Risk of SOFA Deterioration in Conservative Treatment for Emphysematous Pyelonephritis: Pitfalls of Current Trends in Therapeutics from Multicenter Clinical Experience

Abstract

Introduction

We investigated relationships between therapeutic outcomes of patients with emphysematous pyelonephritis (EPN) and changes in the Sequential Organ Failure Assessment (SOFA) score.

Materials and Methods

We retrospectively evaluated EPN patients treated in our hospitals using the SOFA score incorporated in the Sepsis-3 updated in 2016.

Results

Seventeen typical EPN patients were included in this study, and were treated with medical management with no drainage (n = 3), retrograde stenting (n = 10), or percutaneous drainage (n = 3). One patient without drainage died of sepsis, yielding an overall mortality rate of 5.9%. Twelve patients recovered without increase in the SOFA score during hospitalization. However, the SOFA score deteriorated in the other patients from admission, with the initial scores not significantly different from those of the 12 cases. The changes in the SOFA score were significantly affected by the selected approaches of drainage (100% patients for no drainage, 22% for stenting, and 0% for percutaneous drainage, p = 0.029), but not by other clinical data.

Conclusion

Most EPN patients can currently be conservatively managed successfully. However, it should be noted that less-invasive management could cause deterioration in SOFA after admission, yielding a risk of septic mortality.

Introduction

In general, urosepsis is defined as sepsis, which is a systemic response to infection of the urinary tract and male genital organs [1], and comprises 20-30% of all sepsis cases [2]. The severity of sepsis mostly depends upon the host response [1]. Old age, female gender, diabetes mellitus, immunosuppression, use of chemotherapy or steroids, acquired immunodeficiency syndrome, chronic renal failure, anemia, urinary stone sized > 2.5 cm in diameter, and extremely long duration of surgery have been suggested as risk factors for urosepsis [1,3]. The mortality rate of severe sepsis is 20-42%, and approximately 45% of severe sepsis cases originate from pneumonia, with 5-31% from urinary tract infections [4,5].

Emphysematous pyelonephritis (EPN) is an acute ne-crotizing bacterial infection characterized by gas formation in the kidney. EPN usually occurs in patients with diabetes mellitus or urinary tract obstruction [6,7]. EPN occurred in just 2.5% of 120 patients with severe renal infection [3]. However, a high mortality rate of 70-80% was reported in the late 1970s and 16-69% in 1990, primarily due to septic complications [8,9]. Computerized tomography (CT) is clinically valuable for the diagnosis and evaluation of this disease condition [7]. Classification systems were proposed by Wan et al. [8] and Huang et al. [6], and both are based on CT findings. In 1996, Wan et al. [8,10] categorized EPN into Type I and II. Type I EPN refers to renal necrosis with either the total absence of fluid content or the presence of a streaky/ mottled gas pattern. Type II EPN refers to the presence of renal or perirenal fluid in association with a loculated gas pattern or the presence of gas in the collecting system [8]. In 2000, Huang et al. [6] categorized EPN into Class 1-4 as follows: Class 1, gas in the collecting system; Class 2, gas in parenchyma without extension into the extrarenal space; Class 3A, extension of gas into the perinephric space; Class 3B, extension of gas into the paranephric space; and Class 4, bilateral EPN or single-kidney EPN. The differences in radiological features of EPN on CT are associated with the prognosis: mortality rates were 69 and 18% for Types I and II EPN according to Wan's classification [8], respectively. Similarly, the mortality rates for EPN of Classes 1, 2, 3A, 3B, and 4 according to the Huang classification were 0, 10, 29, 19, and 50%, respectively [6].

Over the last 25 years, the overall mortality rate of EPN has greatly improved to 12.5-25% thanks to advances in the early diagnosis and critical management of this life-threatening condition with antibiotics, fluid hydration, oxygen, acid-base balance correction, multi-organ support, and percutaneous catheter drainage (PCD) of the affected kidney(s) [7,9,11,12,13]. Special attention has been paid to the therapeutic efficacy of PCD because it offers a lower mortality rate than medical management alone or emergency nephrectomy [7,11]. Currently, however, the successful outcomes following treatment for EPN do not necessarily depend on the radiological EPN category and PCD. A growing literature describing good conservative management (without PCD or nephrectomy) in various radiological categories of EPN has appeared in the form of case reports [14,15,16] and small case series [17,18,19,20].

Furthermore, numerous investigators demonstrated that risk factors for mortality due to EPN are thrombocy-topenia, shock, altered status of consciousness, and acute impairment of renal function/need for hemodialysis [6,9,10,12,13,17]. Each of the risk factors is commonly incorporated into the Sequential Organ Failure Assessment (SOFA), the score of which grades functional abnormality of organ systems and accounts for clinical interventions and sepsis-related mortality [21]. Definitions of sepsis and septic shock have been recently updated as the third international consensus definitions (Sepsis-3) based on the SOFA score [21]. Here, we aimed to investigate the therapeutic outcomes of EPN patients with respect to SOFA.

Materials and Methods

Study Participants and Ethical Statement

We retrospectively examined medical archives relating to inpatients diagnosed with EPN who were treated in the departments of urology at Yamagata University Hospital and 7 affiliated hospitals (Nihonkai General Hospital, Tsuruoka Municipal Shonai Hospital, Yamagata Prefectural Shinjo Hospital, Yamagata Prefectural Kahoku Hospital, Yamagata Prefectural Central Hospital, Yama-gata City Hospital Saiseikan, and Okitama Public General Hospital) in Yamagata Prefecture from April 1, 2008 to April 30, 2017.

Institutional ethical approval was obtained from the Yama-gata University Faculty of Medicine (approval no. 47 in May 18, 2017). The boards waived the requirement for individual informed consent because the anonymity of the subjects was ensured. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Demographic and Clinical Data

Information on patient's age at presentation, sex, comorbidity, medical history, clinical courses during EPN treatment, laboratory, bacterial, and radiological findings was collected from medical archives. All patients were radiologically categorized using the Wan [8] and Huang [6] classification of EPN on CT findings.

Assessment of Sepsis-Related Organ Dysfunction

Based on patient's data at initial presentation or admission, we retrospectively evaluated all patients using the quick SOFA (qSOFA) score and SOFA score according to the algorithm presented in the Sepsis-3 recommendations [21]. Briefly, the qSOFA consists of the following 3 criteria: respiratory rate ≥ 22/min, altered mentation, and systolic blood pressure ≤ 100 mmHg [21]. The SOFA score assesses and grades dysfunction of 6 different organ systems: respiratory [partial arterial oxygen pressure (PaO₂)/fraction of inspired oxygen (FiO₂) and respiratory support], coagulation (platelet count), liver (bilirubin), cardiovascular (mean arterial blood pressure or catecholamine), neurological (Glasgow coma scale), and renal (creatinine and urine output) [21]. The qSOFA and SOFA scores were assessed on admission (day 1), and SOFA scores were also calculated on the day when patients experienced clinical deterioration. Altered mentation in the qSOFA was judged as a Glasgow coma scale ≤ 14 points. In the Sepsis-3 statement [21], a qSOFA score ≥ 2 and SOFA score ≥ 2 points are recommended as the initial screening and diagnostic cut-off values for sepsis.

To calculate PaO₂/FiO₂ ratios in patients without arterial blood gas results, we used the Ellis inversion [22] of the Severinghaus equation [23] to convert SpO₂ to PaO₂ in patients without measured arterial blood gases. The equation was standardized to body temperature and a pH of 7.40 [23]. FiO₂ for patients receiving supplemental oxygen was estimated as previously reported [23].

The systemic inflammatory response syndrome (SIRS) was defined as the presence of two or more factors, as follows: body temperature > 38°C or < 36°C, heart rate > 90/min, respiratory rate > 20/min or PaCO₂ < 32 mmHg (4.3 kPa), white blood cell count > 12,000/μL or < 4,000/μL, or > 10% immature bands [21,24].

Statistical Analysis

Mann-Whitney's U-test was performed to compare the mean of the 2 groups. Fisher's exact test was used to analyze the relationship between drainage modalities and clinical parameters in cross charts. A p < 0.05 was considered statistically significant. Statistical analysis was done using R freeware version 3.1.0 (http://cran.r-project.org/).

Results

A total of 17 patients were eligible for the present study. Table 1 shows the clinical features of the included patients. The median patient age was 70 years, and there was a preponderance of women and diabetes mellitus as a comorbidity. Two cases had Class 4 EPN, which refers to bilateral lesions in the Huang's classification system [6]. Urine culture revealed that Escherichia coli was the most frequent pathogenic bacteria (80%). In most cases, the same organism was identified in bacterial cultures of urine and blood. Polymicrobial infection was detected in 3 patients (18.8%). The upper urinary tract was obstructed in 70.1% of the EPN patients often due to uro-lithiasis and stenosis.

Table 1.

Clinical characteristics of the 17 EPN patients

Factors	No. of patients	Range	Median	IQR
Age, years	17	[49–94]	70	16
Male/female	5/12
Diabetes mellitus/non-diabeties	14/3
Classification of EPN
Type I/II#	8/9
Class 1/2/3A/3B/4§	9/1/3/2/2
Urinary obstruction/no obstrucion	12/5
Causes of obstruction
UUT stenosis/urolothiasis/urinary retention/others	2/7/1/2
Body temperature (on admission), °C	17	[36.1–41.1]	38.7	1.0
Heart rate (on admission), bpm	17	[81–155]	111	34.0
Blood pressure (on admission)
Systolic, mmHg	17	[72–197]	106	42
Diastolic, mmHg	17	[41–98]	60	19
Shock (systolic pressure ≤ 90 mmHg)	5
Glasgow Coma Scale (on admission), points	17	[6–15]	15	1
Mental disturbance; Glasgow Coma Scale < 15 points	8
Laboratory data§
White blood cell count, /μL	17	[9180–54340]	19510	7670
Platelet count,×104/μL	17	[0.6–41.2]	14.6	12.0
Albumin, g/mL	17	[1.3–3.0]	2.2	0.5
Total bilirubin, mg/dL	17	[0.2–2.4]	0.54	0.22
Creatinine, mg/dL	17	[0.73–6.10]	2.40	2.35
Acute renal impairment (increase in creatinie ≥ 1.0 mg/dL from the baseline)	9
Need for hemodialysis	0
Na, mEq/L	17	[118–144]	132	5
C-reactive protein, mg/dL	17	[12.96–58.66]	26.8	14.0
PT-INR	15	[0.92–1.94]	1.24	0.17
Fibrin degradation product, μg/mL	14	[3.2–79.2]	13.35	23.95
Urine culture, pathogenic microbials
E. coli/K. pneumoniae/E. faecalis/S. marcescens/unknown	12/2/3/1/1
Polymicrobial infection	3
Drainage procedure (no/stent/PCD)	3/11/3
SIRS score (on admission) ≥ 3¶	14
SOFA score (on admission), points¶¶	16	[1–12]	4.50	2.75
Increase in SOFA score from the baseline on admission	5
Duration of EPN treatment, days	17	[5–129]	17	13
Mortality due to EPN	1

UUT = Upper urinary tract; PT-INR = international normalized ratio of prothrombin time; E. coli = Escherichia coli; K. pneumoniae = Klebsiella pneumoniae; E. faecalis = Enterococcus faecalis; S. marcescens = Serratia marcescens;  IQR = interquaterile range.

^#EPN classification by Wan et al. [8].

^§EPN classification by Huang et al. [6].

^¶SIRS score was not determined in 2 patients due to missing data on respiration.

^¶¶SOFA was not scored in a patient due to missing data on arterial oxygen saturation.

^§: Laboratory data are presented as the worst values during hospitalization.

Overall, physical and hematological findings showed severe and acute inflammatory reactions with critical organ dysfunction (Table 1). Several parameters transiently deteriorated within a few days after admission, but improved during hospitalization. The SOFA score on day 1 (at admission) was a median of 4.5. In most patients, the initial SOFA score on day 1 was the worst of the scores, and thereafter slowly improved during the clinical course. However, 5 patients (29.4%) did not follow this trend, and the three of them had an acute increase in SOFA by ≥ 2 points during hospitalization. Figure 1 shows relationships among qSOFA, SIRS and SOFA scores in the EPN patients at admission (day 1). The qSOFA score ≥ 2 excluded 7 patients (53.8%) with SOFA and SIRS ≥ 2 points. No significant differences were found between the initial mean SOFA scores in Wan's Type I and II (p = 0.36), and in Huang's Class 1 and the other classes of EPN (p = 0.79). Because information on respiration was retrospectively unavailable, SOFA, SIRS, and qSOFA scores could not be specifically determined in some of the patients.

Fig. 1.

Relationships among qSOFA, SIRS, and SOFA scores in the 13 patients on admission. A qSOFA score ≥ 2, recommended as the initial screening criterion for sepsis [21], excluded 7 patients (53.8%) with SOFA and SIRS evaluated as ≥ 2 points. In the dotted area 3 cases are plotted, two of whom experienced an increase in SOFA of 2 points compared to the baseline value. A case (marked with an open star) abruptly developed cardio-pulmonary arrest caused by septic EPN (as also shown in Figure 2). Note that 4 patients were excluded from this plot due to missing data on respiration.

Sixteen patients completely recovered, yielding an overall mortality rate of 5.9% (Table 1). Changes in SOFA score after admission were significantly affected by selected approaches of drainage, but not by other clinical factors (Table 2). A patient who had medical therapy without drainage for a mild stricture of the left pelviureteral junction abruptly passed away due to septic complications on day 9 after admission, at which point the corresponding SOFA was unable to be scored due to a lack of hematological data at that time (Fig. 2). The remaining patients with obstruction of the upper urinary tract were successfully treated with conservative management including antibiotics and transurethral/percutaneous drainage.

Table 2.

Differences between patient groups with and without increase in SOFA score

Factors	Changes of SOFA score		p
	No deterioration (n = 12)	Deterioration (n = 5)
Age			0.62
≥70 years old	7	2
< 70 years old	5	3
Sex			0.60
Female	9	3
Male	3	2
Diabetes mellitus			1.00
Yes	10	4
No	2	1
Classification of EPN
Type I	4	4	0.13
Type II	8	1
Class 1	7	2	0.84
Class 2	1	0
Class 3A	2	1
Class 3B	1	1
Class 4	1	1
Obstruction of upper urinary tract			1.00
Yes	7	3
No	4	1
Shock			1.00
Systolic blood pressure≥90 mmHg	8	3
Systolic blood pressure < 90 mmHg	4	2
Mental alteration			1.00
Yes (Glasgow Coma Scale < 15)	6	2
No (Glasgow Coma Scale = 15)	6	3
Leukocytosis			0.62
White blood cell count≥19510<smallcaps>/</smallcaps>μL	7	2
White blood cell count < 19510<smallcaps>/</smallcaps>μL	5	3
Thrombocytopenia			0.13
Platelet count≥14.6×104/dL	8	1
Platelet count < 14.6×104/dL	4	4
Hypoalbuminemia			0.62
Albumin > 2.2 g/mL	5	3
Albumin≤2.2 g/mL	7	2
Acute renal impairment			0.62
Increase in creatinine < 1.0 mg/dL from	5	3
the baseline
Increase in creatinine≥1.0 mg/dL from	7	2
the baseline
Hyponatremia			1.00
Na > 132 mEq/L	6	2
Na≤132 mEq/L	6	3
Inflammation			1.00
C-reactive protein≥26.8 mg/dL	6	3
C-reactive protein < 26.8 mg/dL	6	2
Polymicrobial infection			0.19
Yes	1	2
No	11	3
Drainage			0.029
No drainage	0	3
Ureteral stent	9	2
Percutaneous drainage	3	0

Fig. 2.

Abnormal gaseous lesions detected by CT in a patient who nosocoimially developed fatal urosepsis. CT images demonstrated bilateral (Huang's Class 4) EPN (a and b). In particular, the gaseous lesion in the left EPN extended into the perinephric space (arrow heads in a and b. Abnormal gas was also observed in other sites: the inferior vena cava (arrow, b) and heart (arrows, c). No drainage was done for the left upper urinary obstruction after admission.

Discussion

In the present study, the patients that had clinical characteristics typical of EPN, were mostly women, older than middle aged, had diabetes mellitus as a comorbid-ity, and were infected by Enterobacteriaceae. Regardless of the EPN classification, most of the patients were successfully managed with conservative therapies including retrograde drainage, instead of PCD or nephrectomy. The favorable clinical outcome in the present study was consistent with recent reports of the successful conservative management of EPN [14,15,16,17,18,19,20,25].

In contrast, the SOFA score transiently increased during hospitalization after admission in 100%, 22% and none of the EPN patients with no drainage, ureteral stenting, and PCD, respectively. One patient without drainage nosocomially developed fatal urosepsis in the present study. Great differences in mortality were reported to exist between patients with sepsis present on admission to the hospital and patients who develop sepsis in the hospital (12 and 35%, respectively) [26]. Less-invasive management can cause deterioration in SOFA after admission, yielding a risk of septic mortality.

The definition of sepsis updated in 2016 highlights the significance of organ dysfunction caused by the infection [21]. The SOFA score was adopted for the evaluation of organ dysfunction, and the qSOFA was developed to screen possible sepsis without blood tests in hospital sections outside of intensive care units [21]. An acute change in a total SOFA score ≥ 2 points consequent to infection indicates organ dysfunction, where the baseline SOFA score can be assumed to be 0 in patients not known to have preexisting organ dysfunction. An increase in the SOFA score ≥ 2 points is associated with an in-hospital mortality rate > 10% [21]. Risk factors for EPN mortality were documented by numerous researchers: thrombocytopenia [6,9,10,13], shock [6,12,13], altered sensorium [6,13], and acute renal impairment/hemodialysis [6,10,12,13]. These risk factors are associated with septic complications, and partly constitute the SOFA score. Hypoalbuminemia [12], bacteremia [12], polymicrobial infection [12], conservative treatment [9], Wan's Type I EPN [9], and bilateral EPN [9] were also reported as prognostic factors.

In our cohort, most of the risk factors changed on a day by day basis during treatment, but they did not necessarily lead to fluctuations of the SOFA score. The SOFA score only deteriorated in 5 (29.4%) patients. Three patients presented with acute rises in the SOFA score of ≥ 2 points from the baseline on admission, one of whom died of septic complications. The qSOFA on admission was negative for sepsis in 2 cases, while SIRS criteria and SOFA scored these patients as having sepsis. The results in Figure 2 indicate that a qSOFA of ≥ 2 points may be an insufficient initial screening tool for urosepsis. Respiratory dysfunction has not been reported as a risk factor of EPN mortality [6,9,10,12,13,17]. However, respiratory criteria receive more weight in the scoring of qSOFA than SIRS and SOFA because respiration shares one of the total of 3, 4, and 6 variables constituting the qSOFA, SIRS, and SOFA scoring systems, respectively [21].

Obstruction of the upper urinary tract is the predominant cause of urosepsis [1]. An upper obstruction is referred to as a complicating factor because the septic focus needs to be controlled within the first 6 h from the start of treatment [1]. Immediate ureteral stenting or percutaneous nephrostomy is recommended for the control of this complicating factor [1]. There is no evidence of the superiority of either treatment when ureteral stents are compared to percutaneous nephrostomy in septic patients with obstructed kidneys [1,27]. A recent prospective study demonstrated that retrograde ureteric stenting is as safe and effective in SIRS patients with infected kidneys obstructed by stones as PCD tube insertion [28]. To our knowledge, however, retrograde stenting is not a standard drainage procedure for EPN [11].

Olvera-Posada et al. [17] found that 14 of 15 EPN patients treated with only medical management and 20 of 23 EPN patients receiving ureteral stenting plus medical therapy completely recovered without additional surgical procedures. Recently, Das et al. [18] reported 15 consecutive EPN patients who underwent drainage procedures by transurethral stenting (n = 7), PCD (n = 4), and medical management alone (n = 4), with all patients making a full recovery. In the present study, 13 patients (81.3%) were successfully treated with medical therapy alone (n = 3) or in combination with retrograde stenting (n = 10), consistent with previously reported results [14,15,17,18,19,20]. Seven of the 11 patients treated with transurethral stenting had obstructive EPN categorized as Huang's Class 1. Since Huang's Class 1 EPN represents “pyelitis” with gas in the collecting system [6], transurethral stenting may provide effective drainage in Class 1 EPN with obstruction. In contrast, 5 patients with non-obstructed EPN were successfully managed with conservative therapy alone (n = 1) and in combination with ureteral stenting (n = 2) or PCD (n = 2). Theoretically, the role of retrograde stenting and/or PCD seems unclear unless the specific mode of the upper obstruction is confirmed. However, draining abnormal gas from the body through an indwelling catheter might benefit patients by helping to reduce intrapelvic pressure and remove microbial debris from the renal collecting systems [18]. Das et al. [18] insist that PCD can play a therapeutic role, and that transurethral stenting could be an alternative to PCD, although medical management and drainage procedures are sufficient for the management of EPN. Aggressive medical treatment, including rapid control of glucose, sepsis, and renal failure, provided positive outcomes in Class 4 EPN patients without nephrectomy [15].

There are some limitations to the present study. The study was retrospective in nature and included a small number of patients. Medical records related to respiration were unavailable in several patients, so we were not able to definitely determine qSOFA, SIRS, and SOFA scores in these patients. Therefore, multivariate analysis for the present cohorts could not be performed to statistically investigate prognostic factors. Further prospective and large-scale studies are needed to confirm our findings.

Conclusion

In conclusion, we retrospectively examined 17 typical EPN patients with various radiological types. Sixteen patients were successfully managed with no drainage (n = 2), retrograde stenting (n = 11), and PCD (n = 3). One patient without drainage passed away because of septic EPN, yielding an overall mortality rate of 5.9%. None of the patients underwent nephrectomy. Presently many cases of EPN are managed with conservative procedures with good outcomes, but it should be noted that EPN patients who are treated less invasively tend to experience acute increases in SOFA after the beginning of treatment, even if transient, which presents a great risk of septic mortality.