A case of emphysematous pyelonephritis in an older man with poorly controlled type 2 diabetes mellitus

Abstract

Emphysematous pyelonephritis (EPN) is a necrotizing bacterial infection characterized by gas retention and a poor prognosis. We present the case of a 75-year-old man who was diagnosed early with EPN and received multidisciplinary treatment. He had poorly controlled type 2 diabetes mellitus (DM) and chronic kidney disease (CKD), and was treated with oral hypoglycemic drugs, including a sodium–glucose co-transporter-2 inhibitor. He experienced the onset of back pain in the midsection of his back, tenderness in the costovertebral angle, and a high fever (> 39 °C), accompanied by tachycardia, hypotension, and tachypnea. The patient was diagnosed with pyelonephritis and septic shock. Immediate measures encompassing empirical antibiotic therapy, administration of noradrenaline, blood glucose regulation, and urethral catheterization were implemented. However, due to the persistent fever (> 38 °C) and lack of improvement in his condition, abdominal computed tomography (CT) was repeated on the fourth day. This revealed the presence of gas around the right kidney parenchyma, leading to a diagnosis of EPN that had evolved from acute pyelonephritis. Subsequently, percutaneous drainage of the right kidney parenchyma was performed. Subsequently, multidisciplinary treatment was continued, and his condition gradually improved. Clinicians should evaluate abdominal CT when acute pyelonephritis does not improve within a few days of antibiotic therapy. Disease progression from acute pyelonephritis to EPN should be considered in patients with DM and CKD.

Introduction

Emphysematous pyelonephritis (EPN) is a rare necrotic bacterial infection characterized by the retention of gas in the parenchyma and surrounding tissues of the kidney, often associated with a high mortality rate [1]. Despite its severity, specific treatment policies or guidelines for EPN have not yet been firmly established [2, 3]. In this report, we present a case study of a male patient with poorly controlled type 2 diabetes mellitus (DM). The patient was undergoing treatment with oral hypoglycemic drugs, including a sodium–glucose co-transporter-2 (SGLT2) inhibitor, and subsequently developed EPN following initial treatment for acute pyelonephritis. Through prompt diagnosis and comprehensive multidisciplinary intervention, the patient's life was preserved. In the following sections, we outline the clinical trajectory of this case and offer a literature review.

Case report

A 75-year-old man had a medical history of cerebral infarction at the age of 62, resulting in residual mild right hemiplegia. He was also diagnosed with type 2 DM approximately 1 year prior, alongside hypertension, and chronic kidney disease (CKD), with serum creatinine [Cr] 1.80 mg/dL, estimated glomerular filtration rate [eGFR] 30 ml/min/1.73 m² and urine protein [1+]. His DM management remained suboptimal, with HbA1c levels persistently around 8–9%. Despite the family doctor’s recommendation for intensive insulin therapy, he opted for oral hypoglycemic agents (glimepiride, sitagliptin, and voglibose), and initiated an SGLT2 inhibitor (ipragliflozin) within the last year. He presented at the hospital with pain in the middle of his back 2 days prior and fever and fatigue 1 day prior. Later, he had difficulty moving and developed chills. The patient was transported to our hospital. Upon presentation, he had a fever of > 39 °C, a heart rate of 120 beats per min, a blood pressure of 88/59 mmHg, and tachypnea. Tenderness was detected at the right costovertebral angle and not in the abdominal area. Laboratory data are presented in Table 1. Urinalysis revealed proteinuria, hematuria, glucosuria (due to ipragliflozin), pyuria, and bacteriuria. Blood analyses showed elevations in white blood cell count (WBC, 17,000/μL), C-reactive protein (CRP, 24.80 mg/dL), and procalcitonin (PCT, 290.37 ng/mL), suggesting severe bacterial infection. Blood urea nitrogen (37.0 mg/dL) and serum creatinine (4.22 mg/dL) levels were elevated, and eGFR decreased (12 ml/min/1.73 m²) from the baseline data. Acute exacerbation of CKD was observed. Findings suggestive of disseminated intravascular coagulation (DIC), such as decreased platelets and/or abnormality of coagulation, were not detected. Both blood and urine cultures were positive for gram-negative bacilli. Plain computed tomography (CT) of the abdomen revealed atrophy of the left kidney, increased density of perirenal fat tissues around the right kidney, thickening of Gerota fascia, and mild dilatation of the renal pelvis (Grade 1). Although there were bilateral hydronephrosis and stones in the left renal pelvis, no causes of urinary tract obstruction were detected in the right and left kidneys, pelvis, or ureter. Therefore, urological intervention such as stenting was not performed.

Table 1.

Main laboratory data on day1

Urinalysis			Total protein	7.7	g/dL
SG	1.017		Albumin	4.1	g/dL
pH	5.5		BUN	37	mg/dL
Protein	(1+)		Cre	4.22	mg/dL
Glucose	(4+)		eGFR	12	mL/min/1.73 m2
Ketone	(−)		Na	137	mEq/L
Hematuria	(2+)		K	5.4	mEq/L
	14	/HPF	Cl	99	mEq/L
WBC	> 100	/HPF	AST	21	U/L
Nitrite	(−)		ALT	23	U/L
Bacteria	(3+)		T-bil	1.5	mg/dL
			LDH	239	U/L
Blood analysis			CRP	24.5	mg/dL
WBC	17,000	/μL	Procalcitonin	290.37	ng/mL
Seg	72.0	%	HbA1c	9.1	%
Band	15.0	%	Glucose	301	mg/dL
Mono	1.0	%
Lym	4.0	%	Arterial blood gas
Hb	16.1	g/dL	pH	7.5	mmHg
Ht	46.2	%	pCO2	20.3	mmHg
Plt	16.1 × 104	/μL	pO2	79.4	mmHg
			HCO3−	15.7	mmol/L
PT ratio	1.08		Lactate	38	mg/dL
APTT	28.8	sec

Conversion factors for units: Cr in mg/dL to μmol/L, × 88.4; BUN in mg/dL to mmol/L, × 0.357

WBC white blood cell, Hb hemoglobin, Ht hematocrit, Plt platelet, PT prothrombin time, APTT activated partial thromboplastin time, BUN blood urea nitrogen, Cr creatinine, eGFR estimated glomerular filtration rate, Na sodium, K potassium, Cl chloride, AST aspartate aminotransferase, ALT alanine aminotransferase, T.Bil total bilirubin, LDH lactate dehydrogenase, CRP C-reactive protein, HbA1c hemoglobin A1c

Emphysematous changes were not observed (Fig. 1a). There were no findings suggestive of lung lesions due to pneumonia or pulmonary edema. The patient was diagnosed with right pyelonephritis and septic shock (quick sequential organ failure assessment [qSOFA] score was 2 points). He had no history of urinary tract infection (UTI) and was not diagnosed with any urination problems, such as benign prostatic hyperplasia or neurogenic bladder. The UTI was considered complex because of hyperglycemia. Administration of empirical antibiotics (2.25 g tazobactam/piperacillin intravenously every 12 h) and noradrenalin, blood glucose control, and urethral catheterization were performed immediately after the diagnosis of pyelonephritis. Hemodynamics were maintained by noradrenaline infusion, appropriate fluid replacement, and antibacterial treatment. All oral medications, including SGLT2 inhibitors, were discontinued. However, fever > 38 °C persisted, and no improvement in the inflammatory response or kidney function was observed on the 3rd day (Table 2, Fig. 2). In addition, a decrease in platelet count (75,000/μL) and coagulation abnormalities were detected on the 4th day. Because his DIC score became 4 points, recombinant thrombomodulin therapy was initiated. The plain CT scan was re-examined on the 4th day because of the appearance of right abdominal pain with signs of peritoneal irritation. Abdominal CT revealed residual right hydronephrosis, an enlarged range of increased concentration in the retroperitoneum around the right kidney, and gas formation in the right kidney parenchyma, predominantly perirenal, and retroperitoneum (Fig. 1b). These findings were consistent with EPN. After consultation with the urology department, a ureteral stent was inserted for right hydronephrosis, and percutaneous drainage of the right renal parenchyma was performed (Fig. 3). Subsequently, gamma-globulin for septic shock was initiated. In addition, his kidney function increasingly worsen and his urine output decreased, leading to a diagnosis of stage 3 acute kidney injury (AKI) [4]. Then, continuous hemodiafiltration (CHDF) using AN69ST membrane was initiated due to AKI and a non-renal indication for sepsis with unstable hemodynamic status. The inflammatory response and kidney function improved with continued multidisciplinary treatment. On the 7th day, CHDF could be terminated. Blood and urine cultures at the time of admission and drain cultures showed a β lactamase-producing bacterium, Escherichia coli. Therefore, the antibacterial drug was changed to meropenem (MEPM), considering drug sensitivity. The clinical findings and CRP decreased to approximately 10 mg/dL approximately 3 weeks after the start of the antibacterial drug; however, after that, CRP did not decrease, suggesting residual inflammation in the kidneys. Because we could not decide whether this was due to a continuous active bacterial infection or non-bacterial inflammation caused by the drainage tube, the antibacterial drug was continued until the drainage tube was removed on the 42nd day. Finally, after 46 days of admission, the patient recovered clinically and was discharged. His serum creatinine level was 3.56 mg/dL (eGFR 14 ml/min/1.73 m²) at discharge. The ureteral stent in the right kidney was removed 3 months after discharge, concluding the follow-up.

Fig. 1.

Plain CT findings showing abdominal CT on the 1st and 4th days. a Abdominal CT at admission showed increased lipid density around the right kidney and hydronephrosis; however, emphysematous changes were not observed. b Abdominal CT on the fourth day revealed residual right hydronephrosis, an enlarged range of increased concentration in the retroperitoneum around the right kidney, gas formation in the right kidney parenchyma, perirenal predominance, and the retroperitoneum. CT computed tomography

Table 2.

Main laboratory data on day3

Urinalysis			Total protein	6.2	g/dL
SG	1.022		Albumin	2.9	g/dL
pH	5.5		BUN	50	mg/dL
Protein	(2+)		Cre	4.79	mg/dL
Glucose	(4+)		eGFR	10.5	mL/min/1.73 m2
Ketone	(+−)		Na	143	mEq/L
Hematuria	(2+)		K	4.5	mEq/L
	5–9	/HPF	Cl	107	mEq/L
WBC	55–99	/HPF	AST	26	U/L
Nitrite	(−)		ALT	34	U/L
Bacteria	(−)		T-bil	1.9	mg/dL
			LDH	415	U/L
Blood analysis			CRP	51.4	mg/dL
WBC	15,710	/μL
Seg	71.0	%	Arterial blood gas
Band	20.0	%	pH	7.42	mmHg
Mono	6.0	%	pCO2	27	mmHg
Lym	3.0	%	pO2	53.8	mmHg
Hb	14.7	g/dL	HCO3−	17	mmol/L
Ht	41.2	%	Lactate	60	mg/dL
Plt	8.6 × 104	/μL
PT ratio	1.47
APTT	41.6	sec

Conversion factors for units: Cr in mg/dL to μmol/L, × 88.4; BUN in mg/dL to mmol/L, × 0.357

WBC white blood cell, Hb hemoglobin, Ht hematocrit, Plt platelet, PT prothrombin time, APTT activated partial thromboplastin time, BUN blood urea nitrogen, Cr creatinine, eGFR estimated glomerular filtration rate, Na sodium, K potassium, Cl chloride, AST aspartate aminotransferase, ALT alanine aminotransferase, T.Bil total bilirubin, LDH lactate dehydrogenase, CRP C-reactive protein, HbA1c hemoglobin A1c

Fig. 2.

Clinical course of the current case. CHDF continuous hemodiafiltration, eGFR estimated glomerular filtration rate, CRP C-reactive protein, CT computed tomography, MEPM meropenem, TAZ/PIPC tazobactam/piperacillin, PLT platelet count

Fig. 3.

CT findings after kidney parenchymal drainage. Three percutaneous drains were placed in the right kidney parenchyma under CT guidance. Owing to the extensive inflammatory extent and multiple isolated abscess cavities, a single drainage would be inadequate for drainage. Therefore, drainage catheters were placed in three locations: the emphysema cavity (a) and the main abscess cavity (b, c). CT computed tomography

Regarding the treatment for DM, all drugs taken before admission were discontinued as mentioned above, and glucose levels were controlled using insulin (infusion of insulin in the fluid replacement and bolus insulin sliding scale) during the multidisciplinary treatment. Although insulin secretion was maintained (urinary C-peptide, 151.7 μg/day), hyperglycemia persisted despite oral administration of four kinds of oral hypoglycemic agents. Therefore, maintenance insulin therapy (basal-bolus treatment) was started on the 22nd day. Subsequently, the amount of insulin was adjusted, and the patient was discharged.

Discussion

Emphysematous pyelonephritis (EPN) is a severe necrotizing bacterial infection. The male-to-female ratio is 1:6, and the most common causative organisms are E. coli and, rarely, Klebsiella. More than 90% of the cases are associated with DM, and almost 20–40% of the cases are associated with urinary tract obstruction due to ureteral stones [5]. Several background conditions are thought to be important in the development of EPN. Owing to the increase in glucose levels in the tissues, disorder of tissue blood circulation, and impairment of immunological response, causative bacteria, such as E. coli, induce acid and gas production, resulting in progressive EPN [1]. In our patient, hyperglycemia was observed, and β-C lactamase-producing E. coli was detected in the blood, urine, and drain cultures. Although a previous study in 1985 reported that the mortality rate of EPN was 58.0% [6], recent studies have suggested that the mortality rate has decreased to 14.5–40.0% owing to early diagnosis via improved diagnostic techniques, the use of broad-spectrum antibacterial agents, and drainage treatment [2].

The symptoms of EPN are nonspecific, and commonly include fever, tapping pain at the costovertebral angle, and pyuria, which are similar to the symptoms of general acute pyelonephritis. Laboratory data for EPN are also not specific. Leukocytosis with leftward migration, increased inflammatory reactions and serum creatinine levels indicating acute kidney injury, and pyuria are commonly observed. Poor glycemic control is also detected in patients with DM. CT findings are useful for definitive diagnosis of EPN [5]. The severity of EPN is evaluated by the Wan or Huang classification, based on the extent of the EPN lesions using CT findings. The mortality rate increases with the severity of the classification (Table 3) [5, 7]. The current case corresponded to Type I in the Wan classification and Class 3b in the Huang classification, with estimated mortality rates of 69% and 19%, respectively [5]. In most cases, the clinical course of EPN presents with the condition already being evident at the time of initial symptoms. However, in a few cases, acute bacterial pyelonephritis has progressed to EPN in the clinical course. In the current case, EPN progressed from acute bacterial pyelonephritis. In cases where acute bacterial pyelonephritis progresses to EPN, it is crucial to identify this progression as early as possible to ensure prompt additional therapy and save the patient’s life. The natural history of acute bacterial pyelonephritis indicates that 95% of patients with uncomplicated pyelonephritis usually recover from fever within 48 h after initiation of antimicrobial therapy, and 100% of patients recover from fever within 72 h [8]. The American College of Radiology recommends plain and contrast-enhanced CT for imaging evaluation of acute pyelonephritis when there is no good response within 72 h after initiation of antimicrobial therapy [9]. The European Association of Urology guidelines for urinary tract infection also recommend plain CT to exclude renal abscess or a perirenal abscess if fever persists for 72 h after the start of treatment [10]. Therefore, if patients with pyelonephritis or complicated urinary tract infection still have fever after 72 h, retesting CT is crucial and may lead to an early diagnosis of EPN. In addition, Yamato et al. reported cases in which EPN was newly identified and treated during acute pyelonephritis. They suggested that DM and CKD might be risk factors for EPN during acute bacterial pyelonephritis [11]. In these previous studies, the lack of efficacy of treatment for acute pyelonephritis and worsening of general conditions led to a re-examination of abdominal CT [11, 12]. In the current case, a re-examination of CT was effective for the early detection of progression to EPN, as these previous reports suggested. Therefore, it is important to perform CT when the condition of patients with pyelonephritis does not improve after the initiation of antibiotic therapy.

Table 3.

Two representative classifications of EPN [5, 7]

Classification (Wan et al.)	CT findings
Type I	The destruction of the kidney parenchyma with streaky or mottled gas without fluid retention
Type II	The bubbly gas and fluid retention in and around the kidney

Classification (Huang et al.)	CT findings
Class 1	Gas is confined to the urinary tract
Class 2	Gas extends to the kidney parenchyma
Class 3A	Gas and abscess extend into the kidney myometrium
Class 3B	Gas and abscess extend beyond the kidney myometrium
Class 4	Lesions in both kidneys and solitary kidneys

Regarding its treatment, because EPN is rare, clinical guidelines for treatment strategies are not available. Therefore, urgent nephrectomy and multidisciplinary treatment have been recommended [6]. In recent years, treatment strategies have shifted towards kidney salvage strategies based on antimicrobial therapy with percutaneous drainage and ureteral stenting according to the disease severity [13, 14]. In addition, the mortality rates are decreasing. Rajeshkumar et al. proposed a treatment strategy that includes ureteral stenting, percutaneous drainage, and nephrostomy, along with multidisciplinary treatment encompassing glycemic control and antimicrobial therapy, depending on the severity of the disease [15]. Worsening kidney function requiring renal replacement therapy, thrombocytopenia, and sepsis in patients who have developed EPN may serve as indications for nephrectomy [3]. The current case of EPN was classified as Class 3 in the Huang classification and was evaluated as not suitable for operative nephrectomy due to severe infection and poorly controlled type 2 DM. Surgery could elevate the risks of mortality. Therefore, ureteral stenting and percutaneous drainage were selected for hydronephrosis. Consequently, the right kidney was preserved, and the patient’s life was saved. Based on the findings described above, we need to consider the treatment strategy for individual cases according to the patient’s condition.

The patient was administered an SGLT2 inhibitor for DM. SGLT2 inhibitors selectively inhibit SGLT2, a transporter that regulates glucose reabsorption from the proximal tubules in the kidney, thereby excreting sugar in the urine and controlling blood sugar levels. In 2018, the U.S. Food and Drug Administration issued an advisory stating that SGLT2 inhibitors are linked to a risk of serious urinary tract infections [16]. An increased concentration of sugar in the urine may create favorable conditions for bacterial growth, thereby facilitating the development of UTIs. Recent cohort studies have reported that patients on SGLT2 inhibitors experience less frequent severe UTIs than to those on DPP-4 inhibitors and Glucagon-like peptide-1 receptor agonist [17, 18]. Additionally, the risk of UTI was similar in the group using SGLT2 inhibitors than to the group using other antidiabetic drugs [19]. In addition, in a meta-analysis of randomized controlled trials study of patients aged 65 years and older, the risk of UTIs was similar in SGLT2 inhibitors and placebo [20]. Conversely, in patients aged 65 years and older, the risk of UTI was highest when the patient's age was 75 years or older [21]. Some case reports have described an association between SGLT2 inhibitors and EPN. Wesley et al. reported a case of septic shock due to Serratia marcescens pyelonephritis while on empagliflozin. The patient’s condition improved with antimicrobial therapy, empagliflozin was discontinued, and UTIs did not relapse [22]. Andre et al. also reported a case of severe fungal UTI caused by Candida glabrata while taking empagliflozin [23]. This case developed EPN and a fungal ball formation in the renal pelvis. Similar to the current case, both patients had been taking SGLT2 inhibitors and had no history of UTI. Moreover, since patients with uncontrolled DM often develop neurogenic bladder because of autonomic disorders [24]. In fact, the current case presented bilateral hydronephrosis upon hospital admission despite no findings of urinary tract obstruction. This might be caused by a potentially existing neurogenic bladder and could result in the development of EPN. Thus, patients with uncontrolled DM and urination disorders can be at risk of developing severe UTIs during treatment with SGLT2 inhibitors. Further case reports of EPN in patients treated with SGLT2 inhibitors are needed.

During the treatment of acute pyelonephritis, clinicians should consider the possibility of progression to EPN in patients with DM and CKD. These patients need to be evaluated via CT if their clinical conditions, including fever, do not improve within 72 h of treatment. Throughout the clinical course of treating EPN, clinicians should contemplate kidney parenchymal drainage or surgical nephrectomy when patients present with worsening kidney function and/or coagulation disorders, such as DIC. Although the relationship between EPN and the use of SGLT2 inhibitors is uncertain, attention should be paid to the development of severe UTIs during SGLT2 inhibitor treatment in patients with uncontrolled DM.

Author contributions

All the authors met the ICMJE authorship criteria. All the authors contributed significantly to this work. MN, DY, and TK were treating physicians in the current case and prepared the images and data tables for the manuscript. MN, MH, and DY drafted the manuscript. TK, KH, and YK revised and supervised the manuscript. All authors approved the submission of this manuscript.

Funding

None.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Declaration of Helsinki 1964 and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.