Microalbuminuria in non diabetic population as an marker of nephropathy

Introdução: Anos antes da evolução para diabetes mellitus tipo II, o paciente pode conviver com um período chamado pré-diabetes. A patogênese envolvida no pré-diabetes é a resistência à insulina. Objetivo: Discutir a frequência de microalbuminúria em população não diabética, porém com risco metabólico aumentado, e avaliar a existência de correlação da microalbuminúria com dados do metabolismo glicídico. Métodos: Foram incluídos no estudo 132 pacientes não diabéticos que apresentassem um ou mais fatores de risco para alteração do metabolismo glicídico: hipertensão arterial; obesidade; parentes em primeiro grau com diabetes; indivíduos das etnias hispano-americanas, asiáticas e afro-americanas; mães de recém-nascidos grandes para a idade gestacional (GIG) ou que apresentaram diabetes gestacional; dosagens séricas em jejum de HDL colesterol 250 mg/dL. Resultados: A frequência de microalbuminúria anormal para o método ocorreu em 16%, havendo presença de menores valores de HDL-colesterol e clearance de creatinina nessa mesma população. Considerando a amostra como um todo houve correlação positiva da microalbuminúria com a creatinina sérica e com o ácido úrico. Conclusão: Nosso estudo sugere que a microalbuminúria seja avaliada como marcador de nefropatia incipiente em população não diabética com risco metabólico aumentado. resumo


resumo
Palavras-chave: albuminúria; diabetes mellitus; estado pré-diabético; insuficiência renal crônica.][5][6] The pre-diabetes status may be associated with an increased risk of complications even before the progression to type 2 diabetes.In a study by Rosenbaum et al., 7 they found microalbuminuria in pre-diabetic patients, and that microalbuminuria was considered a marker of endothelial dysfunction and not only nephropathy.Another study showed that microalbuminuria was significantly higher in individuals with pre-diabetes compared to a group with normal glucose levels. 8The association of microalbuminuria with insulin resistance in nondiabetic patients has also been demonstrated. 9,10icroalbuminuria pathogenesis in cases of pre-diabetes is not yet established.Hyperglycemia is suspected of causing renal injury, or there is a direct effect of insulin resistance in various organs triggering endothelial injury. 11A microalbuminuria study in the general population was related to deaths from cardiovascular and non-cardiovascular causes, reinforcing again that microalbuminuria could be a marker of endothelial injury. 12n a study performed in our clinic, we found pre-diabetes in 68% of a population at increased metabolic risk. 13Thus, in addition to the concern for the prevention of T2DM, there is the need to assess the possible existence of endothelial injury in this population.
Thus, we carried out this study with the aim of showing the frequency of microalbuminuria in a nondiabetic population, of high metabolic risk, and to evaluate a possible correlation of microalbuminuria with glucose metabolism data.

Patient selection
A cross-sectional study was carried out from January to December 2010, involving patients consecutively seen at the outpatient clinic of the Clinical Service of the State Public Servant Hospital of São Paulo -Francisco Morato de Oliveira, who met the inclusion criteria and agreed to participate in study.

inclusion criteria
The study included 132 patients who had one or more risk factors for changes in glucose metabolism, namely: high blood pressure (hypertension); body mass index (BMI) ≥ 25 kg/m 2 ; first degree next-ofkin with diabetes; individuals of Hispanic-American ethnic groups, Asians and African-Americans; mothers of babies large for their gestational age (LGA) or with gestational DM; fasting HDL cholesterol serum levels < 35 mg/dL and triglycerides > 250 mg/dL.

exclusion criteria
The exclusion criteria were: previous diagnosis of DM or use of oral hypoglycemic agents or insulin.Hematuria or urinary tract infection at the time of inclusion.

Parameters analyzed
We evaluated the following anthropometric and clinical data: weight, height, waist circumference (WC), hip circumference (HC), blood pressure (BP) and body mass index (BMI) calculated by the ratio of weight in kg by height in squared meters (kg/m 2 ).WC was assessed with the patient standing, placing an inelastic tape at the midpoint between the lowest rib and the anterior superior iliac crest and at the end of expiration, and HC at the height of the trochanter major. 14High Blood Pressure was considered at pressure ≥ 140/90 mmHg on two different occasions or use of antihypertensive medications, regardless of blood pressure levels. 15rom laboratory parameters, patients were subjected to the oral glucose tolerance testing (GTT) 2 hours after ingestion of 75 g glucose, and serum levels of glucose and insulin levels after 8 h of fasting, to be used for calculating the HOMA-IR (fasting blood glucose (mmol/L) x fasting insulin (one/L)/22.5;reference values ≤ 3.4) index. 4The serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and creatinine were evaluated after 12 hours of fasting by standard methods, and to calculate the creatinine clearance we used the simplified MDRD formula. 16Microalbuminuria analysis was carried out in a 24-hour urine sample by the chemiluminescence method (normal value ≤ 20 µg/minute).

diagnostic criteria for Pre-diabetes
We considered a single fasting plasma glucose between 100 to 125 mg/dL or GTT ≥ 140 and ≤ 199 mg/dL values as criteria for the diagnosis of pre-diabetes. 17

StatiStical analySiS
The numerical variables data was expressed as mean ± standard deviation or median with quartiles variation for samples without normal distribution, and percentage for categorical variables.The differences of numerical variables between the two groups were evaluated using the Student t-test or Mann-Whitney test when appropriate.For analysis of categorical variables, we used the chi-square test.Correlations were obtained by Pearson's or Spearman's correlation analysis where appropriate.The values were considered significant when p < 0.05.
The study was approved by the Research Ethics Committee of the same hospital under # 0112/11 and the research subjects signed the informed consent form.
We calculated the HOMA-IR index of 76 patients with a median of 2.1 (1.0-3.8).Comparing this index in patients with normal microalbuminuria (n = 65 who underwent the index) with patients with abnormal microalbuminuria (n = 11 who underwent the index), no statistical difference was found (2.0 (0.9 to 4.5) vs 2.7 (2.1 to 3.2), respectively (Table 1).
Separating patients based on glucose metabolism, we found 58 (44%) patients with normal fasting blood glucose and GTT levels and 74 (56%) with prediabetes.The microalbuminuria comparison between these patients showed higher microalbuminuria values in the pre-diabetic group compared to the euglycemic patients, 7.5 (4.6 to 15.6) vs. 5.6 (3.4 to 9.2) p = 0.03, respectively.
There was no statistically significant correlation between microalbuminuria with glucose or GTT or HOMA-IR or between these anthropometric data; as there was also no correlation with cholesterol and triglycerides data; however, there was a positive correlation between microalbuminuria and serum creatinine (r = 0.6, p < 0.0001), Figure 1; and positive correlation with serum uric acid levels (r = 0.3, p < 0.001), Figure 2.

dIscussIon
Microalbuminuria can be considered an independent cardiovascular risk factor from conventional atherogenic factors such as blood pressure, glucose metabolism, dyslipidemia and smoking, increasing by 2.3 times the risk of cardiovascular events. 18Its definition of normality is based on patients with DM with microalbuminuria levels able to predict their progression to diabetic nephropathy.In the said healthy population, 3 to 15% have microalbuminuria ≥ 15 µg/min, leaving questions about the pathological values of microalbuminuria for the non-diabetic population. 18,19n our study with diabetes-free patients, but with increased metabolic risk, it was shown that abnormal microalbuminuria occurred in 16% of cases.These patients had higher serum creatinine levels and lower HDL-cholesterol levels.In addition, there was a positive correlation between microalbuminuria and serum creatinine and with uric acid levels.
Our findings of low HDL-cholesterol in patients with abnormal microalbuminuria and who, at the same time, had higher serum creatinine, could be related to the pathogenesis of an incipient nephropathy.][24][25][26][27] Histopathology, epidemiological and experimental evidence data suggest that dyslipidemia may start glomerular injury and contribute to the renal disease progression. 28Several studies have shown the relationship between plasma lipoproteins and renal dysfunction in type 2 diabetic patients with microalbuminuria, in which there was a positive association between microalbuminuria and plasma concentrations of lipoproteins containing apolipoprotein E. 29 Another analysis performed on a subset of the ARIC (Atherosclerosis Risk in Communities) study, in order to establish the association between plasma lipids and loss of renal function, concluded that triglycerides and HDLcholesterol levels, but not LDL-cholesterol, were predictive of increased risk of kidney dysfunction. 30he mechanisms that involve dyslipidemia in the  glomerular disease progression would be similar to those involved in atherosclerosis.
In the last decade, uric acid has been reintroduced as a potential mediator of endothelial dysfunction and kidney disease.Serum uric acid levels are correlated with adverse cardiovascular outcomes in the general population. 31Animal studies blame uric acid as a cause of dysfunction and endothelial inflammation, and as a player in the progression of kidney disease. 32A prospective study involving 1.743 Korean men over five years showed through multivariate analysis that high serum uric acid would be an independent risk factor for the development of microalbuminuria. 33here is no pathophysiological explanation for the correlation of microalbuminuria and serum uric acid levels for now, unless the very loss of creatinine clearance that leads to lower renal clearance of this substance.
Our study showed no correlation of microalbuminuria with fasting glucose, GTT or HOMA-IR; however, pre-diabetic patients had higher microalbuminuria values when compared to their euglycemic counterparts.Data on insulin resistance and microalbuminuria is still scarce and unreliable.In a subgroup of nondiabetic patients with hypertriglyceridemia we found an excellent correlation between HOMA-IR and microalbuminúria. 34Our study may have failed to show HOMA-IR relations because of the small number of patients studied.
In conclusion, this study of non-diabetic patients showed that those with normal microalbuminuria had higher serum levels of HDL-cholesterol, lower serum creatinine levels and higher creatinine clearance, compared to those with abnormal microalbuminuria.Patients with pre-diabetes had higher microalbuminuria values than euglycemic patients.Microalbuminuria is still the best marker of diabetic nephropathy, and can be associated with the development of cardiovascular events; however, these are controversial for a non-diabetic population.We can also discuss normal albuminuria values for different populations.From this study, we suggest that microalbuminuria in pre-diabetic patients or patients with metabolic risk be assessed as an incipient nephropathy marker.However, this information should be analyzed taking into consideration that our study had a limited number of patients.

Figure 1 .
Figure 1.Correlation between microalbuminuria and serum creatinine

Figure 2 .
Figure 2. Correlation of microalbuminuria with serum uric acid

tAble 1
data comParison between Patients with normal and abnormal microalbuminuria