Emphysematous Pyelonephritis Clinicoradiological Classification, Management, Prognosis, and Pathogenesis

ORIGINAL INVESTIGATION Emphysematous Pyelonephritis Clinicoradiological Classification, Management, Prognosis, and Pathogenesis

Jeng-Jong Huang, MD; Chin-Chung Tseng, MD

Background: Emphysematous pyelonephritis (EPN) is tients who received antibiotic treatment alone was 40% (2 a rare, severe gas-forming infection of renal paren- of 5 patients). The success rate of management by percu- chyma and its surrounding areas. The radiological clas- taneous catheter drainage (PCD) combined with antibi- sification and adequate therapeutic regimen are contro- otic treatment was 66% (27 of 41 patients). In classes 1 and versial and the prognostic factors and pathogenesis remain 2 EPN, all the patients who were treated using a PCD or uncertain. ureteral catheter combined with antibiotic treatment survived. In extensive EPN (classes 3 and 4), 17 (85%) of the Objectives: To elucidate the clinical features, radio- 20 patients with fewer than 2 risk factors (ie, thrombocy- logical classification, and prognostic factors of EPN; to topenia, acute renal function impairment, disturbance of compare the modalities of management (ie, antibiotic consciousness, or shock) were successfully treated using treatment alone, percutaneous catheter drainage com- PCD combined with antibiotic treatment; and the pa- bined with antibiotic treatment, or nephrectomy) and out- tients with 2 or more risk factors had a significantly higher come among the various radiological classes of EPN; and failure rate than those with no or only 1 risk factors (92% to clarify the gas-forming mechanism and pathogenesis vs 15%, PϽ.001). Eight of the 14 patients who had an un- of EPN by gas analysis and pathological findings. successful treatment using a PCD underwent subsequent nephrectomy, 7 of whom survived. Only 2 patients were Patients and Methods: Forty-eight EPN cases from our managed by direct nephrectomy and survived. The over- institution were enrolled between August 1,1989, and No- all success rate of nephrectomy was 90% (9 of 10 patients). vember 30, 1997. According to the radiological findings The total mortality was 18.8% (9 of 48 patients). Five of on computed tomographic scan, they were classified into the 6 gas samples contained hydrogen (average, 12.8%), the following classes: (1) class 1: gas in the collecting sys- and all had carbon dioxide (average, 14.4%). The patho- tem only; (2) class 2: gas in the renal parenchyma without logical findings from 8 of 10 who underwent nephrec- extension to extrarenal space; (3) class 3A: extension of gas tomy revealed poor perfusion in most cases (ie, infarc- or abscess to perinephric space; class 3B: extension of gas tion, 5 patients; vascular thrombosis, 3 patients; and or abscess to pararenal space; and (4) class 4: bilateral EPN arteriosclerosis and/or glomerulosclerosis, 4 patients). or solitary kidney with EPN. The clinical manifestations, management, and outcome were compared. The gas con- Conclusions: Acute renal infection with E coli or K pneu- tents of specimens from 6 patients were analyzed. The moniae in patients with diabetes mellitus and/or urinary tract pathological findings from 8 patients who received ne- obstruction is the cornerstone for the development of EPN. phrectomy were reviewed. The statistical methods con- Mixed acid fermentation of glucose by Enterobacteria- sisted of the Fisher exact test (2 tailed) for categorical vari- ceae is the major pathway of gas formation. For localized ables and Wilcoxon rank sum test for continuous variables EPN (classes 1 and 2), PCD combined with antibiotic treat- to test the predictors of poor prognosis. ment can provide a good outcome. For extensive EPN (classes 3 and 4) with a more benign manifestation (ie, Ͻ2 Results: Forty-six patients (96%) had diabetes mellitus, risks), when saving of the kidney is possible, PCD com- and 10 (22%) of the 46 also had urinary tract obstruction bined with antibiotic treatment may be attempted due to in the corresponding renoureteral unit. The other 2 non- the high success rate, and may preserve the kidney. How- diabetic patients (4%) had severe hydronephrosis. Twenty- ever, nephrectomy can provide the best management out- one (72%) of the 29 patients with diabetes mellitus also come and should be promptly attempted for extensive EPN Ն had a glycosylated hemoglobin A1c level higher than 0.08. with a fulminant course (ie, 2 risks). Escherichia coli (69%) and Klebsiella pneumoniae (29%) were the most common pathogens. The mortality rate in pa- Arch Intern Med. 2000;160:797-805

MPHYSEMATOUS pyelonephri- tissue.1-7 Emphysematous pyelonephritis tis (EPN) has been defined as occurs almost exclusively in patients with From the Department of a necrotizing infection of the diabetes mellitus (DM), but occasionally Internal Medicine, National renal parenchyma and its sur- in patients without DM along with ob- Cheng Kung University rounding areas that results in struction of the corresponding renoure- Hospital, Tainan, Taiwan, theE presence of gas in the renal paren- teral unit.1,8-10 It deserves special atten- Republic of China. chyma, collecting system, or perinephric tion because of its life-threatening potential

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 PATIENTS AND METHODS in the collecting system only (so-called emphysematous pyelitis); (2) class 2: gas in the renal parenchyma without extension to the extrarenal space; (3) class 3A: extension of PATIENTS gas or abscess to the perinephric space; class 3B: extension of gas or abscess to the pararenal space; and (4) class Among the patients who were admitted to the National Chen 4: bilateral EPN or solitary kidney with EPN (Figures 1, Kung University Hospital, Taiwan, Republic of China, be- 2, 3, and 4). The perinephric space was defined as the area tween August 1, 1989, and November 30, 1997, 48 con- between the fibrous renal capsule and renal fascia. The para- secutive cases were diagnosed as EPN and met all of the renal space was defined as the space beyond the renal fas- following criteria: (1) symptoms and signs of upper UTI, cia and/or extending to the adjacent tissues such as the psoas or fever with a positive urine culture or pyuria without other muscle. The differences of clinical features, management, identified infectious foci; (2) radiological evidence by CT and outcome among the 4 classes were compared and scan of gas accumulation in the collecting system, renal analyzed. Insertion of percutaneous catheter into the parenchyma, or perinephric or pararenal space; (3) no renal or extrarenal lesion was performed via imaging fistula between the urinary tract and bowel; and (4) no guidance (ie, renal CT scan or echography). “Unsuccess- recent history of trauma, urinary catheter insertion, or ful” PCD was defined as progressive or persistent lesions drainage. on imaging studies with clinical manifestations of unstable hemodynamics or prolonged fever after manage- METHODS ment. We also divided our cases into “good” and “poor” outcome groups to elucidate the risk factors. The patients The baseline characteristics, clinical features, and labora- who were successfully treated with antibiotics alone or tory data at the initial presentation, management, and out- using PCD combined with antibiotics were assigned to come were collected by comprehensive review of the medi- the “good” outcome group. The patients who had an cal records. The baseline characteristics included age, sex, unsuccessful PCD followed by nephrectomy or mortality history of DM, status of glucose control (fasting blood glu- were assigned to the “poor” outcome group. These 2 cose level, Ͼ11.1 mmol/L [Ͼ200 mg/dL] or a glyco- groups were compared for baseline characteristics, clinical Ͼ sylated hemoglobin A1c level 0.08 was defined as a glu- features, and laboratory data at the initial presentation. cose level in poor control), and the presence of diabetic Under the guidance of renal echography or CT scan, retinopathy and other underlying diseases. The clinical fea- some gas and pus were aspirated successfully from 6 pa- tures at the initial presentation included the hemody- tients. All the connections of the aspiration system were namic status, renal function, and the degree of conscious- immersed in distilled water. The puncture needle and as- ness. The duration from the onset of symptoms and signs piration tube were sealed with aseptic jelly. The gas samples to diagnosis of EPN were also checked. Shock was defined were aspirated from rubber-sealed collecting syringes with as a systolic blood pressure less than 90 mm Hg. Distur- a gas-tight syringe (for analysis, which used a gas chroma- bance of consciousness included confusion, delirium, stu- tography/thermal conductivity detector and a gas chroma- por, and coma. Leukocytosis was defined as a blood leu- tography/mass spectrometer detector, etc.17 The pus was kocyte count higher than 12 ϫ 109/L. According to the also analyzed for bacterial content and pH value. The patho- criteria of disseminated intravascular coagulation, throm- logical findings from 8 patients who underwent nephrec- bocytopenia was defined as platelet count lower than tomy were analyzed and compared with their radiological 120 ϫ 109/L. Acute renal function impairment was de- manifestations. fined as further elevation of the serum creatinine level more than 88.4 µmol/L (Ͼ1 mg/dL), if the baseline serum cre- STATISTICAL METHODS atinine level of the patient was higher than 265.2 µmol/L (Ͼ3 mg/dL). It was also defined as further elevation of the The differences between the survival and mortality groups serum creatinine level more than 44.2 µmol/L (Ͼ0.5 mg/ were quantified using the Fisher exact test (2 tailed) for dL) if the baseline serum creatinine level was less than 265.2 categorical variables, and the Wilcoxon rank sum test for µmol/L (Ͻ3 mg/dL). Macrohematuria was defined as red continuous variables. To test the predictors of poor prog- blood cells in urinary sediment of more than 100 per high- nosis, the Fisher exact test (2 tailed) was used for categori- power field. Severe proteinuria was defined as a urine pro- cal variables, and the Wilcoxon rank sum test for continu- tein concentration greater than 3 g/L on at least 2 occa- ous variables. The multiple logistic regression test was used sions during hospital admission. to examine the independent prognostic factors for EPN. The Abdominal CT scan and echography were performed differences between the 4 classes of EPN were tested with for all 48 cases. Severe hydronephrosis was defined as the Mantel-Haenszel ␹2 test for categoric variables, and the marked dilatation of renal pelvis and thinning of cortex. Kruskal-Wallis test with ␹2 approximation for continuous According to the radiological findings on the CT scan, they variables. PϽ.05 was taken as the upper level of statistical were classified into the following classes: (1) class 1: gas significance.

and has been generally regarded as a rare renal infec- these cases are being reported in the urology and radi- tion. However, with the more extensive use of abdomi- ology journals,1-22 and less frequently in internal medi- nal ultrasound (echography) and computed tomogra- cine or nephrology journals.23-31 We believe that EPN is phy (CT scan) in the evaluation of patients with symptoms not rare and should be considered an important clinical and signs of sepsis or complicated urinary tract infec- entity. Nevertheless, no large clinical experience of EPN tion (UTI), more cases of EPN are being recognized and concerned with management and prognostic factors has

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 been reported from a single institution. The mechanism pathogenesis of EPN by gas analysis and pathological of gas formation and pathogenesis of EPN are also un- findings. clear. 8 9 10 Ahlering et al, Pontin et al, and Shokeir et al had RESULTS concluded that vigorous resuscitation and appropriate medical treatment should be attempted, but immediate BASELINE CHARACTERISTICS AND nephrectomy should not be delayed for successful man- CLINICAL PRESENTATIONS agement of EPN. However, successful treatment of EPN using percutaneous catheter drainage (PCD) and anti- The mean age of our patients was 60 years (age range, biotic treatment has also been reported.3-5,11-15 There- 37-83 years). Women outnumbered men (41:7). Forty- fore, the adequate therapeutic modalities for EPN are still six patients (96%) had DM. Ten (22%) of them also had controversial. Emphysematous pyelonephritis has been urinary tract obstruction; 2 (4%) had underlying poly- classified according to the location of gas accumulation cystic kidney disease; and 2 (4%) had end-stage renal fail- because of various outcomes.1,26 Nevertheless, the radio- ure. The other 2 patients without DM had severe hydro- logical classification, adequate management, and prog- nephrosis in the corresponding renoureteral unit caused nosis have rarely been well studied. by bladder and ureteral transitional cell carcinoma in one Our objectives in this study included (1) elucidat- case and ureteral stone in the other. Eighteen (69%) of ing the clinical features, radiological classification, and the 26 patients with DM also had diabetic retinopathy; prognostic factors of EPN; (2) comparing the modalities 12 were background; and 6 were proliferative. Twenty- of management (ie, antibiotic treatment alone, PCD one (72%) of the 29 patients with DM had a glyco- combined with antibiotic treatment, or nephrectomy) sylated hemoglobin A1c level higher than 0.08. Clinical and outcome among the various radiological classes of features and laboratory data at the initial presentation are EPN; and (3) clarifying the gas-forming mechanism and given in Table 1. The involved site was more frequent

Figure 1. Class 1 emphysematous pyelonephritis. (See “Methods” Figure 2. Class 2 emphysematous pyelonephritis. (See “Methods” subsection of “Patients and Methods” section for explanation of class.) subsection of “Patients and Methods” section for explanation of class.) Computed tomographic scan demonstrates gas accumulated only in the right Computed tomographic scan shows gas within the right renal parenchyma renal pelvis. A pelvic stone (arrowhead) with hydronephrosis was also found and a right renal stone (arrowhead). in the right kidney.

Figure 3. Left, Class 3A emphysematous pyelonephritis (EPN). (See “Methods” subsection of “Patients and Methods” section for explanation of class.) This computed tomographic scan shows left-sided EPN with extension of gas to the perinephric space (white arrow). Right, Class 3B EPN. Computed tomographic scan shows left-sided EPN with extension of gas to the pararenal space (arrowhead).

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 tality groups are given in Table 2. No significant differences were noted in the patients’ mean age, glycosylated hemogloblin HbA1c level, diabetic retinopathy, urinary tract obstruction, or mean duration from the onset of symptoms and signs to the diagnosis of EPN between the survival and mortality groups (Table 2). Initial presentations of thrombocytopenia, disturbance of consciousness, and shock were significantly associated with mortality (Table 2). Thirty cases were classified as having a good outcome. Sixteen cases were classified as having a poor outcome. The patients in the remaining 2 cases were managed by direct nephrectomy and survived. The comparison Figure 4. Class 4 emphysematous pyelonephritis. (See “Methods” of baseline characteristics, clinical features, and labora- subsection of “Patients and Methods” section for explanation of class.) tory data at the initial presentation between the good and Computed tomographic scan shows accumulation of gas (arrowheads) in poor outcome is given in Table 2. It revealed that throm- both kidneys in a patient with autosomal dominant polycystic kidney disease bocytopenia, disturbance of consciousness, and shock on (different sections). admission to the hospital were significantly associated with poor outcome; and the initial presentations of severe proteinuria and acute renal function impairment Table 1. Clinical Features and Laboratory Data at Initial seemed to be a risk factor of poor outcome (P = .05). Mul- Presentation tiple logistic regression tests showed severe proteinuria (P = .03), thrombocytopenia (P = .05), and disturbance Variable No. (%) of Patients of consciousness (P = .04) on hospital admission as be- Clinical features ing the independent factors for poor outcome. Fever 38 (79) Flank, abdomen, or back pain 34 (71) Nausea, vomiting 8 (17) MANAGEMENT, RADIOLOGICAL Dyspnea 6 (13) CLASSIFICATION, AND OUTCOME Acute renal function impairment 17 (35) Disturbance of consciousness* 9 (19) The modalities of management and outcome in our pa- Shock 14 (29) tients are given in Table 3. The mortality rate of treat- Laboratory data ment with antibiotics alone was 40% (2 of 5 patients). Ͼ Glycosylated hemogloblin A1C 0.08† 21 (72) The success rate of management with PCD combined with Leukocytosis (leukocyte count Ͼ12 ϫ 109/L) 32 (67) Thrombocytopenia (platelet count Ͻ120 ϫ 109/L) 22 (46) antibiotics was 66% (27 of 41 patients). Eight (20%) of Urinalysis 41 cases were unsuccessfully treated by PCD and anti- Pyuria 38 (79) biotics, with clinical manifestations of unstable hemo- Macrohematuria (RBCs Ͼ100 per HPF‡) 6 (13) dynamics or prolonged fever; and 7 of them were suc- Severe proteinuria§ (Ͼ3 g/L) 10 (21) cessfully treated by subsequent nephrectomy. The overall successful rate of nephrectomy was 90% (9 of 10 patients). *Including confusion, delirium, stupor, and coma. The total mortality rate in our cases was 18.8% (9 of 48 †Glycosylated hemogloblin A1C was checked in 29 cases. ‡RBCs indicates red blood cells; HPF, high-power field. patients). §Urine protein was more than 3 g/L on at least 2 occasions during Five patients were seen with gas confined in the col- admission in the hospital. lecting system (class 1, Figure 1), 3 of whom also had severe hydronephrosis at the site of EPN. Eleven pain the left kidney (67 %) than in the right one (25%). tients had gas within the renal parenchyma (class 2, Fig- Urinary tract obstruction also occurred more frequently ure 2). The gas or abscess extended to the perinephric in the left kidney than the right one (64% vs 36%). Patho- space (class 3A, Figure 3, left) in 7 patients, and further gens were identified in 47 (98%) of our 48 cases. Esch- spread to the pararenal space (class 3B, Figure 3, right) erichia coli was the most common organism (69%) cul- in 21 patients. Four patients were grouped into class 4 tured, and Klebsiella pneumoniae was the second (29%). EPN, 3 of whom had bilateral EPN (Figure 4); the other Two patients had E coli infection mixed with group B one had a solitary kidney due to nephrectomy for pre- Streptococcus or Proteus. Bacteremia occurred in more than vious right-sided EPN and suffered from recurrent EPN half of our cases (26/48 [54%]), and all of the organisms in the left kidney.31 No significant differences were noted from blood culture were the same as those found in the in clinical features among these 4 EPN classes. How- urine or pus culture. Anaerobic organisms were not ob- ever, we demonstrated a tendency toward higher mor- tained in our study. tality and failure rate of PCD in extensive disease (classes 3 and 4), and nephrectomy should be considered PROGNOSTIC FACTORS OF MORTALITY AND (Table 4). Patients with class 1 EPN had the best prog- POOR OUTCOME nosis, and all of them survived after receiving relief of the urinary tract obstruction (if existing) and antibiotic The baseline characteristics, clinical features, and labo- treatment. The prognosis of class 2 EPN was as good as ratory data at the initial presentation in survival and mor- that of class 1. Nine patients with class 2 EPN were suc-

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2. Baseline Characteristics and Initial Presentations of Emphysematous Pyelonephritis in Survival vs Mortality and Good vs Poor Outcome Groups*

Survival Mortality Good Outcome† Poor Outcome‡ Variables (n = 39) (n=9) P (n = 30) (n = 16) P Baseline characteristics Mean age, y 59 67 NS 58.7 64.1 NS

Glycosylated hemoglobin A1C (Ͼ0.08) 77 57 NS 74 70 NS Retinopathy 72 50 NS 70 67 NS Urinary tract obstruction 23 33 NS 25 25 NS Initial presentations Duration of symptoms and signs prior to diagnosis, d 8.4 3.7 0.02 8.2 6.1 NS Macrohematuria (RBCs Ͼ100 per HPF)§ 10 13 NS 6 20 NS Severe proteinuria࿣ (Ͼ3 g/L) 18 38 NS 13 40 .05 Thrombocytopenia (platelet Ͻ120 ϫ 109/L) 36 89 Ͻ.01 28 81 Ͻ.001 Acute renal function impairment 28 67 .05 25 56 .05 Disturbance of consciousness¶ 10 56 Ͻ.01 3 50 Ͻ.001 Shock 21 67 .01 17 56 Ͻ.01

*Unless otherwise indicated all values are given as a percentage of the patients. NS indicates not significant. †The patients who were successfully treated with antibiotics alone or percutaneous catheter drainage combined with antibiotics were designated as members of the good outcome group. ‡The patients who had an unsuccessful percutaneous catheter drainage followed by nephrectomy or mortality (9 patients) were designated as member of the poor outcome group. §RBCs indicates red blood cells: HPF, high-power field. ࿣Urine protein level higher than 3 g/L on at least 2 occasions during admission. ¶Including confusion, delirium, stupor, and coma.

Table 3. Management and Outcome in Patients With Table 4. Management and Outcome in Various Radiological Emphysematous Pyelonephritis* Classes and Types of Emphysematous Pyelonephritis (EPN)

No. (%) of Patients/Total No. of Patients PCD Failure, Mortality, Type of EPN No. (%)* No. (%) Management Successful Failure Mortality This series† Antibiotics only 3/5 (60) NA (0) 2/5 (40) Class 1 (n = 5) 0 (0) 0 (0) Direct nephrectomy 2/2 (100) NA (0) 0/2 (0) Class 2 (n = 11) 0 (0) 1 (10) PCD with antibiotics 27/41 (66) 8/41 (20) 6/41 (15) Class 3A (n = 7) 5 (71) 2 (29) PCD failure followed 1/8 (13) NA (0) 1/8 (13) Class 3B (n = 21) 5 (30) 4 (19) by nephrectomy Class 4 (n = 4) 3 (75) 2 (50) Total 9/48 (18.8) Classification of Wan et al2‡ Type 1 (n = 14) 8 (57) 5 (36) *NA indicates not applicable; PCD, percutaneous catheter drainage. Type 2 (n = 34) 6 (18) 4 (12)

cessfully treated with PCD combined with antibiotics; 1 *PCD indicates percutaneous catheter drainage. was managed by direct nephrectomy and survived; the †Class 1 indicates gas in the collecting system only; class 2, gas in the renal parenchyma without extension to the extrarenal space; class 3A, only 1 treated with antibiotics alone died. In class 3A and extension of gas or abscess to the perinephric space; class 3B, extension of class 3B EPN, 61% (17 of 28 patients) were successfully gas or abscess to the pararenal space; and class 4, bilateral EPN or solitary treated with PCD combined with antibiotics, and 11 cases kidney with EPN. ‡Classification of our patients using Wan et al model. Type 1 is (39%) failed with progressive or persistent lesions on im- characterized by parenchymal destruction with either an absence of fluid aging studies and unstable manifestations after manage- collection or a presence of streaky or mottled gas (having a fulminant ment. Seven patients in the 11 cases underwent subse- course) and a mortality rate of 69% (11 of 16 patients). Type 2 is quent nephrectomy, and 6 of them survived after the characterized as either renal or perinephric fluid collection with bubbly or located gas or gas in the collecting system and having a mortality of 18% operation. Class 4 EPN (4 patients) had a higher preva- (4 of 22 patients). lence of severe manifestations and the poorest prognosis (Table 4). Bilateral PCD was performed for 3 patients with bilateral EPN: 1 was successfully treated, 1 GAS ANALYSIS AND PATHOLOGICAL FINDINGS died, and 1 survived after undergoing subsequent nephrectomy. If we take the thrombocytopenia, acute re- The gas samples contained neither oxygen-containing hy- nal function impairment, disturbance of consciousness, drocarbons (eg, alcohol, aldehydes, and organic acids), and shock at the initial presentation as 4 risk factors of nor sulfur-containing compounds. Five of the 6 gas ∼ predicting poor response to PCD combined with antibi- samples contained hydrogen (H2, 3.4 28%; average, ∼ otic treatment, classes 3 and 4 EPN cases with 2 or more 12.8%) and all had carbon dioxide (CO2, 4.0 39.5%; av- risk factors would have significantly higher failure rate erage, 14.4%). The only 1 without H2 was obtained be- of PCD than those with no or only 1 risk factor (92% vs cause H2 itself was used as a carrier gas for gas analy- 16 15%, PϽ.001). sis, and could not detect the H2. Large amounts of

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 tion, since it stresses the relation between acute infectious process and gas formation. Some investigators have suggested that the term emphysematous pyelonephritis should be applied only to gas formed within the renal parenchyma or perinephric space.8-10,21,29 However, oth- ers have advocated that EPN is an infection of the renal parenchyma and perinephric tissue, which results in the presence of gas in the collecting system, renal parenchyma, or perinephric tissue.2-6,20 The latter definition is favored because it includes all the possible manifestations of gas-forming acute renal infections.

CLINICAL FEATURES AND DIAGNOSIS OF EPN Figure 5. Pathological view in nephrectomy from a patient with class 3B emphysematous pyelonephritis demonstrates vascular thrombosis in 2 In our series, EPN preponderantly affected females (fe- vessels (left) and a large infarction (right). This patient with diabetes mellitus male-male ratio, 5.9:1). This result is similar to that of suffered from persistent sepsis after percutaneous catheter drainage and other series,2,9,10 and is supposed to be due to the in- subsquently underwent nephrectomy 18 days after admission to the hospital. creased susceptibility to UTI in females.10 The left kidney was more frequently involved than the right one (67% ∼ nitrogen (N2, 49.6 84.4%; average, 63.5%) and less oxy- vs 25%). This also corresponds to the results of other se- ∼ 1,26 gen (O2, 0.8 10.5%; average, 6.3%) were also identified ries, The preponderance of left-sided urinary tract ob- 16-18 in the gas samples. Trace amounts of ammonia (NH3, struction (64% vs 36% in the right side) may be one of 0.05%) were found in one gas sample; methane (0.06%) the causes. The most common clinical manifestations of and carbon monoxide (0.2%) in another sample. EPN (ie, fever, flank pain, and pyuria) were nonspecific Among the 10 patients who underwent nephrec- and not different from the classic triad of upper UTI other tomy, 8 had complete pathological reports (class 2, 1 pa- than EPN. However, thrombocytopenia (46%), acute re- tient; class 3A, 3 patients; class 3B, 3 patients; and class nal function impairment (35%), disturbance of con- 4, 1 patient). The pathological findings revealed evi- sciousness (19%), and shock (29%) can be the initial pre- dence of impairment of tissue circulation in most cases sentations, especially in severe cases or in patients not (infarction, 5 patients; vascular thrombosis, 3 patients; given an early diagnosis and management of EPN. The and arteriosclerosis and/or glomerulosclerosis, 4 pa- diagnosis of EPN is classically made by demonstrating tients) (Figure 5). The patient with class 2 EPN showed gas in renal or perinephric tissue by plain abdominal x- acute inflammatory cell infiltration with focal necrosis ray film or renal echography. However, gas could be dem- and abscess formation. Patients with class 3A EPN re- onstrated only on 33% of plain abdominal radiographs vealed abscess formation, foci of microinfarction or large by Michaeli et al1 in 1984, and it may be difficult to dis- infarction, vascular thrombosis, arteriosclerosis, arterio- tinguish the necrotic gas-filled area from gas in the bowel nephrosclerosis, interstitial hemorrhage, and chronic by echography. In contrast, CT scan not only can con- pyelonephritis. Empty space was found in 1 patient, pre- firm the diagnosis but also show the extent of disease. sumably caused by previous gas formation. Glomerulo- Therefore, severe manifestations or persistence of fever sclerosis, several Kimmestiel-Wilson nodules, and hya- to resolve after antibiotic treatment in patients with up- linized arteriosclerosis, all suggestive of diabetic per UTI should arouse the suspicion that a serious acute nephropathy, were found in 1 patient. The pathological renal infection, such as acute bacterial nephritis,33 renal findings in patients with class 3B EPN were similar to abscess, or even EPN, is ongoing. The abdominal CT scan those in patients with class 3A EPN, but the inflamma- is necessary for an early diagnosis and further manage- tory lesions had more extension to the perinephric and ment of EPN. pararenal tissue. The pathological result in patient with 1 class 4 EPN showed multiple wedge-shaped necrosis PROGNOSTIC FACTORS FOR EPN surrounded by acute and chronic inflammatory cells and vascular thrombosis, implying multiple septic infarc- Michaeli et al1 attempted to correlate the clinical fea- tion. Diabetic nephropathy was also demonstrated in 1 tures of EPN with outcome. They concluded that age, sex, patient with severe proteinuria who subsequently un- site of infection, serum urea nitrogen level, and blood glu- derwent nephrectomy. cose level were not the prognostic factors, and the best combination of characteristics of EPN with favorable out- COMMENT come was that of a patient with nonobstructive unilat- eral disease receiving combined medical and surgical treat- Kelly and MacCallum23 reported the first case of gas- ment within a short interval of symptom onset. We also forming renal infection (pneumaturia) in 1898. Since then, showed that age, sex, site of infection, and blood glu- a multiplicity of terms such as “renal emphysema,”“pneu- cose level were not associated with mortality or poor out- monephritis,” and “emphysematous pyelonephritis” had come. It has been supposed that high tissue glucose lev- been used to describe this gas-forming infectious dis- els may be a risk for EPN to develop and cause a fulminant ease. As suggested by Schultz and Klorfein32 in 1962, em- course in patients with DM, because it can provide gas- physematous pyelonephritis is the preferred designa- forming microbes with a microenvironment more favor-

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 able for growth and rapid catabolism.16-18 However, we ing simpler descriptive classification: stage I, gas within do not demonstrate that poor control of blood glucose the renal parenchyma or the perinephric tissues; stage levels is a risk factor of poor prognosis for EPN. In our II, the presence of gas in the kidney and its surround- series, urinary tract obstruction was not correlated with ings; and stage III, extension of gas through Gerota’s fas- the outcome because most of our patients with urinary cia or presence of bilateral EPN. However, they did not tract obstruction received drainage by percutaneous neph- demonstrate a significant prognostic implication in this rostomy or ureteral catheter and obtained improvement staging system. The relations between their staging sys- in their conditions soon after management. In our study, tem and management or outcome were not stated. In our the patients initially seen with thrombocytopenia, acute study, we tried to do a more detailed classification ac- renal function impairment, disturbance of conscious- cording to the extension of gas and abscess, and studied ness, and shock were associated with mortality or a poor their prognosis and management. The gas limited in the outcome. Thrombocytopenia was most likely due to dis- collecting system (ie, emphysematous pyelitis) was des- seminated intravascular coagulation in these severe cases. ignated as class 1 EPN because we found various de- Actually, most of them also had prolongation of pro- grees of renal lesions (such as acute bacterial nephri- thrombin time and activated partial thromboplastin time tis33) on the CT scan, and it really was a special form of and increased serum fibrin degradation products or fi- EPN. According to our early observation, the prognosis brin degradation product dimmers. Disturbance of con- of gas extending to the perinephric or pararenal space sciousness implicated dysfunction of the central ner- (ie, class 3A or 3B) was different from gas limited to the vous system, which might be due to poor perfusion or renal parenchyma (ie, class 2). Although there were no metabolic factors. Shock was a sign of collapse of the car- significant differences in the clinical features among the diovascular system. All of the aforementioned signs may 4 classes, we showed a tendency toward higher mortal- represent a dysfunction of the hematologic system, ity rate and failure rate of PCD from class 1 to 4 EPN. kidney(s), central nervous system, and cardiovascular sys- The patients with class 1 EPN had the best prognosis, tem, respectively. Furthermore, the duration from on- and all of them survived by PCD and/or relief of the uri- set of symptoms and signs to diagnosis of EPN in the mor- nary tract obstruction (if it existed) combined with an- tality group, either before or after hospitalization was tibiotic treatment. The prognosis of class 2 EPN was as shorter than that in the survival groups (3.7 days vs 8.4 good as that of class 1 EPN. In class 2 EPN, all patients days, P = .02). Earlier diagnosis may have been made for treated with PCD combined with an antibiotic regimen mortality patients who also had a fulminant course be- were cured. Therefore, PCD and relief of the urinary tract cause physicians paid more attention to these cases. How- obstruction (if it exists) combined with antibiotic treat- ever, their outcomes were still poor. We suggest that pa- ment is the choice of modality for limited disease (class tients who are initially seen with organ systems 1 or 2). For adequate management of extensive EPN with dysfunction will usually run a more rapid course and have gas or abscess extension beyond the renal capsule or bi- a worse outcome. An early diagnosis is necessary, but ag- lateral EPN (class 3 or 4), our study showed that 17 (85%) gressive and adequate management should be applied in of the 20 patients with less than 2 risk factors (ie, throm- these cases. Our results also showed that severe protein- bocytopenia, acute renal function impairment, distur- uria was an independent risk factor of poor outcome, and bance of consciousness, and shock) were successfully it seemed to be a risk factor of extensive disease (class 3 treated with PCD combined with antibiotic treatment; EPN developed in 7 of the 10 patients with severe and the patients with 2 or more risk factors would have proteinuria). However, the cause of severe proteinuria a significantly higher failure rate than those with no or was multifactorial. Fever, underlying glomerulonephri- only 1 risk factor (92% vs 15%, PϽ.001). Nephrectomy tis, and diabetic nephropathy all can contribute to se- can provide the best management outcome (Table 3). But, vere proteinuria. Any analysis of the outcome of pa- the advantages of PCD include drainage of pus, relief of tients with DM who are septic, independent of a diagnosis gas pressure to local circulation, and provide a high suc- of EPN, may reveal the same prognostic determinants, cess rate in extensive EPN. Therefore, we suggest that ie, shock, severe proteinuria, thrombocytopenia, acute for patients with extensive EPN (class 3 or 4) with the renal function impairment, and disturbance of conscious- benign manifestation (ie, Ͻ2 risk factors), PCD com- ness. They are not unique to EPN and may be applied to bined with antibiotic treatment may be attempted ow- other patients with DM and sepsis. Aggressive manage- ing to the high success rate and so preserve their kid- ment should not be delayed. ney. However, nephrectomy can provide the best management outcome and should be promptly at- RADIOLOGICAL CLASSIFICATION, tempted for extensive EPN cases with the fulminant course MANAGEMENT, AND OUTCOME (ie, Ն2 risk factors). In class 4 EPN, bilateral PCD can be tried first because of the high risk of emergency ne- In 1970, Langston and Pfister22 described 3 main radio- phrectomy in these unstable patients, but nephrectomy graphic patterns and postulated that they were corre- should be done if PCD fails. The flowchart for manage- lated with the stage of disease. They were diffuse mot- ment of EPN according to the clinicoradiological classi- tling of the renal parenchyma, bubbly renal parenchyma fication is shown in Figure 6. surrounded by a crescent of gas (perinephric space), and In 1996, Wan et al2 described 2 distinct radiologi- extension through Gerota’s fascia (ie, pararenal space). cal classifications of EPN by CT scan: type 1, having a Because the mottled gas and crescent formation were not fulminant course and a mortality of 69% (11 of 16 pa- frequently found, Michaeli et al1 suggested the follow- tients), is characterized by parenchymal destruction with

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 EPN tous UTI developed. The trace amounts of NH3 and methane in 1 patient may have arisen from degradation of ne- 1. Initial KUB and Renal Echography 2. Subsequent Abdominal CT Scan crotic tissue and the fermentation of amino acids.17 The mechanism of gas chamber (ie, large gas bubbles) Classes 1 and 2 Classes 3A and 3B Class 4 formation has been hypothesized as a series of increased gas production, impaired transportation of gas (Bilateral) PCD Fluid, Electrolyte, and by vascular compromise, creation of a gas chamber, equi- Low Risk Group High Risk Group Glucose Control, (0 or 1 Risk (≥2 Risk Factors)∗ librium of gas chamber and tissue gas, and the expan- Antibiotics and PCD Factor) Failure sion or collapse of a gas chamber.16 We have postulated 4 factors that may be involved in the pathogenesis of EPN, Survival Failure Intensive Care Followed by Nephrectomy including gas-forming bacteria, high tissue glucose level, impaired tissue perfusion, and a defective immune re- Survival or Not sponse (such as DM).17 Twenty-one (72%) of the 29 patients with DM had a level of glycoslyated hemogloblin Figure 6. The flowchart for management of emphysematous pyelonephritis (EPN) according to the clinicoradiological classification. Asterisk indicates HbA1c higher than 0.08, and they had poor control of their the presence of 2 or more of the following risk factors: thrombocytopenia, blood glucose levels before getting EPN. We hypoth- acute renal failure, disturbance of consciousness, and shock. KUB indicates esize that high tissue glucose levels in patients with DM kidneys, ureter, and bladder (plain abdominal radiograph); CT, computed tomography; and PCD, percutaneous catheter drainage. may provide gas-forming microbes with a microenvironment more favorable for their growth and rapid catabolism, which can cause the massive production of gas.16-18 either absence of fluid collection or presence of streaky In 1997, Shokeir et al10 revealed that urinary tract ob- or mottled gas; and type 2, having a mortality of 18% (4 struction was evident in all of their patients without DM of 22 patients), is characterized as either renal or peri- and in half of their patients with DM.In our series, 10 of nephric fluid collection with bubbly or located gas or gas the 46 diabetic patients and both of the patients without in the collecting system (Table 4). According to the patho- DM also had obstruction of the corresponding renoure- logical findings, Wan et al hypothesized that the clini- teral unit with moderate to severe hydronephrosis. The copathological differences between types 1 and 2 EPN unrelieved urinary tract obstruction and hydronephro- are probably related to the difference in severity of im- sis may increase pelvicalyceal pressure and compromise mune compromise and vascular insufficiency in the kid- renal circulation, and result in impaired transportation neys and immunodeficiency in patients with DM. In our of gas and subsequent creation of a gas chamber (ie, EPN). series, we also demonstrated that type 1 (dry) EPN was Impaired tissue perfusion has been speculated as a risk a significant risk factor of poor outcome (PϽ.01). Among factor and a poor prognostic factor for EPN.12,17 How- 14 cases with type 1 EPN, 9 (64%) the extent of disease ever, we do not have sufficient evidence to support this was to the extrarenal tissue or bilateral kidney. In 8 pa- speculation owing to limited pathological reports. The tients with available pathological results, 5 patients had pathological findings revealed the evidence of impaired type 1 EPN, which revealed some degree of vascular tissue perfusion (ie, infarction or vascular thrombosis) thrombosis and wedge infarction (Figure 5). The patho- in most patients with class 3 or 4 EPN, but not in the logical findings of the other 3 patients with type 2 EPN only patient with class 2 EPN. We suppose that exten- revealed only inflammation and abscess formation. Al- sive infarction resulted in the absence of blood supply, though our pathological results support the hypothesis which brought leukocytes and antibiotic treatment into of Wan et al,2 a definite conclusion cannot be made from this area. The infection could not be cleared and the af- such a small number of cases. fected tissue required excision.

MECHANISM OF EPN CONCLUSIONS

Although various theories have been postulated for the Escheria coli or K pneumoniae infection in patients with mechanism of gas formation in EPN,34,35 actual analysis DM and/or urinary tract obstruction is the cornerstone of gas content has rarely been performed.16,17 Most bac- for the development of EPN. In patients with DM, the teria obtain their energy through the fermentation of glu- high level of blood glucose may provide gas-forming mi- cose via the glycolytic pathway. Among these pathways, croorganisms with a more favorable environment for gas only mixed acid fermentation (most Enterobacteria- formation via mixed acid fermentation of glucose. For ceae, eg, E coli, K pneumoniae, and Proteus) and butyric localized EPN (class 1 or 2), PCD and/or relief of the uri- fermentation (Clostridium) can give rise to H2 as an end nary tract obstruction (if it exists) combined with anti- product.36 In our study, 5 of the 6 gas samples con- biotic treatment can provide a good outcome. For ex- tained H2, and all the gas samples contained CO2. More- tensive EPN (class 3 or 4) with a more benign over, 5 cases of E coli and 1 case of K pneumoniae were manifestation (ie, Ͻ2 risk factors), PCD combined with isolated from these patients. Although anaerobic organ- antibiotic treatment may be attempted due to its high suc- isms were not obtained in our study, Clostridium as the cess rate for these patients and preservation of as much causative pathogen has been previously reported.37 There- renal function as possible. However, nephrectomy can fore, mixed acid fermentation of glucose by Enterobac- provide the best management outcome and should be teriaceae and rarely via butyric fermentation of glucose promptly attempted for extensive EPN with a fulminant by anaerobes were the pathways by which emphysema- course (ie, Ն2 risk factors) or for cases with an unsuc-

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 cessful PCD. The flowchart for management of EPN ac- 14. Koh KB, Lam HS, Lee SH. Emphysematous pyelonephritis: drainage or nephrec- cording to the clinicoradiological classification is shown tomy? Br J Urol. 1993;71:609-611. 15. Cardinael AS, Blay DV, Gilbeau JP. Emphysematous pyelonephritis: successful in Figure 6. treatment with percutaneous drainage. AJR Am J Roentgenol. 1995;164:1554- 1555. Accepted for publication June 2, 1999. 16. Yang WH, Shen NC. Gas-forming infection of the urinary tract: an investigation Presented in part as an abstract at the 35th Congress of fermentation as a mechanism. J Urol. 1990;143:960-964. of ERA-EDTA, Rimini, Italy, June 8, 1998. Published as an 17. Huang JJ, Chen KW, Ruaan MK. Mixed acid fermentation of glucose as a mechanism of emphysematous urinary tract infection. J Urol. 1991;146:148-151. abstract Huang JJ, Tseng CC, et al. Gas-forming mecha- 18. Chen KW, Huang JJ, Wu MH, Lin XZ, Chen CY, Ruaan MK. Gas in hepatic veins: nism of emphysematous pyelonephritis (EPN) by gas analy- a rare and critical presentation of emphysematous pyelonephritis. J Urol. 1994; sis and pathology in nephrectomy. Nephrol Dial Trans- 151:125-126. plant. 1998;13:A54. 19. Turman AE, Rutherford C. Emphysematous pyelonephritis with peri-nephric gas. We thank Kuan-Wen Chen, MD, for gas sample col- J Urol. 1971;105;165-170. 20. Lee SE, Yoon DK, Kim YK. Emphysematous pyelonephritis. J Urol. 1997;118: lection, Chi-Hsien Hsu, MD, for radiological classification 916-918. of emphysematous pyelonephritis, How-Ran Gou, MD, PhD, 21. Pode D, Perlberg S, Fine H. Emphysematous renal and perirenal infection in non- for statistical analysis, and Miss Shu-Chen Yang for secre- diabetic patient. Urology. 1985;26:313-315. tarial assistance. 22. Langston CS, Pfister RC. 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