Background
Renal transplantation dramatically improves quality of life and life expectancy compared to conventional hemodialysis in end-stage renal disease (ESRD). In 2010, annual renal transplant rates in the United Stated and Denmark were 57.5 and 41.3 per million population, respectively [
1].
Immunosuppressive therapy in conjunction with per- and post-operative instrumentation of the urinary tract, renders renal transplant (RTx) recipients prone to infectious complications [
2]. In addition, RTx recipients often have various co-morbidities such as cardiovascular disease and diabetes mellitus, further increasing their risk of infection.
The most common bacterial infection following renal transplantation is urinary tract infection (UTI) including pyelonephritis [
3,
4], ranging from 7 to 86 % [
5,
6]. The incidence of UTI among RTx recipients has declined during the past three decades [
7]. However, previous studies have shown that RTx recipients may have an increased risk of UTI compared to the background population [
8‐
10]. It remains controversial whether UTI causes RTx recipients to be prone to graft loss and/or associated with an increased mortality rate.
The purpose of this nationwide population-based study was to determine the incidence of pyelonephritis and to identify risk factors for post-transplant pyelonephritis among RTx recipients and population controls, as well as to determine impact on graft survival and mortality in RTx recipients.
Results
Study population
The study population consisted of 2,656 RTx recipients and 49,226 matched population controls, yielding 14,121 and 447,976 person years of follow-up (PYFU), respectively. Median follow-up period was 4.3 years for RTx recipients and 8.7 years for population controls. A first-time hospitalisation for pyelonephritis was identified in 261 RTx recipients (9.8 %) and 115 population controls (0.2 %).
Incidence of pyelonephritis
The overall IR of first-time hospitalisation for pyelonephritis in the entire study period was 18.5 (CI: 16.4–20.9) per 1,000 PYFU among RTx recipients, and 0.26 (CI: 0.21–0.31) per 1,000 PYFU among population controls. A decrease in IR of first-time hospitalisation for pyelonephritis was observed among RTx recipients from 1990 to 2009, with a maximum of 30.0 hospitalisations per 1,000 PYFU (CI: 21.0–42.0) in 1990–94, and a minimum of 14.0 hospitalisations per 1,000 PYFU (CI: 11.0–17.0) in 2005–09 (Table
1). The relative risk of hospitalisation for pyelonephritis among RTx recipients was 0.46 (CI: 0.31–0.68) in 2005–09 compared to 1990–94.
Table 1
Incidence of first hospitalization for pyelonephritis in renal transplant recipients
Entire study period (1990–09) |
Renal transplant recipients | 261 | 14,121 | 18.5 (16.4–20.9) | 772.0 (57.8–89.7) | <.001 |
Population controls | 115 | 447,976 | 0.26 (0.21–0.31) | |
1990–1994: |
Renal transplant recipients | 35 | 1,175 | 30.0 (21.0–42.0) | 841 (115–-6138) | <.001 |
Population controls | 1 | 28,218 | 0.04 (0.01─0.25) | |
1995–1999: |
Renal transplant recipients | 67 | 2,974 | 23.0 (18.0–29.0) | 178 (94.1–337) | <.0001 |
Population controls | 11 | 86,904 | 0.13 (0.07–0.23) | |
2000–2004: |
Renal transplant recipients | 81 | 4,242 | 19.0 (15.0–24.0 | 75.6 (50.8–112) | <.0001 |
Population controls | 35 | 138,543 | 0.25 (0.18–0.35) | |
2005–2009: |
Renal transplant recipients | 78 | 5,731 | 14.0 (11.0–17.0) | 38.9 (28.1–53.8) | <.0001 |
Population controls | 68 | 194,311 | 0.35 (0.28–0.44) | |
Male: |
Renal transplant recipients | 122 | 9,373 | 13.0 (10.9–15.5) | 69.4(50.3–95.8) | <.0001 |
Population controls | 53 | 282,662.3 | 0.19 (0.14–0.25) | |
Female: |
Renal transplant recipients | 139 | 4,747.2 | 29.3(24.8–34.6) | 78.1(57.9–105) | <.0001 |
Population controls | 62 | 165,314.9 | 0.38(0.29─0.48) | |
<50 years |
Renal transplant recipients | 140 | 7,696 | 18.2(15.4–21.5) | 117 (79.8–170) | <.0001 |
Population controls | 33 | 211,410 | 0.16(0.11–0.22) | |
50–65 years: |
Renal transplant recipients | 98 | 5,235 | 18.7(15.4–22.8) | 81.7 (56.8–118) | <.0001 |
Population controls | 41 | 178,960 | 0.23(0.17–0.31) | |
65 + years: |
Renal transplant recipients | 23 | 1,190 | 19.3(12.8–29.1) | 127.2 (16.3–45.2) | <.0001 |
Population controls | 41 | 57,607 | 0.71(0.52–0.97) | |
The unadjusted risk of pyelonephritis among RTx recipients was very high compared to population controls (IRR = 72.0, CI: 57.8–89.7). Adjusting for calendar periods, age, gender and CCI score, only resulted in a modest change in the relative risk of pyelonephritis among RTx recipients (adjusted IRR = 63.9, CI: 50.2–81.3). The majority of hospitalisations for pyelonephritis (31.8 %) among RTx recipients were seen within the first six months post-transplantation.
Impact of comorbidity on risk of pyelonephritis
The risk of first-time hospitalisation for pyelonephritis was considerably higher in RTx recipients with a medium or high CCI score than in those with low CCI score (Table
2). Comparing RTx recipients without comorbidity (other than ESRD) and population controls without comorbidity yielded an IRR of 73.5 (CI: 56.1–96.3).
Table 2
Incidence rates and rate-ratios for pyelonephritis according to the burden of comorbidity
Renal transplant recipients | Low (0) | 1,393 (52.5) | 131 | 15.9 (13.4–18.9) | 73.5 (56.1–96.3) | <.0001 |
Population controls | Low (0) | 43,253 (87.9) | 88 | 0.22 (0.18–0.27) | 1 (Reference) | |
Renal transplant recipients | Medium (1–2) | 707 (26.6) | 60 | 17.8 (13.9–23.0) | 36.9 (21.5–63.2) | <.0001 |
Population controls | Medium (1–2) | 4,954 (10.1) | 17 | 0.48 (0.30–0.78) | 1 (Reference) | |
Renal transplant recipients | High ≥ 3 | 556 (20.9) | 70 | 27.9 (22.0–35.2) | 16.0 (8.2–31.0) | <.0001 |
Population controls | High ≥ 3 | 1,019 (2.1) | 10 | 1.74 (0.94–3.24) | 1 (Reference) | |
Risk factors for hospitalisation for pyelonephritis among RTx recipients
In RTx recipients risk factors for first-time hospitalisation for pyelonephritis in the adjusted analysis were female gender (IRR = 2.04, CI: 1.59–2.61); high compared to low CCI-score (IRR = 1.96, CI: 1.16–3.31); HLA-DR mismatch ≥2 vs ≤1 (IRR = 1.54, CI: 1.10–2.18); chronic interstitial nephritis (IRR = 2.53, CI: 1.66–3.85); hypertensive kidney disease (IRR = 1.59, CI: 1.06–2.37); polycystic kidney disease (IRR = 1.66, CI: 1.07–2.57); vasculitis (IRR = 2.61, CI: 1.28–5.30); post-transplant time (compared to 0–6 months: 7–12 months: IRR = 0.39, CI: 0.25–0.59 and 13–24 months: IRR = 0.24, CI: 0.16–0.37 and + 24 months: IRR = 0.18, CI: 0.13–0.24); calendar period (compared to 1990–1995: 2000–2004: IRR = 0.62, CI: 0.41–0.94 and 2005–2009: IRR = 0.42, CI: 0.27–0.64) (Table
3).
Table 3
Incidence of first hospitalization for pyelonephritis in renal transplant recipients according to potential risk factors for pyelonephritis
Recipient gender | | | | | |
Male | (122) | 13.0 (10.9–15.5) | 1 (Reference) | 1 (Reference) | |
Female | (139) | 29.3 (24.8–34.6) | 2.25(1.76–2.87) | 2.04(1.59–2.61) | <.001 |
Recipient, CCI-score | | | | | |
Low (0) | 131 | 15.9 (13.4–18.9) | 1 (Reference) | 1 (Reference) | |
Medium (1–2) | 60 | 17.8 (13.9–23.0) | 1.12 (0.83–1.52) | 0.98 (0.71–1.36) | .92 |
High (≥3) | 70 | 27.9 (22.0–35.2) | 1.75 (1.31–2.34) | 1.96 (1.16–3.31) | .01 |
Donor type | | | | | |
Cadaveric donor | 190 | 19.2 (16.6–22.1) | 1 (Reference) | 1 (Reference) | |
Living unrelated donor | 22 | 16.2 (10.7–24.6) | 0.85 (0.54–1.32) | 1.01 (0.65–1.58) | .95 |
Living related donor | 49 | 17.2 (13.0–22.8) | 0.90 (0.66–1.23) | 1.00 (0.71–1.39) | .98 |
HLA mismatch | | | | | |
AB mismatchc
| | | | | |
<3 | 122 | 18.6 (15.5–22.2) | 1 (Reference) | 1 (Reference) | |
≥3 | 46 | 16.6 (12.4–22.2) | 0.90 (0.64–1.26) | 0.88 (0.62–1.25) | .49 |
DR mismatchc
| | | | | |
<2 | 46 | 13.6 (10.2–18.1) | 1 (Reference) | 1 (Reference) | |
2 | 122 | 20.5 (17.2–24.5) | 1.51 (1.07–2.12) | 1.54 (1.10–2.18) | .01 |
Cause of ESRD | | | | | |
Glomerulonephritis | 46 | 10.3 (7.7–13.7) | 1 (Reference) | 1 (Reference) | |
Diabetes mellitus type 1 | 53 | 27.7 (21.2–36.2) | 2.69 (1.81–3.40) | 1.34 (0.73–2.48) | .35 |
Diabetes mellitus type 2 | 4 | 16.8 (6.33–44.9) | 1.64 (0.59–4.55) | 1.00 (0.33–2.99) | 1.00 |
Chronic interestitial nephritis | 44 | 31.7 (23.6–42.6) | 3.08 (2.04–4.66) | 2.53 (1.66–3.85) | <.001 |
Hypertensive kidney disease | 53 | 17.6 (13.4–23.0) | 1.71 (1.15–2.54) | 1.59 (1.06–2.37) | .02 |
Polycystic kidney disease | 39 | 19.2 (14.0–26.3) | 1.87 (1.22–2.86) | 1.66 (1.07–2.57) | .02 |
Vasculitis | 10 | 33.2 (17.9–61.7) | 3.23 (1.63–6.39) | 2.61 (1.28–5.30) | .01 |
Unkown | 12 | 15.9 (9.0–28.0) | 1.55 (0.82–2.92) | 1.18 (0.62–2.27) | .62 |
Posttransplant time | | | | | |
0–6 months | 83 | 69.9(56.4–86.7) | 1 (Reference) | 1 (Reference) | |
7–12 months | 29 | 26.9(18.7–38.7) | 0.38(0.25–0.59) | 0.39(0.25–0.59) | <.001 |
13–24 months | 33 | 16.9 (12.0–23.8) | 0.24 (0.16–0.36) | 0.24 (0.16–0.37) | <.001 |
+24 months | 116 | 11.7(9.8–14.0) | 0.17 (0.13–0.22) | 0.18 (0.13–0.24) | <.001 |
Recipient age | | | | | |
<50 years | 140 | 18.2 (15.4–21.5) | 1 (Reference) | 1 (Reference) | |
50–65 years | 98 | 18.7 (15.4–22.8) | 1.03 (0.79–1.33) | 1.06 (0.80–1.41) | .68 |
+65 years | 23 | 19.3 (12.8–29.1) | 1.06 (0.68–1.65) | 1.21 (0.76–1.93) | .43 |
Calendar period | | | | | |
1990–1994 | 35 | 29.8 (21.4–41.5) | 1 (Reference) | 1 (Reference) | |
1995–1999 | 67 | 22.5 (17.7–28.6) | 0.76 (0.50–1.14) | 0.73 (0.48–1.12) | .16 |
2000–2004 | 81 | 19.1 (15.4–23.7) | 0.64 (0.43–0.95) | 0.62 (0.41–0.94) | .02 |
2005–2009 | 78 | 13.6 (10.9–17.0) | 0.46 (0.31–0.68) | 0.42 (0.27–0.64) | <.001 |
Mortality and risk of graft loss following hospitalisation for pyelonephritis
In persons with pyelonephritis, 90-day mortality was 1.5 % (CI: 0.58–4.06 %) for RTx recipients and 1.8 % (CI: 0.44–6.08 %) for population controls. The combined risk of graft loss and death in RTx recipients following an episode of pyelonephritis compared to those with no admission due to pyelonephritis was 1.22 fold (CI: 1.01–1.48) (Table
4). In addition, when the first 90 days posttransplantation were censored to eliminate the bias from early graft loss/death following transplantation, an episode of pyelonephritis was associated with a 45 % higher risk of graft loss and death (IRR = 1.45, CI: 1.19–1.77) (Table
4).
Table 4
The effect of pyelonephritis on combined endpoint graft function and mortality
+ 0 daysc
| 0 | 7.54 (7.10–8.01) | 1 (reference) | |
| 1 | 9.01 (7.52–10.8) | 1.22 (1.01–1.48) | .043 |
+ 90 daysd
| 0 | 6.41 (6.00–6.85) | 1 (reference) | |
| 1 | 8.97 (7.49–10.7) | 1.45 (1.19–1.77) | ≤.001 |
Validation of discharge diagnosis of pyelonephritis
We reviewed a random sample of 75 medical records with a discharge diagnosis of pyelonephritis. The percentage of episodes recorded in the DNPR fulfilling the criteria for pyelonephritis was 76 % (57/75).
Discussion
In the present study we found that RTx recipients had a 72-fold higher risk of first-time hospitalisation for pyelonephritis compared to matched population controls. Even when adjusting for potential confounders including calendar period, age, gender and CCI score, the risk of pyelonephritis remained highly elevated during the entire study period in RTx recipients. Although the incidence of hospitalisation for pyelonephritis decreased by more than 50 % during the study period our findings confirm that pyelonephritis is a common cause of hospitalisation after renal transplantation. In addition, we found that the combined risk of graft loss and death was increased by 45 % in RTx recipients following an episode of pyelonephritis compared to those with no admission due to pyelonephritis. These interesting findings highlight the potential for improving the prognosis in renal transplant recipients by further reducing the risk of pyelonephritis.
To our knowledge, this study is among the first to investigate the burden of pyelonephritis among RTx recipients and the impact of pyelonephritis on renal graft survival and mortality in a nationwide population based setting over a 20-year period. The strengths of our study include the use of population-based, nationwide cohorts with inclusion of all adult (from 16-years), first-time RTx recipients, minimal loss to follow-up, long study period, and the availability of comprehensive hospitalisation data. The CCI-score enabled us to adjust for underlying diseases, and the large study size yielded estimates with high statistical precision.
The impact of pyelonephritis on graft and patient survival is debated. While short term mortality was low, we found that hospitalisation for pyelonephritis in RTx recipients was associated with persistent increased risk of graft loss and death. Pellé et al. [
16] also found post-transplant pyelonephritis to be an independent risk factor for worse long-term graft survival but found no association with mortality. A study by Giral et al. [
17] also suggested that post-transplant pyelonephritis was linked to decreased graft survival. However, this was only the case when pyelonephritis occurred during the first three months post-transplantation. Contrary to Giral et al. a retrospective study by Abbott et al. [
18] showed that UTI appearing more than six months after renal transplantation was independently associated with worse long term patient survival and risk of graft loss among RTx recipients. However, this study had some limitations, i.e.,co-morbidities were not taken into account. This may have affected the findings. Thus, it seems difficult to conclude whether UTI was the primary cause of graft loss and death or merely a marker of morbidity.
Chuang et al. [
4] also showed that UTI was significantly associated with increased mortality; contrary to Abbott et al. UTI did not increase the risk of renal graft loss. However, the results were not adjusted for co-morbidities and UTI was probably more frequent in the RTx recipients with significant co-morbidities. The above findings are in contrast to Rao KV et al. [
19] who showed that late-onset post-transplant UTI is a benign condition.
The above mentioned studies are characterised by somewhat conflicting data. To some degree, this can be explained by “UTI” referring to different conditions in the urinary system, some mainly involving the lower UTIs and some the upper UTIs. Altogether, the majority of studies including ours indicate that severe UTI (e.g., requiring hospitalization) has a negative impact on graft survival and mortality in RTx recipients.
We also found that the incidence of first-time hospitalisation for pyelonephritis among RTx recipients declined throughout the study period. The reason for this finding is not unambiguous but might be explained by early detection of lower UTIs and treatment prior to development of pyelonephritis. In addition, improved per-operative antibiotic prophylaxis, aseptic surgery, invasive procedures and earlier removal of bladder catheters may have contributed. On the contrary, ureteric stents were likely used less frequently at the beginning of the period, but removal of the stents was probably performed earlier by the end of the study period. In addition, there has been a trend towards lower doses of prednisolone in RTx during the study period, which may reduce the risk of UTI. These potential changes could have contributed to the observed changes in IR, but data was not available.
In our study we found no association between diabetes mellitus and increased risk of UTI in RTx recipients; this is in agreement with some previous studies [
4,
9,
20] but, whereas others have reported that diabetes mellitus increased the risk of developing UTI in RTx recipients [
10,
21,
22]. In our analysis, we only studied the effect of diabetes in patients with diabetes as a cause of ESRD and thus, some patients who had other causes of ESRD may also have had diabetes. However, this proportion of “unregistered” diabetes would likely be low and is unlikely to have a significant effect on the risk estimate. Chuang et al. and Dantes et al. found receiving an organ transplant from deceased donor was independently associated with an increased risk of post-transplant UTI. However, we did not find this association in our present study or in previous studies looking at infection-risk in transplant recipients [
23,
24].
Our study also had some limitations. Coding errors may occur in routine hospital discharge data leading to misclassification of pyelonephritis in both RTx recipients and the general population. Differential misclassification may bias the relative risk estimates; however, according to our diagnosis validation, the degree of misclassification was relative low (the positive predictive value of a pyelonephritis discharge diagnosis was 76 % in our study, which is acceptable and in line with other validation studies). While we did not have access to the remaining patients medical records, we consider our validation sample representative for the remaining study population since coding of discharge diagnoses is generally considered uniform throughout Denmark. In addition, doctors may have a lower threshold for hospital admission of RTx recipients with signs and symptoms of pyelonephritis causing us to overestimate the relative risk of pyelonephritis in RTx recipients. In addition, the threshold for hospitalisation may have changed over time in both groups. Another possible limitation of our study was that we lacked information on some potential risk factors for pyelonephritis such as immunosuppressive regimens and the use of ureteral stents. Interestingly, Snyder et al. only found a weak association between steroid use, immune suppressive regimens and first bacterial infections in United States RTx recipients which suggest that the impact of these limitations is limited [
25].
Abbreviations
CCI, Charlson comorbidity index; CI, confidence interval; CRN, civil registration number; CRS, Danish Civil Registration System; DNPR, The Danish National Registry of Patients; DNR, Danish Nephrology Registry; ESRD, end-stage renal disease; HLA, human leukocyte antigen; IR, incidence rate; IRR, incidence rate-ratio; PYFU, person-years of follow-up; RTx, renal transplant; UTI, urinary tract infection
Acknowledgements
James Heaf and the Danish Society of Nephrology provided access to DNR data.