Part 2:Association Between Multimorbidity And Kidney Function Among Patients With Non-Dialysis-Dependent CKD

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Results:

Other causes of kidney disease included diabetic nephropathy in 502 patients (11.2%)and hypertensive nephrosclerosis in 969 patients (21.6%), whereas the remaining 801 patients (17.9%) had other causes. In the earlier CKD stages(G1 and G2), 81.9% of patients had GCN as the cause of kidney disease. By contrast, the proportion of patients with diabetic nephropathy and hypertensive nephrosclerosis as the cause of kidney disease increased to 30.9% and 26.2% in stage G5, respectively. The mean BMI was 22.9 kg/m². The mean systolic and diastolic blood pressures of patients were 130 and 74 mmHg, respectively.

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The median eGFR was 40.1 mL/min/1.73 m². The median UPCR and median urinary albumin-to-Cr ratio were 0.40 g/GCR and 206.5 mg/GCR, respectively. The group with a lower eGFR had lower total cholesterol, LDL-C, and HDL-C levels but higher TG levels. There was a trend toward higher uric acid and CRP levels and lower albumin levels in the low eGFR group compared with the high eGFR group. The low eGFR group had lower levels of hemoglobin, serum iron, and calcium but higher levels of ferritin, phosphorus, intact PTH, and potassium. Use of antihypertensives, lipid-lowering drugs, insulin, urate-lowering drugs, antiplatelet/anticoagulants, erythropoiesis-stimulating agents, mineral bone disorders-related drugs, uremic toxins, and potassium adsorbents was higher in the low eGFR group compared with the high eGFR group (Supplementary Table 1).Fig.1 shows the distribution of enrolled patients stratified by eGFR and albuminuria1. Risk rankings for adverse outcomes based on eGFR and albuminuria levels stratified 8.6%, 15.6%,18.7%, and 57.0% of the total cohort as mild, moderate, severe, and very severe, respectively. As Fig。2 shows, the number of medications increased linearly with the progression of the CKD stage, and a significant dose-response relationship between polypharmacy and reduced eGFR was observed in the multivariable-adjusted model.

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Independent Associated Factors of Reduced Kidney Function

Table 2 lists the multivariable independent associated factors of an eGFR<60 mL/min/i.73 m². Logistic regression revealed that older age(OR for 10 year increment,1.78;95% CI,1.68-1.90), male sex (OR,1.25;95% CI,1.05-1.50), underlying kidney disease(OR for others,3.46;95% CI:2.74-4.38;OR for hypertensive nephrosclerosis,5.94;95% CI,4.22-8.37; and OR for diabetic nephropathy, 9.59;95%CI,5.39-17.1),history of CVD(OR,1.68;95% CI, 1.26-2.40),hypertension(OR, 2.68;95% CI,2.15-Hypertension was defined as a systolic blood pressure≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg and/or current use of antihypertensive agents.

Diabetes mellitus was identified in patients with a hemoglobin Alc value2 of 6.5%(National Glycohemoglobin Standardization Program), whose underlying kidney disease was diabetic nephropathy, and/or who were receiving treatment with insulin or oral antihyperglycemic drugs.

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Cardiovascular disease was defined as a composite of ischemic heart disease, congestive heart failure, ischemic stroke, hemorrhagic stroke, peripheral artery disease, thoracic aortic aneurysm, and abdominal aortic aneurysm. Variables were selected by a logistic regression model using a stepwise backward method with p<0.05 for remaining variables to determine the independent associated factors for estimated glomerular filtration rate less than 60 mL/min per 1.73 m². CI, 1.07-1.34), and higher UPCR (OR for 1 g/GCR 3.34), diabetes mellitus(OR, 0.71;95% CI, 0.56-0.90), dyslipidemia(OR,1.28; 95% CI,1.07-1.54), increment,1.47;95%CI, 1.34-1.62) were lower BMI（OR for 5 kg/m² decrement，1.20; 95%independently associated with a reduced eGFR.

Abbreviations: CKD, chronic kidney disease. Values are presented as mean (standard deviation) or percentage. Hypertension was defined as a systolic blood pressure≥ 140 mmHg or a diastolic blood pressure ≥ 90 mmHg and/or current use of antihypertensive agents. Diabetes mellitus was identified in patients with a hemoglobin Alc value ≥ 6.5%(National Glycohemoglobin Standardization Program), whose underlying kidney disease was diabetic nephropathy, and/or who were receiving treatment with insulin or oral antihyperglycemic drugs.

Dyslipidemia was defined as a triglyceride concentration ≥ 150 mg/dL,a low-density lipoprotein cholesterol concentration ≥ 140 mg/dL,a high-density lipoprotein cholesterol concentration<40 mg/dL,or use of lipid-lowering medication. Cardiovascular disease was defined as a composite of ischemic heart disease, congestive heart failure, ischemic stroke, hemorrhagic stroke, peripheral artery disease, thoracic aortic aneurysm, and abdominal aortic aneurysm.

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Comorbidities Associated with Reduced Kidney Function

As Table 3 shows, the prevalence of major comorbid conditions, including hypertension, diabetes mellitus, dyslipidemia, prior CVD, cancer, and bone fracture was 3,727(83.3%),1,285(28.7%),2,055 (45.9%),1,041(23.3%),567(12.7%),and 282 (6.3%), respectively. The proportion of patients with these comorbidities was significantly increased in the group with advanced CKD (Supplementary Table 2). Importantly, the cumulative number of comorbidities increased, and the Charlson Comorbidity Index increased in the population with a reduced eGFR(P for trend,<0.001).Table4shows the prevalence and association of comorbidities with an eGFR of <60 mL/min/1.73 m². Of all cardiovascular comorbidities， hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, and congestive heart failure were associated with elevated ORs with an eGFR of<60 mL/min/1.73 m². For non-cardiovascular comorbidities， cancer was a significant risk factor for decreased kidney function, whereas collagen disease and liver disease were associated with lowered ORs with an eGFR of<60 mL/min/1.73 m². Sensitivity analysis

revealed a clearer dose-response relationship between reduced GFR and comorbidity in the model using an eGFR of <45 mL/min/1.73 m²as the dependent variable (Supplementary Table 3). Supplementary Fig.1 shows the dose-response association between eGFR and the number of comorbidities. Furthermore, a significant association between eGFR and comorbidity categories was identified in the multivariable-adjusted linear regression model with eGFR as the dependent variable (Supplementary Table 4).

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Multimorbidity and Reduced Kidney Function

Table 5 demonstrates the association between multimorbidity and reduced eGFR. Compared with the reference group without any comorbidities, adjusted ORs increased linearly as the cumulative number of conditions increased (all 23 registered comorbidities: OR for 1-2 conditions,2.11;95%CI, 1.54-3.41;OR for 3-4 conditions,2.38;95% CI, 1.66-3.41;and OR for≥5 conditions,2.94;95% CI:1.74-4.97; and major comorbidities:OR for 1-2 conditions,2.22;95% CI,1.65-2.97;OR for 3-4 conditions,3.04;95% CI,2.12-4.37;and OR for≥5

Abbreviations: eGFR, estimated glomerular filtration rate; COPD, chronic obstructive pulmonary disease; CI, confidence interval. The denominator was 4,476 patients. Hypertension was defined as a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure > 90 mmHg and/or current treatment with antihypertensive agents.

Diabetes mellitus was identified in patients with a hemoglobin Alc value ≥ 6.5%(National Glycohemoglobin Standardization Program), whose underlying kidney disease was diabetic nephropathy, and/or who were receiving treatment with insulin or oral antihyperglycemic drugs.

Adjusted using the final selected model (age, sex, underlying kidney disease, hypertension, diabetes mellitus, dyslipidemia, history of cardiovascular disease, body mass index, and urinary protein excretion). Variables relevant to the categories were excluded from each model. an eGFR <50 mL/min/1.73 m2² was the cutoff value condition,4.37;95% CI:1.75-10.9).This upward trend was most pronounced with cardiovascular comorbidities(OR for 1-2 conditions,2.34;95% CI, 1.76-3.11;OR for 3-4 conditions,3.29;95% CI, 2.26-4.78;and OR for≥5conditions,7.12;95% CI, 2.05-24.7).There was no significant association between the cumulative number of non-cardiovascular comorbidities and reduced eGFR(P for trend,0.93). As Fig.2 shows, the number of medications increased linearly with the progression of the CKD stage, and a significant dose-response relationship between polypharmacy and reduced eGFR was observed in the multivariable-adjusted model (Table 6).

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