Emphysematous pyelonephritis. Royal Liverpool and Broadgreen University Hospital, Liverpool, UK

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1 ; JOURNAL COMPILATION 2010 Laparoscopic and Robotic Urology EMPHYSEMATOUS PYELONEPHRITIS UBEE ET AL. BJUI Emphysematous pyelonephritis Sarvpreet Singh Ubee 1, Laura McGlynn 2 and Mark Fordham 2 1 Department of Urology, The Heart of England NHS Foundation Trust, Birmingham, UK, 2 Department of Urology, The Royal Liverpool and Broadgreen University Hospital, Liverpool, UK Accepted for publication 25 May 2010 Study Type Therapy (case series) Level of Evidence 4 Emphysematous pyelonephritis (EPN) is an acute severe necrotizing infection of the renal parenchyma and its surrounding tissues that results in the presence of gas in the renal parenchyma, collecting system, or perinephric tissue. The cause for mortality in EPN is primarily due to septic complications. Up to 95% of the cases with EPN have underlying uncontrolled diabetes mellitus. The risk of developing EPN secondary to a urinary tract obstruction is about 25 40%. There are three classifications of EPN based on radiological findings. Acute renal failure, microscopic or macroscopic haematuria, severe proteinuria are other positive findings in EPN. Escherichia coli is the most common causative pathogen with the organism isolated on urine or pus cultures in nearly 70% of the reported cases. What s known on the subject? and What does the study add? Emphysematous pyelonephritis (EPN) is a severe necrotizing infection of the renal parenchyma. The clinical course of EPN can be severe and life-threatening if not recognized and treated promptly. Most of the information has been from case reports, a few large series have also been reported. Using an evidence-based approach, this review describes the pathogenesis, classification, complications, and management of EPN. A plain radiograph shows an abnormal gas shadow in the renal bed raising the suspicion whereas an ultrasound scan or computed tomography (CT) will confirm the presence of intra-renal gas thus supporting the diagnosis of EPN. Gas may extend beyond the site of inflammation to the sub capsular, perinephric and pararenal spaces. In some cases, gas was found to be extending into the scrotal sac and spermatic cord. Subsequent case studies have shown patients being successfully treated with PCD when used in addition to medical management, with significant reduction in the morality rates. PCD should be performed on patients who have localized areas of gas and functioning renal tissue is present. The treatment strategies include MM alone, PCD plus MM, MM plus emergency nephrectomy, and PCD plus MM plus emergency nephrectomy. In small proportion of patients managed with MM and PCD, subsequent nephrectomy will be required and in these patients the reported mortality is 6.6% Nephrectomy in patients with EPN can be simple, radical or laparoscopic. KEYWORDS emphysematous pyelonephritis, diabetes mellitus, escherichia coli, percutaneous drainage, nephrectomy INTRODUCTION Emphysematous pyelonephritis (EPN) is an acute severe necrotizing infection of the renal parenchyma and its surrounding tissues that results in the presence of gas in the renal parenchyma, collecting system or perinephric tissue [1,2]. The first case of gas-forming renal infection was reported by Kelly and MacCullum in 1898 [3]. Since then terms such as renal emphysema, pneumonephritis as well as emphysematous pyelonephritis have been used to describe the gas-forming infection. In 1962, Schultz and Klorfein [4] suggested the use of emphysematous pyelonephritis as the preferred term, as it emphasizes the relationship between infective pathology and gas formation. Some authors have suggested that this term should be applied to gas within the renal parenchyma or perinephric space [5 7], but several other investigators define it as gas within the collecting system, parenchyma, perirenal space, or in any of these [8,9]. Gas in the collecting systems only, emphysematous pyelitis, is a separate condition and could be secondary to instrumentation of the urinary tract. A patient infected with emphysematous pyelitis has an excellent prognosis with medical management (MM), whereas EPN deserves special attention because of its lifethreatening potential with either MM or surgical management. Mortality from EPN is primarily attributable to septic complications. EPN was associated with a mortality rate of up to 78% until the late 1970s but, over the last two decades, improvement in management techniques has reduced the mortality rate to 21% [7,10]. We performed a structured comprehensive literature review within the MEDLINE database and The Cochrane Library Central Search database. The initial search terms were emphysematous pyelonephritis and pyelonephritis. Based on these results, additional searches were performed using the terms percutaneous nephrostomy and nephrectomy. English-language publications were selected and included in this review article. ASSOCIATED FACTORS Diabetes mellitus is the single most common associated factor. Up to 95% of patients with EPN have underlying uncontrolled diabetes mellitus [7,11]. Other reported factors associated with the development of EPN are drug abuse, neurogenic bladder, alcoholism and anatomic anomaly [1,12,13]. There is a preponderance of EPN in females; the female:male ratio reported in relatively , doi: /j x x

2 EMPHYSEMATOUS PYELONEPHRITIS TABLE 1 EPN classification systems Classification Radiological basis Class Michaeli et al. Plain radiograph and I. Gas in the renal parenchyma or perinephric tissue [1] intravenous II. Gas in the kidney and its surroundings pyelogram III. Extension of gas through fascia, or bilateral disease Wan et al. [7] CT I. Renal necrosis with presence of gas but no fluid II. Parenchymal gas associated with fluid in renal parenchyma, perinephric space or collecting system Huang and CT 1. Gas in collecting system only Tseng [14] 2. Parenchymal gas only 3A. Extension of gas into perinephric space 3B. Extension of gas into pararenal space 4. EPN in solitary kidney or bilateral disease small studies is 6 : 1 [10,14,15]. Increased susceptibility to UTI seems to be the reason for the higher incidence in females. The risk of developing EPN secondary to a urinary tract obstruction is 25 40% [1,12]. Although cases of EPN have been reported worldwide, it appears to be geographically more common in Asia with most case studies being reported from there. AETIOLOGY AND PATHOGENESIS Emphysematous pyelonephritis is a severe, necrotizing form of acute bacterial pyelonephritisa and Escherichia coli remains the most common causative pathogen; the organism has been isolated on urine or pus cultures in nearly 70% of the reported cases [16,17]. There have, however, been reports of Proteus mirabilis, Klebsiella pneumoniae, Group D Steptococcus and coagulasenegative Staphylococcus being the causative agent for EPN [16,17]. Anaerobic microorganisms including Clostridium septicum, Candida albicans, Cryptococcus neoformans and Pneumocystis jiroveci have, in rare cases, been reported as the causative pathogen for EPN [7,17]. Bacteraemia is present in more than 50% of the patients and the organisms are the same as those in urine or pus culture [14]. The presence of a less common causative organism on urine or blood culture does not require that patient to be treated for EPN unless there are radiological features to suggest that EPN might be present. Various factors involved in the pathogenesis of this condition have been suggested, including high levels of glucose within the tissues, the presence of gas-forming microorganisms, impaired vascular blood supply, reduced host immunity and the presence of obstruction within the urinary tract. A high level of tissue glucose in association with impaired blood supply to the kidneys, which is prevalent in patients with diabetes, facilitates the process of anaerobic metabolism [16]. Gram-negative facultative anaerobic microorganisms such as E. coli are responsible for the production of gas via the fermentation of glucose and lactate. This process results in the production of high levels of carbon dioxide and hydrogen which accumulate at the site of inflammation. Radiologically guided needle aspiration of the gases released by the tissues was analysed by Huang and Tseng [14] who found carbon dioxide and hydrogen to be the main constituents. Nitrogen and oxygen have also been found along with traces of ammonia, methane and carbon monoxide [14]. Gas may extend beyond the site of inflammation to the sub-capsular, perinephric and pararenal spaces. In some cases, gas was found to be extending into the scrotal sac and spermatic cord [18]. Pathological examination of the kidney reveals features of abscess formation, foci of micro- and macro-infarctions, vascular thrombosis, numerous gas-filled spaces and areas of necrosis surrounded by acute and chronic inflammatory cells implying septic infarction [7,14]. CLASSIFICATION There are three classifications of EPN based on radiological findings (Table 1) [1,7,14]. Michaeli et al. [1] in 1984 were the first to classify EPN based on the findings of plain abdominal film of kidney, ureter and bladder, and intravenous pyelogram. Wan et al. [7] in 1996 categorized their cohort of 38 patients into two groups based on CT findings. They defined Type I EPN as parenchymal destruction with either total absence of fluid content on the CT images or presence of a streaky or mottled gas pattern on radiographs or CT scans, regardless of the absence or presence of bubbly or loculated gas. Type II EPN was defined as either the presence of renal or perirenal fluid in association with a bubbly or loculated gas pattern or as gas in the collecting system with acute bacterial or renal- or perirenal-fluid-containing abscesses. Four years later in 2000, Huang and Tseng published a different classification, which was also based on the CT findings but described in more detail and with more sub-categories than the previous one [14]. They classified EPN as follows: (1) Class 1: gas in the collecting system only; (2) Class 2: gas in the renal parenchyma without extension to extrarenal space; (3) Class 3A: extension of gas or abscess to perinephric space; Class 3B: extension of gas or abscess to pararenal space; and (4) Class 4: bilateral EPN or solitary kidney with EPN. The more detailed classification by Huang and Tseng was to show the correlation between the class of EPN and its management. However, two published meta-analyses [10,11] assessing the risk factors and the management of EPN used the classification described by Wan et al. [7]. The preference for a particular classification rests with the reporting radiologist, but it is important for the treating physician to note the classification used as it will help to plan the patient management, which could be either conservative or surgical. PROGNOSTIC FACTORS Emphysematous pyelonephritis requires urgent attention because of the lifethreatening potential associated with the septic complications. Various risk factors have been identified and reported in the literature. In a meta-analysis by Falagas et al. [11], seven study cohorts were identified and studied for the risk factors affecting mortality

3 UBEE ET AL. The presence of diabetes mellitus appeared to be a common risk factor for EPN but, surprisingly, it is not associated with increased mortality [odds ratio (OR) 0.32, 95% CI ] [11]. Similarly, no significant association could be established between higher mortality in EPN with nephrolithiasis, E. coli or K. pneumoniae aetiology of EPN, age >50 years, female sex, history of UTIs, or alcoholism. Systolic blood pressure less than 90 mmhg, disturbance of consciousness as well as increase in serum creatinine level were found to be associated with higher mortality. The presence of thrombocytopenia (OR 22.68, 95% CI ) and bilateral EPN (OR 5.36, 95% CI ) are both linked with poor prognosis. MM with antibiotics alone is associated with a higher risk of mortality (OR 2.85, 95% CI ) when compared with additional interventions of percutaneous drainage (PCD) of the abscess or nephrectomy [11]. EPN Type I based on Wan et al. s classification is associated with a worse prognosis as result of a more fulminanting clinical course and more extensive parenchymal damage [7]. PRESENTATION Most patients present in the fourth or fifth decade [7,16 19]. The presenting physical symptoms and signs are those of pyelonephritis such as dysuria, fever/rigours, nausea, vomiting, and flank pain [17 19]. Further potential clinical manifestations include acute renal dysfunction, acid-base disturbances on blood gases, hyperglycaemia, thrombocytopenia and impaired consciousness [14,16,18]. Rapid progression to septic shock may occur and may even be the presenting feature in patients with severe emphysematous pyelonephritis [14,17]. Loin tenderness is the most common physical sign and in some cases crepitus around the renal area and the scrotum may also be felt [14,17]. Laboratory data in 70 80% of the reported cases showed leucocytosis while thrombocytopenia was seen in 15 20% of the patients [16,18]. As most of these patients have diabetes, high blood glucose level is a common finding. Acute renal failure, microscopic or macroscopic haematuria and severe proteinuria are other positive findings in EPN [14]. DIAGNOSIS Emphysematous pyelonephritis is a radiological diagnosis which requires imaging, since most of the clinical and the laboratory findings will only indicate sepsis of renal origin. A plain radiograph shows an abnormal gas shadow in the renal bed raising suspicion, whereas an ultrasonography or CT will confirm the presence of intrarenal gas which supports the diagnosis of EPN. CT is preferred as it is more sensitive and it also defines the extent of EPN by identifying features of parenchymal destruction [7,14,16]. Ultrasonography and plain radiograph of the abdomen are only accurate in 69 and 65% of cases, respectively, so abdominal CT is necessary for early diagnosis and further management of EPN [10]. MANAGEMENT In patients who are being treated for pyelonephritis, the radiological diagnosis may be missed, unless appropriate imaging is obtained. This group of patients, along with those who fail to respond to the standard line of treatment of pyelonephritis, should have an urgent CT scan to confirm the diagnosis. Basic resuscitation measures of oxygen, intravenous fluids, acid base balance correction and appropriate antibiotics should be commenced along with good glycaemic control. It is important to maintain a systolic blood pressure of more than 100 mmhg, with fluid resuscitation or inotropic support if required. Meta-analysis of the risk factors affecting the mortality rate concluded that a systolic blood pressure of 90 mmhg adversely affected the mortality rate when compared with a pressure of more than 100 mmhg [11]. If the clinical condition and the laboratory results show deterioration, then the level of care should be stepped up as these patients may require multi-organ support. Gram-negative bacteria remain the most common causative organisms so the initial antibiotic regimen should target them. Aminogycosides, β-lactamase inhibitors, cephalosporins and quinolones can be used and this is guided by the local hospital policy. A combination of aminoglycoside with any of the other three groups can be used in the initial treatment stage. Once the culture report is available, the antibiotics can be changed according to the type and number of organisms along with their individual sensitivities. The accepted treatment of EPN until the late 1980s has been emergency nephrectomy and/or open surgical drainage together with antibiotic therapy, resulting in a reported mortality rate of 40 50% [1,20]. Some of the authors suggested early nephrectomy along with MM to reduce the mortality rate and shorten the recovery period [7,15,20]. Significant advances in the percutaneous catheters used made it possible to have PCD as a treatment option for EPN, which was first shown by Hudson et al. [21]. Subsequent case studies have shown patients being successfully treated with PCD when used in addition to MM, with significant reduction in the mortality rates [17,18]. PCD helps to preserve the function of the affected kidney in about 70% of cases. PCD should be performed on patients who have localized areas of gas and in whom functioning renal tissue is present. A pigtail drain of at least 14 Fr in size should be inserted, ideally with CT guidance which has a better success rate when compared with an ultrasonography. An abscess with loculations or multiple abscesses is not a contraindication for PCD, as more than one catheter can be used to drain all loculations [10]. The abscess, which is technically easier to access and would significantly reduce the pressure on the viable renal tissue, should be targeted first with PCD. The drainage tubes should stay until followup CT shows resolution of the EPN features and until then, if need arises, the tube can be flushed with antibiotic solutions. During the last decade there has been a gradual shift toward a nephron-sparing approach with PCD, with or without elective nephrectomy at a later stage. The treatment strategies include MM alone, PCD plus MM, MM plus emergency nephrectomy, and PCD plus MM plus emergency nephrectomy [10] (Fig. 1). Patients on PCD plus MM benefit from follow-up CT in 4 to 7 weeks as recommended by Chen et al. [22] to look for noncommunicating air/fluid collections. This will also be helpful in planning a nephrectomy for non-responders to PCD plus MM. In a metaanalysis of the management strategies, the most successful management was MM with PCD (30 100%), which was also associated with the lowest mortality at 13.5% (P < 0.001) [10]. In the small proportion of patients managed with MM and PCD, subsequent nephrectomy will be required and in these patients the reported mortality is 6.6% [10]

4 EMPHYSEMATOUS PYELONEPHRITIS FIG. 1. Management algorithm for EPN based on clinico-radiological classification by Huang & Tseng [14]. KUB, plain abdominal film of kidney, ureter and bladder. *Risk factors: diabetes, thrombocytopenia, acute renal failure, altered level of cconsciousness, shock. KUB Gas in renal area Fever, renal angle pain, diabetes CT Renal parenchymal gas (EPN) Fluid, electrolyte, glycaemic control, Antibiotic therapy (MM), Classify EPN Ultrasonography Gas in renal area In conclusion, EPN is a potentially lifethreatening condition which is most commonly associated with poorly controlled diabetes. It requires a high index of suspicion in patients not responding to the routine management of pyelonephritis. It is a radiological diagnosis and CT is the best investigation. Aggressive resuscitation should be given and the condition is currently treated by MM along with PCD. Some patients may not respond and nephrectomy may be required. Reported mortality figures have improved since the 1970s but still are at 13.5% [10]. CONFLICT OF INTEREST None declared. Class 1 & 2 Class 3A & 3B Class 4 MM plus PCD Failed 0 or 1 risk factor* Intensive care & Nephrectomy Successful Assess for renal support In Class 1 and 2 EPN (based on the Huang and Tseng classification) MM alone or combined with PCD can provide a good outcome. In Class 3 and 4 EPN, MM plus PCD provides a survival rate of 85% in patients with fewer than two risk factors, whereas in patients with more than two risk factors MM plus PCD was unsuccessful in 92% of cases. The proportion of non-responders in this group requiring nephrectomy is higher, compared with the Class 1 and 2 EPN [14,17]. Of the 118 patients who underwent PCD only, 15 (13%) required elective nephrectomy [10]. These are patients who do not respond well clinically to MM plus PCD or those who, on nuclear imaging, are found to have a nonfunctioning kidney. Huang and Tseng described a 71% failure rate and a 29% mortality rate in Class 3A after PCD; in 2 risk factors* Bilateral disease Solitary kidney MM plus Bilateral PCD Failed MM plus PCD Class 3B there was a failure rate of 30% and a mortality rate of 19% [14]. Nephrectomy in patients with EPN can be simple, radical or laparoscopic [2,23]. Simple nephrectomy can be carried out with a mortality rate as low as 10% [2,7]. Laparoscopic nephrectomy can be successfully performed in these patients and has the advantage of providing a shortened recovery period and hospital stay [23]. In addition patients with EPN might need renal support measures in the form of dialysis and a recent study concluded that the availability of renal support seems to reduce the mortality rate [17]. The long-term outcome for renal function and the need for further support will depend on the degree and amount of parenchymal loss and coexisting renal disease. REFERENCES 1 Michaeli J, Mogle S, Perlberg S, Heiman S, Caine M. Emphysematous pyelonephritis. J Urol 1984; 131: Pontin AR, Barnes RD, Joffe J, Kahn D. Emphysematous pyelonephritis in diabetic patients. Br J Urol 1995; 75: Kelly HA, Pneumaturia MCWG. JAMA 1898; 31: Schultz EH Jr, Klorfein EH. Emphysematous pyelonephritis. J Urol 1962; 87: Pode DPS, Perlberg S, Fine H. Emphysematous renal and perirenal infection in nondiabetic patient. Urology 1985; 26: Shokeir AA, El-Azab M, Mohsen T, El- Diasty T. Emphysematous pyelonephritis: a 15-year experience with 20 cases. Urology 1997; 87: Wan YL, Lee TY, Bullard MJ, Tsai CC. Acute gas-producing bacterial renal infection: correlation between imaging findings and clinical outcome. Radiology 1996; 198: Lee SE, Yoon DK, Kim YK. Emphysematous pyelonephritis. J Urol 1977; 118: Paivansalo M, Hellstrom P, Siniluoto T, Leinonen A. Emphysematous pyelonephritis: radiologic and clinical findings in six cases. Acta Radiol 1989; 30: Somani BK, Nabi G, Thorpe P et al. Is percutaneous drainage the new gold

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