Clinical Significance of Posttransplantation Vesicoureteral Reflux During Short-Term Period After Kidney Transplantation

Clinical Significance of Posttransplantation Vesicoureteral Reflux During Short-Term Period After Kidney Transplantation G.O. Jung, J.M. Chun, J.B. Park, G.-S. Choi, C.H.D. Kwon, J.W. Joh, S.K. Lee, and S.J. Kim ABSTRACT Background. Urinary tract infection (UTI) may occur in the form of asymptomatic bacteruria but severe cases may cause life-threatening pyelonephritis or sepsis in immunosuppressed kidney transplant recipients. Vesicoureteral reflux (VUR) is one risk factor in the transplanted kidney. But controversy exists regarding the effect of VUR in terms of graft outcomes. The objective of this study was to analyze the clinical outcomes among patients with posttransplantation VUR. Patients and Methods. Between April 2005 and June 2006, we examined 75 patients with functioning grafts for more than 1 year by voiding cystourethrography at 1 year for the grade of posttransplantation VUR: group A, absent (n ⫽ 28) including grade I (n ⫽ 6) and II (n ⫽ 22); group B, including grade III (n ⫽ 17) and IV (n ⫽ 2). Patient characteristics included etiology of end-stage renal disease, duration of dialysis before transplantation, serum creatinine, creatinine clearance at 1 and 12 months after transplantation, and postoperative complications. The presence/absence of UTI, acute rejection, and graft loss were compared for significance. Result. Posttransplantation VUR present in 47/75 patients (61.3%) was over grade III in 19 patients. There was no difference in significant risk factors between the groups as well as between the reflux subgroups. VUR did not influence graft function with the only significant factor being acute cellular rejection. Conclusion. We failed to confirm a risk of developing posttransplantation VUR. Posttransplantation VUR did not negatively affect graft function; acute cellular rejection was the only factor that influenced it. Longer follow-up needs to be performed to clarify the long-term effects of posttransplantation VUR on graft function.

U

RINARY tract infection (UTI) may occur as asymptomatic bacteruria but severe cases may cause lifethreatening pyelonephritis or sepsis in immunosuppressed kidney transplant recipients. Vesicoureteral reflux (VUR) is one risk factor for UTI. Preoperative VUR in recipients has been managed by ureteric reimplantation, endoscopic correction of reflux, native ureteral ligation, and bilateral native nephrectomy during the pretransplantation or posttransplantation phases to prevent UTI.1,2 But controversy exists regarding the effect of VUR on transplanted kidneys in terms of graft outcome.3–5 This study analyzed the impact of posttransplantation VUR on short-term clinical outcomes. We also evaluated whether surgical correction was necessary in the highest grade of posttransplantation VUR.

PATIENTS AND METHODS We retrospectively reviewed patients who had 1-year survival of kidney transplantations between April 2005 and June 2006, and who had undergone voiding cystourethrography before and 12 months thereafter. These 75 cases were of mean age 41.6 years (range, 18 – 64 years). Grading of VUR was performed according to the international grading system using X-ray voiding cystourethrography. The exclusion criteria included the following: (1) age younger than 15 years, (2) end-stage renal disease (ESRD) due to From the Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Address reprint requests to Sung-Joo Kim, Department of Surgery, Samsung Medical Center, 50 Ilwon-Dong, KangnamGu, Seoul 135-710, Korea. E-mail: [email protected]

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0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.06.027

Transplantation Proceedings, 40, 2339 –2341 (2008)

2339

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JUNG, CHUN, PARK ET AL

obstructive uropathy, (3) retransplantation, and (4) renal transplantation combined with another organ. In all recipients, ureteral implantation at the time of kidney transplantation was performed by the extravesical technique of Liche without a stent. To prevent UTI after transplantation, chemoprophylaxis was managed with trimethoprim-sulfamethaxazole for 1 year. If the pretransplantation VUR was greater than grade III, we performed simultaneously nephrectomy of the native kidney at the time of kidney transplantation. The patients were divided into 2 groups according to the grade of posttransplantation VUR: group A consisted of the 57 patients who had no or, grade I or II VUR after 12 months; whereas, group B included 18 patients with grade III or IV. The data included age, gender, dialysis duration before transplantation, immunosuppression, graft type, ischemic time, evidence of acute cellular rejection, UTI, pretransplantation and posttransplantation VUR including grade and bladder capacity, serum creatinine level, creatinine clearance at 1 and 12 months after transplantation, and delta creatinine clearance rate at 1 year. UTI was defined as the presence of ⱖ105 colony forming units per milliliter of bacteria without fever and leukocytosis. Complicated UTI was defined as the association of UTI and fever ⬎38°C. Statistical analysis was performed with Student t test for continuous variables and chi-square test for categorical variables using SPSS 12 (SPSS Inc, Chicago, Ill, United States). Statistical significance was considered when the P value was ⬍.05.

RESULT

The mean patient age was 41.6 years with 43 males and 32 females. Seventeen of the kidneys were from deceased donors and 58 were from living related donors. Twenty patients experienced at least one episode of acute cellular rejection (26.7%) during 1 year follow-up. UTI detected in 18 cases (24%) was complicated in 5/18 instances (6.7%). VUR occurred in 47/75 cases (61.3%), including 6 cases of grade I (12.7%), 22 cases of grade II (46.8%), 17 cases of grade III (36.2%), and 2 cases of grade IV (4.2%; Table 1). No significant difference was shown between the 2 groups in term of age (41.5 ⫾ 11.2 vs 42.0 ⫾ 11.5 years), gender (male:female, 1.16:1 vs 2:1), type of graft, protocol of Table 1. Demographic Details of the 75 Patients Profile

Patients (n ⫽ 75)

Age (y ⫾ SD) Gender Male Female Graft type Living Cadevaric Incidence of ACR Incidence of VUR Grade I Grade II Grade III Grade IV UTI Asymptomatic Complicated

41.6 ⫾ 10.8

Abbreviation: ACR, acute cellular rejection.

%

Table 2. Comparison of the 2 Groups According to Posttransplantation VUR Group A (n ⫽ 57)

Age (y ⫾ SD) Gender Male Female Graft type Living Cadevaric Causes of CRF Unknown IgA nephropathy GN Hypertension DM ADPCK Grade of pretransplantation VUR Grade I and II Grade III and IV* Duration of dialysis (mo) Pretransplantation VCUG bladder volume (mL ⫾ SD) Induction No induction ATG Anti-IL2RA Maintenance Cyclosporine FK 506 Cold ischemic time (min ⫾ SD) Warm ischemic time (min ⫾ SD) Posttransplantation VCUG bladder volume (mL ⫾ SD)

41.5 ⫾ 11

Group B (n ⫽ 18)

P

42.0 ⫾ 11

.82

29 25

14 7

.78 .78

44 13

18 4

.95 .95

30 6 12 5 2 2

8 2 4 2 0 2

.41

6 4 35.8 ⫾ 38.6 337.6 ⫾ 153.1

1 1 29.5 ⫾ 31.4 352.7 ⫾ 117.6

.82

43 3 11

12 2 4

.59

50 7 110.5 ⫾ 93.0

14 4 133.6 ⫾ 116.4

.44

35.5 ⫾ 16.9

31.5 ⫾ 5.3

.34

407.0 ⫾ 96.3

420.0 ⫾ 74.9

.61

.60 .70

.39

Abbreviations: CRF, chronic renal failure; lg, immunoglobulin; GN, glomerulonephritis; DM, diabetes mellitus; ADPCK, autosomal dominant polycystic kidney; NVUR, non-vesicoureteral reflux; VCUG, voiding cystourethrography; ATG - rabbit antithymocyte globulin; anti-IL2RA - antiinterleukin2 receptor antibody. *Nephrectomy with kidney transplantation.

Table 3. Comparison of the 2 Groups According to Clinical Course 43 32

57.3 42.7

58 17 20 47 6 22 17 2

77.3 22.7 26.7 61.3 12.7 46.8 36.2 4.2

13 5

24

Creatinine (mg/dL ⫾ SD) 1 mo 12 mo Creatinine clearance (mL/min ⫾ SD) 1 mo 12 mo Delta Ccr (mL/min/y) Rate of rejection Rate of UTI Asymptomatic Complicated

Group A

Group B

P

1.09 ⫾ 0.27 1.19 ⫾ 0.28

1.20 ⫾ 0.31 1.21 ⫾ 0.23

.15 .75

62.6 ⫾ 14.0 62.3 ⫾ 16.9 0.63 ⫾ 16.2 12 15

63.0 ⫾ 16.6 63.2 ⫾ 13.1 ⫺0.2 ⫾ 13.1 8 3

.92 .83 .84 .05 .53

12 3

1 2

.42 .59

VESICOURETERAL REFLUX

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Table 4. Effect on Graft Function According to Development of ACR and UTI ACR

Creatinine 12 mo Ccr 12 mo

UTI

(⫺)

(⫹)

P

(⫺)

(⫹)

P

1.12 ⫾ 0.23 65.6 ⫾ 15.5

1.40 ⫾ 0.27 54.0 ⫾ 14.2

⬍.0001 .005

1.21 ⫾ 0.28 63.7 ⫾ 15.4

113 ⫾ 0.25 58.6 ⫾ 17.4

.26 .23

immunosuppression, and cause of ESRD. Duration of dialysis, cold ischemic time, warm ischemic time, bladder capacity pretransplantation and posttransplantation, or voiding cystourethrography showed no significant difference (Table 2). The mean value of serum creatinine and creatinine clearance at 1 and 12 months after kidney transplantation was not significant. The incidence of posttransplantation VUR was 61.7% (47/75 cases). Grade III or IV, which raise the possibility of surgical or nonsurgical correction, occurred in 19/75 cases (25.3%). The incidence of acute cellular rejection was 20 cases: group A, 12/57 (21.4%) versus group B, 8/18 (44.4%) (although there was no significant difference [P ⫽ .052]. The prevalence of UTI among group A and B subjects were 15/57 (26.3%) and 3/18 cases (16.7%), respectively, with complicated instances in 3 (5.3%) and 2 cases (11.1%), respectively. There was no significance between the 2 groups in terms of UTI (Table 3). There was a significant difference between graft function and the occurrence of acute cellular rejection (P ⬍ .001). No significant difference emerged between the incidences of UTI and graft function (Table 4). The complication rate among group A was 5/57 (8.75%) (lymphocele, 2 cases; postoperative bleeding, 1 case; and wound complication, 2 cases) and among group B was 1/18 (5.5%) (lymphocele, 1 case) but there was no significant difference between the 2 groups.

episode.7 In our study, the incidence of UTI after transplantation was 24%. This incidence was below the average of other reports. Our lower incidence of UTI during the first year after transplantation may be the effect of nephrectomy when VUR was detected and chemoprophylaxis after transplantation. But the best early strategy to prevent UTI is debatable. In terms of the relation to the clinical course and posttransplantation VUR, Erturk et al1 reported that no significance of surgical correction of VUR before transplantation and persistent VUR in terms of posttransplantation UTI. Fontana et al8 suggested that VUR does not seem to negatively affect graft function. Also, they could not confirm that posttransplantation VUR to the graft correlated with its function or with the incidence of UTI as a reflection of the highest grade of posttransplantation VUR during the short term after transplantation. In the present study, this risk factor only had a bad influence on graft function where there was rejection. In conclusion, although the follow-up period is short, this study showed that the highest grade of posttransplantation VUR had no effect on graft function or prevalence of UTI. Thus, although the highest grade of posttransplantation VUR (grade III or IV) is detected, it would be better to carefully oberve than to consider early surgical correction. However, to clarify, this matter requires medium- and long-term follow-up. REFERENCES

DISCUSSION

The incidence of UTI in renal transplantation patients continues to be high. VUR is a well-recognized risk factors for UTI. When routinely checked, the frequency of VUR to the graft varies from 2% to 86%. In our study the incidence of VUR was 61.3% (47/75 cases) with grade III or IV in 19/75 cases (25.3%). The overall incidence has been even reported to be higher in other studies. The mean cause of the higher incidence VUR is considered to be operative technique. Barrero et al6 recommended a longer submucosal tunnel for an antireflux mechanism in the Lich–Gregoir technique during implantation in children with VUR. In our center, extravesical ureteroneocystomy (Lich’s technique) was performed in all patients. The length of the incised bladder mucosa for ureteral implantation and of the intramuscular tunnel for the antireflux mechanism was only 1 to 1.5 cm and 2 cm, respectively, but we judged these lengths to be not as long as an antireflux mechanism. UTI is a common feature after kidney transplantation with an average of 60% of patients experiencing at least 1

1. Erturk E, Burzon DT, Orloff M, et al: Outcome of patients with vesicoureteral reflux after transplantation: the effect of pretransplantation surgery on posttransplant urinary tract infections. Urology 51(suppl5A):27, 1998 2. Palma PR, Ferreira U, Ikari O, et al: Subureteric lipoinjection for vesicoureteral reflux in renal transplant candidates. Urology 43:174, 1994 3. Park CH, Ryu DS, Kim KS, et al: Vesicoureteric reflux following renal transplantation: significance and risks. Transplant Proc 26:2191, 1994 4. Engelstein D, Dorfman B, Yussim A, et al: A critical appraisal of vesicoureteral reflux in long term renal transplantation recipients: prospective study. Transplant Proc 29:136, 1997 5. Mastrosimone S, Pignata G, Maresca CM, et al: Clinical significance of vesicoureteral reflux after kidney transplantation. Clin Nephrol 40:38, 1993 6. Barrero R, Fijo J, Fernandez-Hurtado M, et al: Vesicoureteral reflux after kidney transplantation in children. Pediatr Transplant 11:498, 2007 7. Part V, Horcickkova M, Matousovic K, et al: Urinary tract infection in renal transplant patients. Infection 13:207, 1985 8. Fontana I, Ginervri F, Arcuri V, et al: Vesicoureteral reflux in pediatric kidney transplants: clinical relevance to graft and patient outcome Pediatr Transplant 3:206, 1999