Autosomal dominant polycystic kidney disease (ADPKD): Evaluation and management of complicated urinary tract infections

INTRODUCTION — This topic will review the approach to patients with autosomal dominant polycystic kidney disease (ADPKD) and complicated urinary tract infection (UTI), which we define as a UTI that has possibly extended beyond the bladder (ie, UTI with fever or other systemic symptoms, suspected or documented pyelonephritis and/or cyst infection, and UTI with sepsis or bacteremia). Evaluation and management of simple cystitis (ie, cystitis symptoms in the absence of fever, flank pain, costovertebral angle tenderness, and other signs of systemic illness) are the same in patients with and without ADPKD. Simple cystitis, therapy of ADPKD, and other kidney manifestations of ADPKD are discussed elsewhere:

●(See "Acute simple cystitis in adult and adolescent females".)

●(See "Acute simple cystitis in adult and adolescent males".)

●(See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)

●(See "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations".)

EPIDEMIOLOGY — UTIs, which include cystitis and complicated UTI, in patients with ADPKD are common although the precise incidence is uncertain. Complicated UTIs in patients with ADPKD are relatively infrequent. An infected cyst and pyelonephritis are the most common types of complicated UTI in ADPKD although complications such as a perinephric abscess and bacteremia can occur [1,2]. In one case series of patients with ADPKD, cyst infections occurred at an approximate rate of 0.01 episode per patient per year and accounted for 11 percent of hospital admissions [3].

SOURCE OF INFECTION — As with UTIs in the general population, UTIs in patients with ADPKD are more likely to occur in females [1,4-6]. The infections are typically caused by gram-negative enteric organisms.

With respect to kidney infections:

●Gram-negative enteric organisms ascend from the bladder among patients with pyelonephritis [1,4-6]. Such infections may be associated with dysuria and frequency due to bladder infection.

●In cyst infection, the source of the organisms is also often a gram-negative enteric organism, with Escherichia coli accounting for approximately 75 percent of cases [3]. However, the causes of cyst infection are often more difficult to document since the cysts may not be in communication with the collecting system and the urine culture is often negative. Support for hematogenous spread has been documented in a case report in which Staphylococcus aureus bacteremia with cyst fluid cultures positive for the same organism and negative urine cultures were identified in an ADPKD patient with a history of intravenous drug use [7]. (See "Bacterial adherence and other virulence factors for urinary tract infection".)

Urinary tract instrumentation can also be a source of infection and should be avoided whenever possible. In addition, approximately 20 percent of patients with ADPKD develop nephrolithiasis, and stones may be a source of recurrent infections. (See "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Nephrolithiasis'.)

CLINICAL FEATURES — The clinical manifestations of a kidney infection in ADPKD include fever and flank pain and usually nausea and vomiting [8]. These infections may be due either to kidney parenchymal infection (acute pyelonephritis) or an infected cyst, and distinguishing between them is often difficult. Of note, even nonfunctional end-stage polycystic kidneys may become infected [9].

With pyelonephritis, the manifestations may be more acute, with features similar to those in any patient without ADPKD. By comparison, patients with a cyst infection frequently have a more insidious presentation and may have a specific area of tenderness that relates to the location of the cyst infection. Importantly, both pyelonephritis and cyst infection may be present simultaneously in a patient with ADPKD.

After kidney transplantation, patients with ADPKD are at higher risk for native kidney infections compared with the general population [9]. The classical signs and symptoms of native kidney cyst infection or pyelonephritis (fever, pain, dysuria) can be minimal or absent in such patients [9,10].

DIAGNOSIS — The diagnosis of a kidney infection in a patient with ADPKD requires a similar approach as in a patient without ADPKD and includes a thorough physical examination, urinalysis, urine Gram stain, urine culture with antimicrobial susceptibility testing, and, in most cases, a blood culture. We reserve initial imaging for patients with severe illness and/or suspected urinary tract obstruction. Computed tomography (CT) scanning of the abdomen and pelvis should be obtained as soon as possible in patients with sepsis or septic shock to identify any evidence of obstruction or abscess that requires urgent source control. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Diagnostic approach'.)

The diagnosis of complicated UTI in patients with ADPKD is the same as that in the general population and is discussed elsewhere. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Diagnosis'.)

An additional diagnostic consideration among patients with ADPKD is whether they have pyelonephritis or a cyst infection. Certain clinical characteristics may suggest one over the other:

●Patients with an infected cyst may have a new area of discrete tenderness on physical examination, whereas pyelonephritis tends to be associated with diffuse flank pain.

●The presence of white cell casts is suggestive of acute pyelonephritis, and the urine culture is typically positive. In contrast, the sediment may be bland and the urine culture may be negative in patients with an infected cyst since cysts may not be in contact with the renal collecting system [1,4,5]. Blood cultures may be positive in both pyelonephritis and cyst infections [7].

As in the general population, pyuria alone without an appropriate clinical picture cannot be used to diagnose UTI. Pyuria is found in up to 45 percent of patients with ADPKD without infection [1].

Traditional radiologic studies (including ultrasound, CT scan, and magnetic resonance imaging) are usually of little help in the initial evaluation since the cyst changes induced by an infection are similar to those with cyst hemorrhage; thus, many uninfected cysts appear abnormal [1]. Gallium or indium scanning localizes only inflammation and is positive in approximately one-half of cases [5]. However, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) or a CT-PET scan may identify kidney and hepatic cyst infections and help differentiate between a kidney and liver cyst infection [11-13].

DIFFERENTIAL DIAGNOSIS — The principal distinction to be made in a patient with ADPKD presenting with flank pain is among a kidney infection, cyst infection, and cyst hemorrhage. Since the symptoms are similar, distinguishing among these disorders is difficult without a positive urine culture. Flank pain in the absence of fever is more likely to result from bleeding into and gradual enlargement of a cyst. However, cyst hemorrhage can be associated with transient fever and leukocytosis. In this setting, findings suggestive of hemorrhage rather than infection are the abrupt onset of pain and the absence of antecedent dysuria and frequency. In a systematic review of 215 cyst infections, of which 119 were kidney infections, abdominal pain, fever, and elevated serum inflammatory markers were consistently present [14]. Urine and blood cultures were frequently negative in this study.

Nephrolithiasis (including staghorn calculi) may also be a source of flank pain in patients with ADPKD, as well as a source of UTIs. Imaging studies will identify the presence of kidney stones. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Diagnostic imaging'.)

MANAGEMENT — The majority of patients with ADPKD and kidney infection eventually respond to appropriate antimicrobial agents. Patients who do not respond to antimicrobial therapy or who have recurrent kidney infection require additional evaluation and may need percutaneous or surgical interventions.

Indications for hospitalization — Factors influencing the decision to admit patients with acute complicated UTI are the same in patients with and without ADPKD. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Indications for hospitalization'.)

Empiric antimicrobial therapy — Empiric antimicrobial therapy should be initiated promptly. When patients have several antibiotic options based on individual characteristics and resistance risk, we suggest either a fluoroquinolone or trimethoprim-sulfamethoxazole rather than other antibiotics. These lipid-soluble agents achieve high levels in cysts, and it is often difficult to distinguish between pyelonephritis and cyst infection. Otherwise, our approach to initial antibiotic selection for kidney infection in patients with ADPKD is similar to our approach for all patients with acute complicated UTI and takes into account disease severity and risk factors for drug resistance, including previous antimicrobial use and results of recent urine cultures (table 1) (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Empiric antimicrobial therapy'.)

Our approach of preferentially selecting cyst-penetrating lipid-soluble antibiotics (ie, fluoroquinolones or trimethoprim-sulfamethoxazole) for treatment of kidney infection in patients with ADPKD, when feasible, can be illustrated by example. In a hospitalized patient without critical illness and without risk for infection with a multidrug-resistant (MDR) organism, our empiric antibiotic regimen would consist of ciprofloxacin or levofloxacin rather than ceftriaxone or piperacillin-tazobactam. By contrast, we would not use fluoroquinolones or trimethoprim-sulfamethoxazole for empiric treatment in patients with critical illness or for hospitalized patients at high risk for MDR infection, because of the high and rising prevalence of resistance.

The ideal initial empiric antibiotic would treat both pyelonephritis and cyst infection. However, it is uncertain whether all antimicrobial agents used for pyelonephritis sufficiently penetrate an infected cyst. Since cysts larger than 2 cm in diameter are not in communication with a filtering glomerulus, the antimicrobial drug must enter the cyst by a mechanism other than glomerular filtration [15]. The major mechanism is diffusion, which is more pronounced with lipid-soluble drugs. Lipid-soluble antibiotics such as the fluoroquinolones and trimethoprim-sulfamethoxazole achieve therapeutic concentrations within cysts [1,7,16-20]. By contrast, beta-lactam antibiotics and aminoglycosides may not penetrate cysts [1,4,8,21].

However, clinical data do not suggest that non-lipid-soluble antimicrobial agents result in worse outcomes. In a retrospective study of 90 patients with ADPKD and kidney cyst infection, therapy with non-lipid-soluble antimicrobials was not associated with treatment failure [22].

Directed antimicrobial therapy

Regimen selection — Results of urine and blood cultures and antimicrobial susceptibility testing should be used to tailor the regimen, if appropriate. In many cases, broad-spectrum empiric regimens can be replaced by a more narrow-spectrum agent. Patients who were initially treated with a parenteral regimen can be switched to an oral agent once symptoms have improved, as culture and susceptibility testing allow.

Our approach to selection of a directed antimicrobial agent is similar to our approach for all patients with acute complicated UTI. However, for the reasons stated above, we preferentially select fluoroquinolones or trimethoprim-sulfamethoxazole if these are active against the cultured pathogen. Doses are the same as those used in patients with complicated UTI without ADPKD. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Regimen selection'.)

If blood and urine cultures remain negative, the approach depends on susceptibility of prior isolates (if available) and the risk of drug resistance. If the patient has no prior resistant isolates and low risk for drug resistance (table 2), we generally transition to an oral fluoroquinolone or trimethoprim-sulfamethoxazole following clinical improvement. If resistance is a concern, we often continue the empirically chosen regimen for the full duration.

Duration of therapy — The duration of therapy depends upon the clinical response and whether the patient has an infected cyst:

●Low suspicion for infected cyst – For patients who have acute pyelonephritis without a suspected infected cyst or abscess, we treat with antimicrobial therapy for a minimum of 10 to 14 days. This course is longer than the 5 to 10 days recommended for patients with pyelonephritis in the general population because of the possibility that a patient with ADPKD may have a concurrent small cyst infection, despite the low clinical suspicion, that is amenable to treatment in this time frame.

●Suspicion for infected cyst – The optimal duration of therapy for infected cysts is unclear. Patients with a presumed or confirmed cyst infection are usually treated for at least four weeks and sometimes for up to six weeks. If the infection recurs after withdrawal of antimicrobials, therapy may have to be reinstituted and continued for two to three months or longer [5]. Support for a prolonged duration comes from observational evidence suggesting that courses shorter than four weeks are associated with a high rate of relapse [22].

In cases of an extremely large cyst infection, antibiotic therapy alone may not be sufficient to successfully treat the infection, and cyst drainage may be indicated. (See 'Refractory or relapsed infection' below.)

Refractory or relapsed infection — Patients whose symptoms do not improve within 72 hours or who have continued fevers for more than one week after initiation of appropriate antibiotics have an inadequate response to antimicrobial therapy. In these patients, and in patients who have relapse of infection after finishing an appropriate course of antimicrobial therapy, we obtain kidney imaging with a contrast-enhanced computed tomography (CT) scan. If available, a CT-positron emission tomography (PET) scan also may be used for initial imaging since this modality is ideally suited to identify an infected cyst. Subsequent management depends on imaging findings.

●Stones or abscess on imaging – CT may identify urinary tract obstruction, most commonly due to a stone. In these cases, decompression of the urinary tract is required. Less frequently, nonobstructing stones act as a nidus of infection and may require removal. (See "Kidney stones in adults: Struvite (infection) stones" and "Kidney stones in adults: Surgical management of kidney and ureteral stones".)

CT also can identify a kidney or perinephric abscess. Management of an abscess may include drainage and is discussed elsewhere. (See "Renal and perinephric abscess".)

●No stones or abscess on imaging – For patients without urinary tract obstruction or abscess who have antibiotic nonresponse, percutaneous or surgical drainage of an infected cyst may be necessary for cure. Large, infected cysts (greater than 3 to 5 cm in diameter) are more likely to fail medical therapy and require drainage [7]. In addition to potential therapeutic benefit, cyst drainage may identify pathogenic organisms resistant to or suboptimally treated by the selected antimicrobial regimen. However, drainage of the cyst may be hard to perform since it is usually difficult to ascertain radiologically which of the many cysts is infected.

Case reports and a limited case series of percutaneous drainage of infected cysts have demonstrated a high success rate [7,23]. However, the efficacy of interventional therapies for infected cysts needs to be evaluated in larger studies.

Surgical nephrectomy is the treatment of last resort for patients with ADPKD and kidney infection because of potential complications and the adverse effects of removing a partially functioning kidney [1]. However, there are a few settings in which nephrectomy is sometimes considered:

●In patients with an emphysematous cyst due to gas-forming organisms [24]. This is a rare complication of kidney cyst infections in ADPKD. However, when present, the mortality rate is high and urgent nephrectomy should be considered.

●Patients with recurrent, recent, or refractory infections who are about to undergo kidney transplantation [25]. In this setting, nephrectomy will minimize the risk of posttransplant infection when immunosuppressive agents are administered to prevent rejection [1]. In the absence of recurrent infections, however, posttransplant rates of UTI are comparable between nephrectomized and non-nephrectomized patients with polycystic kidney disease [10].

●Patients with a staghorn calculus causing recurrent UTIs in a relatively nonfunctioning kidney. (See "Kidney stones in adults: Struvite (infection) stones".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and clinical features – Acute pyelonephritis and infected cysts are the most common causes of complicated UTI in ADPKD. In each of these, flank pain and fever are typically present. Acute pyelonephritis is suggested by the presence of white cell casts, whereas an infected cyst may present with a new area of discrete tenderness and a bland urine sediment. The classical signs and symptoms of native kidney cyst infection or pyelonephritis can be minimal or absent in patients with ADPKD after transplantation (See 'Epidemiology' above and 'Clinical features' above.)

●Diagnosis – In patients suspected of having a kidney infection, a complete history and physical examination should be performed, and a urinalysis, urine culture with antimicrobial susceptibility testing, and blood cultures should be obtained. We reserve initial imaging for patients with severe illness and/or suspected urinary tract obstruction because ultrasound, computed tomography (CT), or magnetic resonance imaging findings are generally nonspecific. (See 'Diagnosis' above.)

●Differential diagnosis – Hemorrhage into a cyst and nephrolithiasis can also cause flank pain. Although fever can be present, cyst hemorrhages are not typically associated with pyuria or a positive urine or blood culture. (See 'Differential diagnosis' above.)

●Indications for hospitalization – Factors influencing the decision to admit patients with acute complicated UTI are the same in patients with and without ADPKD. (See "Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents", section on 'Indications for hospitalization'.)

●Empiric therapy – When patients have several antibiotic options based on individual characteristics and resistance risk, we suggest either a fluoroquinolone or trimethoprim-sulfamethoxazole rather than other antibiotics (Grade 2C). These lipid-soluble agents achieve high levels in cysts, and it is often difficult to distinguish between pyelonephritis and cyst infection. Otherwise, our approach to initial antibiotic selection for kidney infection in patients with ADPKD is similar to our approach for all patients with acute complicated UTI and takes into account disease severity and risk factors for drug resistance, including previous antimicrobial use and results of recent urine cultures (table 1). (See 'Empiric antimicrobial therapy' above.)

●Directed therapy – Urine and blood culture results should be used, if possible, to transition from broad-spectrum empiric regimens to a more narrow-spectrum agent. Patients who were initially treated with a parenteral regimen can be switched to an oral agent once symptoms have improved. (See 'Regimen selection' above.)

●Duration of therapy – For patients who have acute pyelonephritis without a suspected infected cyst or abscess, we treat with antimicrobial therapy for a minimum of 10 to 14 days. For patients with presumed or confirmed cyst infection, we treat with antimicrobial therapy for at least four weeks. Shorter courses have been associated with relapse. (See 'Duration of therapy' above.)

●Refractory infection – In those who do not respond to antibiotic therapy, or who have relapse of infection after finishing an appropriate course, we perform a contrast-enhanced CT scan. If available, a CT-positron emission tomography (PET) scan also may be used. For patients who do not have other complications that may contribute to antibiotic nonresponse (eg, urinary tract obstruction or abscess), we suggest percutaneous or surgical drainage of the presumed infected cyst (Grade 2C). Large, infected cysts (greater than 3 to 5 cm in diameter) are more likely to fail medical therapy and require drainage. In addition to potential therapeutic benefit, cyst drainage may identify pathogenic organisms resistant to or suboptimally treated by the selected antimicrobial regimen. (See 'Refractory or relapsed infection' above.)

●Nephrectomy – Nephrectomy is rarely necessary and is a treatment of last resort. However, nephrectomy may be an option for patients with an emphysematous cyst due to gas-forming organisms; patients with recurrent, recent, or refractory infections who are about to undergo kidney transplantation; or patients with a staghorn calculus causing recurrent UTIs in a relatively nonfunctioning kidney. (See 'Refractory or relapsed infection' above and "Kidney stones in adults: Struvite (infection) stones".)