Pyuria, Urinary Tract Infection and Renal Outcome in Patients with Chronic
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www.nature.com/scientificreports OPEN Pyuria, urinary tract infection and renal outcome in patients with chronic kidney disease stage 3–5 I‑Ching Kuo1,2,6, Jia‑Jung Lee1,6, Daw‑Yang Hwang1,5, Lee‑Moay Lim1, Hugo You‑Hsien Lin1,2, Shang‑Jyh Hwang1,3,4, Hung‑Chun Chen1,3 & Chi‑Chih Hung1* Pyuria is common in chronic kidney disease (CKD), which could be due to either urinary tract infection (UTI) or renal parenchymal infammation. Only little is known regarding the association of pyuria or UTI with renal outcomes. We investigated 3226 patients with stage 3–5 CKD. Pyuria was defned as ≥ 50 WBC per high‑power feld (hpf) and was correlated to old age, female, diabetes, hypoalbuminemia, lower eGFR, and higher infammation status. In Cox regression, patients with more than one episode of pyuria in the frst year (11.8%) had increased risks for end‑stage renal disease (ESRD) [hazard ratio (95% CI): 1.90 (1.58–2.28); p < 0.001], rapid renal function progression [odds ratio (95% CI): 1.49 (1.13–1.95); p = 0.001], and all‑cause mortality [hazard ratio: 1.63 (1.29–2.05); p < 0.001], compared to those without pyuria. In a subgroup analysis, the risk of pyuria for ESRD was modifed by CKD stages. We investigated the efects of UTI (urinary symptoms and treated by antibiotics) and pyuria without UTI (urine WBC < 50 to ≥ 10/hpf without any episodes of ≥ 50 WBC/hpf or UTI), while both groups were associated with clinical outcomes. In conclusion, CKD stage 3–5 patients with frequent pyuria or UTI episodes have increased risks of renal outcomes. Chronic kidney disease (CKD) is a global health problem due to its increasing incidence and prevalence worldwide1. To the best of our knowledge, pyuria is highly prevalent in CKD, which does not always indicate the presence of urinary tract infection (UTI)2,3. While pyuria is broadly defned as the appearance of leukocytes in the urine, various possible causes, including acute febrile illness, structural abnormalities of the genitourinary tract, or interstitial nephritis can also lead to sterile pyuria4. Previous data from a small CKD patient sample by Kwon et al. showed that the degree of pyuria was associated with UTI in patients with CKD, with the majority of their urinary WBCs being neutrophils3. Moreover, Hwang et al. reported that recurrent and persistent pyuria may contribute to the decline of kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD)5. CKD could be a risk factor for UTI, which may be present with asymptomatic bacteriuria or symptomatic UTIs requiring treatment. In addition to reduced host immunity6, comorbidities especially diabetes, advanced age, and urinary tract obstruction are common risks for UTI and CKD progression accordingly 7. A short-term study of single episode UTIs8 and a long-term study of asymptomatic bacteriuria in diabetes revealed that there was no faster decline of renal function 9. In fact, on the contrary, in patients with polycystic kidney disease 5,10 and who had post-kidney transplantation 11, UTI could be associated with renal function progression. Several factors have been proposed, particularly virulence factors such as P fmbriae on uropathogenic E. coli, to induce chronic infammation12,13. More importantly, uremic condition in CKD alters both cellular and humoral immunity, which increases the susceptibility to a broad range of infections. However, whether pyuria or UTI has a negative impact on end-stage renal stage (ESRD) in CKD patients has never been investigated; we test this hypothesis in diferent defnitions from an observational cohort. 1Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou First Road, Kaohsiung 807, Taiwan. 2Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. 3Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 4Institute of Population Sciences, National Health Research Institutes, Miaoli, Taiwan. 5National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. 6These authors contributed equally: I-Ching Kuo and Jia-Jung Lee. *email: [email protected] Scientifc Reports | (2020) 10:19460 | https://doi.org/10.1038/s41598-020-76520-5 1 Vol.:(0123456789) www.nature.com/scientificreports/ All Male Female p-value CKD patients without DM No. of subjects 1778 1033 745 – Pyuria within the frst year 1 episode 79 (4.4%) 19 (1.8%) 60 (8.1%) < 0.001 > 1 episodes 128 (7.2%) 43 (4.2%) 85 (11.1%) < 0.001 CKD patients with DM No. of subjects 1448 827 621 – Pyuria within the frst year 1 episode 120 (8.3%) 35 (4.2%) 85 (13.7%) < 0.001 > 1 episodes 238 (16.4%) 66 (8.0%) 172 (27.7%) < 0.001 Table 1. Pyuria (Urine WBC ≥ 50/hpf) in CKD patients by sex and DM. CKD, Chronic kidney disease; DM, Diabetes mellitus. P < 0.05 indicates a signifcant diference between male and female. Results Pyuria (urine WBC ≥ 50/ hpf) in CKD patients. Out of the total of 3226 patients with stage 3–5 CKD who were not on dialysis, 1366 (42.3%) of them were female and 1448 (44.9%) had type 2 diabetes (Table 1). Pyuria (urine WBC ≥ 50/high power feld [hpf]) within frst year afer enrollment occurred in 8.8% of males and 29.4% of females, while 11.6% non-diabetic patients and 24.8% diabetic patients had pyuria. Female and diabetic patients had more episodes of pyuria. Characteristics and outcomes of patients by pyuria (urine WBC ≥ 50/ hpf). In this cohort, the mean age was 63.5 ± 13.6 years, and eGFR was 24.7 ± 15.1 mL/min/1.73 m2, with a urine protein-to-creatinine ratio (UPCR) of 1125 (411–2553) mg/g (Table 2). Hypertension was present in 67.1% of the patients, and 26.4% of the patients had cardiovascular (CV) disease. Te patients were divided into 3 groups on the basis of pyuria frequency within frst year afer enrollment: no pyuria episode (Group 0), 1 pyuria episode (Group 1) and > 1 pyuria episodes (Group 2) to observe the impact of frequent pyuria. Te progress from pyuria Group 0 to pyuria Group 2 was associated with a gradual increase in the percentage of comorbidities, including ischemic heart disease, congestive heart failure, diabetes mellitus (DM), cancer, hypertension, and CV disease and an increase in age, C-reactive protein (CRP), phosphorus, and UPCR (Table 2). Baseline parameters associated with pyuria (urine WBC ≥ 50/ hpf). In the multivariate logistic regression analysis, older age, females, DM, CV disease, higher CRP, and higher HbA1c had a higher odds ratio (OR) for pyuria (Group 1 and Group 2) (Table 3). In contrast, higher hemoglobin, albumin, cholesterol and eGFR had a lower OR for pyuria. Glomerulonephropathy and proteinuria were not associated with pyuria, whereas tubulointerstitial nephropathy was associated with pyuria. Association between pyuria (urine WBC ≥ 50/ hpf) and clinical outcomes. Afer a median follow- up of 1084 days, 819 (30.8%), 79 (39.7%), and 163 (44.5%) of the patients developed end-stage renal disease (ESRD) in Groups 0, 1, and 2, respectively (Table 2). In the fully adjusted Cox proportional hazards model, Group 2 was associated with an increased risk for ESRD with a hazard ratio (HR) of 1.90 (95% CI, 1.58–2.28, P < 0.001) when compared with Group 0 (Table 4), whereas Group 1 was not associated with an increased risk. Te median eGFR slope was –2.2 mL/min/1.73 m 2/year. Group 0, Group 1, and Group 2 had a rapid eGFR decline (as defned in the methods) for 699 (26.5%), 55 (27.6%), and 146 (40.0%) of the patients, respectively. In a fully adjusted multivariate logistic regression, Group 2 was signifcantly associated with an increased risk for rapid eGFR decline with an odds ratio of 1.49 (95% CI, 1.13–1.95, P = 0.001), whereas Group 1 was not associated with an increased risk (Table 4). Group 0, Group 1, and Group 2 had 374 (14.1%), 44 (22.1%), and 113 (30.9%) patients died, respectively (Table 2). In the fully adjusted Cox proportional hazards model, Group 2 was associated with an increased risk for all-cause mortality with a HR of 1.63 (95% CI, 1.29–2.05, P < 0.001) when compared with Group 0 (Table 4). Diferences between UTI and pyuria without UTI (urine WBC < 50 to ≥ 10/hpf). To clarify the efect of UTI, we divided the patients by episodes of UTI, which was less frequent than pyuria. > 1UTI epi- sode (Group 2, n = 128) was associated with an increased risk of ESRD with a HR of 1.90 (95% CI, 1.58–2.28, P < 0.001) (Table 5). Te associations of > 1UTI episode (Group 2) with rapid GFR decline and all-cause mortal- ity were also signifcant. To clarify the efect of pyuria without UTI, we selected 2661 patients without any UTI episodes and without any high grade urine WBC (≥ 50/hpf) and then divided them by episodes of pyuria (urine WBC < 50 to ≥ 10/hpf). > 2 episodes of pyuria without UTI (Group 2) were associated with an increased risk of ESRD with a HR of 3.53 (95% CI, 2.63–4.75, P < 0.001) (Table 5). > 2 episodes of pyuria without UTI (Group 2) were associated with rapid GFR decline, but not with all-cause mortality. Because the risk of pyuria without UTI for renal outcomes was numerically higher than that with UTI, we further compared the diferences between baseline parameters. eGFR and UPCR were associated with pyuria without UTI, but not with UTI in multivari- ate logistic regression (Supplement Table 3).