Blood pressure variability in diabetic patients with or without albuminuria


 Introduction: Various studies considered albuminuria as one of the first asymptomatic paraclinical manifestation of the micro-vascular damages in type 2 diabetes mellitus (DM). Hypertension (HTN) is common in type 2 DM, which has a correlation with the greater risks of cardiovascular morbidity and death. Objectives: The present research evaluated the relationship between blood pressure (BP) variability in diabetic patients who have or not albuminuria. Patients and Methods: In this analytical-descriptive research, we divided 90 type 2 diabetic patients into two groups of micro-albuminuric (urinary albumin excretion ≥30 mg/d and <300 mg/d) and the normo-albuminuric (urinary albumin excretion <30 mg/d) diabetic patients. We evaluated systolic and diastolic BP and 24-hour Holter monitor BP and heart rate, with respect to their albuminuric states and glomerular filtration rate (GFR) stages. Results: According to the findings, a considerably greater BMI (body mass index) and retinopathy was observed in microalbuminuric group in comparison with the normoalbuminuric group (P<0.05). Additionally, non-dipping pattern was greater in the microalbuminuric patients (P<0.05). In addition, patients were divided into dippers and non-dippers, the mean daytime and nighttime BP and heart rate were compared. Mean arterial BP (MAP) and nighttime BP and substantially in the subgroup of patients with GFR below 60 mL/min, systolic blood pressure (SBP) were considerably greater in the micro-albuminuric patients (P<0.05). Conclusion: In patients with diabetes, the existence of albuminuria is related to the increase in the incidence of non-dipping pattern compared with patients without albuminuria. According to high levels of SBP in albuminuric patients with low GFR, the pattern of HTN and then albuminuria and the subsequent reduction of renal function can be similar to that of type 1 DM patients. Moreover, 24-hour Holter monitoring and BP should be monitored closely in diabetic patients.


Introduction
Hypertension (HTN) has been introduced as one of the key risk factors, both for the coronary artery disease and microvascular complications of diabetes (1). One of the early asymptomatic manifestations of the micro-vascular damages in diabetes is albuminuria which can lead to malfunction of glomerular filtration barriers (2).
Between patients with diabetes, the presence of kidney damage markedly increases cardiovascular risk and health care costs (3). It has recently been indicated that changes in the blood pressure (BP) as well as the average BP possibly correlated with cardiovascular risks (4). Studies in type 1 diabetic patients have shown that high SBP may occur earlier than microalbuminuria and suggested that nocturnal HTN may have a role in predicting individuals at risk for renal dysfunction (5).

Objectives
In this study, we aimed to study the association between BP variability and albuminuria in diabetic patients.

Study design
We conducted a cross-sectional descriptive study on 90 type 2 diabetic patients referred to the endocrine clinic of Loghman-Hakim hospital. Forty-five patients in group A with microalbuminuria (urinary albumin excretion ≥30 mg/d and <300 mg/d) and 45 patients in group B without albuminuria (urinary albumin excretion <30 mg/d) were evaluated. The exclusion criteria were acute infections, inflammations, advanced heart, renal, and liver failure, and malignancy. We gathered data of the BMI (body mass index; kg/m 2 ), age, diabetes duration, history of the chronic diabetes complication (macrovascular, microvascular), and gender. Then, blood samples of all participants were collected and then we measured hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C), fasting blood sugar (FBS), triglyceride, creatinine, highdensity lipoprotein (HDL-C), and total cholesterol. In addition, we used turbidometric test on 24-hour urine collection to determine concentration of the urinary albumin. Moreover, we utilized Cockroft-Gault formula to calculate glomerular filtration rate (GFR mL/min).
Additionally, BP was assessed after ten minutes in the resting position. Accordingly, 24-hour Holter monitoring of BP and heart rate (HR) was also used in all patients to evaluate mean arterial BP (MAP), daytime BP, nighttime BP and nocturnal BP decrease (dipping). Patients were defined as dippers when nighttime systolic BP (SBP) and diastolic BP (DBP) fell more than 10% (normal pattern) and as nondippers when nighttime BP fell less than 10% (abnormal pattern). In both groups, daytime and nighttime and nocturnal BP patterns and the SBP and DBP were compared.

Statistical analysis
For qualitative and quantitative variables, we utilized independent t-test, chi-square and Fisher's exact test for comparing both groups. Also the, level of significance has been considered < 0.05. The data were analyzed by SPSS program (version 24.0) analyzed.

Results
Patients were classified into two groups; microalbuminuria (45 patients; group A) and normoalbuminuria (45 patients; group B). Table 1 displays patients' biochemical and demographic features.
Results did not show any significant differences between the groups in terms of their gender, age, diabetes duration, complications of diabetes, SBP, DBP, LDL-C, HbA1c, cholesterol, HDL-C, and triglyceride levels. BMI and retinopathy in microalbuminuric group were significantly greater than that of normoalbuminuric group (P < 0.05).
Groups A and B were compared separately in terms of dippers and non-dippers. In dippers, night time BP significantly was low in group B (P < 0.05). In nondippers, MAP and nighttime BP considerably were low (P < 0.05, Table 2).
The participants also divided into two sub-groups of GFR <60 mL/min or GFR ≥ 60 mL/min, and the mean daytime and nighttime BP as well as the heart rate were compared in these subgroups (Table 3). In both groups, daytime and nighttime BP was lower in group B, however it has been not significant statistically. In subgroup of the participants who had GFR below 60 mL/min, SBP has been greater in group A compared to group B (P < 0.05).

Discussion
The present study indicates that diabetic patients with albuminuria had a loss of nocturnal BP decline. In fact, albuminuria has been introduced as one of the earliest manifestations of the micro-vascular injuries in diabetes, which is characterized by the onset or progression of diabetic nephropathy (5).   This research revealed greater BMI in the albuminuric patients in comparison with the normo-albuminuric participants, reflecting contribution of overweight and obesity to development of the kidney injury (6,7). In albuminuric patients, retinopathy was found to be higher compared to the normoalbuminuric ones, which confirmed this finding with retinopathy and chronic kidney disease in type 2 diabetes, and is compatible with the study by Kumar et al (8).
We also observed greater nondipping pattern in albuminuric group in BP Holter monitoring. Although in this study, the mean of SBP or DBP and daytime BP showed no difference in both groups, nighttime BP considerably increased in albuminuric group in both dippers and nondippers.
In studies by Okada et al and Torffvit et al, in diabetic patients, the significant relationship of the night time SBP with albuminuria was observed (9,10).
Albuminuria itself is a marker of chronic kidney disease since numerous investigations reflected the increased prevalence of nondippers in chronic kidney disease (11,12). However, few studies have evaluated the association of albuminuria and nocturnal HTN. O'Flynn et al conducted a systematic review and did not find a conclusive association between the isolated nocturnal HTN and the targeted organ damages in diabetes mellitus (13). Gavira et al confirmed the association of elevated nocturnal BP with development of microalbuminuria (14).
Some reports showed significant changes in circadian heart rate in diabetic patients and patients with chronic kidney disease. Knudsen et al showed the impaired nocturnal BP decrease, smoking, and ambulatory BP are robust independent predictors of the development of nephropathy in the patients with type 2 diabetes (15). However, we observed no differences between daytime and nighttime heart rate in the two groups of albuminuria and no albuminuria.
Patients were classified according to GFR, as ≥60 and <60 mL/min since high SBP has been prominent in albuminuric patients with lower GFR.
These findings explained the early pathogenesis of HTN and renal impairment in diabetic patients. These findings are in line with other studies (9,16).
Increased extracellular volume and the predominance of sympathetic activity are thought to be the mechanisms of non-dipping pattern in diabetes (17), while non-dipping was closely associated with autonomic neuropathy and renal injury and proteinuria too (7,15,18).
We excluded higher stages of chronic kidney disease (GFR <30 mL/min) in this study. We think that if we had patients with higher stages of renal failure, we could find more significant differences in BP Holter monitoring in the two groups of chronic kidney disease patients.

Conclusion
Based on results, in diabetic patients who had similar demographic and laboratory characteristics, the existence of albuminuria had an association with the increase in the occurrence of non-dipping patterns compared to patients without albuminuria. Given the high levels of SBP in albuminuric patients with low-GFR, the pattern of HTN, albuminuria, and the subsequent reduction of renal function can be similar to that of patients with type 1 diabetes.

Limitations of the study
Notably, patients with DM with or without HTN, as well as the patients who did not have adequate BP control, did not receive a separate assessment. Because of the limited sample size, the distribution of patients with albuminuria to the two groups of micro-and macroalbuminuria and the comparison of these two groups was not possible. It is recommended that more studies be conducted and that a 24-hour BP Holter should be performed at least once to assess the nighttime BP and the non-dipper BP pattern in patients with diabetes.
ZD, MSM, NM, and MSH conducted the research. ZD and MSM assisted in the preparation of this paper. ZD and MSH procured the resulting paper. The resulting paper has been read by each author and then signed.

Conflicts of interest
It is declared that there are not any conflicts of interest.

Ethical issues
The Declaration of Helsinki and the pertinent instructions of the ethics committee of the Ministry of Health have been followed in each stage of the study. Moreover, each participant has been asked to sign the informed consent forms. In addition, the ethics committee of Shahid Beheshti University of Medical Sciences approved the study (#IR.SBMU.MSP.REC.1396.523). The present research has been extracted from the internal medicine residential thesis of Majid Salmanian Mashhadi. Moreover, ethical issues including plagiarism, double publication, and redundancy have been completely observed by the authors.

Funding/Support
The present research has been funded by Shahid Beheshti University of Medical Sciences. It has been extracted from the residency thesis of Majid Salmanian Mashhadi.