Relationship between prediabetic conditions and microalbuminuria

Abstract

AimMicroalbuminuria is an expected predictor of renal and cardiovascular diseases and even mortality. In this study, it was aimed to elucidate the effect of microalbuminuria with albumin creatinine ratio in pre-diabetic patients and to follow patients for a period of 2 years.MethodsIn this prospective study, we have enrolled 90 patients, including n = 30 impaired glucose tolerance (IGT), n = 30 impaired fasting glucose (IFG), and n = 30 in the control group. The diagnosis of IGT has been established via 75 gr glucose loading. The enrolled patients have been followed up every 6 months for a period of 2 years prospectively. The renal function tests, insulin levels, body mass indexes, uric acid levels, CRP levels, and urinary ACR levels were recorded and monitored every 6 months, and annual data were noted. Individuals who developed diabetes during follow-up were recorded and their treatments were initiated.ResultsAfter a two-year follow-up of the patients, 46.7% (n = 14) of patients with impaired glucose tolerance (IGT) had impaired glucose tolerance again, while 13.3% (4 individuals) had impaired fasting glucose and 23.3% (n = 7) had normal glucose tolerance and 16.7% (n = 5) had diabetes. Similarly, impaired fasting glucose was observed in 66.7% (n = 20) of patients with impaired fasting glucose (IFG) at the beginning, while impaired glucose tolerance was observed in 6.7% (n = 2) and 23.3% (n = 7) had normal glucose tolerance and 3.3% (n = 1) had diabetes.ConclusionRegarding the outcomes of this study, it can be concluded that the prevalence of microalbuminuria has been observed to be higher in pre-diabetic situations such as IFG and IGT. Although both IFG and IGT have the progression potential towards diabetes, IGT should be considered a more serious condition.

Keywords

Introduction

Diabetes mellitus is an emerging health issue with increasing prevalence all over the world, especially due to the increase in type 2 diabetes (type 2 DM). Diabetic nephropathy is one of the major complications of diabetes that outrageously increases cost of care. As the progression of diabetes continues, diabetic renal disease will account for >50% of patients in dialysis units ¹ Additionally, the prevalence of undiagnosed diabetes or prediabetes is considerably high in chronic renal diseases. Cross-sectional studies show that prediabetes is associated with chronic renal failure (CRF), but it is not known whether it will predict CRF in people who do not progress to diabetes. Prospective studies have not demonstrated that prediabetes is an independent risk factor for albuminuria or the frequency of CRF. It is thought that prediabetes may be a causal factor for the development of CRF.^2-3 The American Diabetes Association (ADA) recommends 24hour urine microalbumin testing as the gold standard for nephropathy screening in diabetic patients.⁴ However, difficulties in collecting urine for 24 hours showed that spot urine albumin to creatinine ratio (ACR) measured in diabetic patients can be utilized in the detection of nephropathy in diabetic patients.⁵ However, the validity of ACR in spot urine in prediabetic patients has not yet been clearly demonstrated. The prevalence of microalbuminuria and macroalbuminuria for both types of diabetes is 30-35%.⁶ Albuminuria (albumin to creatinine ratio) or urinary albumin excretion (UAE) should be analyzed 5 years after the diagnosis of type 1 diabetes or at puberty and should be checked at the time of diagnosis and annually thereafter in type 2 diabetes mellitus. The first-morning (or spot) urine is preferred in the analysis of albumin creatinine ratio. It has been stated that rather than progressing to microalbuminuria or macroalbuminuria, the change in UAE must be taken into account.⁷ Normoalbuminuria is defined as <30mg/g ACR in the firstmorning (or spot) urine and <30 mg/day UAE, <20 µg/minutes UAE rate in a 24-hour period. Microalbuminuria is defined as 30 – 300 mg/g ACR in the first-morning (or spot) urine and 30 – 300 mg/day UAE, 20 – 200 µg/minutes UAE rate in a 24-hour period. Macroalbuminuria or clinical albuminuria is defined as >300 mg/g ACR in the first-morning (or spot) urine and >300 mg/day UAE, >200 µg/minutes UAE rate in a 24-hour period. The clinician should bear in mind that heavy exercise, infection, fever, congestive heart failure, hypertension, and remarkable hyperglycemia might elevate UAE. Nephropathy screening tests should not be performed until these problems are solved or controlled. In order to establish a diagnosis of MAU 2 of 3 laboratory results should indicate higher values.⁸ Melsom et al. (2016) reported 1261 nondiabetic patients followed for 5.6 years.⁹ In their study, prediabetes was also observed in the early stages of diabetes as well as glomerular hyperfiltration and albuminuria have been shown to be associated with the development of diabetes.⁹ The measurement of microalbuminuria to investigate early-stage nephropathy in adults eGFR needs to be calculated. In addition, eGFR can be calculated from the MDRD, CKD-EPI, or CockcroftGault formulas by measuring the serum creatinine level.^9-10 To monitor the progression of diabetic nephropathy in patients who develop microalbuminuria, the urine albumin/creatinine ratio should be measured more frequently. Nephropathy is one of the most important causes of morbidity and mortality in adult diabetic patients. Patients with persistent microalbuminuria have a high risk of retinopathy, therefore fundus examination should be performed more closely.¹¹ The inhibition of the renin angiotensin system plays a major role in the prevention of glomerular hypertension and hyperfiltration thus reducing albuminuria and kidney damage. These renal protective effects are mainly due to the vasodilator effect on efferent glomerular arterioles and as a result attributed to a decrease in glomerular pressure. In patients with microalbuminuria, it is appropriate to use an angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to help prevent progression to macroalbuminuria.¹² Glycemic and blood pressure control, treatment of dyslipidemia, and smoking cessation are essential to prevent the progression of nephropathy. In addition, weight loss may play an important role in preventing DRD and slowing its progression. Renal replacement therapy should be applied when end-stage renal failure develops.¹³ In this study, it was aimed to elucidate the effect of microalbuminuria with albumin creatinine ratio in pre-diabetic patients and to follow the patients for a period of 2 years. In this follow-up period, patients with microalbuminuria will be compared with pre-diabetic patients without microalbuminuria and it will be investigated whether microalbuminuria is a risk factor in pre-diabetic patients.

Materials and Methods

In this prospective study, we have enrolled 90 patients, including n = 30 patients with impaired glucose tolerance (IGT), n = 30 patients with impaired fasting glucose (IFG), and n = 30 in the control group. The diagnosis of IGT has been established via 75 gr glucose loading in individuals who have been admitted to the outpatient clinic of our institution. The study has been approved by the Ethics Committee and was conducted according to the Guidelines of the Declaration of Helsinki. Informed consent has been obtained from all participants.
The enrolled patients have been followed up every 6 months for a period of 2 years prospectively. The renal function tests, insulin levels, body mass indexes, uric acid levels, CRP levels, and urinary ACR levels were recorded and monitored every 6 months, and annual data were noted. Individuals who developed diabetes during follow-up were recorded and their treatments were initiated.Inclusion CriteriaThe inclusion criteria were as follows: results of glucose tolerance test (GTT, 75 g), and IFG≥ 100mg/dL. IGT was defined as between 140-199 mg/dL of serum glucose after two-hour oral 75 g glucose consumption.Exclusion CriteriaThe exclusion criteria were hypertension, heart failure, patients with overt diabetes that would cause microalbuminuria, renal failure, pre-existing proteinuria, recent urinary tract infection. Patients who had been using corticosteroids, spironolactone, ACE inhibitors, and ARBs were excluded from the study.Ethical ApprovalThis study was approved by the Ethics Committee of Izmir Katip Celebi University (Date: 24.03.2021, Decision No: 0121)Statistical AnalysisPatient data collected within the scope of the study were analyzed with the IBM Statistical Package for the Social Sciences (SPSS) for Windows 23.0 (IBM Corp., Armonk, NY) package program. Frequency and percentage were given for categorical data, and median, minimum, and maximum descriptive values for continuous data. For comparisons between groups, the Mann Whitney U-Test was used for two groups, the Kruskal Wallis H-Test for more than two groups, and the Pearson Chi-square Test was used to compare categorical variables. The results were considered statistically significant when the p-value was less than 0.05.

Results

Within the scope of the study, the evaluation was made on 90 patients, including n = 30 impaired glucose tolerance (IGT), n = 30 impaired fasting glucose (IFG), and n = 30 in the control group. According to the initial evaluations, there was no statistically significant difference between the three groups in terms of gender (p>0.05). Age, body mass index (BMI), initial laboratory parameters of FBG, PPBG, HBA1C, insulin, BUN, uric acid, urine albumin, urinary creatinine, ACR, and CRP values were found statistically significant between the groups (p<0.05) (Table 1). When the age distribution of the groups, BMI, FBG, HBA1C, insulin, BUN, uric acid, and CRP values were examined, it was seen that the values were higher in the IGT and IFG groups compared to the control group.
The demographic, baseline, and second-year laboratory parameters distribution of 30 patients with impaired glucose tolerance (IGT) and 30 patients with impaired fasting glucose (IFG) included in the study are shown in Table 2. When the table was examined, it was seen that there was a statistically significant difference between the two groups in terms of demographic data, age, and BMI (p<0.05). There was a significant difference between the two groups in PPBG, HBA1C, insulin, urine albumin and ACR parameters (p<0.05).
It was noteworthy that the initial laboratory results of patients with impaired glucose tolerance were higher than those of individuals with impaired fasting glucose. In the second-year laboratory data, significant differences were observed in other parameters other than urine albumin, which were significant in the initial laboratory data such as PPBG, HBA1C, insulin, urine albumin, and ACR (p<0.05). It was observed that the laboratory results of patients with impaired glucose tolerance were higher than the laboratory results of individuals with impaired fasting glucose. These parameters showed significant differences in laboratory parameters in the second year.
After a two-year follow-up of the patients, 46.7% (n = 14) of patients with impaired glucose tolerance (IGT) had impaired glucose tolerance again, while 13.3% (4 individuals) had impaired fasting glucose and 23.3% (n = 7) had normal glucose tolerance and 16.7% (n = 5) had diabetes. Similarly, impaired fasting glucose was observed in 66.7% (n = 20) of patients with impaired fasting glucose (IFG) at the beginning, while impaired glucose tolerance was observed in 6.7% (n = 2) and 23.3% (n = 7) had normal glucose tolerance and 3.3% (n = 1) had diabetes (Figure 1).

Discussion

The prevalence of impaired glucose tolerance worldwide has been stated as 6.7% in the International Diabetes Federation (IDF) atlas (2015). It is estimated that 318 million people are presumed to be pre-diabetic and this number is predicted to reach 481 million people in 2040. The frequency of prediabetes increases with age. The main differences between IFG and IGT can be elaborated as IGT is associated with peripheral insulin resistance (skeletal muscle), while IFG is associated with increased gluconeogenesis. In combined situations, hepatic and extrahepatic insulin resistance and increased gluconeogenesis persist. Isolated first phase insulin secretion defect (early phase) is observed in IFG, while both the first (late phase) and the second phase release defect is associated with IGT.¹⁴ IGT is more closely related to future diabetes and the coexistence of IFG and IGT doubles the risk. IGT has been correlated with increased cardiovascular risks and microvascular complications such as retinopathy and neuropathy.¹⁵
The rate of progression to diabetes from IFG and IGT within 3-5 years is 25%.¹⁶ On the other hand, glucose tolerance remains the same in 50% of the individuals, while 25% returns to normal. Those with additional diabetes clinical risk factors (obesity, family history) have a higher risk of developing diabetes. Additionally, the annual risk of conversion of impaired glucose tolerance to diabetes is 3-11%, while the lifetime risk of type 2 diabetes varies up to 50%.¹⁷ The conversion of pre-diabetes to diabetes in different genetic characteristics is reported as 114.4 versus 2.3/1000 people.¹⁸ In our study half of the patients (46.7%) with IGT had no change in their status in the second year, while 16.7 of them have progressed to diabetes. Additionally, 66.7% of patients with impaired fasting glucose (IFG) at the beginning remained the same within 2 years, while impaired glucose tolerance was observed in 6.7%, 23.3% had normal glucose tolerance and only 3.3% had diabetes. Prediabetes is a major risk factor for diabetic chronic renal failure (CRF). The vast majority of newly diagnosed diabetic patients will develop CRF despite optimal treatment. Prediabetes is about twice as common as diabetes, affects 2035% of adults, and progresses to diabetes after 10 years in approximately 45-50% of individuals. Cross-sectional studies show that prediabetes is associated with CRF, but it is not known whether it will predict CRF in people who do not progress to diabetes.
Previous literature has reported that approximately 1/3 of newly diagnosed diabetics already have kidney damage, indicating a very early onset of renal failure. In the meta-analysis by Echouffo-Tcheugui et al. (2016), 9 cohort studies evaluating a total of 185.452 patients, the relative risk for the development of CRF in prediabetics was found to be 1.11 (CI 951.02 -1.21).¹⁹
In this current study, we have investigated the effect of microalbumin¬uria with albumin to creatinine ratio in prediabetic patients and followed up the patients for a period of 2 years with respect to control group. In this follow-up period, patients with microalbuminuria were compared with pre-diabetic patients without microalbuminuria, and whether microalbuminuria is a risk factor in pre-diabetic patients was investigated.
Similar studies have been published previously elaborating microalbu¬minuria in prediabetic subjects. Franciosi et al. found that microalbuminuria was present in 6.9%, 5.6%, and 4.3% in IFG, IGT, and control groups, re¬spectively.²⁰ Tapp et al. have reported that the prevalence of microalbuminuria was 8.3% in IFG, 9.9% in IGT, and 4.3% in the control group.²¹ It should be kept in mind that different values could be attributed to geographical demographics and laboratory methods. However, it is evident that urine albumin was significantly higher in patients with IFG and IGT.
The association between IFG and microal¬buminuria has been introduced by Meigs in Framingham Offspring Study (2002) two decades ago.²² Bahar et al. (2013) published an important article emphasizing that the prevalence of microal¬buminuria in the IGT group was higher than in the IFG group, and IGT was identified as the most important risk factor for microalbuminuria.²³ Our results were in line with these studies and we have found that the laboratory parameters of patients with impaired glucose tolerance were higher than those of individuals with impaired fasting glucose. These differences such as PPBG, HBA1C, insulin, urine albumin, and ACR were significantly persistent in the second year. It was observed that the laboratory results of patients with impaired glucose tolerance were higher than the laboratory results of individuals with impaired fasting glucose. These parameters showed significant differences in laboratory parameters in the second year.
The main limitation of this study could be attributed to its relatively small sample size. Additionally, the ideal follow-up period should have been at least 5 years in order to accurately observe the development of diabetes and microalbuminuria in renal functions. All the individuals have been performed OGT at the diagnosis stage however, this test had not been reperformed annually.
Since there are few studies emphasizing renal dysfunction that can develop in prediabetic patients, this may be an advantage of this research. Increasing the widespread use of microalbuminuria for the predictive purpose was the main focus of this study leveraging a cost-effective test that can be performed in each hospital in the detection of renal injury that may develop in prediabetic patients. In addition, as in other studies requiring follow-up, the fact that during the two years of follow-up period enabled patients to display a more conscious and careful attitude may be another strength of this study.

Conclusion

Regarding the outcomes of this study, one can conclude that the prevalence of microalbuminuria has been observed higher in pre-diabetic situations such as IFG and IGT. Although both IFG and IGT have the progression potential towards diabetes, IGT is considered a more serious condition.

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