Infections in kidney transplant recipients in tropical countries have an incidence of 50%–70%. Studies have shown a slightly different chronology of infections in tropical countries.[2,3] Awareness of this allows judicious use of limited resources. A study showed that patient and graft survival during COVID pandemic was 95.3% and 97.6%, respectively, irrespective of the development of COVID infection. We present a study of infections in renal transplant recipients with the aim to identify common organisms and highlight differences from established literature. We also studied graft outcomes during the COVID pandemic and assessed factors that predicted overall graft and patient outcomes.
SUBJECTS AND METHODS
This was an ambispective single-center observational study that commenced from November 2019 with retrospective data collection done with the help of medical records and subsequent data collected prospectively from current transplant cases done. Follow-up was done till September 2021. Patients who received living and cadaveric donor kidney transplants in our center from 2011 to 2021 were included. Laboratory investigations included pretransplant baseline routine blood investigations and appropriate transplant workup. Posttransplant data included routine blood investigations and investigations done as per suspicion in cases of infectious disease. These included relevant body fluid studies (blood, urine, pleural fluid, bronchoalveolar lavage, cerebrospinal fluid), serologies, polymerase chain reaction (PCR) tests for cytomegalovirus (CMV), BKV, COVID and Tuberculosis, imaging studies (X-rays, computed tomography scans, magnetic resonance imaging) and graft biopsies. Data were recorded to assess factors affecting patient and graft survival.
Acute graft dysfunction was defined using the AKIN criteria. Chronic graft dysfunction was defined as eGFR <60 ml/min/1.73 m2 in the absence of an acute decline, in patients with functioning grafts at the last follow-up. Graft loss was defined as dialysis dependency or graft loss due to death or eGFR <15 ml/min/1.73 m2. All allograft biopsies were defined using Banff 97 working criteria.
Analysis was done with the use of SPSS version 21 (SPSS Inc., Chicago, IL, USA). Quantitative data were presented as the means ± standard deviations. Association of the variables was analyzed using Chi-square test. Kaplan–Meier survival analysis curve was used to assess graft and patient survival and log rank test was used to compare survivals between two groups - infection and no infection. Univariate odds ratio and their 95% confidence interval were done to identify predictors of chronic graft dysfunction, graft loss, and death. Significant factors in univariate analysis were then included in multivariate Cox proportional hazard regression analysis to adjust for confounding variables for the outcomes of chronic graft dysfunction, graft loss, and death. For statistical significance, P < 0.05 was considered statistically significant.
Declaration of patient consent
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
The study was performed according to the guidelines in Declaration of Helsinki.
The study has been approved by Institutional ethics committee of ABVIMS(IEC/ABVIMS/RMLH/1897).
A total of 289 transplants were done in the study period with 40 patients lost to follow-up [Figure 1]. Two hundred and forty-nine patients were analyzed for infections and 158 patients transplanted between 2015 and 2019 were analyzed for survival [Table 1].
At least one infectious episode occurred in 124 patients (49.79%). Among them, 46.77% had 2 episodes and 14.52% had more than 2 episodes. There were 218 total infectious episodes. 52.3% of infections occurred within the 1st 6 months. Bacterial infections were the most common (40.50%), followed by viral (35.20%), mycobacterial (11%), fungal (8.10%), and parasitic (5.2%). The most common site was the lower respiratory tract (28.90%), followed by urinary tract (23.39%), blood stream (17.43%), gastrointestinal tract (11.47%), skin (5.96%), graft (5.05%), lymph node (3.21%), pleural cavity (1.83%), surgical site (1.38%), and genitourinary tract (0.92%) [Table 2]. Mortality occurred in 32 (14.7%) cases. Lower respiratory tract infections mostly of bacterial etiology led to the highest mortality.
Urinary tract infection (UTI) was the most common bacterial infection comprising 56.4% of all bacterial infections. Escherichia coli and Klebsiella were the most common organisms. 62.5% of UTIs occurred within 6 months after transplantation. Mortality occurred in 4.1% of cases. Bacterial pneumonias comprised 22.3% of bacterial infections. Combination of history, examination, and imaging findings in conjunction with blood cultures, sputum, or bronchoalveolar lavage fluid cultures was used in the diagnosis of bacterial pneumonias. 52.6% of bacterial pneumonia occurred 6 months after transplantation. There was a 100% hospitalization rate in cases of bacterial pneumonia. Mortality in bacterial pneumonia was 52.6%. A single case of pneumocystis pneumonia was diagnosed at 19 months posttransplant. Surgical site infections comprised 1.38% of all infections, with Staphylococcus aureus being the most common organism. Graft pyelonephritis accounted for 9.4% of all bacterial infections, with Klebsiella being the most common organism. Graft pyelonephritis resulted in mortality in 12.5% of cases [Table 3].
Cytomegalovirus was the most common overall organism comprising 18.81 % of total infections. Among CMV cases, 36.5% were CMV disease. Majority (63.41%) of cases occurred in 1 to 6 months posttransplant. Herpes zoster accounted for 5.05% of total cases. 54.5% of zoster infections occurred within 6 months of transplant. All cases of zoster presented as painful shingles, which was diagnosed clinically. None developed disseminated disease. No cases of varicella were documented. COVID-19 pneumonia was seen in 5.50% of total cases. Mortality occurred in 16.67% of cases. BK polyoma virus was seen in 1.38% of all cases.
Invasive fungal infections were more common mostly Aspergillus and Mucor which comprised 76.4 of all fungal cases. The lower respiratory tract (82.3%) was most commonly involved. 76.4% of infections occurred after 6 months. Mucor infections led to 50% mortality. Invasive fungal infections led to hospitalization rates of 88.2%. Candida accounted for 17.6% of all fungal infections. All cases occurred after 6 months.
Tuberculosis comprised 11% of all infections. The most common site of involvement was the lower respiratory tract involved in 43.4% of cases, followed by lymph nodes (30.4%). Majority (65.2%) of cases occurred 6 months after transplantation. Mycobacterial infections led to mortality of 13.04%.
Parasitic infections included 5.20% of all infections. Giardia was the most common parasite accounting for 54.5% of all cases. There were no incidences of hypersensitivity or overwhelming infections.
Acute Graft dysfunction occurred in 78 (36.4%) of total infectious episodes, with LRTIs being the most common associated infection. Majority of acute graft dysfunction was caused by bacterial infections (49.3%). Acute graft dysfunction occurred in 34.6% of cases of UTI. BK virus and fungal infections led to graft dysfunction in 66.67% and 47.06% of cases, respectively. There was a significant difference in the occurrence of graft rejection (P = 0.01) and chronic graft dysfunction (P = 0.03) between patients with and without a history of infection. No significant difference was seen in outcomes of graft loss and death.
Kaplan–Meier analysis showed overall graft survival of 88.53%, 73.75%, and 44.90% at the end of 1, 3, and 5 years, respectively, with a mean survival time of 54.84 months [Figure 2]. There was no significant difference in graft survival between infection and no infection (P = 0.20) with a mean survival time of 58.469 months in patients without infection and 49.887 months in patients with infection [Figure 3]. The overall patient survival was 89.81%, 79.73%, and 74.40% at the end of 1, 3, and at the end of study, respectively, with a mean survival time of 63.765 months [Figure 4]. There was no significant difference in survival between infection and no infection (P = 0.18) with a mean survival time of 67.40 months in patients without infection and 58.14 months in patients with infection [Figure 5].
Factors predicting outcomes
On univariate analysis, recipient age and graft rejection were significant predictors for graft loss. Recipient age of more than 50 years was a significant independent predictor for mortality [Table 4]. On performing multivariate Cox proportional hazard regression, age and rejection were independent significant predictors of graft loss (hazard ratio [HR] – 2.52, 95% confidence interval [CI] – 1.17 – 5.44, P = 0.01: HR – 2.31, 95% CI – 1.26 – 4.26, P = 0.00, respectively).
Univariate analysis showed that donor age more than 50 years odds ratio [OR] = 2.46; 95% CI = 1.08 –5.58; P = 0.03), graft rejection (OR = 4.27; 95% CI = 1.44 – 12.67; P = 0.00), and CMV infections (OR = 2.52; 95% CI = 0.98 – 6.44; P = 0.04) were significant predictors for chronic graft dysfunction. On performing multivariate Cox proportional hazard regression, donor age (HR – 2.26, 95% CI – 0.96 – 5.31, P – 0.05), graft rejection (HR – 4.57, 95% CI – 1.43 – 14.56, P – 0.01), and CMV infection (HR – 2.13, 95% CI – 0.76 – 6.54, P – 0.04) were significant independent predictors of chronic graft dysfunction.
Infections complicate the course of 15%–75% of transplant recipients in tropical countries with mortality ranging from 11 to 60%.[2,3] In our study, 124 (49.7%) patients had at least 1 documented episode of infection. Bacterial infections were most common, followed by viral and mycobacterial infections. Infections resulted in patient mortality in 14.7% of cases. Western countries have a higher occurrence of bacterial infections but a much lower occurrence of viral, fungal, and tubercular infections in comparison to tropical countries [Table 5]. Acute graft dysfunction occurred in 36.4% of cases. There was a significant difference in the occurrence of graft rejection and chronic graft dysfunction between infectious and noninfectious group.
Overall graft survival at 1, 3, and 5 years was lower as compared to other centers with the highest proportion of graft losses occurring during the COVID pandemic. This shows the indirect effects of the pandemic especially in the economically less privileged transplant population. Donor age, CMV infection, and graft rejection were independent predictors of chronic graft dysfunction. Recipient age and graft rejection were independent predictors of graft loss.
UTI was the most common bacterial infection overall with majority of episodes occurring within 6 months of transplant. E. coli and Klebsiella were the most common organisms causing UTI. These findings are consistent with previous studies.[1,10,11]
Bacterial pneumonias mostly occurred after 6 months of transplant with high morbidity and mortality. This finding is consistent with previous studies.[12,13] Previous studies have shown mortality ranging from 11% to 25%.[14,15] Net immunosuppression, late presentation, antibiotic resistance, and immediate intensive care unit (ICU) availability are factors likely contributing to the higher mortality in our study.
Cytomegalovirus was the most common overall organism in our study. Majority of cases occurred between 1 and 6 months which is consistent with available literature. In a study done by John GT from CMC Vellore, CMV disease occurred in 20% of patients. Another study showed CMV comprising 18.5% of cases. Our study shows a higher occurrence of CMV disease. Due to financial constraints our center gives valganciclovir prophylaxis only to affordable patients (<10%) with the rest undergoing PCR testing in case of a clinical indication with subsequent management as necessary.
The onset of the pandemic also led to COVID-19 cases. Depending on severity, these patients were managed by stopping the antimetabolite or stopping all immunosuppression if patient having severe COVID-19 pneumonia with close monitoring of vitals. In some moderate cases, tacrolimus dose was decreased as well. 83.33% of the COVID-19 pneumonia cases survived the infection by following the above protocol. A multicenter study from India applied a similar immunosuppression protocol of stopping antimetabolite drug and maintaining same dose of calcineurin inhibitor (CNI) and steroids. Mortality rates were reported as 14.5% in hospitalized patients, 47% in ICU, and 96.7% in patients using ventilation. None of our transplant patients with COVID-19 were in mechanical ventilation. Mortality seems largely a factor of the underlying severity of the COVID infection. The pandemic halted transplants in more than 95% transplant centers in India. Transplants are now slowly restarting in most centers with precautions regarding this virus. Larger studies are required to frame guidelines on immunosuppression protocols in COVID-19 Pneumonia.
BK polyoma virus was seen in 1.38% of all cases. This distribution is consistent with a previous study done from a hospital with the same patient catchment area. 66.6% of cases occurred within the 1st year of transplant. Majority of patients who developed BKV nephropathy received antithymocyte globulin as induction agent. Graft biopsy and BKV DNA PCR was used to diagnose cases of BKV nephropathy. BK polyoma virus was not associated with any immediate patient mortality. Studies have shown that 10% of kidney transplant recipients develop BKV nephropathy.[20–22] KDIGO recommends monthly screening for BK virus for 3 to 6 months posttransplant and then every 3 months till the end of the first transplant year. However, in a resource-limited setting like India, financial constraints often prevent such meticulous monitoring with BKV often being diagnosed on demand when clinical suspicion warrants a graft biopsy to diagnose the condition. This may have contributed to the lower overall incidence of BKV nephropathy in our study.
Invasive fungal infections were more common with Aspergillus and Mucor as the most common fungi. Majority of fungal infections occurred 6 months posttransplant. Rubins timeline suggests that most fungal infections occur within 6 months of transplant. However, our study shows data consistent with similar studies done in the tropics which show a peak incidence of fungal infections occurring after 6 months of transplant.[10,12,25] Mucor infections led to high mortality. Studies have reported variable mortality rates from Fungal Infections ranging from 20% to 100%.[10,12,26–28] Our center uses a protocol of stopping antimetabolite drug and starting patients on empirical antifungal therapy while awaiting a tissue diagnosis in suspected cases. Target tacrolimus levels are reassessed based on clinical and radiological response to antifungal therapy. All patients are subsequently given antifungal prophylaxis.
Tuberculosis comprised 11% of all infections. This is consistent with past studies done in India.[29,30] The most common site of involvement was the lower respiratory tract. Majority of cases occurred 6 months after transplantation. Other studies done in tropical areas also report an increased incidence of mycobacterial infections after 6 months posttransplant.[3,7,12,31] Mycobacterial infections led to patient mortality of 13.04%. This is much lower than previously cited.[29,30,32,33] We give a fluoroquinolone-based regime for treatment due to the drug interactions between rifampin and CNI which can precipitate graft rejection. Antimetabolites are either stopped or dosage is reduced depending on the severity of the infection. Duration of therapy is usually 12 to 16 months. None of our patients received INH prophylaxis.
Acute Graft dysfunction was seen in 36.4% of all infections. A study reported 26% incidence of graft dysfunction during an infectious episode. 54.55% of graft pyelonephritis cases in our study had graft dysfunction. The impact of graft pyelonephritis on long-term graft function is debated with multiple studies supporting and negating this hypothesis.[34–36] 47.06% of fungal infections were associated with graft dysfunction. A previous study reported graft dysfunction in 66% of cases of fungal infections.
Graft and patient survival
Data from a transplant center in India showed death censored graft survival of 94%, 90% and 79% at 1, 3 and 5 years respectively. Data from a Military Hospital in India revealed estimated graft survival rates at 1, 5, and 10 years after transplant to be 95.4%, 80.5%, and 51.3%, respectively. These results show that graft survival in our center is lower compared to other centers. However, we have not censored death as a cause of graft loss in our study. Furthermore, 39.1% of graft losses occurred during the COVID-19 pandemic. In comparison, 19.5%, 17.3%, and 17.3%, respectively, of total graft losses occurred yearly in the preceding 3 years prior to the pandemic. The pandemic caused a situation unanticipated by both physicians and patients. Issues included restricted travel and access to medications. Many our patients hail from the states of Uttar Pradesh, Bihar, Haryana, and other neighboring states. Most are from financially poor backgrounds and rely on the hospital supply of immunosuppressive medications. Lockdown restricted access for patients to both physicians and a regular drug supply. People within the local vicinity were also affected as travelling and OPD access was restricted. In addition, brand changes of drugs were also an issue. Brand changes can lead to changes in drug levels which in turn can affect overall graft outcomes. It is likely that a combination of these factors led to the high rate of graft loss during the pandemic.
Predictors of graft and patient outcomes
Univariate analysis for predictors of graft loss and death showed recipient age more than 50 years and graft rejection as predictors of graft loss. Multivariate Cox proportional hazard regression analysis showed recipient age more than 50 and graft rejection as significant independent predictors of graft loss. Recipient age more than 50 years was also a significant predictor of death. Infections showed a statistically insignificant result for both graft loss and death. Univariate analysis for chronic graft dysfunction showed donor age, graft rejection, and CMV infections to be significant predictors. Multivariate analysis was done for these three factors and donor age, graft rejection, and CMV were seen to be significant independent predictors of chronic graft dysfunction.
Due to the partial retrospective nature of the study, our study suffers from all the drawbacks inherent to it. We did not have exhaustive vaccination data of past patients due to similar reasons and hence could not compare differences with current patients. Data pertaining to drug compliance, number and types of human leukocyte antigen mismatches, and cardiovascular risk factors were inadequate to accurately estimate the effect on graft function and the differences between infection and noninfection groups. This is the first exhaustive study on posttransplant infectious disease spectrum and various factors affecting graft and patient outcomes from our center and adds to the body of literature required in a developing country especially when considering resource allocation and areas of intervention in a resource-limited setting.
Infections were associated with the development of chronic rejection and chronic graft dysfunction but were not associated with graft loss and death as compared to patients without history of posttransplant infections. Tuberculosis and invasive fungal infections are more common in late transplant period in tropical regions. Recipient age, donor age, graft rejection and CMV infections are important predictors of graft and patient outcomes. The COVID pandemic led to a disproportionately higher rate of graft loss mostly due to indirect effects of the pandemic.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
We acknowledge transplant surgeons from the Department of Urology, Department of Surgery, and Department of Anaesthesia, ABVIMS, Dr. Ram Manohar Lohia Hospital, New Delhi.
1. Jha V, Chugh S, Chugh KS. Infections
in dialysis and transplant patients in tropical countries. Kidney Int 2000;57:S85–93.
2. Gupta KL, Bagai S, Joshi K, Rathi M, Kohli HS, Jha V, et al. Opportunistic infections
occuring in renal transplant
recipients in tropical countries. Indian J Transplant 2019;13:110–4.
3. John GT. Infections
after renal transplantation in India. Indian J Nephrol 2003;13:14.
4. Jha PK, Yadav DK, Siddini V, Bansal SB, Sharma R, Anandh U, et al. Aretrospective multi-Center experience of renal transplants from India during COVID-19 pandemic. Clin Transplant 2021;35:e14423.
5. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network:Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
6. Roufosse C, Simmonds N, Clahsen-van Groningen M, Haas M, Henriksen KJ, Horsfield C, et al. A2018 reference guide to the Banff classification of renal allograft pathology. Transplantation 2018;102:1795–814.
7. Sriperumbuduri S, Kalidindi K, Guditi S, Taduri G. Declining trend of infections
in renal transplant
recipients in a tertiary care hospital from India. Indian J Transplant 2017;11:143–8.
8. Maraha B, Bonten H, van Hooff H, Fiolet H, Buiting AG, Stobberingh EE. Infectious complications and antibiotic use in renal transplant
recipients during a 1-year follow-up. Clin Microbiol Infect 2001;7:619–25.
9. Cowan J, Bennett A, Fergusson N, McLean C, Mallick R, Cameron DW, et al. Incidence rate of post-kidney transplant infection:A retrospective cohort study examining infection rates at a large Canadian multicenter tertiary-care facility. Can J Kidney Health Dis 2018;5.
10. Gupta RK. Opportunistic infections
in renal allograft recipients. Transplant Proc 2007;39:731–3.
11. Al Midani A, Elands S, Collier S, Harber M, Shendi AM. Impact of urinary tract infections
in kidney transplant recipients:A 4-year single-Center experience. Transplant Proc 2018;50:3351–5.
12. Gupta KL, Bagai S, Joshi K, Rathi M, Kohli HS, Jha V, et al. Oppurtunistic infections
occuring in renal transplant
recipients in tropical countries. Indian J of Transplant 2019;13:110–4.
13. Jha V. Post-transplant infections
:An ounce of prevention. Indian J Nephrol 2010;20:171–8.
14. Kara S, Sen N, Kursun E, Yabanoğlu H, Yıldırım S, Akçay Ş, et al. Pneumonia in renal transplant
recipients:A single-Center study. Exp Clin Transplant 2018;16 Suppl 1 122–5.
15. Dizdar OS, Ersoy A, Akalin H. Pneumonia after kidney transplant:Incidence, risk factors, and mortality. Exp Clin Transplant 2014;12:205–11.
16. Maggiore U, Abramowicz D, Crespo M, Mariat C, Mjoen G, Peruzzi L, et al. How should I manage immunosuppression in a kidney transplant patient with COVID-19?An ERA-EDTA DESCARTES expert opinion. Nephrol Dial Transplant 2020;35:899–904.
17. Kute VB, Bhalla AK, Guleria S, Ray DS, Bahadur MM, Shingare A, et al. Clinical profile and outcome of COVID-19 in 250 kidney transplant recipients:A multicenter cohort study from India. Transplantation 2021;105:851–60.
18. Kute V, Ramesh V, Shroff S, Guleria S, Prakash J. Deceased-donor organ transplantation in India:Current status, challenges, and solutions. Exp Clin Transplant 2020;18:31–42.
19. Gupta P, Gupta A, Bhalla AK, Malik M, Gupta A, Bhargava V, et al. BK virus nephropathy in living donor renal allograft recipients:An observational study from a large transplant Center in India. Saudi J Kidney Dis Transpl 2018;29:1366–70.
20. Hirsch HH, Randhawa P AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant 2013;13 Suppl 4 179–88.
21. Hirsch HH. BK virus:Opportunity makes a pathogen. Clin Infect Dis 2005;41:354–60.
22. Dadhania D, Snopkowski C, Ding R, Muthukumar T, Chang C, Aull M, et al. Epidemiology of BK virus in renal allograft recipients:Independent risk factors for BK virus replication. Transplantation 2008;86:521–8.
23. Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients:A summary. Kidney Int 2010;77:299–311.
24. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998;338:1741–51.
25. Gupta KL. Fungal infections
and the kidney. Indian J Nephrol 2001;11:147.
26. Shekar M, Elumalai R, Elayaperumal I, Yelahanka RP, Anandkumar DG, Bandi VK, et al. Prevalence and outcome of systemic fungal infections
in renal transplant
recipients –A tertiary care experience. Saudi J Kidney Dis Transpl 2019;30:1137–43.
27. Patel MH, Patel RD, Vanikar AV, Kanodia KV, Suthar KS, Nigam LK, et al. Invasive fungal infections
in renal transplant
patients:A single Center study. Ren Fail 2017;39:294–8.
28. Gupta KL, Bagai S, Ramachandran R, Kumar V, Rathi M, Kohli HS, et al. Fungal
infection in post-renal transplant
patient:Single-Center experience. Indian J Pathol Microbiol 2020;63:587–92.
29. John GT, Shankar V, Abraham AM, Mukundan U, Thomas PP, Jacob CK. Risk factors for post-transplant tuberculosis
. Kidney Int 2001;60:1148–53.
30. Sakhuja V, Jha V, Varma PP, Joshi K, Chugh KS. The high incidence of tuberculosis
among renal transplant
recipients in India. Transplantation 1996;61:211–5.
31. Fishman JA. Infection in organ transplantation. Am J Transplant 2017;17:856–79.
32. Singh N, Paterson DL. Mycobacterium tuberculosis
infection in solid-organ transplant recipients:Impact and implications for management. Clin Infect Dis 1998;27:1266–77.
33. Sundaram M, Adhikary SD, John GT, Kekre NS. Tuberculosis
in renal transplant
recipients. Indian J Urol 2008;24:396–400.
34. Bodro M, Sanclemente G, Lipperheide I, Allali M, Marco F, Bosch J, et al. Impact of urinary tract infections
on short-term kidney graft outcome. Clin Microbiol Infect 2015;21:8.e1–8.
35. Pellé G, Vimont S, Levy PP, Hertig A, Ouali N, Chassin C, et al. Acute pyelonephritis represents a risk factor impairing long-term kidney graft function. Am J Transplant 2007;7:899–907.
36. Kamath NS, John GT, Neelakantan N, Kirubakaran MG, Jacob CK. Acute graft pyelonephritis following renal transplantation. Transpl Infect Dis 2006;8:140–7.
37. Mukhopadhyay P, Gupta K L, Kumar V, Ramachandran R, Rathi M, Sharma A, et al. Predictors of allograft survival in living donor renal transplant
recipients. Indian J Transplant 2017;11:42–8.
38. Varma PP, Hooda AK, Sinha T, Chopra GS, Karan SC, Sethi GS, et al. Renal transplantation –An experience of 500 patients. Med J Armed Forces India 2007;63:107–11.