MICROALBUMINURIA AND DIABETES MELLITUS

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National Center for Diabetes and Endocrinology P.O.Box 80010, Tripoli, Libya E-mail: [email protected] Vuk Vrhovac Institute, University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Dugi dol 4a, HR-10000 Zagreb, Croatia

MICROALBUMINURIA AND DIABETES MELLITUS Salah R. Saleh Ben Hamed1, Pajica Pavkoviæ2, @eljko Metelko2

THE PHYSIOLOGICAL STRUCTURE AND FUNCTION OF THE KIDNEY The kidneys are bean-shaped, reddish-brown organs that are located retroperitoneally on either side of the vertebral column, extending from the 12th thoracic vertebra to the 3rd lumbar vertebra. Each kidney is approximately 11.0 cm in length, 5.0-7.0 cm in diameter, and 2.5 cm in thickness. Externally at the portion of the kidney there is a notch called the hilum, where renal artery and vein, lymphatics, nerves and renal pelvis are located. Internally the kidneys are composed of the cortex and the medulla. Uriniferous tubule is the functional unit of the kidney. It consists of the nephron and the collecting duct. It is estimated that a pair of kidneys contain 2.5 million nephrons. The nephron is a unique and complex structure. Nephrons are classified into cortical and juxtamedullary nephrons. Each nephron consists of the Bowman’s capsule, proximal convoluted tubule, loop of Henle, and distal convoluted tubule. Many distal tubules empty into one collecting duct or tubule. Bowman’s capsule is a cup-like structure that surrounds the capillary network called glomerulus, two of them together being called renal corpuscle. The corpuscle has a vascular pole and urinary pole. Renal glomerulus is a vascular component of the nephron which consists of glomerular capillaries and intraglomerular mesangium. The glomerular basement membrane is a three layered structure consisting of lamina rara

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externa, lamina densa and lamina rara interna. The filtration of blood takes place in the renal capsule across the glomerular filtration membrane or bloodurine barrier, which is made up of the following layers: fenestrated endothelium, glomerular basement membrane and slit membrane. The glomerular mesangium comprises mesangial cells and mesangial matrix. From the capsular space the glomerular filtrate drains into the proximal convoluted tubule, loop of Henle and distal convoluted tubule. The urine passes from the distal convoluted tubule into the collecting tubule and collecting duct. The main function of the kidneys is to excrete the waste products of the metabolism, to regulate the body concentration of water and salt in order to maintain the appropriate acid-base balance of plasma, and serves as an endocrine organ secreting erythropoietin, renin and prostaglandins (1). DIABETIC NEPHROPATHY The development of diabetic nephropathy is characterized by a progressive increase in the excretion of protein, particularly albumin, an early and continuing rise in systemic blood pressure, and a late decline in glomerular filtration rate, leading eventually to end-stage renal failure. In addition to these central abnormalities, type 1 and type 2 diabetes patients with

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S. R. Saleh Ben Hamed, P. Pavkoviæ, @. Metelko / MICROALBUMINURIA AND DIABETES MELLITUS

nephropathy can be distinguished from their normoalbuminuric peers by the presence of other metabolic and clinical abnormalities (2). EPIDEMIOLOGY: INCIDENCE AND PREVALENCE In diabetic patients with proteinuria the relative mortality is about 40 times higher than in diabetics without proteinuria. Renal damage is a serious complication of diabetes mellitus (DM). It is estimated that death due to renal disease is 17 times more common in diabetics than in nondiabetics. Diabetic nephropathy is the most important cause of death in type 1 diabetic patients, of whom 30%-40% eventually develop end-stage renal failure. Death due to diabetic nephropathy with renal failure is less common in type 2 DM. The relative risk of renal mortality in diabetic patients diagnosed after the age of 45 years is estimated to be twofold that in nondiabetic patients. However, proteinuria as an indicator of renal involvement is not uncommon in patients with type 2 DM. It is now established that in both type 1 and 2 DM, urinary excretion of small amounts of albumin (microalbuminuria) is predictive of morbidity and mortality due to renal complications and cardiovascular disease (3). When diabetic nephropathy is diagnosed by the classical methods such as detection of proteinuria on urine analysis or decrease in creatinine clearance, little can be done to prevent the progressive downhill course to renal failure. However, the progression of diabetic nephropathy in type 1 diabetic individuals with microalbuminuria has been reported to be retarded by good glycemic control. In addition, tight blood pressure control has also been noted to reduce microalbuminuria, particularly with the use of ACE inhibitors. Five years from the onset of diabetes, the risk of nephropathy rises rapidly, peaks during the second decade and then declines, although nephropathy is often considered together with retinopathy as a microangiopathic complication. Reports on nephropathy developing in some patients with apparently well controlled diabetes and not developing in some patients even after years of severe hyperglycemia implicate some background predisposition (4).

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ETIOLOGY OF DIABETIC NEPHROPATHY Diabetes mellitus is one of the systemic diseases affecting the kidneys. Diabetic nephropathy would have developed in about one third of patients who have had type 1 DM for more than 20 years. The incidence of nephropathy in type 2 DM is uncertain. Mortality and morbidity in these patients are due to cardiovascular disease accelerated by hypertension and hyperlipidemia (3). Biochemical, hormonal, immunologic and rheologic factors are important in the pathogenesis of diabetic nephropathy. A) Biochemical factors include hyperglycemia and glycosylated proteins in blood and basement membrane of the kidneys (5). B) Hormonal factors: higher levels of growth hormone are believed to promote basement membrane thickening in diabetes with coincidental hypopituitarism and increased basement membrane thickening in experimental animals given growth hormone injections (6). C) Immunologic factors: both exogenous and endogenous insulin anti-insulin antibody complex mediated immunologic factors also contribute to the basement membrane thickening (insulin autoantibodies, IAA) (7). D) Rheologic factors: reduced red blood cell (RBC) deformability due to glycosylation and fibrin deposition resulting from altered permeability and hypercoagulability. With the deposition of fibrin, electron microscopic lesions are converted into light microscopic ones, although basement membrane is thickened in diabetic nephropathy due to various factors mentioned above. So, kidney functions as a ’poor filter’ (8). PATHOGENESIS OF DIABETIC NEPHROPATHY Both type 1 and type 2 DM are characterized by hyperglycemia, a relative or absolute lack of insulin, and the development of diabetes induced vascular changes. A large number of human studies provide support for the concept that the microvascular complications of diabetes mellitus are dependent on

S. R. Saleh Ben Hamed, P. Pavkoviæ, @. Metelko / MICROALBUMINURIA AND DIABETES MELLITUS

hyperglycemia. There are four potential biochemical pathways linking hyperglycemia to the changes within the kidney, which can plausibly be linked to the functional, structural changes characterizing diabetic nephropathy. These are: polyol pathway, nonenzymatic glycation, glucose auto-oxidation and de novo synthesis of diglycerol leading to protein kinase C and phospholipase A2 activation. FUNCTIONAL CHANGES IN DIABETIC NEPHROPATHY Cardinal functional changes characterize the natural history of diabetic nephropathy: changes in the glomerular filtration rate (GFR); proteinuria and albuminuria; and arterial blood changes. There are 5 stages which apply mostly to type 1 DM but some may also be seen in type 2 DM (9).

Changes in glomerular filtration rate (GFR) Several studies have shown that in both type 2 and type 1 diabetic patients, GFR is elevated in the newly diagnosed patients and is significantly related to the increase in the kidney size. So, GFR is higher than normal in stage 1 of glomerular hypertrophy and hyperfiltration. It may exceed 150 ml/min. With the increase in protein excretion there is a tendency of GFR to fall to lower level but not below the normal range during the 2nd and 3rd stages of diabetic nephropathy. With the onset of persistent proteinuria, GFR progressively falls and culminates in the end stage renal disease (ESRD) in months to a year if left untreated. GFR correlates positively with HbA1c. Raised urinary albumin excretion is also associated with HbA1c in patients with incipient nephropathy. The rate of progression of nephropathy is correlated with metabolic control. So far there is no clinical indication for renal biopsy in patients with microalbuminuria including morphometry (10). Proteinuria and albuminuria Proteinuria, more specifically albuminuria, is the earliest and most sensitive predictor of diabetic nephropathy. Physiologically, the upper normal range of urinary protein excretion is 150 mg/24 h. Direct

Diabetologia Croatica 31-4, 2002

determination of urinary albumin greatly improves sensitivity. The upper limit of albumin excretion of 30 mg/24 h is equivalent to approximately 20 ì g/min (11). Microalbuminuria (below 200 ì g/min or 300 mg/day) cannot be detected by albustix method but with more sensitive methods such as ELISA and microalbustixdistix (12). Overt nephropathy, the onset of clinical phase of diabetic nephropathy, is signaled by the presence of persistent proteinuria, i.e. albumin excretion rate (AER) >200 ì g/min or 300 mg/day, usually accompanied by retinopathy, hypertension, declining GFR and plasma lipid abnormalities. With the progression of nephropathy AER increases to an arbitrary level of >300 mg/24 h, and in later stages proteinuria may be within the nephritic range. Arterial pressure changes Patients are usually normotensive until albuminuria supervenes. Once microalbuminuria has appeared, blood pressure starts to rise. Concomitantly an abnormal blood pressure profile is noted with a diminished nocturnal fall and increase during exercise. Hypertension is the consequence of renal parenchymal changes in type 1 DM. Type 2 diabetic patients may be hypertensive for years prior to the onset of overt diabetes. At the time of diagnosis of type 2 DM, hypertension is found in approximately 70%-80% of patients. Still blood pressure raises further in those patients who subsequently develop diabetic nephropathy (13). Mogensen et al. have characterized the progression of diabetic renal disease according to stages (14), as shown in Table 1. MICROALBUMINURIA Definition of microalbuminuria The term microalbuminuria has been used to describe an amount of albumin in the urine which is less than can be detected by ordinary clinical tests such as albustix, but is otherwise still associated with future disease (15,16). Microalbuminuria has been defined using different units of measurements. According to the Gento-Montecatini Convention, microalbuminuria is present when the urinary albumin excretion rate

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Present at d i ag nosi s of Increased ki d ney si ze, d i ab etes (reversi b le i ncreased g lomerular w i th g ood control) si ze

Almost all p ati ents normoalb umi nuri c i n fi rst 5 years

Typ i cally after 6-15 years (i n R35% of p ati ents)

1 Acute renal hypertrophy hyperfunction

2 Normoalbuminuria (UAE