Presence of Vesicoureteral Reflux in the Graft Kidney Does Not Adversely Affect Long-Term Graft Outcome in Kidney Transplant Recipients

Presence of Vesicoureteral Reflux in the Graft Kidney Does Not Adversely Affect Long-Term Graft Outcome in Kidney Transplant Recipients

Presence of Vesicoureteral Reflux in the Graft Kidney Does Not Adversely Affect Long-Term Graft Outcome in Kidney Transplant Recipients S. Lee, H.H. Mo...

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Presence of Vesicoureteral Reflux in the Graft Kidney Does Not Adversely Affect Long-Term Graft Outcome in Kidney Transplant Recipients S. Lee, H.H. Moon, T.-S. Kim, Y. Roh, S. Song, M. Shin, J.M. Kim, C.H.D. Kwon, J.-W. Joh, S.-K. Lee, W.S. Huh, H.Y. Oh, and S.-J. Kim ABSTRACT Introduction. We studied the incidence of vesicoureteral reflux (VUR) in the graft kidney and its effect on the occurrence of urinary tract infection (UTI) and long-term graft function. Methods. We performed a retrospective analysis of 64 adult kidney transplant recipients based upon voiding cystourethrography at 12 months post-transplantation. Patients underwent analysis of survival, incidence of UTIs beyond 1 year, and graft function. Results. Thirty-seven male and 27 female patients in the study populations showed a mean age 42 years. VUR in the transplanted kidney at 12 months post-transplant occurred among 78.1% (50/64) of subjects: grade I (n ¼ 6), grade II (n ¼ 30), or grade III (n ¼ 14) reflux. Patients followed for a median 61 months (range 44e74s) showed 11 cases of UTIs in 9 subjects. There were no significant differences in clinical characteristics or incidence of, UTIs according to the presence or severity of VUR (P ¼ .81) or the Serum creatinine and estimated glomerular filtration rate values at 12, 36, 48, or 60 months post-transplantation. Conclusions. VUR present in 78.1% of patients after kidney transplantation affected neither graft functions or graft survival. The incidence of UTI did not differ according to the presence of VUR.

V

ESICOURETERAL REFLUX (VUR) is the abnormal movement of urine from the bladder into the ureter or kidney. VUR frequently observed in kidney transplantation (KT) may relate to the occurrence of adverse events such as urinary tract infection (UTI). However, several authors have reported varying results regarding the overall incidence of VUR in this setting. Also, there is controversy as to whether the presence of VUR in the graft has detrimental effects on its function and outcome.1e3 In this study, we performed voiding cystourethrography (VCUG) on KT recipients displaying normal graft function at 12 months, seeking to study the incidence of VUR as well as its impact on the occurrence of UTI and on long-term graft function. PATIENTS AND METHODS Patient Characteristics From April 2005 to January 2007, the 266 patients who underwent KT for end-stage renal disease were followed regularly in the outpatient clinic. At 12 months they were assessed for inclusion in the study, for VUR evaluation by VCUG namely age above 18 years 0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.057 2984

and presence of stable graft function. Patients were excluded if they had experienced a UTI during the first post-transplant year. Patients who gave written informed consent were included in the study. If the patient did not have evidence of an ongoing UTI, VCUG was performed to identify the presence of VUR in the transplanted kidney. VCUG was ultimately performed on 64 individuals. No prophylactic antibiotics were prescribed before or after VCUG. This cohort was followed for patient and graft survivals, UTI incidence and graft function, as assessed by serum creatinine

From the Department of Surgery (S.L., H.H.M., T.-S.K., Y.R., S.S., M.S., J.M.K., C.H.D.K., J.-W.J., S.-K.L., S.-J.K.) and Department of Medicine (W.S.H., H.Y.O.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to Sung-Joo Kim, MD, PhD, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnamgu, Seoul 135- 710, Korea. E-mail: [email protected]

Crown Copyright ª 2013 Published by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 45, 2984e2987 (2013)

PRESENCE OF VESICOURETERAL REFLUX

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Table 1. Patient Characteristics Characteristics, n (%)

Gender Male Female Age (y, mean  SD) Graft type Living donor Deceased donor PRA 2nd KT HLA mismatch Vesicoureteral reflux No reflux Grade I Grade II Grade III

n ¼ 64

37 (57.8) 27 (42.2) 42  12 49 (76.6) 15 (23.4)

14 6 30 14

(21.8) (9.5) (46.9) (21.8)

SD, standard deviation; PRA, panel-reactive antibody; KT, kidney transplantation; HLA, human leukocyte antigen.

and estimated glomerular filtration rate (eGFR), which was calculated by the Modification of Diet in Renal Disease formula. The presence of UTI was routinely assessed at each visit to the outpatient clinic. UTI was considered to be present when >105 colony-forming units of a single organism were cultured from a midstream urine or when the clinical and urine laboratory data suggested an infection no microbiologic isolation followed by complete resolvation with antibiotic therapy.4 Treatment with empirical antibiotics was begun as soon as UTI was clinically suspected; The regimen was adjusted based upon urine culture results. Reconstruction of the continuity of the urinary tract during kidney transplantation was performed using the extravesical LichGregoir ureteroneocystostomy, technique. This study was approved by our Institutional Review Board.

Classification of VUR VUR was classified according to the International Reflux group based upon the degree of reflux and presence of ureteral or renal pelvis dilatation on VCUG.5 Grade I VUR is reflux into a nondilated ureter; grade II, into the renal pelvis and calyces without dilatation. Grade III is mild to moderate dilatation of the ureter, renal pelvis, and calyces with minimal blunting of the fornices; grade IV, dilatation of the renal pelvis and calyces with moderate ureteral tortuosity; and grade V, gross dilatation of the ureter, pelvis and calyces; with ureteral tortuosity and loss of papillary impressions.

Immunosuppression KT recipients were prescribed basiliximab or thymoglobulin induction for immunosuppression during the operation. Maintenance immunosuppression consisted of a calcineurin inhibitor (cyclosporine or tacrolimus), mycophenolate mofetil and steroids.

Statistical Analysis Independent sample t-tests (or Mann-Whitney test, when necessary) were used to compare continuous variables; c2 tests (or Fisher exact test, when necessary), for categorical variables. Multiple linear regression was employed analyze factors contributing to posttransplant renal function as measured by serum creatinine. A

Table 2. Characteristics and Clinical Outcome of Patients According to Degree of Vesicoureteral Reflux No reflux (n ¼ 14)

Gender Male Female Age (y, mean  SD) Cause of ESRD Diabetes mellitus Hypertension Glomerulonephritis IgA nephropathy PCKD Unknown Graft type Living donor Deceased donor Cold ischemia time (min, median  IQR) Bladder capacity (mL, median  IQR) Urinary tract infection Yes No

6 (57.1%) 8 (42.9%) 42.6  12.7 2 (14.3%) 0 2 (14.3%) 1 (7.1%) 1 (7.1%) 8 (57.1%)

Mild reflex (n ¼ 36)

Moderate reflux (n ¼ 14)

P value

25 (30.6%) 6 (57.1%) .10 11 (69.4%) 8 (42.9%) 39.8  9.9 45.9  13.9 .23 2 2 5 8

(5.6%) (5.6%) (13.9%) (22.2%) 0 19 (52.8%)

1 1 4 3 1 4

(7.1%) (7.1%) (28.6%) (21.4%) (7.1%) (28.6%)

.56

10 (28.6%) 27 (25.0%) 12 (14.3%) .78 4 (71.4%) 9 (75.0%) 2 (85.7%) 112  96.8 75.5  61.8 56.5  38.5 .18

410  167.5 430  140

2 (16.7) 12 (83.3)

4 (11.9) 32 (88.1)

400  92.5 .56

3 (18.2) 11 (31.8)

.71

ESRD, end-stage renal disease; PCKD, polycystic kidney disease; SD, standard deviation; eGFR, estimated glomerular filtration rate; IQR, interquartile range.

mixed model was used to compare within-group, between-group, and interaction effects of repeated measured of serum creatinine and eGFR. All analyses were performed with IBM SPSS Statistics version 17 program. Results were considered to be significant when P values were less than .05.

RESULTS Incidence and Severity of VUR

The 37 male and 27 female patients in the study population. Showed a mean age 42 years. Their characteristics are outlined in Table 1. The median time to the 64 VCUG examinations was 12 months following transplantation (range, 10e18). Incidence of VUR in the transplanted kidney at 12 months posttransplant was 78.1% (50/64). They included grade I (n ¼ 6), grade II (n ¼ 30), grade III (n ¼ 14) degrees of reflux. There were no cases of grade IV or V reflux. Clinical Outcome of KT Recipients

Patients were followed for a median of 61 months (range 44e74) after transplantation and 49 months (range, 31e61) after VCUG. There were no graft losses during this period except for 1 patient who with a functioning graft died due to fulminant hepatitis with subsequent hepatic failure. During this period we observed 11 cases of UTIs in 9 patients. Median time between KT and first UTI episode was 32 months (range 13e68). All UTIs required hospital admission; they were resolved with antibiotic therapy.

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Table 3. Multivariate Analysis of Renal Function Measured by Serum Creatinine at 36, 48 and 60 Months After Kidney Transplantation According to Various Clinical Factors 36 mo

Age Donor type Deceased donor Living donor Acute rejection Yes No Urinary tract infection* Yes No Vesicoureteral reflux No reflux Mild reflux Moderate reflux

48 mo

HR

95% CI

P value

HR

0.005

0.012e0.001

.101

0.005

0.071

0.096e0.238

.399

0.102

0.063e0.267

0.009

0.052 0.029

95% CI

60 mo P value

HR

95% CI

P value

0.014e.004

.310

0.003

0.012e0.005

.406

0.167

0.068e0.402

.160

0.129

0.099e0.356

.258

.221

0.042

0.191e0.274

.721

0.155

0.093e0.404

.213

0.201e0.219

.930

0.174

0.125e0.473

.249

0.074

0.238e0.387

.631

0.201e0.219 0.203e0.145

.600 .739

0.079 0.089

0.364e0.205 0.158e0.336

.579 .475

0.107 0.014

0.478e0.263 0.249e0.221

.560 .903

HR, hazard ratio; CI, confidence interval. *Urinary tract infection after 1 year post-transplant.

Positive urine culture results in 10/11 cases showed the causative pathogens to be Escherchia coli (n ¼ 7) cases and K pneumoniae (n ¼ 3) cases. Four UTIs occurred within 1 week following VCUG. Urinary complications such as urinary leakage or ureteral stricture were not observed in these patients during the study period. No patient required surgical treatment (eg, ureteroureterostomy) to correct a severe VUR with recurrent UTI.

Outcome of Graft Function According to VUR Severity

Fig 1. Serum creatinine following kidney transplantation according to presence and severity of vesicoureteral reflux at 12-month post-transplant voiding cystourethrography.

Fig 2. Estimated glomerular filtration rate (eGFR) following kidney transplantation according to presence and severity of vesicoureteral reflux at 12-month post-transplant voiding cystourethrography.

Patients were classified into 3 groups according to the presence and degree of VUR: no reflux group, grade I and grade II as mild reflux, and grade III as moderate reflux. Patients in the 3 groups did not show significant differences either in terms of their clinical characteristics (Table 2) or incidence of UTIs (P ¼ .81). We employed multivariate analysis to analyze the contribution of various clinical factors to post-transplant

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PRESENCE OF VESICOURETERAL REFLUX

renal function as measured by serum creatinine at 36, 48, and 60 months. The included clinical factors were recipient age, donor type, acute rejection episode, presence of UTI after 1 year post-transplant, and VUR. All factors, including the existence and severity of VUR, did not significantly influence graft function (Table 3). Change in graft function was assessed by serum creatinine and eGFR during a median follow-up of 61 months. There were no significant differences among the 3 groups in serum creatinine (P ¼ .13) or eGFR (P ¼ .78) at 12, 36, 48, or 60 months posttransplantation. Changes in serum creatinine (P ¼ .16) and eGFR (P ¼ .12) over time after transplantation were not different among the 3 groups (Figs 1 and 2). DISCUSSION

The true incidence of VUR after KT remains a topic of controversy. Incidences of VUR among routine examinations of transplant recipients range from 1 to 86%.6e9 However, the reported incidence of VUR when a VCUG is performed among cases of recurrent UTI is usually less than 2%.10,11 This obvious discrepancy shows that the majority of VUR in KT recipients remain asymptomatic, possibly due to the mild severity of the reflux. A study of 37 KT recipients who underwent VCUGs at 12 months showed VUR in 41% of patients; grade I VUR comprised the majority of cases (26%). There were no grade IV or V VUR.12 The present study, investigating the presence of VUR on a routine VCUG performed at 12 months post-KT, showed 36/50 patients with mild VUR (grade I or II), while none had grade IV or V VUR. Our patients’ urinary tract reconstruction procedures were performed by the Lich-Gregoir ureteroneocystostomy technique. The submucosal tunnel constructed with this technique is intended to act as an antireflux mechanism. However, published reports do not support the effectiveness of the intended antireflux function. Analyses comparing VUR in KT recipients after antireflux and non-antireflux ureteroneoeystostomy could not show meaningful differences between the 2 groups.13,14 The effects of VUR on KT recipient outcomes of graft function, graft survival, or UTIs prevalence are unclear. In the past it was believed that VUR may have detrimental effects on the grafted kidney leading to functional, deterioration mimicking chronic rejection.15 Other studies have shown conflicting results ranging from no effect to increased graft.1,2,8 Our results showed no difference in graft survival or incidence of UTI between patients with no VUR, mild VUR, or moderate VUR after median of 61 months, followup. Graft function, as assessed by serum creatinine and eGFR, and change in graft function were not different during the 5 years following KT in these patients. An important detail that should be pointed out is that 4 cases of UTI were diagnosed within 1 week following VCUG. A causal relationship can be speculated between

the 2 events, considering their temporal relationship. Given the fact that in our study, the presence of VUR at 12 months post-KT did not affect graft function or the incidence of UTI or graft failure, VCUG as a part of routine post-KT evaluation for VUR should be considered with caution. In conclusion, among a cohort of KT recipients who underwent routine VCUG at 12 months post-KT, VUR was present in 78.1% of cases. However, the presence of VUR did not affect graft function or survival. The incidence of UTI was also not different according to the presence of VUR, but 4 patients experienced procedure-related UTI following VCUG. Thus it can be suggested that routine analyses for presence of VUR should not be considered; VCUG should be performed with caution in KT recipients.

REFERENCES 1. Engelstein D, Dorfman B, Yussim A, et al. A critical appraisal of vesicoureteral reflux in long-term renal transplantation recipients: prospective study. Transplant Proc. 1997;29:136. 2. Mastrosimone S, Pignata G, Maresca MC, et al. Clinical significance of vesicoureteral reflux after kidney transplantation. Clin Nephrol. 1993;40:38. 3. Park CH, Ryu DS, Kim KS, et al. Vesicoureteric reflux following renal transplantation: significance and risks. Transplant Proc. 1994;26:2191. 4. Trouillhet I, Benito N, Cervera C, et al. Influence of age in renal transplant infections: cases and controls study. Transplantation. 2005;80:989. 5. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. Pediatrics. 1981;67:392. 6. Hooghe L, Kinnaert P, Schulman CC, et al. Ureterocystostomy in renal transplantation: comparison of endo- and extravesical anastomoses. World J Surg. 1977;2:231. 7. Barry JM. Unstented extravesical ureteroneocystostomy in kidney transplantation. J Urol. 1983;129:918. 8. Jung GO, Chun JM, Park JB, et al. Clinical significance of posttransplantation vesicoureteral reflux during short-term period after kidney transplantation. Transplant Proc. 2008;40:2339. 9. Latchamsetty KC, Mital D, Jensik S, et al. Use of collagen injections for vesicoureteral reflux in transplanted kidneys. Transplant Proc. 2003;35:1378. 10. Moreira P, Parada B, Figueiredo A, et al. Comparative study between two techniques of ureteroneocystostomy: Taguchi and Lich-Gregoir. Transplant Proc. 2007;39:2480. 11. Secin FP, Rovegno AR, Marrugat RE, et al. Comparing Taguchi and Lich-Gregoir ureterovesical reimplantation techniques for kidney transplants. J Urol. 2002;168:926. 12. Favi E, Spagnoletti G, Valentini AL, et al. Long-term clinical impact of vesicoureteral reflux in kidney transplantation. Transplant Proc. 2009;41:1218. 13. Lucas BA, McRoberts JW, Curtis JJ, et al. Controversy in renal transplantation: antireflux versus non-antireflux ureteroneocystostomy. J Urol. 1979;121:156. 14. Starzl TE, Shapiro R, Tzakis A, et al. A new technique of extravesical ureteroneocystostomy for renal transplantation. Transplant Proc. 1989;21:3856. 15. Mathew TH, Kincaid-Smith P, Vikraman P. Risks of vesicoureteric reflux in the transplanted kidney. N Engl J Med. 1977;297:414.