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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2020  |  Volume : 31  |  Issue : 2  |  Page : 415-422
Biopsy-proven acute graft pyelonephritis: A retrospective study from sindh institute of urology and transplantation


1 Department of Nephrology and Renal Transplantation, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
2 Department of Radiology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan

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Date of Submission15-Oct-2018
Date of Decision15-Nov-2018
Date of Acceptance19-Nov-2018
Date of Web Publication09-May-2020
 

   Abstract 


How to cite this article:
Idrees MK, Sadiq S, Ali T, Rehman IU, Akhtar SF. Biopsy-proven acute graft pyelonephritis: A retrospective study from sindh institute of urology and transplantation. Saudi J Kidney Dis Transpl 2020;31:415-22

How to cite this URL:
Idrees MK, Sadiq S, Ali T, Rehman IU, Akhtar SF. Biopsy-proven acute graft pyelonephritis: A retrospective study from sindh institute of urology and transplantation. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Jul 13];31:415-22. Available from: http://www.sjkdt.org/text.asp?2020/31/2/415/284016


This retrospective study was conducted at Sindh Institute of Urology and Transplantation, Karachi, Pakistan, to evaluate and compare the predisposing factors, effect of antibiotic therapy, and long-term prognosis of culture-positive and culture-negative graft pyelonephritis among live-related kidney transplant recipients who had biopsy-proven graft pyelonephritis from 1985 to March 2015. Data included patients’ demographics, serum creatinine at discharge, at diagnosis of graft pyelonephritis, four weeks after completion of antibiotics, and at the last visit, and urine culture growth. Mean and standard deviation were determined for age, duration, and creatinine levels while Chi-square test was used to compare categorical variables. Out of 4200 recipients, 166 (124 males and 42 females) had biopsy-proven graft pyelonephritis (mean age: 30.19 ± 10.47 years) and 59 had urine culture positive while 107 had urine culture negative. Escherichia coli was the most common pathogen, followed by Klebsiella and Pseudomonas aeruginosa. Graft dysfunction was present in 99 patients while 116 patients had adverse outcome. There was no statistically significant difference in demographics, graft dysfunction, and adverse outcome between culture-positive and culture-negative pyelonephritis. Acute graft pyelonephritis can impair graft function causing considerable morbidity. Culture- negative graft pyelonephritis is an increasingly recognized entity and its management is challenging, and it may be empirically treated with antibiotics according to local culture and sensitivity data available for the population.


   Introduction Top


Strong induction and maintenance immuno- suppression in renal transplantation has revolu- tionized the management of end-stage renal disease (ESRD) but at the cost of predisposition to various bacterial, viral, and fungal infections. These infections remain a significant cause of morbidity and mortality among renal transplant recipients.[1] Urinary tract infection (UTI) is the most common posttransplant bacterial infection affecting about one-third of renal transplant recipients.[2] Graft pyelonephritis frequently results in graft dysfunction which may result in decreased graft and patient survival as well as acute rejection by alloimmunization.[3]

Asymptomatic rise in serum creatinine is sometimes the sole presentation of graft pyelonephritis, and it is indistinguishable from acute rejection. Due to this, graft biopsy is mandatory for workup of graft dysfunction if its cause is not obvious. Cartery et al[4] have recommended kidney allograft biopsies in patients in whom kidney function remains impaired at one month after UTI. In a report from our institution, there were 79 cases (6.5%) of biopsy-proven acute pyelonephritis out of 1210 graft biopsies.[5] Graft pyelonephritis is usually diagnosed on the basis of symptoms (fever, dysuria, and allograft site pain), allograft tenderness, positive urine culture, and allograft biopsy findings. However, there are instances of graft pyelonephritis with negative urine culture.

Bracewell et al[6] from Columbus, Ohio, reported a series of graft pyelonephritis with negative urine culture. Similarly, Varma et al[7] from New Delhi reported that 19% of the patients with histopathologic features of graft pyelonephritis had negative urine culture.

Gregg et al[8] have reported that 40 (2.2%) out of 1798 patients had neutrophilic infiltrates in graft biopsies as an unexpected finding in patients with posttransplant renal dysfunction. The outcome was better among those treated with antibiotics favoring the views that these infiltrates are of infectious etiology. At our institution, we come across transplant recipients that have culture-negative graft pyelonephritis and graft dysfunction, and it remains a dilemma whether to treat culture-negative graft pyelonephritis and its prognosis is unknown.

We did a retrospective analysis of all the patients with biopsy-proven graft pyelonephritis to evaluate the predisposing factors, effect of antibiotic therapy, and long-term prognosis of both culture-positive and culture-negative graft pyelonephritis cases.


   Patients and Methods Top


This retrospective study conducted at Sindh Institute of Urology and Transplantation Karachi, Pakistan, included all the renal transplant recipients who had biopsy-proven graft pyelonephritis from 1985 to March 2015. The study was done according to institutional ethical guidelines. Data were collected from patients’ record and included patients’ demo-graphics, primary disease, donor age and relationship with recipient, posttransplant period and time of occurrence of graft pyelonephritis, serum creatinine at discharge (best creatinine achieved), at diagnosis of graft pyelonephritis, four weeks after completion of antibiotics, and at the last visit, urine culture, immunosuppression protocol (induction and maintenance), rejection episodes and its treatment, cytomegalovirus (CMV) infection, cold ischemia time (CIT), delayed graft function, and Double-J stent. Graft dysfunction was defined as more than 25% rise in baseline serum creatinine. Failure of creatinine level to decrease to <25% over baseline was labeled as an adverse outcome of the graft. Patients with graft dysfunction were thoroughly investigated to find the causes of rise in serum creatinine, including routine blood examination, urine dipstick and microscopy, urine culture, ultra- sonography (size, echogenicity, hydronephro- sis, and perigraft collection), blood flow on Doppler ultrasonography, calcineurin inhibitor drug level, CMV antigenemia assay, BK/ polyomavirus DNA in blood and urine, and any other investigation if indicated. All renal transplant recipients had urine examination (dipstick for protein, pus cells, and blood) on each outpatient visit and urine culture if there was leukocyturia or positive nitrite. Patients with no obvious cause of graft dysfunction [normal calcineurin inhibitor (CNI) levels and no abnormality on ultrasonography) had graft biopsy (light microscopy and immunofluo- rescence ± C4d staining]. Graft biopsy was also done when graft function did not improve with suitable IV antibiotic therapy or crea- tinine keep on rising despite antibiotic therapy. Acute graft pyelonephritis was labeled when there were histopathological features including presence of neutrophils in tubular lumina forming casts/tubular microabscesses, neutro- philic interstitial inflammation, and tubular neutrophil rimming. The biopsies were reviewed by two experienced histopathologists. Patients with positive urine culture were treated according to sensitivity while those with negative urine culture were treated empirically with antibiotics in accordance with hospital antibiogram. Patients were treated with antibiotics for four to six weeks including paren- teral antibiotics at least for initial three weeks.

All the data were entered in IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA) and analyzed for variables. Mean and standard deviation were determined for variables including age, duration of transplant, and creatinine levels.

Chi-square test was used to compare the categorical variables while noncategorical variables were compared using Student’s t- test. Statistical significance was determined by calculation of P <0.05 which was taken as statistically significant.


   Results Top


There were 4200 patients with ESRD who had live-related renal transplantation at SIUT from 1985 to March 2015. Out of these, 166 (124 males and 42 females) had biopsy-proven graft pyelonephritis.

Most of the patients were young, with a mean age of 30.19 ± 10.47 years [Table 1]. The etiology of ESRD was unknown in about half (82) patients as they had small shrunken kidneys at time of diagnosis of ESRD. However, their clinical features were consistent with chronic glomerulonephritis (GN), and native renal biopsy had not been done. Renal stones, biopsy-proven chronic GN, and neurogenic bladder were the top three most common causes of ESRD. All the patients had live-related (blood relation and spouse as donor) renal transplant at our institute. Males outnumbered females as donors, but this difference was not statistically significant P = 0.807). Brother (68), mother (33), and sister (27) were the most common donors, followed by son (15), wife/spouse (11), and father (9). Fifty-nine patients had one haplotype and three antigen match, 42 had one haplotype and four antigen match, and nine had identical haplotype and three had zero antigen match with donor. Maintenance immunosuppression consisted of prednisolone, antiproliferative agent (azathioprine/mycophenolate mofetil), and calcineurin inhibitor (cyclosporine/tacro- limus). CIT ranged from 100 min to 356 min with mean CIT 169.04 ± 52.78 min, and there was no statistically significant difference between culture-positive and culture-negative patients. Most of the culture-negative pyelonephritis patients had an asymptomatic rise in serum creatinine detected on routine follow- up, and there were either no pus cells (27 patients) or insignificant pyuria (1-2 pus cells/HPF) on urine examination. Therefore, graft biopsy was done with suspicion of acute rejection or CNI toxicity. Among culture- positive pyelonephritis, most patients had symptoms (dysuria, suprapubic discomfort, pain at graft site, fever, and urine felt to be hot). Leukocyturia/pyuria was present in most of these patients. Graft biopsy was done for graft dysfunction when no obvious cause was found (no obstruction/hydronephroureter, normal vascularity on Doppler, and CNI level in range) and among all the patients with UTI who have graft dysfunction. Among few patients with urosepsis, biopsy was delayed till sepsis was controlled with antibiotics and supportive measures. Seventeen (3 culture positive and 14 culture negative) patients had more than one episodes of biopsy-proven graft pyelonephritis. Possible anatomic causes of recurrent UTI (such as obstruction and vesico- ureteric reflux) were investigated in these patients. Significant vesicoureteral reflux (VUR) was found in seven (2 culture positive and 5 culture negative) patients with recurrent pyelonephritis. Inflammatory markers (ESR and C-reactive protein [CRP]) were raised in both the groups, and there was no significant difference between the two groups.
Table 1: Patient's demographics and characteristics.

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Out of 166 patients with biopsy-proven graft pyelonephritis, 59 had urine culture positive while 107 had urine culture negative (twice repeated). Among urine culture-positive patients, Escherichia coli was the most common pathogen, followed by Klebsiella and Pseudomonas aeruginosa [Table 2]. Among urine culture-negative pyelonephritis patients with bland urinalysis, biopsy tissue was sent for culture in four patients, and it yielded bacterial growth in two patients. Graft dysfunction was present in 99 out of 166 patients at presentation. The remaining patients either had subsequent worsening of graft function or did not respond to initial management and consequently had graft biopsy.
Table 2: Urine microbiology.

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Adverse outcome was recorded in 116 patients out of 166. The baseline creatinine of patients with culture-positive pyelonephritis was lower than those with culture-negative pyelonephritis. Rise in creatinine, posttreat- ment creatinine, and last creatinine were higher in the culture-positive group, but none of these were statistically significant [Table 3]. There was no statistically significant difference in ages of the transplant recipients, ages of the donors, gender proportion, graft dysfunction, and adverse outcome between culture-positive and culture-negative pyelonephritis groups. Till the mid of 2015, out of 166 patients, 39 had serum creatinine above 3 mg/dL and five patients had lost the graft.
Table 3: Risk factors of graft pyelonephritis.

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   Discussion Top


In this retrospective study, we have tried to study the demographics and outcome of culture-positive and culture-negative graft pyelonephritis patients. Culture-negative graft pyelonephritis is infrequently mentioned in literature. About 4% of our transplant recipients had biopsy-proven graft pyelonephritis. This is quite low in comparison to high frequency of UTI (33%) among the transplant recipients as reported by Iqbal.[9] This is much less than 10% incidence of acute graft pyelonephritis reported from India[7] and Korea.[10] The lower incidence of graft pyelonephritis among our patients could be due to lower threshold for investigation, routine urine testing, and prompt treatment of UTI. Untreated lower UTI can lead to pyelonephritis. All of our patients had live-related kidney transplant, had privilege of free treatment, and were highly motivated. They reported even minor symptoms and therefore diagnosed and treated well in time.

Most of our patients were young (mean age: 30.19 ± 10.47 years), and males outnumber females. It may be due to occurrence of renal failure at comparatively younger age and social deprivation of females among South Asian population.[11] The primary disease remains unknown among half of the patients because of late presentation when both kidneys are already shrunken and renal biopsy not possible.[11] Most of the patients with culture-positive pyelonephritis had symptoms and pyuria, but culture-negative patients had asymptomatic rise of serum creatinine. Twenty-seven patients did not have any pyuria while insignificant pyuria was present in two- third of the patients with culture-negative pyelonephritis. Gregg et al[8] reported that among patients with asymptomatic graft pyelonephritis, only 42.2% of the patients had urine culture positive and none had symptoms of UTI or pyelonephritis. Varma et al reported fever and dysuria among two-third of the patients with pyelonephritis while 19% of the patients with biopsy-proven graft pyelonephritis did not have any symptoms of UTI or pyelonephritis.[7]

Out of 166 patients, 107 patients had culture- negative pyelonephritis. This is surprising, but we are not the first to report it. Al-Khayyat et al[12] reported a case of suspected acute rejection with no symptoms of pyelonephritis turned out to have acute graft pyelonephritis on allograft biopsy. Culture negativity with no urinary abnormality or insignificant pyuria in 64% of the patients in our study is much higher than 19% reported by Varma et al[7] from India. None of the patients received antibiotics within two weeks before their visit and before submitting the urine for culture. Our institutional laboratory maintains desirable standards, and all the samples are handled as per standard. We could not find any obvious reason for this high percentage of culture negativity. Most of the centers do not perform graft biopsy on clinical suspicion of graft pyelonephritis. Interestingly, two biopsy specimens submitted for culture had bacterial growth in the absence of positive urine culture. Claus Brun had reported three positive renal biopsy cultures (out of 60 biopsies of pyelonephritis) that had negative urine cultures.[13] The significance of this phenomenon is yet not clear. Gram-negative bacteria predominate among those with positive culture, and it concurs with pattern from our center.[9] The initial response and outcome of the graft function is not statistically different among culture-positive and culture-negative pyelonephritis.

Bracewell et al from Columbus, Ohio, reported poor response to empiric therapy and early loss of renal allograft after culture-negative pyelonephritis.[6] In our study, 116 (70%) out of 166 patients had an adverse outcome of graft function despite prolonged antibiotic therapy, even those who had known culture sensitivity and escalating the therapy in case of earlier poor response. This concurs with findings of Varma et al[7] but contrary to favorable response reported by some other studies.[14],[15] One possible explanation for asymptomatic graft pyelonephritis and its sequel could be ascending asymptomatic bacteriuria due to VUR causing damage to the parenchyma, but it is yet speculation, and the benefit of screening and treating asymptomatic bacteriuria is of no apparent benefit.[16] A recent study from The Netherlands[17] showed that posttransplant VUR does not correlate with early bacteriuria, renal function, and graft survival. Prior history of rejection, CMV infection, and recurrent pyelonephritis might have contributed to progressive deterioration of graft function among these patients.[18] Singh et al[19] found that preceding asymptomatic bacteriuria is a risk factor for graft pyelonephritis.

There are a number of limitations of this study. In the initial period, there was a lack of markers of antibody-mediated rejection such as C4d staining was not available and some cases with concomitant lymphocytic infiltrates (along with neutrophilic tubulitis) having concurrent acute rejection might have been missed.[20] Inflammatory markers (ESR and CRP) usually do not help differentiate graft pyelonephritis and acute rejection. Procalci- tonin helps differentiate acute bacterial infections from acute rejection.[21] It was not widely available at our center, and we did not utilize it in all the patients because of cost. Researchers have tried various surrogates (Cylex ImmuKnow Cell Function Assay and delta neutrophil index) to differentiate infection and rejection among renal transplant recipients, but most of these have no definite conclusion.[22],[23] There are few reports of the use of nuclear magnetic resonance and non- contrast computed tomography scans for diagnosis of graft pyelonephritis, but its use is limited.[24]

In kidney transplant recipients, due to immunosuppression, classical features of acute pyelonephritis (flank pain, dysuria, fevers, and raised inflammatory markers) are masked or not present, and up to 50% of the cases of acute graft pyelonephritis are asymptomatic. Urine microbiology is also unhelpful in the diagnosis of UTIs in transplantation with more than 50% of the cases of allograft biopsies showing features of acute graft pyelonephritis despite negative urine microbiology. Acute graft pyelonephritis is, therefore, commonly determined coincidentally from histopathology of an allograft biopsy.


   Conclusion Top


Acute graft pyelonephritis affects a considerable number of live-related renal transplant recipients, and it can impair graft function causing considerable morbidity. Culture- negative graft pyelonephritis is an increasingly recognized entity and its management is challenging. Until more evidence becomes available, it may be empirically treated with antibiotics according to local culture and sensitivity data available for the population.

Conflict of interest: None declared.



 
   References Top

1.
Khoury JA, Brennan DC. Infectious complications in kidney transplant recipients: Review of the literature. Saudi J Kidney Dis Transpl 2005;16:453-97  Back to cited text no. 1
    
2.
Sousa SR, Galante NZ, Barbosa DA, Pestana JO. Incidence of infectious complications and their risk factors in the first year after renal transplantation. J Bras Nefrol 2010;32:75-82  Back to cited text no. 2
    
3.
Audard V, Amor M, Desvaux D, et al. Acute graft pyelonephritis: A potential cause of acute rejection in renal transplant. Transplantation 2005;80:1128-30  Back to cited text no. 3
    
4.
Cartery C, Guilbeau-Frugier C, Esposito L, et al. Systematic kidney biopsies after acute allograft pyelonephritis. Exp Clin Transplant 2013;11:239-44  Back to cited text no. 4
    
5.
Kazi JI, Mubarak M. Biopsy findings in renal allograft dysfunction in a live related renal transplant program. J Transplant Technol Res 2012;2:108  Back to cited text no. 5
    
6.
Bracewell A, Nori U, Balada JM, Nadasdy T, Satoskar A. Pyelonephritis in Renal Allografts - Biopsy or Cultures? Poster Presented at 102nd USCAP Annual Meeting Baltimore MD: March, 2013. Kidney Mod Pathol 2013; 26:383-96  Back to cited text no. 6
    
7.
Varma PP, Jairam A, Hooda AK, Badwal S. Renal outcome in biopsy proven cases of graft pyelonephritis. Indian J Nephrol 2014;24:161- 5  Back to cited text no. 7
    
8.
Gregg K, Milagros S, Johnson K, Kaul D. Asymptomatic acute transplant pyelonephritis: A single-center experience. Am J Transplant 2013;13 (Suppl 5). Available at: https:// atcmeetingabstracts.com/abstract/asymptomati c-acute-transplant-pyelonpehritis-a-single- center-experience/. Cited April 9, 2020  Back to cited text no. 8
    
9.
Iqbal T, Naqvi R, Akhter SF. Frequency of urinary tract infection in renal transplant recipients and effect on graft function. J Pak Med Assoc 2010;60:826-9  Back to cited text no. 9
    
10.
Lee YJ, Kang NR, Lee JE, et al. Acute graft pyelonephritis after kidney transplantation: Clinical manifestations and the impact on long-term allograft outcome. Korean J Nephrol 2009;28:310-6  Back to cited text no. 10
    
11.
Rehman IU, Idrees MK, Shoukat . Outcome of end-stage renal disease patients with advanced uremia and acidemia. J Coll Physicians Surg Pak 2016;26:31-5  Back to cited text no. 11
    
12.
Al-Khayyat H, Toussaint N, Holt S, Hughes P. Gram-negative sepsis following biopsy of a transplant recipient with asymptomatic allograft pyelonephritis. CEN Case Rep 2017; 6:46-9  Back to cited text no. 12
    
13.
Brun C, Raaschou F. Percutaneous renal biopsy in pyelonephritis. In: Wolstenholme GE, Cameron MP, editors. Ciba Foundation Symposium - Renal Biopsy: Clincal and Pathological Significance. Chichester, UK: John Wiley & Sons, Ltd.; 1961  Back to cited text no. 13
    
14.
Fiorante S, Fernandez-Ruiz M, Lopez- Medrano F, et al. Acute graft pyelonephritis in renal transplant recipients: Incidence, risk factors and long-term outcome. Nephrol Dial Transplant 2011;26:1065-73  Back to cited text no. 14
    
15.
Golębiewska J, Dębska-Slizien A, Zadrozny D, Rutkowski B. Acute graft pyelonephritis during the first year after renal transplantation. Transplant Proc 2014;46:2743-7  Back to cited text no. 15
    
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Origuen J, Lopez-Medrano F, Fernandez-Ruiz M, et al. Should asymptomatic bacteriuria be systematically treated in kidney transplant recipients? Results from a randomized controlled trial. Am J Transplant 2016;16: 2943-53  Back to cited text no. 16
    
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Molenaar NM, Minnee RC, Bemelman FJ, Idu MM. Vesicoureteral reflux in kidney transplantation. Prog Transplant 2017;27:196-9  Back to cited text no. 17
    
18.
Helantera I, Koskinen P, Tornroth T, Loginov R, Gronhagen-Riska C, Lautenschlager I. The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients. Transplantation 2003;75:1858-64  Back to cited text no. 18
    
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Singh R, Geerlings SE, Peters-Sengers H, et al. Incidence, risk factors, and the impact of allograft pyelonephritis on renal allograft function. Transpl Infect Dis 2016;18:647-60  Back to cited text no. 19
    
20.
Fonseca LE Jr., Shapiro R, Randhawa PS. Occurrence of urinary tract infection in patients with renal allograft biopsies showing neutrophilic tubulitis. Mod Pathol 2003;16: 281-5  Back to cited text no. 20
    
21.
Savaş BozbaŞ, Er Dedekarginoglu B, Ulubay G, Haberal M. Role of serum procalcitonin levels in solid-organ transplant patients. Exp Clin Transplant 2016;14:116-20  Back to cited text no. 21
    
22.
Shin DH, Kim EJ, Kim SJ, Park JY, Oh J. Delta neutrophil index as a marker for differential diagnosis between acute graft pyelo-nephritis and acute graft rejection. PLoS One 2015;10:e0135819  Back to cited text no. 22
    
23.
Wang Z, Liu X, Lu P, et al. Performance of the ImmuKnow assay in differentiating infection and acute rejection after kidney transplantation: A meta-analysis. Transplant Proc 2014;46:3343-51  Back to cited text no. 23
    
24.
Piccoli GB, Picciotto G, Rossetti M, et al. Imaging data suggesting acute pyelonephritis in the kidney graft: Report of five cases with atypical clinical presentation. Int J Antimicrob Agents 2006;28 Suppl 1:S64-71.  Back to cited text no. 24
    

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Correspondence Address:
Muhammad Khalid Idrees
Department of Nephrology and Renal Transplantation, Sindh Institute of Urology and Transplantation, Karachi
Pakistan
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DOI: 10.4103/1319-2442.284016

PMID: 32394914

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