Complicated UTIs with diabetes mellitus

Author

Jun Kamei (Department of Urology, Jichi Medical University, Tochigi, Japan)

Shingo Yamamoto (Department of Urology, Hyogo College of Medicine, Hyogo, Japan)

Abstract

Patients with diabetes mellitus (DM) sometimes exhibited impaired immune function and aggravated infectious diseases. Urinary tract infection (UTI) is one of the major complications of DM. A systematic literature search was performed in PubMed and Cochrane Library using the following keywords: diabetes mellitus, urinary tract infection, asymptomatic bacteriuria, emphysematous pyelonephritis, emphysematous cystitis, renal papillary necrosis, and SGLT2 inhibitors. The treatment of UTI in DM patients is not different from that in non-DM patients, and asymptomatic bacteriuria should not be screened or treated. Emphysematous pyelonephritis is a life-threatening renal infection with gas in the renal parenchyma or perirenal space, and 95% of affected patients had DM. Abdominal computed tomography is useful for diagnosis and determining treatment strategies. Medical management and percutaneous drainage are standard initial treatment, and subsequent nephrectomy for non-responders is considered. Nephrectomy, as an initial treatment, should be limited to a selected group of patients with severe conditions. In contrast, antibiotics, glycemic control, and bladder drainage are adequate treatment for most cases of emphysematous cystitis. Sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly increased the incidence of genital tract infection, but not that of UTI, pyelonephritis, or urosepsis.

Summary of Recommendation

1. The treatment of urinary tract infection (UTI) in patients with diabetes mellitus (DM) does not differ from that in non-DM patients in terms of antimicrobial choice or duration of therapy. (LE: 4, GR: C)

2. Screening and treatment of asymptomatic bacteriuria is not recommended in non-pregnant female DM patients of any age. (LE: 1b, GR: A)

3. In emphysematous pyelonephritis, abdominal computed tomography is a useful imaging examination to confirm the presence and extent of parenchymal gas. (LE: 3b, GR: B)

4. In emphysematous pyelonephritis, medical management and percutaneous drainage should be considered initial treatment. Nephrectomy, as an initial treatment, is limited to selected patients with, both, extension of gas into the perinephric or pararenal space, and for patients with two or more risk factors (e.g., acute renal failure, shock, thrombocytopenia, and altered level of consciousness). (LE: 4, GR: C)

5. In emphysematous cystitis, systemic antimicrobials, bladder drainage, and glycemic control are adequate therapy. (LE: 4, GR: C)

6. Sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly increased the incidence of genital tract infection, but may not increase the incidence of UTI, pyelonephritis or urosepsis. The association of SGLT2 inhibitor and UTI are still unclear. (LE: 1a, GR: A)

Introduction

Urinary tract infection (UTI) is a significant problem in patients with diabetes mellitus (DM). All types of UTI, including bacteriuria or upper urinary tract infection, are increased in DM patients, and the number of hospitalizations for the treatment for pyelonephritis or bilateral renal infection is increased in DM patients compared with their non-DM counterparts.

Furthermore, DM patients have a higher risk for severe urosepsis such as intra- or perirenal abscesses or emphysematous UTI. In addition, several recent studies discussed whether sodium-glucose co-transporter 2 (SGLT2) inhibitors, a type of hypoglycemic agents, increased the prevalence of urogenital tract infection.

Herein, we will discuss the etiology and clinical features of UTI with DM, severe urosepsis associated with DM, and the association of UTI and SGLT2 inhibitors.

Methods

A systematic literature search was performed in PubMed and Cochrane Library using the following keywords: diabetes mellitus, urinary tract infection, asymptomatic bacteriuria, emphysematous pyelonephritis (EPN), emphysematous cystitis, renal papillary necrosis, and SGLT2 inhibitors, and following limitations: clinical studies, English, abstract available, only peer reviewed.

Results

Epidemiology

Both type 1 and 2 DM increase the risk of UTI and bacteriuria caused by Enterobacteriaceae. The reported relative risk (RR) of symptomatic UTI for DM patients ranged from 1.5 to 2.2 compared with non-DM patients, and the risk is increased in those taking oral medications, on insulin therapy, or with longer diabetes duration (1-5). Two nationwide database studies in the United Kingdom and United States revealed that the prevalence of UTI is significantly higher in type 2 DM patients than in non-DM patients (4.7% vs 3.0% and 9.4% vs 5.7%, RR 1.53 and 1.54, respectively) (4, 5). Moreover, these studies demonstrated that the prevalence of UTI in DM patients was increased in both sexes in all age groups.

The incidence of recurrent UTI is also increased by DM. In a US database study, the prevalence rates of recurrent UTI in type 2 DM and non-DM patients are 1.6% and 0.6%, respectively (4). In a Dutch national survey of general practice, the RR of UTI recurrence in type 1 and type 2 DM patients are 3.4 and 1.4, respectively, compared with non-DM patients (3).

In addition, DM increases the risk of acute pyelonephritis and severe urosepsis, such as EPN or renal abscess (6, 7). In a large case-control study, acute pyelonephritis occurred 4.1 times more in pre-menopausal women with DM than in those without DM (8). Another study reported that female and male DM patients are 5.9–24.1 and 3.4–17.0, respectively, times more frequently hospitalized for acute pyelonephritis than non-DM patients (9).

Pathogenesis

Several mechanisms are thought to be associated with UTI in DM patients (7, 10). Bacteria may grow more rapidly in the urine of DM patients with higher glucose level. In an in vitro study evaluating the growth rate of Escherichia coli strains in human urine with and without added glucose, bacteria grew faster in urine with higher concentrations of glucose (11). However, to the best of our knowledge, no well-designed studies have demonstrated the direct association between serum or urine glucose level and risk of UTI; thus, further studies are needed to determine the effect of glucosuria on UTI in DM patients (7, 10). Hyperglycemic condition in DM patients impaired granulocyte function and immune systems (12). Lower urinary interleukin-6 and -8 levels were found in female DM patients with asymptomatic bacteriuria than in those without (13). Furthermore, autonomic diabetic neuropathy induces neurogenic lower urinary tract dysfunction and increases residual urine volume. However, there is little information about whether post-void residual volume increases the risk of UTI in DM patients; thus, further studies are needed.

Bacteriology

The bacteria isolated from DM patients with UTI are similar to those found in non-DM patients with complicated UTI. The most common pathogens are E. coli, and other pathogens isolated frequently are Klebsiella spp., Enterobacter spp., Proteus spp., Group B Streptococci, and Enterococcus faecalis (7, 14, 15). The increase in antimicrobial resistant strains in DM patients with UTI is controversial (14-17).

Clinical feature and treatment

General principles of medical treatment in UTI with DM

The treatment of symptomatic UTI in DM patients is similar to that in non-DM patients in terms of antimicrobial agent or duration of therapy (7, 18) (LE: 4, GR: C). Acute cystitis in women with good glucose control and without long-term complications should be managed as uncomplicated UTI, with short-term antibiotic use. In contrast, other UTI types in DM patients are usually treated as complicated infections (7, 19). Empiric antibiotics should be chosen on the basis of the local susceptibility patterns of pathogens.

The general advice for preventing UTI should be provided to DM patients, especially after an initial episode of UTI, even though there is limited evidence on the preventive management of UTI specific to DM patients (6, 20). General preventive strategies include sufficient fluid intake, complete bladder emptying during voiding, less use of spermicides, and restrictive catheter use (21). A small randomized, placebo-controlled study revealed that taking a cup of cranberry juice once daily prevented the recurrence of UTI in female patients (22). Several studies suggested the preventive effects of oral or vaginal lactobacillus or estriol for UTI recurrence, and these agents may be also useful (23). These strategies may be also useful for DM patients with recurrent UTI.

Compared with non-DM patients, DM patients with acute pyelonephritis tend to develop a more severe condition such as bacteremia, have longer hospitalization, or die (24, 25). Bilateral acute pyelonephritis is also more common in DM patients (20, 26). Furthermore, acute pyelonephritis in DM patients sometimes demonstrates milder symptoms. In a multicenter study of women with community-acquired acute pyelonephritis, DM patients had a more severe infection and longer hospitalization but showed less clear clinical findings than non-DM patients (27). Therefore, pyelonephritis in DM patients with severe symptoms including nausea, vomiting, or metabolic alterations should be treated with initial intravenous antibiotics post-hospitalization; those with mild to moderate symptoms may be treated with oral antibiotics (7, 19). In addition to antimicrobial treatment, glycemic control with insulin or hypoglycemic agents is also important (6). Surgical drainage, debridement, or computed tomography (CT)-guided drainage may be considered necessary depending on the patients’ condition (28). Almost all patients with emphysematous cystitis and pyelonephritis present with DM.

Asymptomatic bacteriuria

A meta-analysis reported that asymptomatic bacteriuria was observed in 12.2% and 4.5% of patients with and without DM, and the prevalence was 3.0 and 3.2 times higher in patients with type 1 and 2 DM than in those without (29). The prevalence was higher in both women (14.2 vs 5.1%, odds ratio [OR] 2.6) and men (2.3 vs 0.8%, OR 3.7). It also reported that a history of UTI was associated with asymptomatic bacteriuria (OR 1.6). A prospective study following female DM patients with asymptomatic bacteriuria for 3 years reported that asymptomatic bacteriuria persisted or recurred mostly in women (30). Furthermore, a placebo-controlled double-blinded randomized study revealed that antibiotic treatment for asymptomatic bacteriuria in non-pregnant DM patients did not reduce the incidence of symptomatic UTI or pyelonephritis or shorten hospitalization for UTI (31). Taking these results, screening or antibiotic treatment of asymptomatic bacteriuria in DM patients is not recommended (LE: 1b, GR: A).

Emphysematous UTIs

Emphysematous pyelonephritis (EPN)

EPN is a severe and life-threatening necrotizing renal and perirenal infection with gas in the renal parenchyma, collecting system, or perinephric tissue. The recent mortality rate from EPN is 25% (32). Underlying poorly controlled DM is present in up to 95% of the affected patients, and the female-to-male ratio reported in meta-analyses was 4–6:1 (32, 33). The incidence of developing EPN secondary to ureteral obstruction was 25%–40% (34).

The most common pathogens are E. coli and Klebsiella, followed by Proteus (34, 35). The diagnosis of EPN is often delayed because the clinical manifestations are nonspecific and are similar to classic upper UTI (fever, flank pain, and pyuria). Therefore, in a patient with UTI, if the fever does not subside after 3–4 days of antibiotic treatment, EPN, renal abscess, or papillary necrosis should be considered. CT finding of the localization of gas in the intrarenal or perinephric space or to the collecting system is crucial in determining therapy and prognosis.

Diagnosis

EPN requires a radiological diagnosis. Conventional radiography may demonstrate gas bubbles overlying the renal fossa. Ultrasonography (US) characteristically shows an enlarged kidney containing high-amplitude echoes within the renal parenchyma. CT is the definitive modality for diagnosing EPN to confirm the presence and extent of parenchymal gas (35). (LE: 3b, GR: B)

In 2000, Huang et al. reported a classification system based on CT findings, which is most commonly used for deciding management strategies (36). The classification is based on the location of the gas in the kidney as follows:

Class 1: Gas in the collecting system only

Class 2: Gas in the renal parenchyma

Class 3A: Extension of gas or abscess to the perinephric space

Class 3B: Extension of gas or abscess to the pararenal space

Class 4: Bilateral EPN or solitary kidney with EPN

Prognostic indicators

Huang et al. reported that acute renal failure, shock, thrombocytopenia, and impaired consciousness were significantly associated with mortality from EPN and defined as risk factors (36). A meta-analysis evaluating seven study cohorts identified that conservative treatment alone (OR 2.85), bilateral EPN (OR 5.36), thrombocytopenia (OR 22.68), and renal necrosis with gas but no fluid (OR 2.53) were significantly associated with increased mortality (32). In this meta-analysis, systolic blood pressure <90 mmHg, serum creatinine >2.5 mg/dl, and disturbance of consciousness were also found to be associated with higher mortality.

Management

The initial management of a patient with EPN is done by resuscitation; maintaining the fluid/hemodynamic status, controlling DM, and using antibiotics to target Gram-negative bacteria. Appropriated ureteral drainage by percutaneous nephrostomy or ureteral stent should be performed if ureteric obstruction is present (35). Emergency nephrectomy has been considered useful until the late 1980s, but recent studies have reported that percutaneous drainage (PCD) helped preserve the function of the affected kidney in approximately 70% of cases (34). There has been a gradual shift to a nephron-sparing approach with PCD, and emergency nephrectomy as initial treatment has been limited to selected patients.

Surgical interventions

In a meta-analysis, medical management and PCD was the most successful management (30%–100%) with the lowest mortality at 13.5% (34). Therefore, medical management with PCD and subsequent nephrectomy for non-responders alone are considered the standard treatment strategy, and nephrectomy as initial treatment should be limited to a selected group of patients with severe conditions (33, 34, 36). (LE: 4, GR: C) For glycemic control, intravenous insulin is ideal, and at times, rates of up to 20–30 units of regular insulin hourly may be required for sepsis patients (37). (GR: C)

Huang et al. suggested the following management strategies based on their classification (36). Class 1 and 2 EPN can be managed with medical management alone or combined with PCD. In Class 3 with 0 or 1 risk factor (e.g., thrombocytopenia, shock, acute renal failure, altered level of consciousness) and Class 4 EPN, the survival rate with medical management with PCD is 85%. In Class 3 EPN with >2 risk factors, medical management and PCD were unsuccessful in 92% of cases, and emergency nephrectomy as initial treatment should be considered. Elective nephrectomy should be considered in non-responders to medical management and PCD.

Emphysematous cystitis

Emphysematous cystitis results from a primary infection of the bladder. Emphysematous cystitis is rare and is characterized by pockets of gas in and around the bladder wall produced by bacterial or fungal fermentation. The condition may result in a “cobblestone” appearance with a translucent line of air outlining the bladder wall. CT is considered useful in its diagnosis because of its high sensitivity and specificity in the detection of abnormal gas and its anatomical extension (38).

A review of 135 cases of emphysematous cystitis reported that 64% of patients were female and 67% had DM. E. coli was most commonly isolated (39-41). In general, systemic antimicrobials and relief of any complicating bladder outlet obstruction, if present, are adequate therapies. (LE: 4, GR: B) Most patients (90%) can be treated with medical management, and surgical treatment was limited to those with poor response to initial treatment or severe necrotizing infections. The reported mortality rate was approximately 7% (39-41).

Papillary necrosis

Renal papillary necrosis has a variable clinical course that ranges from a chronic and relapsing form to an acute, rapidly progressive form. Papillary necrosis is common in DM patients and particularly associated with acute pyelonephritis. It is associated with permanent renal parenchymal scarring, although it is difficult to exclude obstruction of sloughed papillae as the cause of the nephropathy. Compromised perfusion caused by vasculitis in DM, tuberculosis, or the curtailment of flow observed in hemoglobinopathy, analgesic nephropathy, or acute urinary obstruction also set the stage for ischemic changes in the medullary pyramid (42).

Renal papillary necrosis should be considered in DM patients with pyelonephritis not responding well to antibiotic therapy (43). Common symptoms are fever, chills, flank and/or abdominal pain, and hematuria (44, 45). Renal papillary necrosis is a radiologic diagnosis confirmed by histology of the voided medullary tissue. CT demonstrates necrotic papillae allowing for the diagnosis to be made.

The treatment of renal papillary necrosis includes aggressive antibiotic therapy when infection is present. Relief of the obstruction may be required as well. The prognosis for this condition is not well defined.

Association of urogenital tract infections and SGLT2 inhibitors

The kidney plays an important role in glucose homeostasis, not only in gluconeogenesis, but also in reabsorbing filtered glucose via transporters called SGLT. SGLT2 inhibitors, one of the newest classes of hypoglycemic agents, block the reabsorption of filtered glucose, leading to glucosuria and improvements in glycemic control and HbA1c levels (46).

Higher urine glucose level induced by SGLT2 inhibitors may increase urogenital tract infection caused by promoting growth of microorganisms in urine. Earlier meta-analyses for evaluating the efficacy of SGLT2 inhibitors raised concerns about adverse events of genitourinary infections, but the findings were inconsistent (47-50). Recently, several meta-analyses evaluating the effect of SGLT2 inhibitors on genitourinary infection have been published.

Effects of SGLT2 inhibitors on UTI

Four meta-analyses focusing on the effects of SGLT2 inhibitors on UTI and/or GTI were identified (51-54). Only one meta-analysis reported that the risk of UTI in the SGLT2 inhibitor group was significantly higher than that in the control group (9.0% vs 8.6%, RR 1.18), and canagliflozin and dapagliflozin increased the risk of UTI significantly compared with placebo regardless of the dose (RR 1.15 and RR 1.67, respectively) (51). Two other meta-analyses concluded that the risk of UTI was not increased with SGLT2 inhibitors compared with placebo or control (52, 53). Puckrin et al. evaluated only dapagliflozin 10 mg daily and found that it was associated with a significantly increased risk of UTI compared with placebo (RR 1.33), and SGLT2 inhibitors did not increase the risk of urosepsis compared with placebo (0.25% vs 0.15%), or pyelonephritis compared with placebo (0.34% vs 0.43%) or an active comparator (0.15% vs 0.08%) (52). A network meta-analysis concluded that only dapagliflozin had a dose-response relationship with UTI (54). A recent larger retrospective population-based study in Canada also concluded that SGLT2 inhibitor use was not statistically associated with increased risk of UTI (55).

Taking these results, the effect of SGLT2 inhibitors on the risk of UTI may be limited but remains unclear. Further prospective studies and meta-analyses will be required.

Effects of SGLT2 inhibitors on GTI

Three meta-analyses evaluated the effect of SGLT2 inhibitors on GTI (52-54). These analyses concluded that SGLT2 inhibitors significantly increased the risk of GTI compared with both placebo and control (RR 3.21–5.23) and that canagliflozin, dapagliflozin, and empagliflozin were associated with a significantly higher risk of GTI. A network meta-analysis concluded that dapagliflozin showed a dose-response relationship with GTI (54). A population-based study in Canada reported that SGLT2 inhibitors increased the risk of genital mycotic infection within 120 days in both sexes (RR: female 2.36, male 1.91) (55).

Further Research

To our knowledge, no prospective studies with larger cohort or randomized controlled studies have evaluated appropriate management strategies for emphysematous UTI. Furthermore, the evidence of the association of SGLT2 inhibitors and UTI (including urosepsis or pyelonephritis) is still insufficient. Further studies focusing on whether SGLT2 inhibitors increase the prevalence of several type of UTI will be needed.

Conclusions

DM increases the risk of all types of UTI, and the treatment of UTI in DM patients is not different from that in non-DM patients. The choice and duration of antibiotics should be similar to conventional UTI treatment, and asymptomatic bacteriuria should not be treated. Most patients with emphysematous UTIs showed DM; diabetic control, empiric antibiotic use, and appropriate drainage should be considered as the initial therapy for, both, EPN and cystitis patients except for patients with Class 3 EPN with poor prognostic factors. Moreover, SGLT2 inhibitors increase the risk of GTI but may not increase that of UTI.

Conflict of Interest of each author

There is no conflict of interest to declare.

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