| Abstract|| |
There is a high prevalence of diabetes mellitus in the population of Saudi Arabia with the majority having non-insulin dependent diabetes mellitus (NIDDM). Random mid-day urine samples were obtained from 100 male [37 insulin dependants DM (IDDM) and 63 NIDDM] and 100 female (51 IDDM and 49 NIDDM) diabetic patients. Eighty-four patients were hypertensive (46 males and 28 females). One hundred and fiftyfive subjects, not under medication and without clinical evidence of renal disease, hypertension, or diabetes mellitus were used as controls. Two urinary enzymes, N-acetyl-βD-glucosaminidase (NAG) and alanine amino-peptidase (AAP) were measured in the urine, together with total protein and creatinine concentration. Microalbuminuria, glucose and pH were measured using test strips. Increased levels of both NAG and AAP were found in the diabetic subjects. Increased excretion of both these enzymes as well as microalbuminuria was found in the hypertensive groups. The high levels of urinary enzymes found, suggest that renal complications were prevalent in the groups studied. Because of the high incidence of diabetes in Saudi Arabia, a screening program should be established which would include urinary biomarkers for the early detection of renal damage.
Keywords: Diabetic nephropathy, N-acetyl-β-D-glucosaminidase, Alanine aminopeptidase, Microalbuminuria, Hypertension
|How to cite this article:|
Lary SA. Urinary Enzymes and Microalbuminuria as Indicators of Renal Involvement in Patients with Diabetes Mellitus in Saudi Arabia. Saudi J Kidney Dis Transpl 2004;15:18-26
|How to cite this URL:|
Lary SA. Urinary Enzymes and Microalbuminuria as Indicators of Renal Involvement in Patients with Diabetes Mellitus in Saudi Arabia. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2019 Jul 20];15:18-26. Available from: http://www.sjkdt.org/text.asp?2004/15/1/18/32961
| Introduction|| |
The prevalence of diabetes mellitus in the majority of developing countries is 1-2%  and the more prevalent form is non-insulin diabetes (NIDDM). In the Middle East, however, a prevalence of 2-3% has been reported. This rises to 90% in those aged 60 years and above.  The incidence of diabetes mellitus is particularly high in the populations of Saudi Arabia; for example, in Riyadh city, it has been reported to be six percent of the of adult male population over the age of 35 years.  In one study carried out in Jeddah, it was found to be as high as 30% in the group studied.  In another study of fasting hyperglycemia carried out with members of the population of Khaibar, a prevalence of 15% was found. 
It was also found that the prevalence of diabetes in the Saudi population was higher in urban areas (males 12%, females 14%) than in rural areas (males 7%, females 7.7%). In urban females aged 51-60 years, the highest prevalence was 49% while in the rural females of similar age, it was only 29%.  This high prevalence found in the Kingdom could be related to first cousin marriages, which accounts for 52% of all marriages. Gene hypothesis could also explain the dramatic rise in diabetes mellitus in Saudi Arabia. The prevalence of diabetes mellitus in the near future will rapidly increase that it will become 4050% in 2020, especially with the high prevalence of obesity in school children. 
NIDDM is the major form of diabetes mellitus found in Saudi Arabia and most of the patients are obese at first diagnosis. , Adult Saudi diabetes patients tolerate hyperglycemia well and are Ketoacidosis resistant.  Type II diabetes mellitus comprises 90% of diabetes in Saudi Arabia and obesity predisposes to insulin resistance. 
Among the complications associated with diabetes mellitus, liver disease is the most common. Atherosclerosis, retinopathy, and macroproteinuria are less common in Saudis than in other populations. ,
Renal complications have received little attention and detailed information on diabetic nephropathy in Saudi Arabia is not available. 
Renal complications frequently develop into end-stage renal failure requiring hemodialysis and further detailed studies are therefore justified. The current methodology used to monitor renal involvement in diabetes mellitus in Saudi Arabia lacks sensitivity and does not provide an early indication among diabetic ethnic groups who vary in their response to diabetes mellitus.  Thus, further studies of the Saudi population are therefore of epidemiological interest.
Extensive studies have been carried out in the new millennium and many workers have investigated the prevalence and the impact of diabetes mellitus in Saudi Arabia. They include: the evaluation of the prevalence and risk factors of hypercholesterolemia (HC) in renal transplant population,  retinopathy as a predictor of diabetic nephropathy,  nephropathy and urinary tract infection, ,,, obesity and hypertension in diabetes mellitus, ,, glycemic control and ketoacidosis, , risk factors of coronary artery and macrovascular diseases, ,,, diabetic neuropathy, ,,, bacteriological studies, isolation, sources and types of infection and risk factors, ,,, autoimmune disease and endocrinology , and finally gestational diabetes and prenatal loss in pregnancy. ,
In the present study, two urinary enzymes  that provide an early indication of renal damage were assayed. In addition, some commonly used parameters indicative of the presence of diabetes  were also measured. Groups of NIDDM and IDDM patients were compared with a control group and since hypertension  is known to influence the development of complications, patients were also sub-divided on the basis of blood pressure.
| Patients, Materials and Methods|| |
Non-diabetic subjects : the control group consisted of one hundred and fifty-five normal subjects (96 females, 59 males), aged 30.19 + 1.34 years, who were attending King Abdulaziz University Hospital and King Fahad General Hospital for routine medical check-up and who had no evidence of renal disease, hypertension or diabetes mellitus. None were receiving any medication all were non-smokers. The body mass index was 23.17 + 1.69 kg/m 2 among males 22.36 + 4.44 kg/m 2 among females.
Diabetic patients: Two hundred diabetic patients were studied: one hundred females (51 IDDM, 49 NIDDM) and one hundred males (37 IDDM, 63 NIDDM). The age of the diabetic subjects was 48.88+ 13.1 years. The majority of patients attended the King Fahad General Hospital, the King Fahd Military Hospital or the Al-Aziziah Center of Diabetes and Hypertension. The body mass index was 26.28 + 4.0 kg/m 2 for males and 23.27 + 3.73 kg/m 2 for females. Eighty-four patients from the diabetic population were hypertensive (46 males and 28 females) and their blood pressure ranged between 160/100 to 200/120 mmHg. The HbA1c values were 6.25 + 0.53 mg/dl for males and 5.96 + 0.44 mg/dl for females. Both the control subjects and the patients provided a mid-day urine sample. Control subjects provided a brief medical history, which included personal details. Data obtained for each individual included body mass, temperature, blood pressure and the pulse rate.
Clinical and Laboratory Methods: The urine samples were divided into three aliquot; one (5ml) was stored at -20 0 C until required, while the second (3ml) was stored in 30% glycerol for the assay of alanine aminopeptidase (AAP), and the third sample was used immediately without storage.
Urinary NAG activity (µmol/MNP released /h/l) was measured without freezing,  using a commercially available colorimetric kit assay based on MNPGIcNAc substrate (PPR Diagnostics Ltd, London E1 9AT, UK). The developed color was measured using a Novaspec II spectrophotometer (Pharmacia Ltd). Urinary creatinine concentration (mmol /L) was determined using the Bonsens and Taussky method  based on the Jaffe' reaction.  The determination of creatinine was carried out in order to correct for variations caused by changes in urine flow.  The AAP activity (µ/mol Cr) was determined according to the method of Mattenheimer et al.  Urinary total protein (mg/mmolCr) was assayed according to the method of Bradford  using Coomassie Brillian Blue G-250 (merck Chemicals Ltd, Poole, England). The Microltest strips (Boehringer Ltd) were used to detect microalbuminuria (mg/L). This test allows specific detection of human albumin (<200 mg/l) and the intensity of the dye, checked exactly after five minutes, is directly proportional to the albumin (mg/L) content of the urine. Urine pH and glucose (mg/L) were detected using Combur-Test strips (Boehringer Ltd.). Glycosilated hemoglobin (HBA1c) was determined using an Abbott IMX glucated hemoglobin test; , the reference range used was HbA1c (%) 4.4-6.9 mg/dl.
| Results|| |
The clinical and biochemical features of the studied groups are shown in [Table - 1]. Urine samples from healthy Saudi subjects without any history of renal disease, hypertension or diabetes mellitus were free of glucose, had normal pH, as well as NAG,  and AAP  activities. There was no microalbuminuria  or overt proteinuria [Table - 2]. No significant differences were found between males and females and therefore the data was pooled for the whole group.
When urine samples from 200 diabetic subjects were analyzed and compared with the control group [Table - 3], NAG activities were increased four-fold, AAP two-fold, microalbuminuria four-fold and total protein three-fold and were all significantly elevated. Similar results were obtained for both male and female patients.
The diabetic patients were sub-divided into the four categories, normotensive IDDM and NIDDM, and hypertensive IDDM and NIDDM. The data obtained for the four subgroups is given in [Table - 4]. Little difference was observed between the values for the individual sub-groups. There was an indication from the protein and microalbuminuria data that hypertension may have had an additive effect.
| Discussion|| |
Diabetic nephropathy is one of the most devastating kidney diseases, its incidence is increasing and its treatment is expensive.  The influence of ethnicity on the prevalence of, for example, microalbuminuria in NIDDM is interesting.  Higher rates have been reported in non-white populations compared with white (European) populations. The severity and outcome of diabetic nephropathy in general is less favorable among such ethnic groups as Native Americans, American Blacks and Hispanics than among whites. The cumulative risk of nephropathy in people with the NIDDM varies from 25 % in individuals of European origin to around 50% in other ethnic groups such as Afro-Caribbean, Asian Indians and Japanese.  Indeed, the study of the Indo-Asian population in the UK has shown  that the age at onset of type II diabetes is relatively young and its prevalence increases with age reaching 30% of this population at greater than 60 years of age. There is evidence that the Saudi population would also provide a model for further research but overriding that is the need to provide effective treatment for a population in which ESRD is common.
Urinary NAG has also been shown to vary in different populations and may also be an indicator of early hypertensive disease.  Screening of all diabetic patients for early indicators of diabetic nephropathy has been advocated.  since it is now known that improved blood glucose control,  together with antihypertensive therapy  preserve renal function and are highly cost effective because treatment of ESRD is so expensive.
In the present study, a number of markers for diabetic nephropathy have been assayed in Saudi control and diabetic patients. To our knowledge, this is the first report aimed at defining possible early markers of nephropathy in the assessment of diabetic nephropathy in the Saudi population. Both NAG and AAP activities were found to be highly elevated in the urine of both normotensive and hypertensive IDDM and NIDDM patients when compared to the normal reference range. Several studies have indicated that urinary NAG levels rise prior to occurrence of microalbuminuria , suggesting that the known sequence of events that occurs in the kidney  may be reflected by qualitative and quantitative changes in markers in the urine. Previous studies have shown a relationship between urinary NAG and retinopathy  and microalbuminuria and NAG with retinopathy. ,
The presence of elevated NAG and microalbuminuria in all the diabetic patients investigated, with or without hypertension, suggests that they have a high risk of developing diabetic nephropathy with the possibility of progressing to ESRD. The similarity in the data among both normotensive and hypertensive individuals was a surprise, since previous studies  suggest that microalbuminuria is higher in the hypertensive individuals. Viberti and Messent  have correlated microalbuminuria and subsequent proteinuria with increased blood pressure. Also, the prevalence of hypertension has been shown to increase with increasing microalbuminuria. , Several studies have correlated increased blood pressure in IDDM diabetics with a progression to microalbuminuria and incipient or overt nephropathy. , Vascular complications may be protected by maintenance of low diastolic blood pressure  and the life expectancy in diabetics with hypertension is less when compared with diabetics without hypertension. 
In summary, the data presented here suggests that diabetic nephropathy may be more prevalent in Saudi Arabia than hitherto thought and that its relationship to hypertension in a defined Saudi population is worthy of a more detailed investigation. Such a study should include the assay of urinary enzymes and a wider selection of proteins than just albumin. This would enable a decision to be made as to which groups of tests are the most appropriate and to fully characterize nephropathy and the effect of hypertension in a defined ethnic group from the Middle East.
| Acknowledgement|| |
We acknowledge the support of Professor Ossama Shobokshi, (Minister of Health, Kingdom of Saudi Arabia) for his continuous help and support and Dr. Adel Mohamed Ali, Director of Genetics and Immunology Technologies Laboratory for providing the glycated haemoglobin data. We, also acknowledge Professor R. price, King's College London for his support and advice.
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Sahira A Lary
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah
[Table - 1], [Table - 2], [Table - 3], [Table - 4]