliximab as induction therapy (73.7%) (Table 1). Median esti- post-transplant, due to insufficient dose adjustment in patients mated creatinine clearance was 45.4 mL/min (6.3–290.4 mL/min) with rapidly increasing renal function. Less than 10% were over- on Day 30 and 50.8 mL/min (78.8–154.8 mL/min) on Day 60. dosed (43/609; 7.1%) and only 20% of the patients received rec- ommended dosing (137/606; 22.6%). For 29 patients, no data Valganciclovir dosing were available on laboratory values or on daily valganciclovir During this analysis, a large heterogeneity in valganciclovir dos- dose at Day 30 post-transplant. Three patients were excluded ing became obvious (Table 2 and Figure 1), as in daily routine from analysis due to graft loss within 30 days post-transplant. Table 1. Demographics Valganciclovir dosing related to CG-CrCl on Day 30 (n¼ 606) Recommended Characteristics All patients Underdosing dosing Overdosing Total number 635 426 137 43 Age at transplantation (years6 SD***) 516 14 496 14 546 13 556 13 Female, n (%)* 253 (39.8) 155 (36.4) 61 (44.5) 24 (55.8) Deceased donor, n (%)* 465 (73.2) 299 (71.4) 106 (77.4) 37 (86.0) CMV high-risk patients (Dþ/R), n (%) 103 (16.2) 75 (17.9) 21 (15.9) 5 (11.6) Prophylaxis duration (days6 SD) 1296 68 1276 67 1346 69 1356 71 Prophylaxis daily dose (mg6 SD***) 2486 152 2276 119 3156 210 2566 160 Immunosuppressive treatment Mycophenolic acid at tx, n (%) 568 (89.4) 381 (89.4) 117 (85.4) 37 (86.0) Tacrolimus at tx, n (%) 211 (33.2) 134 (31.5) 50 (36.5) 19 (44.2) Cyclosporine at tx, n (%) 396 (62.4) 272 (63.8) 85 (62.0) 25 (58.1) Methylprednisolone at tx, n (%) 601 (99.0) 424 (99.3) 134 (97.8) 43 (100.0) Methylprednisolone at Day 365 post-tx, n (%) 83 (13.1) 59 (13.8) 16 (11.7) 5 (11.6) Steroid dose on Day 30 post-tx, median (min–max) (mg) 20 (0–500) 20 (4–500) 20 (4–250) 20 (12–32) Steroid dose on Day 60 post-tx, median (min–max) (mg) 12 (4–500) 12 (4–500) 12 (4–20) 12 (6–20) Induction therapy Basiliximab, n (%)*** 468 (73.7) 347 (81.5) 91 (66.4) 29 (67.4) Daclizumab, n (%) 23 (3.6) 9 (2.1) 10 (7.3) 3 (7.0) ATG, n (%) 7 (1.1) 5 (1.2) 1 (0.7) 1 (2.05) No induction therapy, n (%)* 137 (21.6) 70 (16.4) 37 (27.0) 11 (25.6) *P< 0.05, **P< 0.001, ***P< 0.0001. tx, transplant. Table 2. Overview of dosing recommendations and the actual dose used in relation to CG-CrCl on Day 30 post-transplant CG-CrCL: CG-CrCL: CG-CrCl: CG-CrCl: CG-CrCl: <10 mL/min 10–25 mL/min 25–40 mL/min 40–60 mL/min >60 mL/min Recommended dosing No dosing 450 mg twice weekly 450 mg every 450 mg daily 900 mg daily recommendation second day n 8 82 154 184 178 Actual valganciclovir 112.56148.8 130.8683.1 201.9696.26 267.46132.2 404.16196.4 a,b dose (mg) Most frequent prescribed 450 mg once weekly, 450 mg twice weekly, 450 mg thrice weekly, 450 mg thrice weekly, 450 mg daily, dosing recommendation, 4 (50.0) 32 (39.0) 54 (35.1) 61 (33.2) 101 (56.7) n (%) Second most frequent No drug, 2 (25.0) 450 mg once weekly, 450 mg twice weekly, 450 mg daily, 450 mg thrice weekly, prescribed dose, n (%) 28 (34.1) 43 (27.9) 30 (16.9) 30 (16.9) Charite ´ transplant centre. Mean6 SD. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CMV prophylaxis after renal transplantation | 567 Fig. 1. Different dosing frequencies according to CG-CrCl classes on Day 30. High variability in dosing frequency was observed for creatinine clearance estimated by CG-CrCl <25 mL/min. Most patients were underdosed who had CG-CrCl >25 mL/min. For CG-CrCl <10 mL/min overdosing was observed, although valganciclovir administration is not recommended due to prescribing information. These patients received valganciclovir 450 mg once weekly. Inside the bars of the diagram the per- centage of patients in each group is shown. Median daily dose (192.9 mg/day, range 0–450 mg/day) was prophylaxis duration for patients who developed CMV viraemia lowest for underdosed patients on Day 30 while for patients during prophylaxis was 87 days (min–max: 5–269 days), 25% of with recommended dosing (median: 450 mg/day, range: patients received 66 days and 75% of patients 126 days of prophy- 0–900 mg/day) and overdosed patients the median daily dose laxis. Patients developing CMV viraemia after prophylaxis was the same (median: 225 mg/day, range: 64.3–900 mg/day). received valganciclovir for a median of 90 days (min–max: 5–275), There was heterogeneity in prescribing frequency in patients with 25% of patients receiving it for 75 days and 75% of patients with estimated creatinine clearance between 10 and 60 mL/min for 126 days. There was no significant difference in the severity (Figure 1). Although no recommendations are given for values and hospitalization rate between patients developing CMV virae- below 10 mL/min, in six of eight patients (75.0%) valganciclovir mia during or after prophylaxis (data not shown). The incidence was prescribed once weekly and most patients with low renal of patients with CMV viraemia was comparable between under- function (CG-CrCl<10 mL/min) were overdosed. Similarly, almost dosed, overdosed and recommended dosing (Figure 3). The 90% of patients with values >60 mL/min were underdosed, receiv- results were similar on Day 60 (data not shown). ing only 450 mg/day. For GFR >40 mL/min valganciclovir was pre- Logistic regression revealed that Dþ/R patients were at scribed most frequently once daily (53/184, 28.8%) and even more greater risk of developing CMV viraemia (Table 4). CMV-positive often for GFR>60 mL/min (n¼ 101/178, 56.7%), while recom- patients had significantly shorter prophylaxis duration. A trend to mended dosing of 900 mg remained low (16/178, 9.0%). Similar lower CG-CrCl values in CMV-PCR-positive patients was observed. results were obtained on Day 60 (data not shown). Dose levels dif- Multivariable logistic regression analysis did not confirm renal fered largely from the recommendations in the prescribing infor- function as a risk factor. Correct valganciclovir dosing, underdos- mation. The mean daily dose was lower than the recommended ing and overdosing did not have a significant impact for develop- dose for the estimated creatinine clearance for GFR classes 40– ing subsequent CMV viraemia. Similar results were obtained for 60 mL/min and CG-CrCl> 60 mL/min, while higher doses were pre- Day 60. Immunosuppressive medication like steroid doses and scribed for creatinine clearance<10 mL/min (Table 2). MPA intake were not identified as risk factors. Calcineurin inhibi- tor trough levels were comparable between both groups. CMV viraemia and disease Overall, 112 patients (17.6%) were tested CMV-PCR positive at Leucopenia any time during the first post-transplant year (Table 3). Most During prophylaxis, 166 (26.1%) patients developed leucopenia, patients with positive CMV-PCR (59/635; 9.3%) remained asymp- most of them mild leucopenia (<3500/mL) (109/635, 17.2%) tomatic. Only 27/635 patients (4.3%) required hospitalization for (Table 3). Patients who developed leucopenia were overdosed CMV infection during the first year after transplantation; 3/112 on Day 30 (7.4% versus 5.5%) in comparison with patients with- (2.7%) patients developed CMV resistance. out leucopenia (P¼ not significant). Median time to CMV viraemia was 151 (12–359) days post- As a consequence of leucopenia, valganciclovir prophylaxis transplant. In 23/635 (3.6%) patients, CMV viraemia was observed was stopped in 28/166 (17.0%) patients, dose reductions were during prophylaxis with a median of 88 days (12–271) after trans- performed in 25/166 (15.1%) and in 5/166 (3.0%) patients valgan- plantation (Figure 2). Half of these patients remained asympto- ciclovir prophylaxis was paused. However, in most patients matic (13/23, 56.5%), 4/23 (17.6%) developed mild symptoms while (104/166 patients, 62.7%) no changes in prophylaxis treatment only 6/23 (26.1%) had a severe clinical course. After prophylaxis, were made because leucopenia was mild. For four patients, no 89/635 (14.0%) patients developed CMV viraemia with a median time of 171 (28–359) days post-transplant (Figure 2). Median data were available. One patient with leucopenia during Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 568 | O. Rissling et al. Fig. 2. CMV viraemia development within 1 year post-transplant. The ﬁgure shows the Kaplan–Meier plot for CMV viraemia development during prophylaxis (n¼ 23) and after prophylaxis (n¼ 89). CMV viraemia occurred at a median of 88 days (12–271 days) during prophylaxis while after prophylaxis the median time was 171 days (28–359 days). Median valganciclovir prophylaxis duration for patients developing CMV during prophylaxis was 87 days (min–max: 5–269 days) and a median of 90 days for patients who developed CMV after prophylaxis (min–max: 5–275 days). Fig. 3. Valganciclovir dosing frequency in relation to CG-CrCl on Day 30 post-transplant. The ﬁgure shows the dosing frequency in relation to CG-CrCl on Day 30 post- transplant for patients who developed CMV viraemia, leucopenia and neutropenia after Day 30. Most patients received lower doses than recommended. No difference in CMV viraemia, leucopenia or neutropenia occurrence was found. prophylaxis received filgastrim and developed CMV viraemia information on MPA dose adjustments were available in 2/162 5 months after the prophylaxis ended. patients (1.2%). In total, 162/166 (97.8%) patients with leucopenia were on The median methylprednisolone dose at the time of MPA treatment at the time of leucopenia. In those patients, leucopenia was 8 mg. The most significant risk factors for leu- MPA dose reductions were performed in 78/162 (48.1%) patients, copenia were low CG-CrCl and Dþ/R status. Various valganci- MPA treatment was paused in 7/162 (4.3%) patients, and in 69/ clovir dosing on Day 30 or Day 60 was not identified as a 162 (42.6%) patients no changes in MPA therapy were per- risk factor for leucopenia occurrence. Univariate analysis formed. In one patient, MPA dose was increased and no revealed that younger patients and patients with living donors Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CMV prophylaxis after renal transplantation | 569 were at lower risk for developing leucopenia but this Neutropenia during prophylaxis was not confirmed in multivariable analysis (Table 5). Only 48 (7.6%) patients of the overall cohort developed neutro- Immunosuppressive medication such as calcineurin inhibi- penia during prophylaxis (Table 3). Most of the patients had tors, MPA intake or steroids were not identified as risk factors mild neutropenia and neutropenia occurred together with leu- forleucopeniaorCMV infections. copenia in 85.4% of all cases. Dosing frequency was comparable between patients with and without neutropenia on Days 30 (P¼ 0.936) and 60 (P¼ 0.790). Due to lower incidence of neutrope- Table 3. Outcome within 1 year post-transplant (tx) in 635 patients nia no logistic regression was performed. who received valganciclovir prophylaxis Outcome Patients, n (%) Discussion Graft loss within 1 year after tx 14 (2.2) In this retrospective study, valganciclovir dosing pattern was Death within 1 year after tx 13 (2.2) thoroughly evaluated and outcome analysed in a large cohort of Biopsy-proven acute rejection 112 (17.6) renal transplanted patients receiving valganciclovir for CMV CMV viraemia positive prophylaxis. The focus of this analysis was to investigate val- Total number of patients 112 (17.6) ganciclovir dose in relation to estimated creatinine clearance Asymptomatic 59 (9.3) (by CG) in relation to the prescribing behaviour of physicians Mild CMV infection 31 (4.9) and its impact on CMV viraemia and adverse effects such as Severe CMV infection 22 (3.5) leucopenia and neutropenia. Patients required hospitalization 27 (4.3) Median time to CMV-PCR-positive result (range) (days)87.5 (12–259) First, we observed large differences in valganciclovir dosing, Leucopenia during prophylaxis especially in patients with estimated CG creatinine clearance Total number of patients 166 (26.1) <25 mL/min. After renal transplantation, GFR values are chang- Mild leucopenia (deﬁned as<3500/mL) 109 (17.2) ing rapidly and the recommended valganciclovir dose was fre- Severe leucopenia (deﬁned as<1500 mL) 58 (9.1) quently not prescribed. Although it was intended to prescribe Leucopenia associated with CMV infection 8 (4.8) valganciclovir according to the product information, this was Median time to leucopenia, median days (range) 70 (4–270) obviously not achieved in daily routine of a large outpatient Neutropenia during prophylaxis transplant clinic. The main problem was insufficient dose Neutropenia 48 (7.6) adjustments in patients with rapidly improving renal function Together with leucopenia 41 (6.4) after transplantation. Obviously, there is a need for better moni- Mild neutropenia (deﬁned as<1500/mL) 40 (6.3) Severe neutropenia (deﬁned as<500/mL) 8 (1.3) toring of drugs with renal elimination, eventually through elec- tronic online information systems. Given the fact that BANFF 09 Category 2, 4. prophylaxis lasted >200 days in some patients, this may Table 4. Multivariable logistic regression of risk factors for CMV viraemia CMV positive (n¼ 107) CMV negative (n¼ 499) Odds ratio Lower 95% CI Upper 95% CI P-value Day 30 post-tx High-risk patients (Dþ/R) 42 (39.3) 65 (13.0) 13,401 6.651 27.000 <0.001 Deceased donor 89 (83.2) 351 (70.3) 1.417 0.726 2.766 0.307 Underdosing 71 (66.4) 355 (71.1) 0.870 0.474 1.597 0.654 a,b Recommended dosing 27 (25.2) 110 (22.0) 0.840 Overdosing 9 (8.4) 34 (6.8) 1.108 0.390 3.150 0.847 CG-CrCl (mL/min) 36.7 (6.3–120.1) 47.4 (7.6–290.4) 0.992 0.978 1.006 0.250 c,d Steroid dose (mg) 20 (12–500) 20 (4–50) 1.032 0.980 1.086 0.233 Prophylaxis duration 89.5 (5–275) 112 (5–365) 0.983 0.977 0.989 <0.001 Age (years) 56 (18–76) 50 (18–78) 1.019 0.997 1.041 0.094 CMV positive (n¼112) CMV negative (n¼522) Odds ratio Lower 95% CI Upper 95% CI P-value Day 60 post-tx High-risk patients (Dþ/R) 42 (37.5) 65 (12.5) 17,677 7.449 41.950 <0.001 Deceased donor 90 (80.4) 372 (71.3) 1.358 0.639 2.885 0.427 Underdosing 86 (76.8) 405 (77.6) 1.177 0.536 2.586 0.684 a,b Recommended dosing 19 (17.0) 96 (18.4) 0.668 Overdosing 7 (6.3) 21 (4.0) 0.655 0.153 2.803 0.569 CG-CrCl (mL/min) 41.6 (8.8–146.3) 53.1 (10.5–154.8) 0.996 0.980 1.013 0.675 c,e Steroid dose (mg) 12 (4–16) 12 (4–40) 0.983 0.908 1.064 0.664 Prophylaxis duration 91.0 (5.0–275.0) 112.5 (7.0–365.0) 0.978 0.971 0.986 <0.001 Age (years) 57 (18–76) 50 (18–78) 1.027 1.000 1.056 0.053 Number of patients (%). Reference. Median (min–max). Converted to methylprednisolone equivalent doses. Induction therapy included (ATG, basiliximab, daclizumab). tx, transplant; CI, conﬁdence interval. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 570 | O. Rissling et al. Table 5. Multivariable logistic regression of risk factors for leucopenia Leucopenia (n¼ 143) No leucopenia (n¼ 348) Odds ratio Lower 95% CI Upper 95% CI P-value Day 30 post-tx High-risk patients 39 (26.2) 42 (12.1) 2.450 1.407 4.264 0.002 Deceased donor 126 (84.6) 244 (68.5) 1.349 0.747 2.439 0.321 Underdosing 99 (69.2) 255 (73.3) 1.001 0.590 1.701 0.996 a,b Recommended dosing 38 (26.6) 72 (20.7) 0 0.945 Overdosing 11 (7.7) 19 (5.5) 0.864 0.339 2.198 0.758 CG-CrCl (mL/min) 35.6 (7.6–105.1) 51.3 (7.2–290.4) 0.968 0.955 0.981 <0.001 Age at tx (years) 62 (22–77) 49 (18–78) 1.004 0.985 1.024 0.687 Leucopenia (n¼ 125) No leucopenia (n¼ 358) Odds ratio Lower 95% CI Upper 95% CI P-value Day 60 post-tx High-risk pts 36 (28.8) 42 (12.2) 2.806 1.594 4.938 <0.001 Deceased donor 104 (83.2) 246 (68.9) 1.289 0.695 2.388 0.420 Underdosing 94 (74.6) 94 (74.6) 1.209 0.675 2.167 0.523 a,b Recommended dosing 24 (19.0) 24 (19.0) 0.762 Overdosing 8 (6.3) 9 (2.5) 1.400 0.448 4.380 0.563 CG-CrCl (mL/min) 39.0 (10.8–103.5) 58.4 (11.9–122.7) 0.970 0.956 0.984 <0.001 Age at tx (years) 62 (23–77) 49 (17–78) 1.009 0.988 1.030 0.398 Number of patients (%). Reference. Median (min–max). tx, transplant; CI, conﬁdence interval. indicate that prophylaxis stop was simply forgotten in clinical Ganciclovir-resistant CMV disease occurs in <1% of solid organ recipients. One of the indicators of drug-resistant CMV routine. In our cohort, 70% of patients received a lower than recom- disease is that despite treatment the viral load persists, pla- teaus or even rises . In our cohort, only three patients devel- mended dose of valganciclovir, 10% a higher dose and only oped ganciclovir-resistant disease. Comparable results were 20% received the recommended dose. Most underdosed patients observed in high-risk kidney transplant patients receiving low- had good renal function (CG-CrCl>60 mL/min) and received dose valganciclovir prophylaxis treatment  or standard val- 450 mg daily instead of 900 mg and 450 mg every second day ganciclovir prophylaxis dose [19, 20]. Recent reviews and guide- instead of 450 mg daily in patients with CG-CrCl of 40–60 mL/ lines also suggest low risk of drug-resistant CMV disease with min. In large prospective studies, 900 mg daily dose of valganci- universal prophylaxis most likely due to the highly effective clovir was used for prophylaxis of CMV infection in patients prophylaxis, which prohibits high viral replication and the with good renal function. Unfortunately, the efficacy of lower development of resistance in those patients [3, 18]. doses was not tested in prospective randomized trials [8, 15]. Finally, a pharmacodynamic analysis revealed an improved Even though most patients were underdosed in this study, CMV suppression of CMV viraemia and delayed development of CMV viraemia frequency was not significantly higher than in the cor- viraemia after 900 mg valganciclovir prophylaxis compared rect dosing group. Logistic regression did not detect underdos- with standard oral ganciclovir treatment . Given the fact ing as a risk factor for CMV viraemia. Instead, well-known risk that ganciclovir AUC is comparable between 1 g ganciclovir 0–24 h factors, such as high-risk constellation of transplant patients every 8 h and 450 mg valganciclovir , the current valganciclo- and duration of therapy, were found. Dþ/R patients were 13- vir dosing recommendations have to be questioned and further times more likely to develop CMV viraemia. Posadas Salas et al. investigations on low- versus high-dose valganciclovir for CMV  found that 50% of patients received the recommended prophylaxis are needed. dose, the other half received lower or higher doses than appro- Renal function was significantly lower in patients develop- priate, which confirms the difficulty of appropriate dosing in ing CMV viraemia (P< 0.001) but was not identified as a risk fac- renal transplant patients. Given the good results on outcome, tor, which is in line with results of another retrospective with only 4.3% hospitalizations due to CMV infections, the analysis in CMV high-risk patients and a post hoc analysis of obvious underdosing had no detrimental effects on outcome. a randomized trial . In the latter one, patients never achiev- This observation is supported by other recent studies demon- ing a creatinine clearance >60 mL/min were at greater risk for strating a similar effect of low-dose valganciclovir versus rec- CMV development . ommended dose on CMV infection and an improved outcome of Differences in CMV infection frequency were found in leucopenia occurrence in renal transplant patients [9, 16]. patients in relation to the immunosuppressive therapy used. Surprisingly, similar to our findings, higher doses were even Induction therapy was performed most often with basiliximab associated with a higher prevalence of CMV infections. It was but induction therapy was not identified as a risk factor for CMV explained by inability of an adequate immune response after infection in this cohort. Similar to these findings, another clini- drug discontinuation because of the insufficient exposure of the cal trial did not find any difference between CMV infection inci- host to low CMV viraemia levels during prophylaxis [9, 17]. A dence between patients who received induction therapy with meta-analysis confirmed the effectivness of lower doses for basiliximab or anti-thymocyte globulin (ATG) or no induction renal transplant patients with different serostatus . therapy . The low frequency of CMV viraemia in our cohort Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CMV prophylaxis after renal transplantation | 571 was comparable to a tacrolimus–MPA-treated group where Dþ/ valganciclovir prophylaxis treatment was paused or stopped, R patients received prophylaxis therapy . Even lower inci- because risk for infection was low at the end of prophylaxis in dence of CMV infections of <6% was observed in everolimus- combination with low steroid doses. treated patients compared with MPA therapy [24, 25] or sotras- Neutropenia is one of the most common side effects of val- taurin treatment . Almost 90% of our patients received MPA. ganciclovir . The number of patients who developed neutrope- Therefore, comparison to other immunosuppressive medica- nia (<1500/mL) in our centre was 46 (7.5%), with only 8 (1.8%) tions, such as everolimus, was not considered as appropriate. patients with severe neutropenia (<500/mL), which was compara- Leucopenia, as a side effect, was observed non-significantly ble to another study  and lower than in other studies [26, 34, more often in overdosed patients and less in underdosed 36]. Most of the patients in our cohort experienced leucopenia patients. Multivariable logistic regression did not show valganci- (41/635 patients, 6.5%). Although overdosing was observed in the clovir overdosing as a risk factor for developing leucopenia, neutropenia-positive group the differences in valganciclovir dos- instead Dþ/R patients and low renal function were identified. ing were not significant (Figure 3). This is in agreement with Similar to these findings some studies showed that higher val- another study where no statistically significant association of ganciclovir doses were associated with a high leucopenia inci- valganciclovir dosing and neutropenia was found . A strong dence [9, 11, 16, 27]. Only a weak correlation between ganciclovir link between neutropenia and MPA was observed in patients on overexposure and haematologic side effects was found in MPA–tacrolimus treatment. Here, a higher incidence was another study . observed compared with patients on MPA–cyclosporine treat- Due to low renal function, which is common in the early kid- ment . It was explained by the lower MPA concentrations in ney post-transplant period, 7-o-mycophenolic acid glucuronide patients on MPA–cyclosporine therapy in contrast to MPA–tacro- (MPAG) is accumulated, which can displace mycophenolic acid limus treatment due to inhibition of the enterohepatic recircula- (MPA) from albumin binding, causing a higher free fraction of tion by cyclosporine leading to lower MPA concentrations [36, 37]. MPA and a larger bone marrow suppression . Therefore, the MPA dose reductions due to side effects are associated with a risk of developing leucopenia could be higher in patients with higher risk of acute rejections [36, 38]. Therefore, therapy with G- poor renal function taking MPA. However, MPA intake was not CSF and/or valganciclovir therapy stop may be an alternative if identified as a significant risk factor in univariable analysis. neutropenia is observed . However, more studies investigat- Again, the analysis is limited by the fact that 90% of patients ing the risk of malignancies or other adverse events after G-CSF received MPA. In our study, the incidence for leucopenia devel- application are needed . opment during prophylaxis was higher (16.6%) than in another There are some limitations in this retrospective study. study where patients were treated with MPA but without val- Prospective, randomized studies are needed to investigate the ganciclovir co-treatment (9.9%) . This indicates patients safety, tolerability and outcome of low dose versus standard receiving both drugs are more prone to leucopenia than with dose for valganciclovir prophylaxis after transplantation in a MPA alone or without either treatment option. In this context, it large cohort. For more precise analysis of valganciclovir dosing, is important to mention that also steroid sparing/withdrawal plasma concentrations are needed to establish a link to the therapy may lead to significantly higher frequency of leucope- pharmacodynamic response, which was not available for this nia [30, 31]. However, steroid doses were comparable between analysis. Some patient characteristics were not evenly balanced both groups and were not identified as a risk factor. Bactrim in our cohort. Therefore, caution is required, as for any other may have influenced leucopenia development as well, but as retrospective study, in the interpretation of the results. Due to universal prophylaxis was used; no further analysis on the the retrospective nature of the study, patient compliance was impact of Bactrim could be performed. also not determined. In our cohort, induction therapy with basiliximab, daclizu- In conclusion, valganciclovir is considered to have a compa- mab and ATG did not influence leucopenia development and rable tolerability and safety profile, even though high variability was not identified as a risk factor. Leucopenia is seen as a typi- in dosing patterns was observed in patients with low renal func- cal side effect of ATG : in one study, more patients in the tion (<25 mL/min). Standard dose or low dose of valganciclovir ATG group than in the basiliximab group developed leucopenia was comparable regarding CMV prevention and adverse events, (<2500/mm ) early after transplantation . A retrospective with fewer patients developing leucopenia with application of analysis revealed ATG use and African-American race as risk one dosing step below the recommended one without increas- factors for leucopenia . However, because of the predomi- ing the risk for developing CMV viraemia. nance of Caucasians and infrequent use of ATG, we could not investigate these risk factors in our cohort. Similar to another retrospective analysis , we identified Funding low GFR as a risk factor for leucopenia. Given the fact that we This work was funded by Roche. observed a large heterogeneity in the dose adjustments accord- ing to renal function this may indicate some overdosing in patients with low renal function. Also, Dþ/R patients were Conflict of interest statement almost three times more likely to develop leucopenia. This O.R. received an honorarium from Roche. M.N. has received two patient group may need a close follow-up after transplantation. travel grants in 2017 from Pfizer Germany. S.B. has received Although patients in the leucopenia group were older, age could honoraria and travel grants from Bristol-Myers Squibb, not be identified as a risk factor for leucopenia. Novartis, Roche, Pfizer and Alexion Astellas. O.S. has received Granulocyte colony-stimulating factor (G-CSF) use was reported in other transplant centres as a frequent (7.8–49%) an honorarium from Roche and Astellas. K.B. has received research funds and/or honoraria from Abbvie, Alexion, Astellas, treatment option for leucopenia [22, 27, 30]. In our cohort, only one patient was treated with filgastrim for leucopenia. The Bristol-Myers Squibb, Chiesi, Fresenius, Genentech, Hexal, most frequent treatment options for severe leucopenia were Novartis, Otsuka, Pfizer, Roche, Shire, Siemens and Veloxis MPA and/or valganciclovir dose reductions. In many cases, Pharma. D.S., A.H. and H.-H.N. have nothing to disclose. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/564/4803074 by Ed 'DeepDyve' Gillespie user on 07 August 2018 572 | O. Rissling et al. 18. Razonable RR, Hayden RT. 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Clinical Kidney Journal – Oxford University Press
Published: Aug 1, 2018
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