Key words : Asymptomatic bacteriuria, Indication biopsy, Kidney transplant, Urinary tract infection

Introduction
With an incidence ranging from 30% to 60%, urinary tract infection (UTI) is the most common bacterial infection in kidney transplant recipients.^1,2 In addition, asymptomatic bacteriuria (AB), which is defined as the quantitative isolation of a bacterial species (105 colony-forming units [CFU]/mL) from a single, clean-catch urine specimen unaccompanied by signs of UTI (eg, dysuria, frequency, fever), may occur in 3.4% to 51% of kidney transplant recipients.^3-5 However, it is not always possible to distinguish AB and UTI with the symptoms and signs mentioned above, particularly in a transplant patient who has received a denervated organ and has been constantly using immunosuppressive medications.^4-6 Although the frequency of UTI and AB is high, the risk of progression to tubulointerstitial nephritis (pyelonephritis) in the allograft is low. Indeed, in a surveillance study from Spain, the incidence of pyelonephritis in kidney transplant recipients was 3.7%, although in earlier studies it was reported to range from 10% to 26%.^2,7-9 The inconsistency between these rates depends on the definition of posttransplant pyelonephritis by different centers using different diagnostic criteria and methods.

Asymptomatic bacteriuria is not a clinical condition that requires close follow-up and treatment. On the other hand, graft pyelonephritis requires prompt treatment both because of its detrimental effect on graft and patient outcomes and its potential to induce acute rejection.^2,10-12

In this study, we examined the clinical and biochemical features of patients with acute pyelonephritis (APN), which were confirmed by indication and/or protocol biopsies, among the 769 kidney transplants performed in our center during the previous 16 years. We divided patients with APN into 2 different time intervals for our analyses (within 6 months and more than 6 months posttransplant). The rationale behind the division into 2 groups was based on the high-risk period during the first 6 months posttransplant. From our examination of clinical and laboratory results, we aimed to create an algorithm that would be useful in predicting pyelonephritis cases occurring at different periods after transplant.

Materials and Methods
This cohort (prospective observational) study was performed at the University of Health Sciences-Bozyaka Teaching and Research Hospital Organ Transplantation Center (Izmir, Turkey). Adult (age ≥18 years) patients who underwent kidney transplant between January 2003 and December 2019 were included. Informed consent was obtained from all individual participants included in the study. Patient information was accessed from regularly kept medical records and were reviewed until death or until patients were lost to follow-up.

All kidney transplant recipients are invited to routine outpatient clinic follow-up once every 15 days for the first 3 months after transplant and then once per month until the first year. During outpatient visits, routine urine cultures and antibiograms are obtained from all patients with urological symptoms or those who are asymptomatic but having pyuria and/or bacteriuria in urine analyses. A medium flow and single clean-catch urine sample or a sample collected through catheterization (for patients with neurological bladder) is used for urine culture. A Sysmex fully automated urine chemistry analyzer (UC-3500) is used for urine biochemistry and microscopic analysis. The BD Phoenix automated identification and susceptibility testing system is used for the detection of antimicrobial resistance (Becton-Dickinson Biosciences).

As per our surgical protocol, we place the urinary catheter in the bladder and use a double J catheter for ureteroneocystostomy anastomosis for all kidney transplant recipients. The urinary catheter is withdrawn within 6 days, with the double J catheter removed within 4 to 6 weeks after the operation. After removal, all double J catheters are sent to our microbiology laboratory for culture and susceptibility testing. All kidney transplant recipients receive prophylactic trimethoprim-sulfamethoxazole for 6 months posttransplant.

Antithymocyte globulin (2-4 mg/kg/day; ATG-Fresenius S 20 mg/mL, Fresenius Biotech) is used for induction immunosuppression, and maintenance immunosuppression consists of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate mofetil or mycophenolic acid), and methylprednisolone.

Optimal trough blood concentrations of tacrolimus and cyclosporine are kept between 5.0 and 10.0 ng/mL and 100 and 250 ng/mL, respectively, for the first year posttransplant.

Study definitions and interventions
Asymptomatic bacteriuria is defined as isolation of a bacterial species in a quantitative count ≥105 CFU/mL in a clean-catch voiding urine sample and ≥100 CFU/mL in catheter urine sample. Patients with AB receive no medical intervention.3

Urinary tract infection is defined as the presence of fever and dysuria with or without suprapubic and/or allograft pain, positive urine culture (with or without bloodstream infection), leukocytosis (>10 000 white blood cells/mm³), and increased high-sensitivity C-reactive protein (hs-CRP) and/or procalcitonin levels.¹³ Patients with UTI receive appropriate antibiotic treatment for an average of 14 days. Maintenance immunosuppressive therapy is reduced by half for the first 3 days and then gradually increased according to the clinical course of the patient.

Acute pyelonephritis refers to UTI with acute graft dysfunction. For patients with APN, a Tru-cut biopsy is performed immediately. Maintenance immunosuppressive therapy is decreased, and appropriate antibiotic treatment is started for an average of 14 to 21 days. If possible, a protocol biopsy is performed after the medical treatment.

Pathological evaluation
In our center, we perform implantation biopsies routinely immediately after revascularization of the allograft and then protocol biopsies at months 3 and 6 posttransplant unless the patient refuses. In addition, patients admitted with graft dysfunction are almost always evaluated histopathologically by indication biopsy. All biopsies were reviewed as per the 2018 version of the Banff classification of renal allograft pathology.¹⁴ Thus, all biopsies performed before 2018 were revised.

Detected lesions (inflammation [i], tubulitis [t], intimal arteritis [v], glomerulitis [g], glomerular sclerosis [gs], peritubular capillaritis [ptc], interstitial fibrosis [co], tubular atrophy, vascular fibrous intimal thickening [cv], arteriolar hyalinosis [ah]) were scored accordingly. Thus, both the severity of the infection and the underlying chronic parenchymal changes were determined.

All biopsy specimens were examined by the same nephropathologist (F. Alkan-Taşlı) to prevent interobserver variability. Paraffin-embedded tissue block sections were stained with hematoxylin-eosin, periodic acid-Schiff, trichrome, and methenamine silver. Immunohistochemistry staining for C4d and simian virus 40 (SV40) was applied to all biopsies. A marked interstitial inflammation with dominant polymorphonuclear cells, neutrophilic tubulitis, neutrophil plugs within tubules, and occasional tubular destruction and microabscesses is considered most likely APN. Humoral rejection was excluded by negative C4d staining.

In this study, we excluded all cases that might overlap with acute rejection, including suspicious (borderline) lesions (tubulitis score >0 and inflammation score ≤1). Twelve patients had both histopathological findings specific to acute allograft pyelonephritis and inflammatory infiltration consisting of T lymphocytes in the tubulointerstitial area (inflammation 1, tubulitis 1). These patients received 3 doses of 500 mg/day pulse steroid therapy in addition to antibiotic therapy. These cases were excluded from the study because of APN treatment protocol violation. Therefore, all of the 18 cases reported here had neutrophilic tubulitis (±glomerulitis), tubular neutrophilic plugs, and dominant neutrophilic infiltration in the interstitium with C4d (negative) and SV40 (negative) immunohistochemistry. A typical biopsy sample specific to patients in our study is shown in detail in Figure 1.

Statistical analyses
Continuous variables are expressed as means with standard deviation and were compared using t tests. Categorical variables were evaluated using the chi-square or Fisher exact test. All statistical tests were 2-tailed. P < .05 indicated statistical significance.

Results
We performed 769 kidney transplant procedures between January 2003 and December 2019. In these patients, 1177 total kidney biopsies (implantation, protocol, or indication biopsies) were performed during the same period. In the first year after transplant, 203 patients (26.4%) were treated at least once for UTI. In 185 patients, UTI was not accompanied by graft dysfunction. In addition, no histopathological findings of APN in the allograft were shown in any of the 166 protocol or indication biopsies performed for these 185 cases. Furthermore, none of these cases developed APN in the follow-up period. In total, 18 patients (2.3%) with a diagnosis of APN were included in the study. These patients received kidneys from different donors. The mean age of the donors was 46.3 ± 12.7 years (range, 19-71 years). One patient received a kidney from a bacteremic donor. Demographics and possible risk factors of these 18 patients are shown in Table 1.

The mean follow-up was 48.0 ± 28.4 months (range, 6-111 mo). In all cases except one, APN was diagnosed with indication biopsies because of acute graft dysfunction accompanied by signs and symptoms of UTI. In one patient, whose primary kidney disease was neurogenic bladder, APN was diagnosed by protocol biopsy. She underwent regular transurethral catheterizations on average 6 times per day after transplant and had previously been hospitalized twice due to UTIs. She described dysuria that lasted for 2 days 1 week before the protocol biopsy.

Ten patients (56%) had a history of at least 1 episode of AB and/or UTI prior to the development of APN. The microorganisms responsible for episodes of clinical APN were Escherichia coli (n = 6), Klebsiella pneumoniae (n = 3), and Enterococcus faecalis (n = 1). Interestingly, in 8 patients (44%), no organisms were detected in consecutive urine cultures before the diagnosis of APN and afterward. The APN periods and related infection parameters, kidney function, and graft outcomes are shown in Table 2.

When the study group (n = 18 patients) was evaluated together, all patients diagnosed with APN unexceptionally had graft dysfunction at the time of admission. There was a significant difference between the mean serum creatinine values before and after the diagnosis of APN (1.44 ± 0.38 vs 3.33 ± 1.9 mg/dL; t test = -4.2 and P < .001). In addition, the mean leukocyte (12 974 ± 6817/mm3 vs 6752±3425/mm3) and hs-CRP values (74.9 ± 84.8 mg/L vs 7.44 ± 7.5 mg/L) before and after treatment for APN were also significantly different (t test for white blood cell = 3.36, P = .002; and t test for hs-CRP = 2.97, P = .006).

However, as shown in Table 2, when we examined APN patients at the 2 different time periods, we observed that the history and infection parameters in these groups were quite different from each other. Detailed clinicopathological analyses of the groups are presented below.

Group 1
Group 1 included 9 patients diagnosed with APN in the first 6 months posttransplant. All patients had acute graft dysfunction at the time of admission; however, only 2 patients (22%) were having mild dysuria and pollakiuria accompanied by significant leukocytosis (≥10 000/mm³). Urine culture was positive in 4 cases. Escherichia coli and Klebsiella pneumoniae were identified in 3 patients and 1 patient, respectively. Of the remaining 5 patients, 3 had no history of previous AB or UTI and positive urine culture. Two patients stated that they used irregular trimethoprim-sulfamethoxazole and quinolone antibiotics due to intermittent dysuria in the previous 2 weeks before biopsy. It is possible that the urine culture was false-negative due to preceding antibiotics prior to collection of the urine culture. None of the patients in this group had a previous history of acute rejection. For all the reasons mentioned above, these patients underwent indication biopsy. On the other hand, the excellent response of these patients to medical treatment with complete recovery of baseline graft function was a remarkable feature of this group. During a mean follow-up of 3 years, graft loss did not occur in any of the 9 patients. Three patients had 1 episode of relapsing UTI and recovered with appropriate treatment.

In group 1, 1 patient received a kidney from a bacteremic donor. The donor had extended spectrum beta-lactamase plus Klebsiella pneumoniae growth in the tracheal aspiration culture and inducible beta-lactamase plus Morganella morganii growth in the urine culture. The indication biopsy of this patient on postoperative day 14 revealed graft infection despite the previous administration of meropenem (3 g/day) to the donor for 2 days before organ retrieval and to the recipient for 7 days after implantation. We did not isolate any bacterial species in consecutive urine cultures from the recipient before and after the biopsy. In this patient, subclinical T-cell-mediated acute rejection was detected in a protocol biopsy performed 3 weeks after pyelonephritis treatment. He responded well to the pulse steroid treatment.

The implantation biopsy evaluation for group 1 showed a score for interstitial fibrosis-tubular atrophy (cict score) of 0; thus, parenchymal scar tissue was not present in all allografts. Biopsies showed gs1 and ah1 detected in 2 patients and cv1 in 3 patients. The indication biopsy evaluation for group 1 showed that cict score was still 0 in all cases. All patients had neutrophilic tubulitis, inflammation, and tubular neutrophilic plugs. Three patients had g1 neutrophilic glomerulitis. The average glomerulitis, inflammation (i), and tubulitis (t) scores were 0.47 ± 0.2, 1.8 ± 0.6, and 1.3 ± 0.47, respectively. None of the patients had i3t3 with or without g1 in the biopsy specimen.

Group 2
Patients in group 2 included those with pyelonephritis at 6 months or later after transplant and who had at least 2 of the following laboratory findings: leukocytosis (≥10 000/mm³), neutrophilia, and high CRP values at admission. Six patients were symptomatic and had simultaneous urine culture positivity. It was noteworthy that 6 of 9 patients (66%) had a previous history of AB (15 episodes) and UTI (4 episodes) before the diagnosis of APN. Furthermore, 3 patients had a previous history of biopsy-proven mixed-type acute rejection episodes, which were treated successfully by pulse steroids + high-dose intravenous immunoglobulins and immunoadsorption sessions.

Group 2 did not respond well to APN treatment. Indeed, only 2 patients responded to medical treatment and attained baseline kidney function values without any graft loss. The remaining 7 patients did not attain baseline kidney function following the treatment. Despite 14 days of treatment, recurrent pyelonephritis was subsequently detected in 3 patients in the following months. In all recurrent cases, the microorganism responsible for the first APN episode was cultivated in repeated urine cultures (true recurrence).

In addition, 4 patients (44%) lost their graft during the average 5-year follow-up period. Among these, 1 patient with a primary finding of diabetic nephropathy experienced recurrent mixed-type rejection episodes in the first 6 months and presented with APN in a kidney with a background of chronic mixed-type rejection. He also had a previous history of UTI. He did not benefit from antibiotherapy and had a progressive course, leading to graft and retroperitoneal abscess requiring surgical exploration and graft nephrectomy. This patient died at month 13 after transplant due to pneumonia. Three patients (17%) returned to hemodialysis, and 1 patient had graft nephrectomy. The common clinical features of these patients included numerous diagnoses of AB, inpatient treatment at least twice for UTI, and development of APN at least 1 year posttransplant. In addition, 2 of these 3 patients also had mixed-type acute rejection episodes prior to APN diagnosis.

The implantation biopsy evaluation for group 2 showed that cict score was 0. However, 1 patient had mild arteriolar hyalinosis (ah1), and 3 patients had mild fibrous arteriolar wall thickening (cv1) and global sclerotic glomeruli (gs1). The indication biopsy evaluation for group 2 showed that 2 patients had ci1, ct1 lesions. Another 2 patients had mild (gs1) and severe (gs3) global sclerosis in the glomeruli. New vascular lesions (cv1 with or without ah1) were observed in 3 patients. All patients had tubular neutrophilic plugs. Three patients had (g1) neutrophilic glomerulitis accompanied by neutrophilic i3, t2 lesions. Average inflammation (i) and tubulitis (t) scores were 2.2 ± 0.7 and 1.7 ± 0.5, respectively.

Group 1 versus group 2 comparisons
When the 2 groups were compared in terms of inflammation and tubulitis scores in diagnostic biopsies, there were no statistically significant differences. The analysis of variance post hoc test for inflammation and tubulitis in the 2 groups were as follows. Inflammation difference in group 1 versus group 2 showed difference = 0.4000 (95%CI, -0.4222 to 1.2222; P = .4361). Tubulitis difference in group 1 versus group 2 showed difference = 0.4000 (95%CI, -0.2221 to 1.0221; P = .2485).

Scores for gs, cv, ci, and ct (each of which imply chronic fibrous vascular and parenchymal changes) were calculated for patient implantation, protocol, and indication biopsies. When the sums of scores (gs + cv + ci + ct) of the 2 groups were compared, the extent of chronic fibrous changes in the indication biopsies was significantly higher in group 2 patients (t test = 5.97, P = .0014).

Survival data
At mean follow-up of 48.0 ± 28.4 months, 14 patients (78%) were alive with a functioning graft. The final control serum creatinine and glomerular filtration rates of patients who survived were 1.85 ± 0.82 mg/dL and 43.0 ± 17.0 mL/min/1.72 m², respectively.

Discussion

In kidney transplant recipients, there is a clear consensus on the definition, management, and prognosis of AB.^3,4,15 Studies have shown that the incidence of posttransplant AB is between 5% and 20% and that the risk of consequent pyelonephritis is less than 10%, which does not differ in patients who have or have not received antibiotic treatment for AB.^4,5,13,15,16 However, there are still differences in the definition of posttransplant APN. In some studies, the diagnosis is based directly on clinical and laboratory findings (especially urine culture)^1,12,13; however, in others, a kidney biopsy is almost always incorporated in the APN diagnosis.^2,17,18 Rather than a diagnosis based on clinical findings specific to UTI, all patients in our study were admitted with graft dysfunction and received biopsies, which revealed neutrophilic tubulitis and interstitial inflammation without concurrent lymphocytic tubulitis or C4d positivity.

Among half of the patients in our study, APN was observed in the first 6 months posttransplant when the cumulative immunosuppressive drug dosage had peaked.^1,12 During this period, the symptoms specific to UTI were mild or ambiguous, urine culture positivity was rare, and laboratory findings were not decisive.^19,20 Indeed, in our study, concomitant UTI or AB with positive urine culture was present in about 40% of the patients who were diagnosed with APN in the first 6 months. Similarly, in another study, UTI symptoms with or without urine culture positivity were found in only 2 of 5 kidney transplant recipients (40%) in which APN early after transplant was diagnosed by scintigraphy and confirmative magnetic resonance imaging.²¹ Thus, a kidney biopsy seems indispensable for the diagnosis of APN in patients who present with only graft dysfunction within 6 months after transplant.

Clinical reports have shown that specific histo-pathological features of APN in biopsy are not necessarily accompanied by urine culture positivity. For example, Gupta and colleagues observed concomitant urine culture positivity in only 18 of 33 (54%) allograft biopsies with neutrophilic tubulitis and intratubular neutrophil clusters.¹⁷ Oghumu and colleagues reported concomitant positive urine cultures in 33% of the biopsies with features of APN.⁶ However, in 2 other studies, urine culture confirmed UTI in 21 of 26 patients (81%) with a biopsy diagnosis of APN.^2,18

In patients with APN during the first 6 months posttransplant, the ambiguous nature of clinical and laboratory findings and the scarcity of preceding AB or UTI may be attributed to steroid use and long-term antibiotic prophylaxis for pneumocystis pneumonia.^22,23 In our study, patients in group 1 responded well to APN treatment and did not experience any impairment to graft function. This success might be largely due to early biopsy diagnosis of APN and the implementation of appropriate treatment. Therefore, a diagnostic biopsy is of great importance in patients who present with graft dysfunction and vague urinary symptoms in the first 6 months after transplant.^2,17,18,20 The detection of high leukocyte (>10 000/mm3), neutrophil (>75%), and hs-CRP values in almost all patients diagnosed with APN beyond month 6 posttransplant supported a bacterial infection. Also, 4 patients in this group had a previous history of numerous AB and UTI episodes. If graft dysfunction is mild in these cases and there is no previous acute rejection history, antibiotic therapy may be considered initially. This may be followed by an early protocol biopsy to determine the response to treatment and the extent of residual histopathological damage in the allograft, particularly for those with an history of AB and/or UTI.^9,11

In our study, we observed no statistical difference between the intensity of inflammation and tubulitis in the indication biopsies of all patients in both groups. That is, the histopathological response to infection was almost similar in different periods and in different patients. In contrast, the sum of scores of chronic parenchymal changes (gs + cv + ci + ct) was significantly higher in group 2 patients. The excessive chronic changes in this group could be due to previous rejection, multiple episodes of AB or UTI, longer exposure to calcineurin inhibitors, and other immunological and nonimmunological factors.¹¹ In addition, because the worst responses to APN therapy were observed in patients with previous antibody-mediated rejection episodes, a pretreatment biopsy could be planned in these patients to elucidate any concomitant pathology.^17,18

Conclusion and forward suggestions
Our 4 general conclusions and suggestions are summarized below.

First, we provided clarification on the clinical and laboratory differences between UTI and pyelonephritis definitions. Second, in our study patients, no treatment was applied to any patient with AB/pyuria. The absence of any chronic damage in tubulointerstitial structures in patients with biopsy-proven graft pyelonephritis in the first 6 months after transplant supported the appropriateness of this approach. Third, in group 2, relapsing pyelonephritis was observed in one-third of patients despite intensive antibiotic therapy. In this regard, new studies are needed to determine the optimal duration of treatment for allograft APN in the late posttransplant period. Fourth, clinical and laboratory findings did not support a diagnosis of APN in at least half of our patients diagnosed with APN in the first 6 months after transplant. However, graft dysfunction was evident in all of these patients. Therefore, a diagnostic biopsy is essential in these patients.

References:

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