Utility of urinary presepsin in the diagnosis of pyelonephritis: A cross-sectional study

doi:10.21203/rs.3.rs-2506205/v1

Download PDF

Research Article

Utility of urinary presepsin in the diagnosis of pyelonephritis: A cross-sectional study

https://doi.org/10.21203/rs.3.rs-2506205/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 31 May, 2023

Read the published version in BMC Infectious Diseases →

You are reading this latest preprint version

Background: Presepsin is produced during the phagocytosis of bacteria by granulocytes. Presepsin increases at the site of infection; however, thesignificance of urinary presepsin in pyelonephritis is unknown. This study aimed to evaluate whether measuring urinary presepsin can distinguish between pyelonephritis and non-pyelonephritis.

Methods: Across-sectional study of patients with suspected pyelonephritis was conducted. Urinary presepsin at admission was compared between the pyelonephritis and non-pyelonephritis groups using the Mann–Whitney test. The predictive accuracy of urinary presepsin for diagnosing pyelonephritis was evaluated by the area under the receiver operating characteristics (ROC) analysiscurve.

Results: A total of 35 eligible participants were included in the pyelonephritis group and 25 in the non-pyelonephritis group. The median urinary presepsin level was 2232.0 (interquartile range [IQR], 1029.0–3907.0) pg/mL in the pyelonephritis group and 1348.0 (IQR, 614.5–2304.8) pg/mL in the non-pyelonephritis group. Urinary presepsin concentrations were significantly higher in the pyelonephritis group than in the non-pyelonephritis group (P = 0.023). ROC analysis of urinary presepsin revealed a cutoff value of 3650 pg/mL to distinguish between the pyelonephritis and non-pyelonephritis groups. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for the diagnosis of pyelonephritis were 0.40 (95% confidence interval [CI], 0.24–0.58), 0.96 (95% CI, 0.79–1.00), 0.93 (95% CI, 0.68–1.00), 0.52 (95% CI, 0.37–0.68), 9.60 (95% CI, 1.35–68.23), and 0.62 (95% CI, 0.47–0.83), respectively.

Conclusions: The measurement of urinary presepsin is useful in differentiating pyelonephritis from other diseases.

presepsin

pyelonephritis

pyuria

receiver operating characteristics

Pyelonephritis is a common disease that is more likely to occur in young women and older individuals. The symptoms and severity of the disease range widely. In most patients, the symptoms are mild back pain and fever, but septic shock can also occur [1]. If severe sepsis or septic shock occurs, the mortality rate is reported to be 20–50% [2, 3]. Accurate diagnosis and early treatment are important. Although there is no consensus on the diagnostic criteria for pyelonephritis [4], detecting bacteria in urine culture is crucial. However, obtaining the results of urine culture can take several days; hence, they are not useful for the early diagnosis of pyelonephritis. Pyuria is another characteristic finding of pyelonephritis and can be detected early. However, pyuria can also be detected in asymptomatic bacteriuria. Hence, the presence of pyuria does not prove pyelonephritis. There are no tools that can quickly distinguish between pyelonephritis and non-pyelonephritis. Presepsin, a granulocyte degradation product, is produced when granulocytes phagocytose bacteria [5]. Presepsin has been attracting attention as a useful marker for diagnosis and prognosis in sepsis [6]. Since presepsin production is increased at the site of infection, its measurement in the joint fluid is effective in differentiating pyogenic arthritis from crystalline arthritis [7]. The cerebrospinal fluid presepsin is also useful for the diagnosis and prognosis of post-neurosurgical ventriculitis/meningitis [8]. The significance of urinary presepsin in diagnosing pyelonephritis is unknown. This study aimed to evaluate whether measuring urinary presepsin can distinguish between pyelonephritis and non-pyelonephritis.

Study design and participants

This was a cross-sectional study performed on 132 patients admitted to Jikei University Daisan Hospital with suspected pyelonephritis from October 2019 to November 2021. The inclusion criteria for the study were (1) patients over 20 years, (2) patients with a fever of 37.5°C or higher, (3) and patients with a urine sedimentation test showing over 10 cells/high power field. Acute pyelonephritis was defined as a patient having back pain or costovertebral angle tenderness and urine culture revealing a bacterial count of 10⁵/liter or higher. Patients not meeting the definition of acute pyelonephritis were defined as the non-pyelonephritis group. The exclusion criteria for the study were (1) patients receiving antibiotics within a week before admission, (2) patients with indwelling urinary catheters, (3) patients with anatomical abnormalities in the urinary tract, and (4) patients on dialysis.

Study measurements

The patients’ age, gender, body temperature, past medical history, and the results of blood and urine cultures at the time of admission were collected. All patients underwent blood sampling for serum C-reactive protein, procalcitonin, creatinine, and presepsin on admission day. Urinary presepsin was also measured on admission day. Serum and urinary presepsin concentrations were measured by a PathFast immunoanalyzer presepsin kit (LSI Medicine, Tokyo, Japan).

Statistical analysis

The Bell curve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan) was used for all the statistical analyses. The Mann–Whitney U test was used to compare the age, urinary presepsin, serum C-reactive protein, procalcitonin, creatinine, estimated glomerular filtration rate, and serum presepsin. The chi-square test was used to compare the sex, past medical history, and bacteremia. The predictive accuracy of urinary presepsin and serum presepsin for diagnosing acute pyelonephritis was evaluated by the area under the curve (AUC) of ROC analysis. The Youden index was used to calculate optimal cutoff values for each measurement result. The cutoff values were used to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR−) for each measure. The P-values of < 0.05 were considered statistically significant.

Baseline characteristics of participants

Among the 132 participants who met the inclusion criteria, 60 participants were included in this study (41 participants were post-antibiotic, 11 participants had indwelling catheters, 18 participants had anatomical abnormalities in the urinary tract, and two participants were on dialysis). The participants were divided into two groups: acute pyelonephritis (n = 35) and non-pyelonephritis (n = 25). The average age of all participants was 77.6 years, and 78.3% of the participants were female patients. There were no significant differences between the two groups for age, sex, background disease, or immunosuppressive drug use. The bacteremia rate was significantly higher in the acute pyelonephritis group (P = 0.044). There were also no significant differences in the renal function, serum C-reactive protein, presepsin, or procalcitonin between the acute pyelonephritis and non-pyelonephritis groups (Table 1).

Table 1

Baseline characteristics of participants.
	Acute pyelonephritis (n = 35)	Non-pyelonephritis (n = 25)	P-value
Age (years)	85 [78.0–90.5]	81 [56.0–88.0]	0.064
Female sex	25 (71)	22 (88)	0.125
Diabetes mellitus	9 (26)	4 (16)	0.368
Liver cirrhosis	0 (0)	1 (4.0)	0.233
Chronic heart failure	3 (8.6)	2 (8.0)	0.937
Cerebrovascular disorder	9 (26)	2 (8.0)	0.080
Malignant tumor	3 (8.6)	3 (12)	0.663
Autoimmune disease	8 (23)	5 (20)	0.791
Immunosuppressor	7 (20)	3 (12)	0.412
Bacteremia	8 (23)	1 (4.0)	0.044
Creatinine (mg/dL)	0.90 [0.68–1.25]	0.84 [0.51–1.07]	0.161
eGFR (mL/min/1.73 m²)	49.0 [38.0–66.5]	64.0 [42.0–100.0]	0.122
C-reactive protein (mg/L)	113.4 [50.3–194.1]	88.9 [29.0–148.9]	0.393
Serum Presepsin (pg/mL)	361 [302–589]	386 [251–650]	0.844
Procalcitonin (ng/mL)	0.38 [0.17–2.06]	0.19 [0.08–0.94]	0.097
Values are expressed as number (%) or median [interquartile range, IQR]. Abbreviations: eGFR estimated glomerular filtration rate.

The final diagnosis in the non-pyelonephritis group is shown in Table 2.

Table 2

Final diagnosis in the non-pyelonephritis group.
Diagnosis	Number of cases (%)
Pneumonia	11 (44)
Enterocolitis	2 (8)
Crystal arthritis	2 (8)
Giant cell arthritis	1 (4)
Microscopic polyangiitis	1 (4)
Adult-onset Still's disease	1 (4)
Viral meningitis	1 (4)
Cholangitis	1 (4)
Histiocytic necrotizing lymphadenitis	1 (4)
Hemophagocytic lymphohistiocytosis	1 (4)
Hematoma	1 (4)
Ovarian hemorrhage	1 (4)
Drug fever	1 (4)

Comparison of urinary presepsin concentrations in acute pyelonephritis and non-pyelonephritis groups

The median urinary presepsin level was 2232.0 (interquartile range [IQR], 1029.0–3907.0) pg/mL in the acute pyelonephritis group and 1348.0 (IQR, 614.5–2304.8) pg/mL in the non-pyelonephritis group. Urinary presepsin concentrations were significantly higher in the acute pyelonephritis group than in the non-pyelonephritis group (P = 0.023) (Fig. 1).

The accuracy of urinary presepsin in the diagnosis of acute pyelonephritis

ROC curve analysis of urinary presepsin revealed a cutoff value of 3650 pg/mL to distinguish the acute pyelonephritis and non-pyelonephritis groups (Fig. 2). The value of AUC was 0.66 (95% confidence interval [CI], 0.52–0.80). Using the calculated cutoff values, sensitivity, specificity, PPV, NPV, LR+, and LR − for the diagnosis of acute pyelonephritis were 0.40 (95% CI, 0.24–0.58), 0.96 (95% CI, 0.79–1.00), 0.93 (95% CI, 0.68–1.00), 0.52 (95% CI, 0.37–0.68), 9.60 (95% CI, 1.35–68.23), and 0.62 (95% CI, 0.47–0.83), respectively. Compared to serum presepsin, urinary presepsin was a more accurate indicator of sensitivity, specificity, PPV, NPV, LR+, and LR− (Table 3).

Table 3

Ability of urinary presepsin and serum presepsin to detect acute pyelonephritis.
	AUC	Cutoff	Sensitivity	Specificity	PPV	NPV	LR+	LR-
Urinary presepsin	0.66 [0.52– 0.80]	3650 pg/mL	0.40 [0.24– 0.58]	0.96 [0.79– 1.00]	0.93 [0.68– 1.00]	0.52 [0.37– 0.68]	9.60 [1.35– 68.23]	0.62 [0.47– 0.83]
Serum presepsin	0.50 [0.34– 0.66]	1522 pg/mL	0.03 [0.00– 0.16]	0.84 [0.64– 0.95]	0.20 [0.01– 0.72]	0.40 [0.26– 0.54]	0.19 [0.02– 1.59]	1.15 [0.96– 1.38]

Results are expressed as values [95% confidence interval].

Abbreviations: AUC, area under the ROC curve; PPV, positive predictive value; NPV, negative predictive value; LR+, positive likelihood ratio; LR−, negative likelihood ratio.

This study revealed that urinary presepsin was significantly elevated in the acute pyelonephritis group compared with the non-pyelonephritis group. On the contrary, serum CRP, procalcitonin, and presepsin were not significantly different between the pyelonephritis and the non-pyelonephritis groups. These results suggest that measuring urinary presepsin in patients with fever and pyuria may provide an early indication of pyelonephritis.

When granulocytes phagocytose bacteria, CD14 is taken into the cells and degraded by proteases. The degraded CD14 becomes soluble CD14, which is detected as presepsin [5]. Presepsin is one of the biomarkers elevated in bacterial infections because of this production mechanism [9]. In pyelonephritis with bacteremia, serum presepsin levels are increased [10]. Furthermore, serum presepsin concentration correlates with sepsis severity. It is a more useful biomarker than PCT in predicting disease severity [11]. In pyelonephritis, granulocytes phagocytose bacteria in the urinary tract. This may result in increased local presepsin production and high urinary presepsin levels. For diagnosing pyelonephritis, urine culture results need to be awaited. However, it takes several days to obtain the urine culture results. On the contrary, urinary presepsin can be measured in 15 min. Therefore, it may contribute to an earlier diagnosis of pyelonephritis, which may help in reducing unnecessary antibiotic usage.

The results of ROC curve analysis revealed that urinary presepsin has higher sensitivity, specificity, PPV, NPV, LR+, and LR− than serum presepsin in the diagnosis of acute pyelonephritis. Traditionally, the assessment for acute pyelonephritis is often performed by using leukocyte esterase, an enzyme released by leukocytes, and nitrites as some bacteria reduce urinary nitrates to nitrites. When either leukocyte elastase or nitrite is positive, a diagnosis of acute pyelonephritis can be made with a sensitivity of 75%, specificity of 82%, LR+ of 4.2, and LR− of 0.3 [12]. Although urinary presepsin is inferior to the combination of leukocyte elastase and nitrites in sensitivity, it may be superior in specificity, LR+, and LR−. Urinary presepsin may be a useful test for making the definitive diagnosis of acute pyelonephritis.

This study has several limitations. First, the sample size was small because the patients with factors that might affect urinary presepsin levels were excluded from this study. To clarify the generalizability of the results, further investigations are required. Second, this study included patients with fever and pyuria. Patients without fever were not included in this study. Additionally, severe cases and older patients with pyelonephritis not presenting with fever were not included in this study. Hence, additional studies are needed. Third, patients with catheter-related urinary tract infections, anatomical abnormalities of the urinary tract, and hemodialysis patients were excluded from this study. It is unclear whether urinary presepsin measurement would be useful in these patients. Finally, this study was conducted with a single-center design. Further investigations at other facilities are required.

In conclusion, urinary presepsin measurement is useful in differentiating pyelonephritis from other diseases. We have shown that urinary presepsin has high specificity, PPV, and LR+ in the diagnosis of pyelonephritis. Urinary presepsin provides immediate results and may contribute to appropriate antibiotic use.

AUC: Area under the curve; LR: Likelihood ratio; NPV: Negative predictive value; PPV: Positive predictive value; ROC: Receiver operating characteristics

Ethics approval and consent to participate

The present study was carried out in accordance with the principles of the Declaration

of Helsinki and approved by the Ethics Committee of the Jikei University School of Medicine, and written informed consent was obtained from the participants.

Consent for publication

We have obtained informed consent from all the participants to publish the information in an online open-access publication.

Availability of data and materials

The used and/or analyzed data during the current study is available from the corresponding author on reasonable request.

Competing interests

The authors have no conflicts of interest to declare.

Funding

This research was not supported by any funding.

Author Contributions

All authors conceived and designed the study and took responsibility for the accuracy of data analysis. RY and KN measured the samples. RY and YI analyzed and interpreted the data. RY wrote the first version of the manuscript. All authors critically revised the manuscript.

Acknowledgements

The authors would like to thank Professor Masato Matsushima, Jikei University School of Medicine, for his support in preparing the protocol.

James R Johnson, Thomas A Russo. Acute pyelonephritis in adults. N Engl J Med. 2018;378:48-59.
D C Angus, W T Linde-Zwirble, J Lidicker, G Clermont, J Carcillo, M R Pinsky. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303-10.
Mitchell M Levy, Antonio Artigas, Gary S Phillips, Andrew Rhodes, Richard Beale, Tiffany Osborn, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012;12:919-24.
Giorgina B Piccoli, V Consiglio, L Colla, P Mesiano, A Magnano, M Burdese, et al. Antibiotic treatment for acute 'uncomplicated' or 'primary' pyelonephritis: a systematic, 'semantic revision'. Int J Antimicrob Agents. 2006;28:S49-63.
Yasuyuki Arai, Kiyomi Mizugishi, Kazuhiko Nonomura, Katsuki Naitoh, Akifumi Takaori-Kondo, Kouhei Yamashita. Phagocytosis by human monocytes is required for the secretion of presepsin. J Infect Chemother. 2015;21:564-9.
Sukyo Lee, Juhyun Song, Dae Won Park, Hyeri Seok, Sejoong Ahn, Jooyeong Kim, et al. Diagnostic and prognostic value of presepsin and procalcitonin in non-infectious organ failure, sepsis, and septic shock: a prospective observational study according to the Sepsis-3 definitions. BMC Infect Dis. 2022;22:8.
Takashi Imagama, Kazushige Seki, Toshihiro Seki, Atsunori Tokushige, Yuta Matsuki, Kazuhiro Yamazaki, et al. Synovial fluid presepsin as a novel biomarker for the rapid differential diagnosis of native joint septic arthritis from crystal arthritis. Int J Infect Dis. 2021;102:472-7.
Guanghui Zheng, Chenxi Zhang, Guojun Zhang, Chunqing Shao. Evaluation of the diagnostic and prognostic value of CSF presepsin levels in patients with postneurosurgical ventriculitis/meningitis. Infect Drug Resist. 2021;14:2901-9.
Mohammad Yousef Memar, Hossein Bannazadeh Baghi. Presepsin: A promising biomarker for the detection of bacterial infections. Biomed Pharmacother. 2019;111:649-56.
Yann-Erick Claessens, Eloise Trabattoni, Sophie Grabar, Laurent Quinquis, Guillaume Der Sahakian, Marine Anselmo, et al. Plasmatic presepsin (sCD14-ST) concentrations in acute pyelonephritis in adult patients. Clin Chim Acta. 2017;464:182-8.
Yasunori Yaegashi, Kamon Shirakawa, Nobuhiro Sato, Yasushi Suzuki, Masahiro Kojika, Satoko Imai, et al. Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis. J Infect Chemother. 2005;11:234-8.
Stephen Bent, Brahmajee K Nallamothu, David L Simel, Stephan D Fihn, Sanjay Saint. Does this woman have an acute uncomplicated urinary tract infection? JAMA. 2002;287:2701-10.

No competing interests reported.

Download PDF

Journal Publication

published 31 May, 2023

Read the published version in BMC Infectious Diseases →

Editorial decision: Major revision
04 May, 2023
Reviews received at journal
04 May, 2023
Reviewers agreed at journal
10 Mar, 2023
Reviews received at journal
08 Feb, 2023
Reviewers agreed at journal
03 Feb, 2023
Reviewers agreed at journal
03 Feb, 2023
Reviewers invited by journal
03 Feb, 2023
Editor assigned by journal
03 Feb, 2023
Editor invited by journal
03 Feb, 2023
Submission checks completed at journal
03 Feb, 2023
First submitted to journal
23 Jan, 2023

You are reading this latest preprint version

Utility of urinary presepsin in the diagnosis of pyelonephritis: A cross-sectional study

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Methods

Study design and participants

Study measurements

Statistical analysis

Results

Baseline characteristics of participants

Comparison of urinary presepsin concentrations in acute pyelonephritis and non-pyelonephritis groups

The accuracy of urinary presepsin in the diagnosis of acute pyelonephritis

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1