Traditional and Non-traditional Clinical and Biochemical Risk Factors for Altered Kidney Function in Type II Diabetes mellitus Patients

Abstract

Background:Exploring the risk factors associated with increased albumin excretion is necessary in patients with type 2 diabetes mellitus, due to the fact that such patients are exposed to an increased risk of progression to diabetic kidney disease and that non-traditional newly emerging factors could be corrected in order to reduce the progression rate.

Material and methods:218 patients with type 2 diabetes mellitus were investigated regarding their urinary albumin/creatinine ratio. Clinical and laboratory data was collected from them, with biochemical investigations including serum uric acid and serum 25-hydroxi-vitamin D (25-OH-vitamin D) measurements. The prevalence of traditional and non-traditional risk factors for increased albumin excretion rate (albumin/creatinine ratio>30 mg/g), hyperuricemia and 25-OH-vitamin D deficiency, was determined after dividing patients into two groups, one with microalbuminuria and the other one with micro- or macroalbuminuria.

Results:Of all patients, 104 (47.93%) had microalbuminuria, while 9.22% (20) presented macroalbuminuria. Poor glucose control (HbA1c .7%), female sex, hyperuricemia (uric acid .7 mg/dL), vitamin D deficiency (25-OH-vitamin D .50 nmol/L), hypertension (systolic hypertension or diastolic hypertension or hypertension treatment) and hypertriglyceridemia (triglycerides .150 mg/dL) had a statistically significant higher prevalence (p<0.05) in the 124 patients with microalbuminuria or macroalbuminuria compared to the 94 subjects wit normaoalbuminuria.

Conclusion:Glucose control, hypertension and dyslipidemia are relevant traditional risk factors for an altered kidney function defined as urinary albumin/creatinine ratio >30 mg/g. However, hyperuricemia and 25-OH-vitamin D deficiency are long time ignored factors that could play an important role in the progression towards diabetic kidney disease.

Keywords:albuminuria, diabetic kidney disease, glucose control, hyperuricemia, vitamin D deficiency.

INTRODUCTION

Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus (DM), epidemiological data showing that DKD is the most common cause for end stage kidney disease (ESRD) in developed countries (1). Hyperglycemia is the most studied risk factor for kidney damage in patients with diabetes, being considered as the key element for the development of glomerular lesions (1). Increased oxidative stress has been proposed as the essential mechanism for glomerular damage in DKD (2). Therefore, reduction of oxidative stress seemed the best option for the prevention of glomerular damage and data from animal model studies proved that antioxidants are effective in reducing the development of hyperglycemia-induced glomerular lesions (3). However, in meta-analysis, the benefit of antioxidants such as vitamin C, selenium, vitamin E, methionine and ubiquinone has not been demonstrated in humans (4). Moreover, data from studies that explored the role of glucose control on DKD development showed a 50% decline in DKD incidence among patients with an average HbA1c of 7% versus patients with an average HbA1c of 9%, but failed to prove that an intensive glucose control with a Hb1c <7% could determine an additional benefit in the reduction of DKD incidence. These findings suggest that, while hyperglycemia is important, there are other factors involved in the pathogenesis of DKD. Hypertension is obviously another independent risk factor for DKD progression and excess cardiovascular morbidity (5, 6). These factors are traditional risk factors for DKD and of course their implications have been thoroughly detailed in the literature. Hyperuricemia and vitamin D deficiency are among less explored or non-traditional risk factors for DKD.

Our study aimed to explore the relationship between certain classical risk factors (glycemic control, diabetes duration, hypertension, dyslipidemia) and less explored or even controversial (hyperuricemia, vitamin D deficiency) risk factors, on one hand, and albumin excretion, marker of DKD presence, on the other hand, in patients with type 2 diabetes mellitus (T2DM).

MATERIAL AND METHODS

Our study included 218 patients with T2DM who were under surveillance at the Clinical County Emergency Hospital of Oradea, Bihor county, Romania. The following inclusion criteria were used: age range between 18 and 75 years old, confirmed T2DM, signed informed consent for participation in the present study. Patients with end stage kidney disease defined as GFR<15 mL/min/1.73 m2 or undergoing dialysis, those suffering from hepatic cirrhosis, severe hypertension defined as SBP .180 mm Hg or diastolic blood pressure (DBP) .120 mm Hg, glomerulonephritis or tubulointerstitial nephritis, patients with HbA1c <12%, leukocyturia defined as >five leucocytes on urinary sediment examined in high power field, and those diagnosed with chronic urinary tract infections or recently diagnosed with acute urinary tract infection were all excluded.

Patients were selected by the following method in order to ensure the representativeness of our study results. Each patient who presented for one-day hospitalization in the Diabetes Clinic on a Friday between 1 August 2018 and 1 March 2019 was considered for being included in the study. A total of 320 patients were eligible for the study but after applying the inclusion and exclusion criteria only 218 of them remained in the study. The most frequent reason of exclusion was the presence of abnormal urine sediment examination with presence of leukocyturia as a possible indicator of urinary tract infection.

The research was conducted according to the principles of the Helsinki Declaration and with the approval of the Ethics Commission of the Clinical County Emergency Hospital of Oradea. Physical examination, recording of medical history, measurement of systolic blood pressure (SBP) and DBP, blood tests and urine tests were performed. The usual blood tests included haemoleucogram, fasting glycaemia, urea, creatinine, liver function tests, HbA1c, total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol. Glomerular filtration rate (GFR) was calculated using CKD-EPI equation. General urine examination and microscopic urine examination was performed. All above-mentioned examinations were done in the hospital laboratory. Special tests or those which were less frequently used in our hospital have been also performed, including determination of albumin/creatinine ratio in random spot urine, serum uric acid and serum 25-OH-vitamin D. Urinary albumin/creatinine ratio was measured using immune turbidimetry, 25-OH-Vitamin D determination was performed using electrochemiluminescence immunoassay and uric acid was measured using the enzymatic colorimetric method.

Presence of microalbuminuria or macroalbuminuria were considered as diagnostic criteria for altered kidney function. Microalbuminuria was defined as a urinary albumin/creatinine ratio of 30-300 mg/g and macroalbuminuria as a urinary/ creatinine ratio .300 mg/g. Vitamin D status was divided into two categories: sufficient (25-OH-Vitamin D >50 nmol/L) and deficient (25-OH-vitamin D.50 nmol/L). Hyperuricemia was defined as a serum uric acid .7 mg/dL. A level of HbA1c <7% showed a good glucose control. Hypercholesterolemia was defined as serum cholesterol .200 mg/dL, hypertriglyceridemia as serum triglycerides .150 mg/dL, raised LDL-cholesterol as LDL levels .100 mg/dL and low HDL-cholesterol as HDL levels .40 mg/dL for men and .50 mg/dL for women.

RESULTS

The clinical and biochemical characteristic of the 218 T2DM patients are described in Table 1. The mean duration of the disease was 6.42 years. Of all patients, 94 (42.85%) had normoalbuminuria, 104 (47.93%) microalbuminuria and 20 (9.22%) macro albuminuria.

Comparing the categories of patients with normoalbuminuria (n=94) and microalbuminuria (n=104) (Table 2) pointed to several factors that were more frequently seen to have a statistically significant association with the presence of microalbuminuria: female sex (50.96% males in the microalbuminuria group vs 67.74% males in the normoalbuminuria group, p=0.01), low-glucose control (mean HbA1c 8.35% vs 7.80%, p<0.01), hypertension presence (59.61% vs 45.16%, p<0.01), SBD values (mean SBP 135.25 mm Hg vs 128.55 mm Hg, p<0.01), DBP values (mean DBP 83 mm Hg vs 79.23 mm Hg, p <0.01) and vitamin D deficiency (mean values 40.54 nmol/L vs 45.40 nmol/L, p=0.04).

When patients were classified into two categories (Figure 1), a group with altered glomerular function (including all patients with either microalbuminuria and macro albuminuria) and another one with normal glomerular function (noromoalbuminuria), the following traditional risk factors (p<0.05) for altered glomerular function were found: poor glycemic control (p=0.04), fe-male sex (p=0.03), hyperuricemia (p=0.01), vitamin D deficiency (p<0.01), hypertension (systolic hypertension or diastolic hypertension or hypertension treatment) (p<0.01), hypertriglyceridemia (p=0.01).

DISCUSSION

In our study, the non-traditional risk factors for decreased renal function, defined as microalbuminuria or macroalbuminuria, were uric acid and 25-OH-Vitamin D. The association between hyperuricemia and albuminuria has been explored in the literature. High levels of serum uric acid are considered as predictors of renal dysfunction in patients with or without diabetes mellitus (7). The relationship between uric acid and chronic kidney disease is controversial. Initially, hyperuricemia was deemed only as a consequence of CKD as a result of decreased glomerular filtration. However, recent studies proved that hyperuricemia could induce a significant renal damage. Experimental studies on rats proved that induction of hyperuricemia determined a significant raise in blood pressure, a high level of oxidative stress, and in the end, occurrence of glomerular hypertension (8). In patients who either had higher levels of uric acid or needed allopurinol treatment, DKD progression was significantly faster (9). In our study, a high hyperuricemia prevalence (21.77%) was seen in patients with micro- or macroalbuminuria. The investigation of such associations and screening of hyperuricemia among patients with diabetes is very important, given that current ongoing trials are testing a hypothesis according to which uric acid reduction with allopurinol could delay DKD progression and decrease GFR loss (10).

Vitamin D plays an important role both in the pathogenesis of T2DM and CKD. In animal models, vitamin D deficiency was associated with a reduced secretion capacity of â cells (11). Therefore, one possible association of vitamin D deficiency and increased albuminuria is the poor glycemic control for which vitamin D deficiency could be a contributor. Vitamin D deficiency has been demonstrated to be a contributor to albuminuria in diabetes mellitus patients. Paricalcitol administration to correct vitamin D deficiency in patients with diabetic nephropathy has been demonstrated to reduce the level of albuminuria (11). Also, low levels of vitamin D are associated with increased mortality and cardiovascular events in patients with CKD (12). In our study, the prevalence of vitamin D deficiency has very high in patients with increased albumin excretion (74.19%). Another important aspect is the high prevalence of micro- and macroalbuminuria in our study; thus, 57.85% of all patients had an increased albumin excretion. The values are significantly higher than those reported by large-population studies, in which albuminuria was found in only 39% of patients – DEMAND study (13) – or 40% of patients (MAP study (14). A possible explanation could be that our study included patients who needed hospital care, albeit for only one day hospitalization, and who had a relatively poor glucose control with a mean HbA1c of 8.11%.

CONCLUSIONS

In our study, poor glycaemic control, hypertension diagnosis, female sex, older age and hypertriglyceridemia were traditional risk factors for increased urinary albumin excretion. A statistically significant higher prevalence of hyperuricemia and 25-OH-Vitamin D deficiency was found among diabetes patients with increased urinary albumin excretion. While it is generally agreed that control of modifiable traditional risk factors is mandatory for patients with diabetes, data from the literature revealed that hyperuricemia and vitamin D deficiency correction were also important, showing that screening for the presence of these two factors in patients with type 2 diabetes was mandatory.

Conflict of interests: none declared

Financial support: none declared.

TABLE 1.

Patient clinical characteristics

TABLE 2.

Clinical and biochemical differences according to creatine ratio

FIGURE 1.

Prevalence of cardiovascular risk factors among patients with and without increased albumin excretion