UTI in Renal Transplant Patients

Urinary tract infection and kidney transplant

UTI, especially recurrent UTI, is a common problem in recipients after kidney transplantation (KTX). Acute UTI not only affects a patient’s well-being but also gives rise to several issues that must be addressed in a transplant recipient. These include interaction of antibiotic medication with immunosuppression, the isolation of and infection with resistant bacteria, growth of Candida spp. due to antibiotic treatment, and finally recurrent UTI. Most importantly, urosepsis with impairment of graft function are potential long-term sequelae of recurrent UTI in KTX recipients.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168.

UTIs after kidney transplantation have important implications. They may be associated with bacteremia and may require hospitalization. The recurrent nature of the problem necessitates the use of multiple courses of antibiotic therapy, which are not only costly but can result in bacterial resistance and contribute to erratic levels of immunosuppression.²Lorenj EC, Cosio FG. The impact of urinary tract infections in renal transplant patients. Kidney International 2010;78: 719–721.

Current guidelines simply recommend that kidney transplant recipients receive posttransplant UTI prophylaxis with trimethoprim –sulfamethoxazole and that patients with allograft pyelonephritis receive intravenous antibiotics in the hospital.²Lorenj EC, Cosio FG. The impact of urinary tract infections in renal transplant patients. Kidney International 2010;78: 719–721.

Types of infection after renal transplant

According to the guidelines of the European Association of Urology (EAU), the types of UTI after renal transplant are described below in Table 1.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168.

Clinical presentation of UTI after renal transplant

UTI classically presents with dysuria, urinary frequency/urgency and suprapubic pain. Pain and tenderness over the renal allograft or costo-vertebral region may indicate upper urinary tract involvement. Some patients may primarily present with fever, malaise or a nonspecific sepsis syndrome without symptoms localized to the urinary tract.³Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.

Most importantly, transplant dysfunction plus fever in a transplant recipient is highly suggestive of UTI, irrespective of the patient’s subjective well-being.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168.

Underlying causes and predisposing factors

The risk factors for the development of posttransplant UTI are multifactorial and are determined by the interaction between host factors, pathologic agents and anatomical abnormalities.³Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.

The underlying causes and predisposing factors of UTI are described as follows in Table 2.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168.

Diagnosis

Typically, diagnosis of a symptomatic UTI includes a quantitative count of bacteria (≥ 105) in an appropriately collected urine specimen in the presence of symptoms or signs of urinary infection. Not all organisms found in urine cultures are pathogens. Urine cultures containing multiple organisms(i.e. “mixed flora”) indicate that contamination has most likely occurred. Other true pathogens may not grow well on routine culture media (e.g. unusual pathogens such as Corynebacterium urealyticum or M. tuberculosis) and specific culture media may need to be requested. The usefulness of leukocyte esterase and nitrite screening by dipstick has not been demonstrated in renal transplant recipients. Imaging with renal ultrasound or noncontrast CT scan should be considered to assess for complications such as obstruction and abscess, particularly in patients not fully responding to initial therapy or in patients with signs of severe infection.³Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.

Intervention

The overall treatment strategy depends on the severity of illness. Selection of antimicrobial agents should be based on local epidemiological data and the patient’s history of resistant organisms. In clinical situations with severe infection with sepsis, the option of reduction/discontinuation of immune suppression should also be considered.³Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.

Asymptomatic bacteriuria

Ideally transplant recipient patients presenting with asymptomatic bacteriuria within three months of transplant should be treated in order to prevent symptomatic UTIs, which have been associated with an increased risk of acute allograft rejection.⁴Lee JR, Bang H, Dadhania D, et al. Independent risk factors for urinary tract infection and for subsequent bacteremia or acute cellular rejection: a single-center report of 1166 kidney allograft recipients. Transplantation 2013; 96:732

Presently there is no consensus regarding whether to treat later-onset asymptomatic bacteriuria. El Amari EB et al conducted a study that included patients with asymptomatic E. coli and Enterococcus bacteriuria, who presented more than one month post-transplant. In this study it was concluded that the presence of pyuria may be used to identify patients most likely to benefit from antibiotic treatment . Compared with patients with bacteriuria but no pyuria, patients with bacteriuria and pyuria were more likely to clear bacteriuria with antibiotic administration.⁵El Amari EB, Hadaya K, Bühler L, et al. Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients. Nephrol Dial Transplant 2011; 26:4109.

Determining the identity and antibiotic susceptibilities of the causative organism before commencing treatment, is strongly recommended. Selection of an oral antibiotic is based upon the susceptibility pattern of the micro-organism. Commonly used regimens for patients with normal renal function are ciprofloxacin 250 mg orally twice daily, amoxicillin 500 mg orally three times daily, and nitrofurantoin 100 mg orally twice daily (provided estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m²). The dosing of ciprofloxacin and amoxicillin must be adjusted in patients with reduced renal function, and nitrofurantoin is contraindicated in patients with creatinine clearance <60 mL/min.

The American Geriatrics Society 2015 Beers Criteria Update Expert Panel has revised its recommendation to avoid use of nitrofurantoin in renal impairment from patients with a creatinine clearance (Clcr) of less than 60 mL/min to those with a Clcr of less than 30 mL/min, based on two retrospective studies that identified the safety and efficacy of nitrofurantoin in this population.⁶Hoang P1, Salbu RL. Updated Nitrofurantoin Recommendations in the Elderly: A Closer Look at the Evidence. Consult Pharm. 2016; 31(7):381–4. doi: 10.4140/TCP.n.2016.381.

Uncomplicated UTI

Uncomplicated urinary tract infections (UTIs) in women are a common problem in primary care.⁷Mckinnell JA et al. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis. Mayo Clin Proc. 2011;86(6):480–488.

For many years, trimethoprim-sulfamethoxazole (TMPSMX) was the preferred antibiotic for the treatment of UTI, given its efficacy and low cost. However, development of a high prevalence of TMP-SMX resistance among uropathogens 3-5 has discouraged use of this drug in many communities.⁷Mckinnell JA et al. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis. Mayo Clin Proc. 2011;86(6):480–488.

An effective alternative for many clinicians has been the fluoroquinolone class of antibiotics, which achieve high concentrations in the urine and have excellent activity against most uropathogens. Of note, the 2011 Infectious Diseases Society of America (IDSA) guidelines on the treatment of UTIs discourage use of fluoroquinolones for acute, uncomplicated UTI. Experts are concerned about overuse of fluoroquinolones leading to increased prevalence of fluoroquinolone-resistant pathogens that has major implications for the treatment of more serious infections, such as community-acquired pneumonia, health care–associated pneumonia, and complicated UTIs.7

Nitrofurantoin has been used for decades as an alternative treatment of uncomplicated UTIs. Additionally, nitrofurantoin has retained a high prevalence of sensitivity to most uropathogens and has a favourable side-effect profile. A recently published randomized trial demonstrated that nitrofurantoin for 5 days is as effective as TMP-SMX for 3 days in treating acute UTI in women. Moreover, nitrofurantoin, like TMP-SMX, is less expensive than fluoroquinolones in many communities.⁷Mckinnell JA et al. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis. Mayo Clin Proc. 2011;86(6):480–488.

The antibiotic nitrofurantoin is commonly used to treat uncomplicated urinary tract infections. However, when this drug is used by patients with reduced kidney function, its urine concentration may be subtherapeutic.¹⁰Singh N et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. CMAJ 2015;187 (9): 648–656.

Nitrofurantoin is to be taken along with food or milk to suppress the GI irritation which is usually known to occur with its consumption. Modified release (MR) nitrofurantoin formulations are preferred over the conventional formulations because the former maintain urinary concentration over duration of 12 hours, decrease dosage frequency to twice a day, better gastrointestinal tolerability and enhanced patient compliance. When nitrofurantoin MR formulation is given, a part of the drug is released immediately and gets rapidly accumulated in urine for immediate action within first hour while the remaining drug is released steadily and continuously for the whole day to maintain adequate urinary concentration. Nitrofurantoin MR formulation for uncomplicated UTIs consist of 100 mg PO two times per day for 7 days. Long-term suppressive therapy consists of 50 to 100 mg PO at bedtime.8,9 Nitrofurantoin is contraindicated once serum creatinine is 3.0 mg% or more.

Recurrent UTI

There are no studies to show the optimal duration of antibiotic treatment for recurrent UTI (three or more episodes of UTI in one year). The duration of therapy for complicated UTI in kidney transplant recipients is typically 14 to 21 days, but, in some situations, a longer course may be necessary. As an example, recurrent UTIs associated with an indwelling source (such as infected cysts in native kidneys) can require up to four to six weeks of therapy.

In other situations, therapy for recurrent UTIs can be discontinued after a shorter period, and the patient can be transitioned to prophylactic antibiotics.

Recurrent UTIs after renal transplant can contribute to increased morbidity and may also be associated with graft loss and mortality. Though several risk factors like female gender, diabetes mellitus, presence of ureteric stents, native kidney disease with urological malformations and re-transplantation have been associated with recurrent UTIs after renal transplant, vesicoureteric reflux appears to be a unique risk factor in this patient population.¹¹Mitra S, Alangaden GJ. Recurrent urinary tract infections in kidney transplant recipients. Curr Infect Dis Rep. 2011;13 (6):579–87.

Anatomic and functional abnormalities should be identified and corrected in renal transplant patients with recurrent symptomatic UTI. Patients should be reminded of basic infection prevention measures, such as hydration, frequent voiding, and for females to void after sexual intercourse and wiping from front to back with toilet tissue. The figure 1 outlines the evaluation and management of recurrent UTI in renal transplant patients.³Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.

Prophylaxis

Prevention of UTI should receive highest priority with a particular attention given to treatment of existing infections, and correction of structural abnormalities of the urinary tract when present in the potential recipients prior to transplantation.³Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.

Removal of the catheter as early as 36–48 h after KTX was found to be favourable.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168. The voiding situation must be assessed in recurrent UTI and complete bladder emptying should be achieved, at times with clean intermittent catheterisation.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168. Long-term administration of TMP at 160 mg and SMZ at 800 mg for 6 months, especially in high-risk patients with urinary reflux, re-transplantation, and/or voiding disorders, is recommended.¹Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168.

Concerning the dose of antibiotics, Khosroshahi et al. reported a reduction of UTI from 50% to 25% if the TMP-SMZ dose was doubled.¹²Khosroshahi HT, Mogaddam AN, Shoja MM. Efficacy of high-dose trimethoprim- sulfamethoxazol prophylaxis on early urinary tract infection after renal transplantation. Transplant Proc. 2006;38(7):2062–4.

Conclusion

Urinary tract infection (UTI) is the most common infection after kidney transplantation. In adults, urinary tract infection (UTI) after renal transplantation has been associated with significant morbidity. The use of postoperative antibiotic prophylaxis has reduced dramatically the incidence of UTI after renal transplantation in the past few decades. Nevertheless, the rates of serious post transplantation complications that are associated with UTI, such as bacterial septicemia, remain high for patients.¹³Dharnidharka VR et al. Effects of Urinary Tract Infection on Outcomes after Renal Transplantation in Children. Clin J Am Soc Nephrol 2007; 2: 100–106.

References

1. Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology 2012; 10:162–168.
2. Lorenj EC, Cosio FG. The impact of urinary tract infections in renal transplant patients. Kidney International 2010;78: 719–721.
3. Parasuraman R, Julian K. Urinary Tract Infections in Solid Organ Transplantation. American Journal of Transplantation 2013; 13: 327–336.
4. Lee JR, Bang H, Dadhania D, et al. Independent risk factors for urinary tract infection and for subsequent bacteremia or acute cellular rejection: a single-center report of 1166 kidney allograft recipients. Transplantation 2013; 96:732
5. El Amari EB, Hadaya K, Bühler L, et al. Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients. Nephrol Dial Transplant 2011; 26:4109.
6. Hoang P1, Salbu RL. Updated Nitrofurantoin Recommendations in the Elderly: A Closer Look at the Evidence. Consult Pharm. 2016; 31(7):381–4. doi: 10.4140/TCP.n.2016.381.
7. Mckinnell JA et al. Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis. Mayo Clin Proc. 2011;86(6):480–488.
8. Spencer RC, Moseley DJ, Greensmith MJ. Nitrofurantoin modified release versus trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. J Antimicrob Chemother. 1994 May; 33 Suppl A: 121–9.
9. Antimicrobial Prescribing Guidelines in General Practice; National Health Service; 2012; v1.0: 14–19.
10. Singh N et al. Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women. CMAJ 2015;187 (9): 648–656.
11. Mitra S, Alangaden GJ. Recurrent urinary tract infections in kidney transplant recipients. Curr Infect Dis Rep. 2011;13 (6):579–87.
12. Khosroshahi HT, Mogaddam AN, Shoja MM. Efficacy of high-dose trimethoprim- sulfamethoxazol prophylaxis on early urinary tract infection after renal transplantation. Transplant Proc. 2006;38(7):2062–4.
13. Dharnidharka VR et al. Effects of Urinary Tract Infection on Outcomes after Renal Transplantation in Children. Clin J Am Soc Nephrol 2007; 2: 100–106.