Infectious Complications in the First Year Post Renal Transplantation

Infectious Complications in the First Year Post Renal Transplantation G. Kosmadakis, G.L. Daikos, I.D. Pavlopoulou, A. Gobou, A. Kostakis, H. Tzanatou-Exarchou, and J.N. Boletis ABSTRACT Background. The aim of this study was a prospective assessment and determination of risk factors for infections among renal transplant recipients (Rtr) during the 1st year after renal transplantation (Rtx). Methods. From June 2004 to October 2005, we performed 133 Rtx in 88 men and 45 women of overall mean age of 46 ⫾ 14 years (range; 13–75). Results. During the first year post-Rtx, 88 (58 men and 30 women) infectious episodes were observed in 60 patients (45%). Thirty-nine (65%) required ⱖ1 hospitalization. Most common was urinary tract infections (UTI; 54 episodes; 61%). The causative organism was identified in 61 of the 88 (69%) episodes: In 51 it was bacterial, in 8 cytomegalovirus (CMV), and in 2 fungi. Forty-three episodes (49%) were observed during the first 3 months; 22 (25%) between 3 and 6 months and 23 (26%) between 6 and 12 months post-Rtx. There were no significant differences between patients with versus without hospitalization owing to infections with regard to recipient gender and age, duration of dialysis pre-Rtx, donor kidney source, acute rejection episodes, donor age, or arterial hypertension. Diabetes was a significant risk factor for infections (odds ratio [OR], 1.154; 95% confidence interval [CI], 1.045–1.274; P ⫽ .001], as well as an immunosuppressive regimen that included tacrolimus, mammalian target of rapamycin inhibitor, corticosteroids, and anti-interleukin-2 monoclonal antibody as initial treatment (OR, 3.053; 95% CI, 1.007–9.349; P ⫽ .043). There was an increased prevalence of CMV infections after the chemoprophylaxis period (OR, 0.456; 95% CI, 0.358 – 0.580; P ⫽ .002). Mean duration of hospitalization was 11.5 days (range, 2–109). In 3 of 133 (5%) Rtr, the outcome was fatal. Conclusion. The frequency of infections during the 1 st year post-Rtx is influenced by the primary disease of the Rtr as well by the choice of immunosuppressive regimen. UTI remains the commonest infection, accounting for half of all infections in the first 3 months post-Rtx. There was an increased risk for CMV infection after the chemoprophylaxis period. N THE EARLY years of transplantation, infection represented a serious therapeutic challenge. It was the commonest cause of death among renal transplant recipients (Rtr).1 Strategies to optimize immunosuppression and the development of antirejection agents with more specific targets have significantly reduced infection-related complications. However, infections are still the second most common cause of death among Rtr, namely, 20.9% of recipients in the United States (2005–2007) with the commonest cause being cardiovascular events.2 Although the overall prevalence of infections and their associated mortality have decreased over time since the early days of

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transplantation, they have remained stable over recent years.3,4 Urinary tract infections (UTI) are the leading cause of infection and hospitalization in renal transplant recipients albeit without contributing significantly to mortality with sepsis and pneumonia causing 70% of deaths.2,5 From the Renal Transplant Unit (G.K., A.G., J.N.B.), Laiko Hospital, and the University of Athens (G.L.D., I.D.P., A.K., H.T.-E.), Athens, Greece. Address reprint requests to George Kosmadakis, 35 Metsovou str, 10683, Athens, Greece. E-mail: George.kosmadakis@ gmail.com

© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.10.047

Transplantation Proceedings, 45, 1579 –1583 (2013)

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Acute rejection episodes, the most frequent cause of hospitalization during the 1980s and 1990s, have significantly decreased since then. Patients transplanted in the United States during 2000 showed a hazard ratio for hospitalization due to infections that was double that for rejection during the first 2 years post-renal transplantation (Rtx).2 Although the high prevalence of infections in renal transplant recipients is ascribed to the consequences of immunosuppressive treatment, infection-associated mortality among dialysis patients on the waiting list for renal transplantation is greater than that observed among agematched transplant recipients.6 The main risk factors for developing infections in Rtr include environmental exposure and intensity of immunosuppression. The increasing well-being associated with successful Rtx may contribute to exposure or contact with environmental pathogenic agents by enabling recipients to expand their lifestyle, for example, with increased travel and participation in sporting activities. Other factors influencing infection risk include the duration and intensity of the immunosuppressive regimen, including any preexistent immunosuppression before transplantation; the presence of foreign bodies; leukopenia and lymphocytopenia; metabolic conditions including uremia, malnutrition, and diabetes mellitus; infection with immunomodulating viruses such as Hepatitis B and C, cytomegalovirus (CMV), and Ebstein-Barr virus.7,8 Herein we have reported our single-center experience with infections in the first 12 months after Rtx using present immunosuppressive regimens. MATERIALS AND METHODS This prospective, observational study was performed in the Transplant Unit of a 450-bed tertiary care hospital located in Athens, Greece. All patients underwent Rtx between July 2004 and October 2005, being monitored for all infectious episodes within 1 year after transplantation. Collected information included patient demographics, underlying disease, dialysis modality or previous renal transplant, induction and maintenance immunosuppressive regimens, donor characteristics, and detailed information on each infectious episode.

Perioperative and Postoperative Care The kidney graft was placed in the right or left iliac fossa; the native kidneys were not removed. A pig tail ureteric catheter placed in the majority of recipients was removed at 1–3 months postoperatively. Urethral catheters were usually removed 1 week after surgery. Intraoperatively, all patients received methylprednisolone (500 mg) and cefazoline (1 g) intravenously. The choice of the immunosuppressive regimen was based on specific characteristics of recipients and donors, including age, history of hypertension or diabetes, levels of cytotoxic antibodies, histocompatibility status, human leukocyteantigen mismatches, and cold ischemia period. All recipients received induction therapy with an anti-interleukin (IL)2 receptor antagonist (daclizumab [n ⫽ 57] or basiliximab (n ⫽ 63). Maintenance immunosuppression included 2 drugs among mycophenolate mofetil, calcineurin inhibitors (cyclosporine or tacroli-

KOSMADAKIS, DAIKOS, PAVLOPOULOU ET AL mus), or mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) together with methylprednisolone at an initial dose 20 mg/d tapered to 4 mg/d by the end of 3 months posttransplantation. All patients received prophylaxis for 3 months with co-trimoxazole and valgancyclovir in doses adjusted for the recipient renal function. CMV serologic status of recipients and donors was determined by measuring specific immunoglobulin G (IgG) antibodies to CMV using an enzyme-linked immunosorbent assay method with Biokit reagents (Barcelona, Spain) in accordance with the manufacturer’s instructions. After discharge, all patients were followed at the outpatient clinic: Weekly for the first month and monthly thereafter. Routine laboratory tests were performed at each visit with additional diagnostic investigations when indicated.

Definitions An infectious episode was defined as a confirmed infection requiring hospital admission or every febrile episode with a clinicolaboratory diagnosis of infection. The site of infection was determined as urinary, intra-abdominal, vascular catheter-related, pulmonary, soft tissue, primary bloodstream, or unknown, according to Centers for Disease Control and Prevention definitions.9 CMV infection was defined as isolation of CMV virus or detection of viral proteins or nucleic acids in the blood. CMV disease was associated with the presence of organ-specific signs and/or symptoms.10 The study was approved by our institutional review board.

Statistical Analysis Data were analyzed using SPSS statistics software version 15 for Windows (SPSS, Inc., Chicago, Ill). Comparisons used the Chisquare test for categorical variables and Student’s t-test or the Mann–Whitney U test for continuous variables, as appropriate. To measure odds ratios of categorical data and their significance, we used the crosstabs method with risk estimation. All tests were 2 tailed; P ⬍ .05 was considered to be significant.

RESULTS Patient Characteristics

One hundred thirty-three patients (133) of overall mean age of 46 ⫾ 14 years (median, 47; range, 13–75), underwent Rtx during the study period. The grafts were obtained from a living donor in 63 and from a deceased donor in 70 cases. Before Rtx, 127 patients had been on hemodialysis and 11 on peritoneal dialysis. Eighteen had previously undergone a Rtx. The main causes of renal failure were polycystic kidney disease (n ⫽ 17; 12.8%), diabetic nephropathy (n ⫽ 8; 6%), IgA nephropathy (n ⫽ 9; 6.8%), vasculitis (n ⫽ 4; 3%), reflux nephropathy (n ⫽ 11; 8.3%), tubulointerstitial nephritis (n ⫽ 5; 3.8%), chronic glomerulonephritis (n ⫽ 8; 6%), focal segmental glomerulosclerosis (n ⫽ 11; 8.3%) or other diseases (n ⫽ 14; 10.6%), whereas the underlying disease was not identified among the remaining 46 patients (34.4%). One hundred five recipients (79%) were CMV seropositive and 28 (21%) seronegative. Regarding donors, 101 (76 %) were CMV positive and 32 (24%) CMV negative. Infection Episodes

During the study period, 88 infectious episodes occurred in 60 patients: 39 (65%) had one; 17, two; two, three; one,

INFECTIOUS COMPLICATIONS

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four; and another one, five infectious episodes. The most common infections are shown in Table 1. One third of UTIs were associated with bacteremia. Nearly half of all infective episodes (43/88; 49%) occurred during the first 3 months after transplantation, 22 (25%) between 3 and 6 months, and 23 (26%), between 6 and 12 months. The mean duration of hospital stay for each infectious episode was 14.23 ⫾ 13.05 days (median, 11.5; range, 2–109). None of 8 patients with active CMV infection were recipient negative (R⫺) and donor negative (D⫺); 3 were R⫹/D⫺ (new infections) and 5 R⫹/D⫹ (reactivations). All CMV infections occurred after discontinuation of CMV prophylaxis: two between 3 and 6 months and six between 6 and 12 months after transplantation. Two of these patients were considered to have CMV disease (pneumonia, 1; colitis, 1) and six, CMV syndrome. All patients were treated successfully with gancyclovir (Table 2). Risk Factors

To identify possible prognostic or risk factors, we compared the characteristics of the 60 patients with infections with the 73 patients without infections (Table 3). The only significant risk factor for infections during the first year post-Rtx were diabetic nephropathy as the cause of end-stage renal disease (ESRD) (odds ratio [OR], 1.154; (95% confidence interval [CI], 1.045–1.274; P ⫽ .001); and an immunosuppressive protocol including tacrolimus–mTOR inhibitor– steroids with anti-IL2R monoclonal antibody (OR, 3.053; 95% CI, 1.007–9.349; P ⫽ .043). There was an increased prevalence of CMV infection after the completion of valgancyclovir prophylaxis (OR, 0.456; 95% CI, 0.358 – 0.580; P ⫽ .002), associated with a previous duration of hospitalization for the infection episode of ⬎21 days (OR, 6.222; 95% CI, 1.407–27.518; P ⫽ .008). There were no other differences between patients with CMV and those with other infections (Table 4). Outcome

Three of 60 patients (5%) with infectious episodes had fatal outcomes. A 53-year-old man admitted 4 months after transplantation with a respiratory infection; died 5 days later. A 66-year-old man admitted 9 months after transplantation with respiratory a infection died 34 days later, after a prolonged period of artificial ventilation: due to a respiratory infection with Pseudomonas aeruginosa and Klebsiella

Table 2. Infective Agents in Different Time Periods After Renal Transplantation Causative Agent

0–3 Months

Bacteria E coli K pneumoniae P aeruginosa Enterococci S aureus Other Viruses CMV Fungi C albicans P jiroveci Unknown

32 17 3 4 2 4 2 0 0 0 — — 11

3–6 Months 6–12 Months Total, n (%)

12 5 1 0 3 2 1 2 2 1 — 1 7

7 5 1 0 0 0 1 6 6 1 1 9

51 (58) 27 5 4 5 6 4 8 (9) 8 2 (2) 1 1 27 (31)

pneumoniae, as well as Enterococcus fecalis bacteraemia. A 43-year-old male Rtr was admitted 6 weeks after transplantation with septic shock owing to necrotizing cholecystitis and succumbed 3 days later with acute respiratory distress syndrome. DISCUSSION

In the present study, we have described the characteristics of infections among Rtr in the first year post-transplantation. Nearly half of our patients were admitted for an infectious episode during that time period. In a Dutch study in 2001, 71% of recipients were admitted with an episode during the first year post-transplantation, a rate significantly higher than ours.11 Almost one third of the infectious episodes happened during the first month, an alarming prevalence comparable to that described in the literature. By the end of the 3rd month, we observed half of the total number of infectious episodes. The United States Renal Data System has reported admission rates owing to infections during the first year post-transplant to rise from 32% to 38% between 1994 and 2004. This incidence was lower than that in study, possibly owing to variable criteria for patient admission and the presence of day care units in many US centers that have contributed to reduced hospital in-patient admissions.12,13 These variables reflect the difficulty in comparing infection prevalences among centers and countries. Nevertheless, our study confirmed that post-transplant infection is a persis-

Table 1. Type of Infection in Different Periods Post-transplantation Site of Infection

0–3 months, n

3–6 months, n

6–12 months, n

Total, n (%)

Urinary tract Respiratory Skin/soft tissue Intra-abdominal Intravascular line Primary bacteremia Other Total, n (%)

31 5 — 1 3 1 2 43 (49)

6 6 1 2 — — 7 22 (25)

9 5 1 — — — 8 23 (26)

46 (53) 16 (18) 2 (2) 3 (3.5) 3 (3.5) 1 (1) 17 (19) 88 (100)

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KOSMADAKIS, DAIKOS, PAVLOPOULOU ET AL Table 3. Characteristics of Renal Transplant Recipients With and Without Infection

Gender (male/female) Recipient age (⬍65/ⱖ65 yrs) Renal replacement therapy (⬍5/ⱖ5 yrs) Primary renal disease (diabetic nephropathy/other) Acute rejection episode (yes/no) Induction immunosuppressive regimen (Tac-mTORi-Cs-anti-IL2R/other) Renal allograft donor (living/deceased) Donor arterial hypertension (yes/no) Donor age (⬍65/ⱖ65 yrs)

With Infection

Without Infection

OR (95% CI)

P

43/17 55/5 43/17 8/52 5/55 49/11

45/28 67/6 50/23 0/73 3/70 68/5

0.635 (0.305–1.323) 1.015 (0.294–3.505) 0.859 (0.407–1.815) 1.154 (1.045–1.274) 0.471 (0.108–2.059) 3.053 (1.007–9.349)

.224 .981 .691 .001 .308 .043

24/36 28/32 41/19

29/44 36/37 58/15

0.989 (0.492–1.986) 1.112 (0.561–2.204) 1.792 (0.816–3.933)

.974 .761 .144

Abbreviations: CI, confidence interval; IL, interleukin; mTORi, mammalian target of rapamycin inhibitor (sirolimus or everolimus); OR, odds ratio; Tac, tacrolimus.

tent and significant problem, despite newer immunosuppressive regimens and newer molecular diagnostic techniques.14 Among our cohort, the majority (61%) of infections during the first year post-transplantation were UTIs, mainly owing to Enterobacteriacae. This observation agrees with data from the United States and Holland where 40%– 60% of infections occurred in the urinary tract.11,15 In our study the most common bacterial cause of UTI was Escherichia coli in half of the cases, similar to the prevalence in the Dutch study.11 In the study from the United States, the commonest cause was Enterococcus spp. (one third of cases) and E coli, the second commonest (one fifth), presumably reflecting geographic differences in the prevalence of uropathogenic organisms.12 The prevalences of lower respiratory tract and CMV infections were similar to other recent reports.4,7 The 8 cases of hospitalization owing to CMV infections were all observed after the end of the 3-month chemoprophylaxis period, as reported elsewhere.16 A greater incidence was also observed among recipients of a CMV-seropositive donor kidney after the end of chemoprophylaxis period.17 Compared with non-CMV infection episodes, CMV disease showed a higher risk of a hospitalization over 21 days. In a recent Italian study on the prevalence their etiology and time of infections showed similar results to our study.18

Despite the proven effectiveness of prophylaxis of bacterial, P jiroveci and CMV infections, it seems that the first 3 months after transplantation remain the most dangerous concerning infectious episodes.19 The causative agents were isolated in two thirds of the episodes (61/88 episodes; 69%) and in almost half of them, E coli (27 episodes). When we reviewed the effects of immunosuppressive regimens, the regimen including tacrolimus–sirolimus/ everolimus–methylprednisolone– daclizumab was associated with significantly higher infection rates. The patients who received this intensive immunosuppressive regimen usually were characterized as high immunologic risk, namely, an high percentage of cytotoxic antibodies and/or positive B-flow cross-match. All patients with diabetes as the primary renal disease in our study were admitted with an infectious episode during the first year post-transplantation.20,21 This observation suggests the need for qualitative and quantitative modifications of prophylaxis schemes may be useful in these patients. The infection-related mortality during the first year postRtx was 5% for patients admitted with infections and 2.2% of the total cohort of transplanted patients. In a singlecenter, prospective trial by Maraha et al with relatively similar study characteristics, the mortality rate owing to infections was 2.7%, which was slightly higher than that in

Table 4. Comparison of Renal Transplant Recipients With and Without CMV Infection

Gender (male/female) Recipient age (⬍65/ⱖ65 yrs) Transplantation duration (⬍3/ⱖ3 mos) Renal replacement therapy (⬍5/ⱖ5 yrs) CMV donor (IgG⫹/IgG⫺) CMV recipient (IgG⫹/IgG⫺) Induction immun/nosuppression (Tac-mTORi-Cs-anti-IL2R/other) Renal allograft donor (living/Nonliving) Donor age (⬍65/ⱖ65 yrs) Duration of hospital Stay (⬍21/⬎21 days)

No CMV infection

CMV infection

OR (95% CI)

P

52/28 62/18 44/36 54/26 23/57 17/63 17/63 34/46 42/38

6/2 7/1 0/8 6/2 2/6 3/5 2/6 3/5 6/2

0.520 (0.101–2.677) 0.424 (0.050–3.616) 0.456 (0.358–0.580) 1.019 (0.236–4.403) 1.625 (0.184–14.382 0.548 (0.124–2.424) 1.042 (0.198–5.483) 0.944 (0.236–3.785) 0.308 (0.60–1.577)

.096 .420 .002 .980 .660 .423 .961 .936 .140

71/9

4/4

6.222 (1.407–27.518)

.008

Abbreviations: CI, confidence interval; CMV, cytomegalovirus; Cs, cyclosporine; IgG, immunoglobulin G; IL, interleukin; mTORi, mammalian target of rapamycin inhibitor; OR, odds ratio; Tac, tacrolimus. Prophylaxis with valgancyclovir was given in all patient for 3 months post-transplantation.

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the present study.11 Mortality rates have improved in the long term, but they have remained relatively stable over the last years. In a recent study from Spain, infections were the second commonest cause of death among renal Rtr; they have not decreased during the last 10 years.22 In our study, it is worth noting that no UTI was fatal, despite one third of them being accompanied by septicemia. REFERENCES 1. Washer GF, Schröter GP, Starzl TE, et al. Causes of death after kidney transplantation. JAMA. 1983;250:49 –54. 2. USRDS. Annual report 2009. 3. Snyder JJ, Israni AK, Peng Y, et al. Rates of first infection following kidney transplant in the United States. Kidney Int. 2009;75:317–326. 4. USRDS. Annual reports. 2000 –2008. 5. Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant. 2001;16(8):1545–1549. 6. Meier-Kriesche HU. Ojo Ao, Hanson JA, et al. Exponentially increased risk of infectious death in older renal transplant recipients. Kidney Int. 2001;59:1539 –1543. 7. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357:2601–2614. 8. KDIGO clinical practice guidelines for the care of kidney transplant recipients. Am J Transplant. 2009;Suppl 3):44 – 66. 9. Garner JS, Jarvis WR, Emori TG, et al. CDC definitions for nosocomial infections, 1988. Am J Infect Control. 1988;16:128 –140. 10. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34:1094 –1097. 11. Maraha B, Bonten H, van Hooff H, et al. Infectious complications and antibiotic use in renal transplant recipients during a 1-year follow-up. Clin Microbiol Infect. 2001;7:619 – 625.

1583 12. Dharnidharka VR, Caillard S, Agodoa LY, et al. Infection frequency and profile in different age groups of kidney transplant recipients. Transplantation. 2006;81:1662–1667. 13. USRDS. Renal Data Report, 2007. 14. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357:2601–2614. 15. Alangaden GJ, Thyagarajan R, Gruber SA, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant. 2006;20:401– 409. 16. RH Rubin. Nephrology forum: Infectious disease complications of renal transplantation Kidney Int. 1993;44:221–236. 17. Cervera C, Pineda M, Linares L, et al. Impact of valganciclovir prophylaxis on the development of severe late-cytomegalovirus disease in high-risk solid organ transplant recipients. Transplant Proc. 2007;39:2228 –2230. 18. Veroux M, Giuffrida G, Corona D, et al. Infective complications in renal allograft recipients: epidemiology and outcome. Transplant Proc. 2008;40:1873–1876. 19. Fox BC, Sollinger HW, Belzer FO, et al. A prospective, randomized, double-blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med. 1990; 89:255–274. 20. Rossing P. Diabetic nephropathy: worldwide epidemic and effects of current treatment on natural history. Curr Diab Rep. 2006;6:479 – 483. 21. Peleg AY, Weerarathna T, McCarthy JS, et al. Common infections in diabetes: pathogenesis, management and relationship to glycaemic control. Diabetes Metab Res Rev. 2007;23:3–13. 22. Linares L, Cofán F, Cervera C. Infection-related mortality in a large cohort of renal transplant recipients. Transplant Proc. 2007;39:2225–2227.