A Diabetic Patient with Prolonged Hyperammonemia Due to Urinary Tract Infection Caused by Urease-producing Bacteria

Abstract

Obstructive tract infection caused by urease-producing bacteria can lead to hyperammonemia. We herein report a 73-year-old woman with diabetes and compensated liver cirrhosis who developed obstructive pyelonephritis. Her consciousness level declined on day 3 of hospitalization. Blood tests revealed an elevated ammonia level of 140 μg/dL. Urine and blood cultures identified Proteus mirabilis as a urease-producing bacterium. The treatment included double J (WJ) catheter insertion and administration of antimicrobial agents. On day 7 of hospitalization, the ammonia level gradually decreased, and the patient's consciousness improved. However, despite these interventions, perinephric overflow of urine persisted, necessitating nephrectomy.

Introduction

Hyperammonemia is commonly associated with advanced liver disease. We herein report a case of impaired consciousness resulting from obstructive urinary tract infection caused by a urease-producing bacterium, leading to hyperammonemia. We provide a literature review to further discuss this case.

Case Report

We encountered a 73-year-old woman with a history of rheumatoid arthritis (currently taking 5 mg prednisolone orally), moderately controlled diabetes (HbA1c 7.2%), and compensated liver cirrhosis. The patient was admitted to our hospital after a four-day period with a decreased appetite, nausea, and difficulty moving. Upon admission, the patient exhibited a clear consciousness. Perinephric overflow of urine and an increased fat density around the left kidney (Figure) were observed on computed tomography (CT), leading to a diagnosis of obstructive urinary tract infection with urinary obstruction caused by debris. Blood tests revealed an increased white blood cell count (9.38×10³/μL), elevated level of C-reactive protein (CRP; 11.65 mg/dL), and hyperglycemia (322 mg/dL). A urinalysis revealed the presence of blood and pus in the urine.

Figure.

Computed tomography images of the abdomen showing urinary extravasation into the left renal periphery.

The patient underwent treatment that included blood glucose control, insertion of a double J (WJ) catheter, and administration of cefozopran hydrochloride. On day 3 of hospitalization, the patient showed a decline in consciousness (Glasgow Coma Scale, E1V1M1). However, she had no signs of nuchal rigidity or ocular deviation. Magnetic resonance imaging and a cerebrospinal fluid examination did not reveal any significant abnormalities, except for hyperglycemia. Blood tests on the next day showed improved CRP levels but persistent hyperglycemia and dehydration, along with an ammonia level of 148 μg/dL, suggesting impaired consciousness due to hyperammonemia (Table 1). The patient had compensated liver cirrhosis (Table 2). However, no apparent causes of hyperammonemia, such as medication use, gastrointestinal bleeding, or seizures, were identified.

Table 1.

Laboratory Data of Patients on the Day of Coma Onset.

Biochemistry
Total protein		5.6	g/dL		Hemoglobin A1c		7.2	％
Albumin		3.2	g/dL		Ammonia		143	μg/dL
Total bilirubin		1.85	mg/dL		Immunoglobulin G		466	mg/dL
Alanine transaminase		20	U/L		Immunoglobulin A		352	mg/dL
Aspartate transaminase		16	U/L		Immunoglobulin M		170	mg/dL
Lactate dehydrogenase		449	U/L		TSH		4.45	μIU/mL
γ-glutamyl transpeptidase		33	U/L		Free T3		1.13	pg/mL
Creatinine		1.22	mg/dL		Free T4		0.57	ng/mL
Blood urea nitrogen		63	mg/dL		Thyroglobulin		28.2	ng/mL
Creatine kinase		350	U/L		Anti-TgAb		<10	IU/mL
Na		144	mmol/L		Anti-TPOAb		1.9	IU/mL
K		4.7	mmol/L		C-reactive protein		3.65	mg/dL
Cl		112	mmol/L		Procalcitonin		±
Ca		9.0	mg/dL				0.35	ng/mL
Inorganic P		3.1	mg/dL		NT-proBNP		16,517.2	pg/mL
Glucose		316	mg/dL		β-D-Glucan		<5.0	pg/mL
Blood gas analysis (O2 2L/min)
pH		7.56			CSF
pO2		72.5	mmHg		Opening pressure		13	mmH2O
pCO2		24.0	mmHg		Appearance		Cler, colorless
HCO3-		18.6	mmol/L		White cell count		1	/μL
Base excess		-2.4	mmol/L		Lymphocytes		1	/μL
Urinalysis					Neutrophils		<1	/μL
pH		7.0			Protein		81	mg/dL
Protein		+1			Glucose		190	mg/dL
Sugar		±			Glucose CSF/serum ratio		0.60
Ketone		-			Culture		Nagative
Red blood cell		>100	/HPF		VZV immunoglobulin M		±
White blood cell		>100	/HPF		VZV immunoglobulin G		-
Bacteria		-	/HPF		HSV immunoglobulin M		-
Complete blood count					HSV immunoglobulin G		-
White blood cell		10.59	×103/μL		CMV immunoglobulin M		-
Red blood cell		4.56	×106/μL		CMV immunoglobulin G		-
Hemoglobin		15.2	g/dL
Platelet		121	×103/μL

TSH: thyroid-stimulating hormone, TgAb: thyroglobulin antibody, TPOAb: thyroid peroxidase antibody, NT-proBNP: N-terminal pro-brain natriuretic peptide, CSF: cerebrospinal fluid, VZV: varicella zoster virus, HSV: herpes simplex virus, CMV: cytomegalovirus

Table 2.

Liver Fibrosis Test Results and Liver Ultrasound Findings.

Liver fibrosis
Fibrosis 4 index		2.91
Hyaluronic acid		200	ng/mL
M2BPGi		1.48	C.O.I
Autotaxin		0.768	mg/L
Liver ultrasound
LSM of SWE		8.29-9.40	kPa
		F2
Attenuation imaging		33-66	％
		0.72-0.77	dB/cm/MHz
		S2

M2BPGi: Mac2-binding protein glucosylation isomer, LSM: liver stiffness measurement, SWE: shear wave elastography

On day 5 of hospitalization, branched-chain amino acids were added, and the antibiotic was changed from cefozopran hydrate, a broad-spectrum agent, to meropenem hydrate. Fluid resuscitation and blood glucose control were maintained. By day 6 of hospitalization, the serum ammonia levels had increased to 153 μg/dL, and her impaired consciousness persisted. However, on day 7, ammonia levels had decreased to 89 μg/dL, and the patient's level of consciousness improved. Urine and blood cultures obtained on the first day of admission revealed the presence of the urease-producing bacterium Proteus mirabilis (Table 3), confirming obstructive urinary tract infection as the cause of hyperammonemia. The underlying cause of liver cirrhosis was suspected to be non-alcoholic steatohepatitis (NASH), as antibodies were negative, and a liver biopsy was not performed. Mild liver fibrosis was observed, and the patient presented with compensated cirrhosis.

Table 3.

Antimicrobial Susceptibility of Proteus mirabilis.

Antibiotic		MIC		Susceptibility
Ampicillin		<8		Susceptible
Piperacillin		<8		Susceptible
Ceftriaxone		<1		Susceptible
Ceftazidime		<4		Susceptible
Cefepime		<2		Susceptible
Meropenem		<1		Susceptible
Cefmetazole		<8		Susceptible
Amikacin		<4		Susceptible
Minocycline		8		Intermediate
Levofloxacin		<0.5		Susceptible
Flomoxef		<8		Susceptible
Sulfamethoxazole/trimethoprim		>2		Resistant

Proteus mirabilis with the same antibiotic susceptibility was detected in urine and blood cultures collected on day 1 of admission.

MIC: minimum inhibitory concentration

Meropenem hydrate administration was discontinued on day 14 of hospitalization. During the hospital stay, the WJ catheter was replaced, with modifications made to its length and side holes, on days 17 and 30. On day 21, left retroperitoneal drainage was performed, resulting in daily drainage of 900-1,000 mL of urine. However, the ureteral fistula did not improve, and perinephric urine overflow persisted. Urine culture from the retroperitoneal drain showed the disappearance of P. mirabilis and the presence of Candida albicans. Despite continued retroperitoneal drainage, the urine drainage volume did not decrease.

Given the risk of new infections and decreased activities of daily living (ADL) with the long-term presence of a retroperitoneal drain, as well as complaints of poorly controlled pain, laparoscopic left nephrectomy was performed on day 38. Inflammatory cell infiltration was observed in the renal pelvis and parenchyma, but no malignant findings were observed.

The postoperative course was uneventful and the patient underwent rehabilitation. She was discharged on day 77 of hospitalization.

Discussion

In the present case, the level of consciousness improved as the blood ammonia levels decreased. Although the possibility of sepsis due to urinary tract infection was considered, the white blood cell count and CRP level showed a tendency to improve at the onset of consciousness impairment, and no findings suggesting vital abnormalities or sepsis were observed. While the ammonia level was mildly elevated, dehydration and high blood glucose levels may have contributed to the worsening of impaired consciousness. However, it is suggested that high blood ammonia levels were the primary cause of impaired consciousness in this case.

Common causes of high blood ammonia levels include liver failure, portosystemic shunts, medications, gastrointestinal bleeding, and seizures. In the present case, although the patient had liver cirrhosis, it was in a compensated stage without evidence of deterioration. Although cirrhosis may have contributed to the exacerbation of hyperammonemia, obstructive urinary tract infections caused by urease-producing bacteria are thought to be the main cause of hyperammonemia.

Infection with urease-producing bacteria leads to the breakdown of urea into ammonia in urine. In cases where the urinary tract is obstructed, the bladder and renal pelvis become distended, allowing ammonia to be absorbed directly into the systemic circulation from the surrounding venous plexus, bypassing the liver, and causing hyperammonemia (1).

Bacteria such as P. mirabilis, Pseudomonas aeruginosa, Klebsiella spp., Morganella morganii, and Corynebacterium reportedly produce urease (2). Proteus mirabilis, the causative bacterium in this case, is known to cause various infections in wounds, the eyes, the intestines, and the urinary tract and is frequently associated with catheter-related urinary tract infections (3). It is known to infect immunocompromised patients, such as those with diabetes mellitus, and previous reports have indicated that 36.77% of diabetic patients admitted to surgical wards or intensive-care units were infected with P. mirabilis or Providencia stuartii, compared to 4.04% of non-diabetic patients (4). Given that the present case involved a moderately controlled diabetic patient, the risk of infection with P. mirabilis was presumed to be high.

After researching cases of hyperammonemia associated with tract infections since 2000, we found a total of 10 cases, which are summarized in Table 4 (1,2,5-11). These cases predominantly occurred in elderly individuals, with the incidence being higher among those with underlying urological and gynecological conditions than in others. The most commonly observed causative bacteria were P. mirabilis and K. pneumoniae.

Table 4.

Literature Review of Cases of Hyperammonemia Associated with Urinary Tract Infections.

Ref	Old, gender	Underlying disease	Causative agents	Consciousness disorder	NH3 [μg/dL]	Treatment	Time to improvement
1	69, male	Prostatic hyperplasia	Proteus mirabilis	+	279	Antibiotics, lactulose, drainage of bladder
2	44, female	Chronic dysuria	Corynebacterium species	+	406	Drainage of bladder	3 days
5	88, female	Hepatitis C virus-related cirrhosis, hepatocellular carcinoma, chronic dysuria	Proteus mirabilis	Japan Coma Scale 20	168	Branched-chain amino acid, antibiotics, drainage of bladder	About 8 days
5	81, female	Hepatitis C virus-related cirrhosis, hepatocellular carcinoma, heart failure	Klebsiella pneumoniae	Japan Coma Scale 3	125	Branched-chain amino acid, antibiotics	49 days
6	52, female	Cervical cancer, post-radiotherapy vesicointestinal fistula	Klebsiella pneumoniae	+	175	Antibiotics, percutaneous nephrostomy	5 days
7	80, female	Genital prolapse	Proteus mirabilis	+	182	Antibiotics, drainage of bladder	3 days
8	80, female	Urinary retention	Klebsiella pneumoniae	Glasgow Coma Scale 8	151	Antibiotics, drainage of bladder	5 days
9	84, female	Hypothyroidism, hypotonic bladder, several bladder diverticulum	Arthrobacter cumminsii	Japan Coma Scale 20	197	Antibiotics, lactulose, branched-chain amino acid	7 days
10	94, female	Lumbar spinal stenosis	Corynebacterium species	Glasgow Coma Scale E1V1M5	272	Drainage of bladder, continuous urinary lavage	1 day
11	83, female	Chronic heart failure, hypertension, chronic obstructive pulmonary disease, chronic renal failure, monoclonal gammopathy of undetermined significance	Morganella morganii	+	196	Branched-chain amino acid, antibiotics, lactulose,
Our case	73, female	Diabetes mellitus, rheumatoid arthritis	Proteus mirabilis	Glasgow Coma Scale E1V1M1	148	Branched-chain amino acid, antibiotics, retroperitoneal drainage, nephrectomy	5 days

While many cases of consciousness impairment showed improvement within one week, there have been reported cases (7,8,10) in which prompt resolution of obstructive urinary tract obstruction led to rapid improvement of hyperammonemia and subsequent resolution of consciousness impairment. In cases that required a longer duration of improvement (5), additional time was needed to investigate the underlying cause of hyperammonemia. However, following the administration of antimicrobial agents for tract infection, consciousness impairment improved.

In the present case, there was a urinary fistula in the ureter, leading to continuous urinary leakage into the retroperitoneum. It is believed that insufficient drainage was performed using only a ureteral stent, resulting in prolonged hyperammonemia and impaired consciousness. In the case of urease-producing bacteria-induced urinary tract infections, relieving urinary tract obstruction and promptly establishing drainage are considered crucial for early recovery. It is possible that, in the present case, early implementation of retroperitoneal drainage may have accelerated the improvement in the consciousness level.

Many previously reported cases primarily involved urinary voiding difficulties, and improvement was often achieved through the use of bladder catheters or bladder lavage (1,2,5,7,8,10). One patient with a vesicointestinal fistula required percutaneous nephrostomy (6), but cases necessitating retroperitoneal drainage or kidney removal, as in the present patient, were not documented.

Conclusion

In conclusion, it is important to recognize that, while liver dysfunction is commonly associated with hyperammonemia, obstructive urinary tract infection caused by urease-producing bacteria can also serve as a causative factor.

The authors state that they have no Conflict of Interest (COI).