The Association of Perioperative Glycated Hemoglobin (Hemoglobin A1C) and the Risk of Sepsis after Ureteroscopy with Laser Lithotripsy

Abstract

Purpose:

Elevated glycated hemoglobin A1c (HbA1c) has not been specifically evaluated as a risk factor for urosepsis after kidney stone procedures. Moreover, there are no current guidelines for perioperative HbA1c optimization, nor recommendations for the optimal timing to treat non-urgent kidney stones in the setting of poor glycemic control. We evaluated the association between perioperative HbA1c levels and sepsis risk after ureteroscopy with lithotripsy.

Methods:

Patients undergoing ureteroscopy with lithotripsy from January 2020 to June 2023 at a tertiary center were retrospectively reviewed. Postoperative sepsis was defined as Systemic Inflammatory Response Syndrome scores ≥2 within 30 days after ureteroscopy. The risk of sepsis at various HbA1c thresholds was evaluated via multivariate logistic regression.

Results:

A total of 1454 patients underwent ureteroscopy with lithotripsy, and 319 patients had HbA1c collected within 90 days of their procedures. The mean preoperative Charlson Comorbidity Index (CCI) score was 3.22 (±2.77). An increased risk of sepsis was observed among patients with HbA1c levels between 8.0% and 9.9% (odds ratio [OR] 4.42, p = 0.025) and ≥10% (OR 8.17, p = 0.003). Positive preoperative urine culture despite treatment (OR 4.53, p < 0.001) and higher CCI (OR 1.17, p = 0.045) were also associated with increased odds of sepsis.

Conclusion:

The odds of sepsis after ureteroscopy with lithotripsy follow a dose–response relationship with elevated perioperative HbA1c. These data underscore the clinical utility of incorporating HbA1c into preprocedural optimization and may justify certain patients to delay elective ureteroscopy to improve glycemic control before endourologic intervention.

Introduction

Sepsis secondary to a urinary tract source is a known complication of urolithiasis procedures that can lead to considerable morbidity and mortality. Efforts to reduce the risk of sepsis after urolithiasis procedures include proper perioperative antibiotic treatment of urinary tract infection and urinary tract decompression in infected and obstructed states, as reflected in current American Urological Association (AUA) guidelines.^1,2 Additional maneuvers to decrease the risk of sepsis have also been studied, including the use of ureteral access sheaths and intraoperative intrarenal pressure monitoring devices. Previous studies have demonstrated that several medical conditions can increase the risk of urosepsis including diabetes mellitus, heart disease, and immunosuppression.^3–5 The incidence of postoperative sepsis varies from 0.2% to 17.8%.⁶ In a study surveying a commercial insurance database, postoperative sepsis after kidney stone procedures was found to increase costs by $31,843, suggesting a significant clinical and economic burden.^7,8

Hemoglobin A1c (HbA1c) is a serological biomarker that represents a patient’s glycemic levels for the past 3 months. It has emerged as a more accurate predictor of adverse postoperative outcomes than a diagnosis of diabetes alone.⁹ Although the link between elevated HbA1c and postoperative sepsis is well established, this relationship has not been specifically evaluated in the setting of kidney stone procedures. In addition, the current AUA guidelines for kidney stone management do not mention the use of perioperative HbA1c levels in assessing a patient’s risk for postoperative sepsis.^10,11

Developing criteria for preoperative HbA1c optimization is promising given that kidney stone procedures are often nonemergent and elective. Establishing the relationship between optimal HbA1c thresholds and sepsis after kidney stone procedures may therefore enable urologists to stratify patients and potentially postpone high-risk elective endourologic interventions. This study aimed to evaluate the association between perioperative HbA1c levels and postoperative sepsis after ureteroscopy with lithotripsy. We hypothesized that increasing perioperative HbA1c would be associated with a heightened risk of postoperative sepsis.

Patients and Methods

Patient selection

This is a retrospective observational study of adult patients (age 18 and older) who underwent ureteroscopy with laser lithotripsy (URS-LL) at our tertiary care medical center between January 2020 and June 2023. Patients who did not have at least one HbA1c laboratory value available in the electronic medical record (EMR) within 3 months before or after the procedure were excluded. The index date was defined as the date of the kidney stone procedure. Patients who underwent multiple stone procedures were treated as individual cases as the risk of sepsis was present with each case. This retrospective study received approval from the Columbia University Irving Medical Center institutional review board (protocol number AAAQ9654).

Data source

Information was collected retrospectively from the EMR system, which contained data from both inpatient and outpatient encounters relating to the procedure. Patients who underwent URS-LL were identified using Current Procedural Terminology® and International Classification of Diseases, Tenth Revision, Procedure Coding System codes (Supplementary Table S1).

Statistical analysis

Demographic and clinical characteristics as of the index date were reported, including age, sex, race, ethnicity, insurance status, and the Charlson Comorbidity Index (CCI) score. Perioperative HbA1c was defined as the value closest to the index procedure date. All categorical variables were reported using counts and percentages, whereas all continuous variables were reported using means and standard deviations.

Outcomes

The primary outcome, postoperative sepsis, was defined as Systemic Inflammatory Response Syndrome (SIRS) scores ≥2 within 30 days after ureteroscopy. The specific SIRS criteria used were those described in the American College of Chest Physicians/Society of Critical Care Medicine guidelines, including (1) body temperature over 38 or under 36°C, (2) heart rate greater than 90 beats/minute, (3) respiratory rate greater than 20 breaths/minute, or (4) leukocyte count greater than 12,000 or less than 4000/µL.¹² Our study did not use CO₂ partial pressure or the percentage of immature leukocyte bands to evaluate sepsis because these data were unavailable.

The risk of sepsis was evaluated via multivariate logistic regression. Outcomes were reported as odds ratios (OR) with associated 95% confidence intervals (CI). Results were considered statistically significant with two-sided p-values of <0.05.

To identify a potentially useful clinical threshold for HbA1c, we conducted a univariate receiver operating characteristic curve analysis of sepsis (binary outcome) vs perioperative HbA1c (continuous predictor). We reported the maximum Youden index, the difference between the true positive and false positive rates (sensitivity + specificity – 1), across all HbA1c levels in the data. All analyses were conducted using RStudio (R version 4.2.2).

Results

We identified 1454 URS-LL procedures. Of these, 319 cases from 272 patients had HbA1c laboratory values available within 90 days of their procedures (Fig. 1), comprising our final study population. The mean age was 60 years old and 153 (48%) were men. Most patients had Medicare insurance (39%) (Table 1). The highest reported racial and ethnic categories were White and Hispanic patients, 34% and 43%, respectively. Bilateral URS-LL procedures were also considered in this analysis (11%).

FIG. 1.

Sample selection.

Table 1.

Baseline Characteristics

Demographics	All patients (N = 319)	No sepsis (N = 268)	Sepsis (N = 51)	p-Value
Age (mean [SD])	60 (±15)	60 (±15)	60 (±16)	0.852
Sex (N [%])				0.769
Women	166 (52%)	138 (51%)	28 (55%)
Men	153 (48%)	130 (49%)	23 (45%)
Race (N [%])				0.052
White	110 (34%)	95 (35%)	15 (29%)
Black or African American	39 (12%)	31 (12%)	8 (16%)
Other	147 (47%)	127 (46%)	20 (39%)
Unknown/Not reported	23 (7.2%)	15 (5.6%)	8 (16%)
Ethnicity (N [%])				0.003**
Hispanic or Latino	138 (43%)	124 (46%)	14 (27%)
Non-Hispanic	132 (41%)	110 (41%)	22 (43%)
Unknown/Not reported	49 (15%)	34 (13%)	15 (29%)
Insurance status (N [%])				0.154
Private insurance	71 (22%)	65 (24%)	6 (12%)
Medicare	124 (39%)	101 (38%)	23 (45%)
Medicaid	97 (30%)	77 (29%)	20 (39%)
Self-Pay	1 (0.3%)	1 (0.4%)	0 (0%)
Unknown/Not reported	26 (8.2%)	24 (9.0%)	2 (3.9%)

**p < 0.01.

SD = standard deviation.

The number of cases with postoperative sepsis (SIRS ≥2) in our study cohort was 51 (16%) (Table 2). The baseline sepsis rate for URS-LL procedures during the study period, with or without HbA1c, was 3.8% (based on diagnosis codes in subsequent encounters) (Supplementary Table S2). The mean length of procedures was 69 minutes, and the mean total stone burden was 16 mm (the sum of the largest dimension of all stones on a CT scan). Ninety-two (29%) cases had positive preoperative urine cultures, which were all treated with courses of culture-specific antibiotics prior to the procedure. 148 (46%) of the cases had either a stent or percutaneous nephrostomy tube in place prior to the procedure. The mean preoperative CCI score was 3.22 (±2.77) and the mean HbA1c value was 6.37 (±1.42). Thirty-three percent of patients had HbA1c values <5.7%, which is the cutoff for normal blood sugar. Thirty-six percent had HbA1c values of 5.7% to 6.4%, which is considered the pre-diabetes range. Nineteen percent had HbA1c values between 6.5% and 7.9%, 7.2% had HbA1c values between 8.0% and 9.9%, and 4.7% had HbA1c values ≥10%.

Table 2.

Clinical Characteristics

	All patients (N = 319)	No sepsis (N = 268)	Sepsis (N = 51)	p-Value
Year (N [%])				0.695
2020	77 (24%)	62 (23%)	15 (29%)
2021	115 (36%)	96 (36%)	19 (37%)
2022	109 (34%)	94 (35%)	15 (29%)
2023	21 (6.0%)	18 (6.2%)	3 (5.4%)
CCI score (mean [SD])	3.22 (±2.77)	3.01 (±2.53)	4.33 (±3.58)	0.002**
Kidney stone location (N [%])				0.815
Kidney	116 (36%)	98 (37%)	18 (35%)
Ureters	96 (30%)	82 (31%)	14 (27%)
Both	107 (34%)	88 (33%)	19 (37%)
Bilateral URS-LL (N [%])	36 (11%)	30 (11%)	6 (12%)	0.906
Stone size (in mm) (mean [SD])	16 (±11)	15 (±10)	20 (±15)	0.002**
Preoperative stent or PCN placed (N [%])				0.002**
Stent	128 (40%)	104 (39%)	24 (47%)
PCN	20 (6.3%)	12 (4.5%)	8 (16%)
Reason placed				0.007**
Pain	19 (6.0%)	17 (6.3%)	2 (3.9%)
Septic stone	65 (20%)	45 (17%)	20 (39%)
Prior URS	46 (14%)	39 (15%)	7 (14%)
Acute kidney injury	12 (3.8%)	9 (3.4%)	3 (5.9%)
Unknown	6 (1.9%)	6 (2.2%)	0 (0%)
Access sheath used (N [%])	35 (11%)	26 (9.7%)	9 (18%)	0.097
Length of procedure (minutes)	69 (±45)	65 (±37)	93 (±70)	<0.001***
Positive preoperative urine culture (N [%])	92 (29%)	62 (23%)	30 (59%)	<0.001***
Readmission within 30 days (N [%])	16 (5.0%)	9 (3.4%)	7 (14%)	0.002**
Timing of sepsis (mean [SD]) (days)	—	—	0.80 (±2.98)	—
(N [%])
Early post-op (Day 0–1)	—	—	47 (92%)	—
Within first week (Day 2–7)	—	—	3 (5.9%)	—
Late post-op (Day 8–30)	—	—	1 (2.0%)	—
Immunosuppressed (N [%])	28 (8.8%)	22 (8.2%)	6 (12%)	0.412
Perioperative hemoglobin A1c values
(mean [SD])	6.37 (±1.42)	6.23 (±1.28)	7.09 (±1.82)	<0.001***
(N [%])				<0.001***
<5.7%	105 (33%)	93 (35%)	12 (24%)
5.7%–6.4%	114 (36%)	105 (39%)	9 (18%)
6.5%–7.9%	62 (19%)	44 (16%)	18 (35%)
8.0%–9.9%	23 (7.2%)	18 (6.7%)	5 (9.8%)
≥10%	15 (4.7%)	8 (3.0%)	7 (14%)
Days from HbA1c to procedure (mean [SD])	37 (±27)	37 (±27)	36 (±26)	0.819

**p < 0.01; ***p < 0.001.

CCI = Charlson Comorbidity Index; HbA1c = hemoglobin A1c; PCN = percutaneous nephrostomy; URS-LL = ureteroscopy with laser lithotripsy.

A ureteral access sheath was used in 35 cases. Among patients who developed sepsis, 18% used access sheaths, compared with 10% in those who did not develop sepsis. Sepsis episodes most commonly occurred during postoperative day 0 or 1 (92%), though three patients were readmitted within the first week postoperatively, and one patient returned with sepsis and abdominal pain 20 days later. All-cause 30-day readmission rates were 14% and 3.4% for patients with and without sepsis, respectively.

In multivariate logistic regression analysis, higher perioperative HbA1c levels were significantly associated with increased odds of postoperative sepsis (Table 3). The dose response to higher HbA1c levels is illustrated in Figure 2. There was no heightened risk of sepsis for patients with pre-diabetic range HbA1c levels, however, highly elevated HbA1c conferred sepsis risk: 8.0% to 9.9% (OR 4.42, p = 0.025) and ≥10% (OR 8.17, p = 0.003). A separate multivariate logistic regression with HbA1c as a continuous variable demonstrated a 1.50 times increase (1.21–1.85, p < 0.001) in odds of sepsis per percent increase in HbA1c.

Table 3.

Logistic Regression of Risk Factors Associated with Developing Sepsis After Ureteroscopy with Laser Lithotripsy

	Odds ratio	CI (95%)	p-Value
HbA1c
<5.7%	Reference
5.7%–6.4%	0.92	(0.32, 2.59)	0.868
6.5%–7.9%	2.54	(0.88, 7.31)	0.085
8.0%–9.9%	4.42	(1.20, 16.26)	0.025*
≥10%	8.17	(2.01, 33.25)	0.003**
Sex
Male	Reference
Female	1.15	(0.52, 2.54)	0.724
Age	0.97	(0.94, 1.00)	0.043*
Race
White	Reference
Black or African American	0.90	(0.29, 2.86)	0.864
Other	1.24	(0.38, 4.04)	0.726
Unknown	1.97	(0.46, 8.41)	0.362
Ethnicity
Non-Hispanic	Reference
Hispanic	0.33	(0.09, 1.15)	0.082
Unknown	1.54	(0.52, 4.56)	0.433
CCI	1.17	(1.00, 1.37)	0.045*
Stone location
Kidney	Reference
Ureter	1.79	(0.61, 5.24)	0.286
Both	2.44	(0.95, 6.24)	0.063
Stone size	1.01	(0.97, 1.05)	0.557
Stent placement
No stent or PCN	Reference
Stent	0.76	(0.31, 1.82)	0.533
PCN	2.15	(0.53, 8.74)	0.285
Length of procedure	1.01	(1.00, 1.02)	0.074
Positive pre-op urine culture	4.53	(1.86, 11.01)	<0.001***

*p < 0.05; **p < 0.01, ***p < 0.001.

CI = confidence interval.

FIG. 2.

Odds of sepsis after kidney stone intervention stratified by HbA1c level.

Positive preoperative urine culture, despite adequate preoperative treatment, (OR 4.53, p < 0.001) and higher CCI scores (OR 1.17, p = 0.045) were also associated with increased odds of sepsis. There was a decreased odds of sepsis for every year increase in age (OR 0.97, p = 0.043). There were no statistically significant variations in the odds of sepsis based on the placement of a ureteral stent or nephrostomy tube, stone size, stone location, or length of the procedure.

A receiver operative curve, based on a univariate model, was utilized to identify an HbA1c threshold that would optimally distinguish between patients who developed sepsis postoperatively and those who did not. We identified 6.5% as the optimal cutoff for predicting sepsis after ureteroscopy (Fig. 3), which maximized the Youden index, the difference between the true positive and false positive rates of the univariate model. The maximum Youden index was 0.33, and the area under the curve for this model was 0.66.

FIG. 3.

Perioperative hemoglobin A1c thresholds vs sensitivity and specificity. Area under receiver operating characteristic curve = 0.66

Discussion

In this retrospective, single-center study, we discovered increasing odds of sepsis after URS-LL with elevated perioperative HbA1c values, in a dose-response fashion. When compared to those with perioperative HbA1c values <5.7%, patients with HbA1c values between 8.0% and 9.9% and ≥10% had more than 4-fold and 8-fold increased odds of postoperative sepsis, respectively. This analysis accounted for several other known risk factors for sepsis. Our findings provide preliminary evidence of a strong relationship between elevated HbA1c values and postoperative sepsis after URS for the first time and suggest preoperative optimization of HbA1c values may mitigate postoperative sepsis risk, especially in elective procedures.

Although the link between elevated HbA1c and risk for sepsis after surgery is well known, it has not been evaluated in the setting of URS-LL specifically. Several risk factors for sepsis after ureteroscopy have been independently identified including positive urine culture, high irrigation pressures, longer surgical time, and history of diabetes.¹³ A unique opportunity for preoperative HbA1c optimization exists for patients with kidney stones because intervention is often non-emergent and/or elective; urologists may opt to delay procedures so that a patient may optimize their diabetes management through diet and medication. Furthermore, there are no current guidelines for ideal perioperative HbA1c values for stone procedures, nor are there recommendations for the optimal timing to treat non-urgent obstructing stones.

Diabetes has been closely linked with postoperative complications following several types of urologic surgeries, although our study is the first to report such a relationship in the setting of URS-LL. One study of 310 patients examining the role of postoperative blood glucose identified that higher preoperative blood glucose levels were significantly associated with longer length of stay after percutaneous nephrolithotomy (PCNL).¹⁴ Several studies have identified that diabetes is associated with SIRS following PCNL.^15,16 The role of HbA1c has been investigated extensively in the setting of penile implant operations with several studies reporting significantly increased postoperative infections in those with elevated perioperative HbA1c values.^17,18 These studies have guided urologists to delay penile implantation procedures until HbA1c values can be lowered to an acceptable amount. In the same vein, it is possible that sepsis after kidney stone procedures may be mitigated with reductions in HbA1c prior to intervention.

Glucose control plays an important role in the immune system and thus HbA1c has become an important marker for clinicians to capture a patient’s glucose control over 3 months. The majority of the knowledge regarding the impact of HbA1c on postoperative complications stems from research in non-urologic studies. A study of 622 patients undergoing non-cardiac surgery discovered that HbA1c levels >8% were associated with significantly longer length of stay.¹⁹ Higher HbA1c value was independently identified as a risk factor for complications after colorectal surgeries.²⁰ This information is valuable for surgeons as they can utilize HbA1c levels to better predict the risk of complications after surgeries.

Several clinical factors have been previously identified as risk factors for postoperative sepsis after kidney stone procedures. A recent meta-analysis by Bhojani et al. identified positive preoperative urine culture as a strong risk factor for sepsis after ureteroscopy with OR = 3.56 (p < 0.001) over six studies.⁶ In our study, we report a similar relationship with positive urine culture having 4.53 times increased odds of sepsis. The same meta-analysis reported a history of diabetes mellitus had increased odds of sepsis (OR = 2.04, p = 0.04, 6 studies); however, HbA1c was not studied as a specific risk factor.⁶ In our study, highly elevated HbA1c values carried the highest odds of sepsis compared to all other risk factors.

This study has several limitations. First, as with any retrospective cohort study, there may be unobserved variables that influence a patient’s likelihood of becoming septic after a procedure. However, we queried the medical records for factors relevant to postoperative sepsis. These data are from one tertiary medical center comprising four surgeons and are subject to selection bias, which limits the generalizability of these results to all kidney stone patients. In addition, requiring patients who had HbA1c values tested within 90 days of their procedures may have selected patients with higher rates of health care engagement, or alternatively, greater difficulty with blood sugar control. The patients that had HbA1c in our EMR system were also more likely involved in our system for their overall care, limiting the data on patients managed at our tertiary care center for just their endourologic procedure. Relatedly, our reference HbA1c range <5.7% may have excluded many non-diabetics who did not have bloodwork. Based on ICD diagnosis codes, 15% of patients had diabetes in the cohort excluded by HbA1c availability. However, if those in the reference group with HbA1c values being checked perioperatively were considered sicker and more at risk for sepsis than those without HbA1c values being checked, then this would theoretically lessen the magnitude of the findings in our multivariate analysis. To that end, our study population demonstrated a postoperative sepsis rate (16%) that is higher than expected and higher than the sepsis rate among all URS-LL patients (3.8%) during this study period, which is likely a result of this selection bias based on HbA1c availability.

Many known risk factors for postprocedural sepsis were not significant in our multivariate model, which may reflect our limited sample size and restrictive inclusion criteria. Owing to the lack of uncommon clinical events in our dataset, we were also unable to examine other events such as intensive care unit (ICU) admission, death, or readmission. Lastly, there are inherent limitations with our primary outcome variable (SIRS score ≥2) as a proxy for sepsis. The most common critique is a low specificity for sepsis because of the equal weight assigned to the temperature, heart rate, respiratory rate, and white blood cell count criteria.²¹ A recent study of two multicenter prospective trials found that quick Sequential Organ Failure Assessment was superior to SIRS in reflecting sepsis with greater specificity (90.8% vs 72.4%) after PCNL.²² However, Glasgow Coma Scale values were not reliably recorded for our patient cohort. Future studies may incorporate a prospective design, larger sample sizes from multiple institutions, and a more specific outcome variable to address these limitations.

Conclusion

This is the first study to report the association of HbA1c values perioperatively with sepsis after URS-LL. We found a strong dose-response relationship between the odds of postoperative sepsis and increasing HbA1c values. Consideration should be taken to postpone elective stone procedures in patients with higher HbA1c levels to potentially reduce the risk of postoperative sepsis. Multi-institutional studies and/or larger patient cohorts are needed to better understand the association between HbA1c values and postoperative sepsis. We also hope to be able to examine the impact on other clinical events like readmission rates or ICU admission with a larger sample size. Further prospective interventional investigation is needed to determine whether reducing HbA1c prior to endourologic stone procedures actually mitigates the risk of postoperative sepsis.

Abbreviations Used

AUA

American Urological Association

CCI

Charlson Comorbidity Index

CI

confidence interval

CT

computed tomography

EMR

electronic medical record

HbA1c

hemoglobin A1c

OR

odds ratio

PCN

percutaneous nephrostomy

PCNL

percutaneous nephrolithotomy

SIRS

Systemic Inflammatory Response Syndrome

URS-LL

ureteroscopy with laser lithotripsy

Authors’ Contributions

R.B.: Methodology, data curation, statistical analysis, and writing (original draft). J.L. and A.B.: Methodology, data validation, and writing (original draft). O.S.: Conceptualization and writing (reviewing and editing).

Author Disclosure Statement

There are no conflicts of interest relevant to this study. O.S. is a member of the advisory boards for Ambu, Boston Scientific, and Coloplast. He is also a lecturer for Coloplast. A.B. is a consultant for Johnson & Johnson.

Funding Information

R.B. was supported by a National Institutes of Health’s T35 training grant (5T35DK093430) from June to August 2023.