J Am Soc Nephrol 14: 1396–1405, 2003

Diabetic Nephropathy in Type 2 Prevention and Patient Management

GUNTER WOLF* and EBERHARD RITZ† *Department of Medicine, Division of , University of Hamburg, Hamburg, Germany; and †Department of Internal Medicine, Renal Unit, Ruperto Carola University, Heidelberg, Germany.

It is an irony of medical progress that the renal involvement in genetic (7) as well as environmental factors. In subgroups of diabetes mellitus type 2 had been considered twenty years ago patients with , monogenetic causes have been (1) as a benign condition for the without causing renal identified, but which genes are responsible for the more com- function loss greater than expected from the “normal” aging mon polygenic forms is still unclear (8). process. In contrast, today it has become the single most common cause of end-stage renal disease (ESRD) in the entire How Do Microvascular Complications, Including Western world (2–4). Apart from the individual human suf- Renal Disease, Develop? fering that cannot be expressed in numbers, patients with type Recent evidence suggests that increased superoxide forma- 2 diabetes undergoing maintenance dialysis consume signifi- tion after high glucose–induced throughput in the mitochon- cantly more financial resources than those with nondiabetic drial electron-transport chain generates reactive oxygen spe- ESRD. In addition, type 2 diabetic patients do poorly on cies, which are involved in the development of diabetic dialysis and have an excess mortality (5). An interdisciplinary complications (9). Particularly in the development of diabetic approach is needed for patients with type 2 diabetes and nephropathy, proteins modified by glucose or glucose-derived nephrologists must deal with a spectrum of comorbidity be- products such as methylglyoxal, i.e., Amadori products, and sides diabetic nephropathy. The famous Dr. Elliot P. Joslin advanced glycation end products (AGE) play a pivotal role (1869–1962) stated: “With a missionary zeal, one must convert (10). Increased mitochondrial oxydation of glucose also acti- not only the patient’s mind and soul, but also his doctor to the vates protein kinase C (PKC) (9) and subsequently mitogen- realization that it is worth the effort to control the disease as activated protein kinases (MAPK) (11). Transforming growth shown by the sugar-free urine, normal blood sugar and cho- factor-␤ (TGF-␤) appears to be crucial in the development of lesterol” (6). We posit that a similar approach is also indicated renal hypertrophy and accumulation of extracellular matrix with respect to prevention and treatment of nephropathy in (12). Renal hypertrophy is an early event; irreversible changes patients with type 2 diabetes mellitus. such as and tubulointerstitial fibrosis are preceded by hypertrophy (12). Parallel to and to some extent Some Factors Involved in the Genesis of Diabetic concomitant with renal hypertrophy, hyperfiltration and intra- Nephropathy in Type 2 Diabetes renal develop in type 1 (10) as well as in type 2 To understand therapeutic interventions, it is mandatory to diabetes (13). Both hemodynamic and structural changes are briefly provide an (incomplete) review of the salient patho- important and are interrelated. For example, high glucose stim- physiologic mechanisms involved in the genesis of renal dis- ulates the synthesis of angiotensinogen and angiotensin II ease in diabetes. (AngII) (14). This polypeptide exerts hemodynamic as well as Type 2 diabetes is characterized by resistance, i.e., trophic, inflammatory, and profibrogenic effects on renal cells the failure to respond to normal concentrations of insulin, and (15). On the other hand, shear stress and mechanical strain, this is accompanied by compensatory hyperinsulinemia, al- resulting from altered glomerular hemodynamics and glomer- though the kinetics of insulin secretion are abnormal very ular hypertension, induce the autocrine and/or paracrine release early. In later stages, ␤ cell secretion fails to overcome insulin of cytokines and growth factors (14), which in turn plays a role resistance (7). Increased lipolysis with fatty acid release and in genesis of glomerulosclerosis and interstitial fibrosis. accumulation of fat in parenchymal organs further aggravate The risk of nephropathy is strongly determined by genetic the metabolic disturbance. is the result of factors. (16) as well as renal disease (17) cluster within families. A positive family history is clin- ically useful to identify patients with type 2 diabetes at high Correspondence to: Prof. Dr. Eberhard Ritz, Klinikum der Universita¨t Heidelberg, Sektion Nephrologie, Bergheimer Str.56a, D-69115 Heidelberg, Germany. Phone: renal risk. There has been an intense effort to identify the genes 49-6221-91120; Fax: 49-6221-162476; E-mail: [email protected] coding for renal risk. The complexity of candidate gene anal- 1046-6673/1405-1396 ysis is exemplified by controversial results concerning the Journal of the American Society of Nephrology insertion/deletion polymorphism of the angiotensin-converting Copyright © 2003 by the American Society of Nephrology enzyme (ACE). The current majority opinion is that, at least in DOI: 10.1097/01.ASN.0000065639.19190.CF certain ethnic populations, this polymorphism is associated J Am Soc Nephrol 14: 1396–1405, 2003 DN in Type 2 Diabetes Prevention and Patient Management 1397 with progression of diabetic renal disease but is not useful to absence of confounding factors such as fever, physical exer- predict development of diabetic nephropathy (18,19). Posi- cise, , uncontrolled hypertension, uncon- tional analysis has also identified putative loci associated with trolled , or congestive heart failure. There is a higher renal risk, at least in selected populations (20), but the progressive increase of renal (and cardiovascular) risk with generalizability of the results and the functional role of the increasing albumin excretion rates (26,27). This is true even for hypothetical genes have not yet been clarified. urinary albumin concentrations within the upper normal range, so that the cut-off must be interpreted with a grain of salt. How to Diagnose Type 2 Diabetes? Thickening of the glomerular causing Recently, the American Diabetes Association (ADA) rec- textural abnormalities and abnormal chemical composition as ommended diagnosis of type 2 diabetes on the basis of a fasting well as loss of negative electric charges had in the past been plasma glucose concentration Ն 126 mg/dl (7.0 mmol/L) on thought to be the major cause of MA. More recently, distur- two different days or a casual plasma glucose concentration Ն bances of the number and function of and specifi- 200 mg/dl (11.1 mmol/L) at any time of the day without regard cally the function of the slit membrane are thought to be at least to time elapsed since the last meal (21). In contrast, the WHO equally important (28). MA is not only a predictor of future continues to recommend oral glucose tolerance testing. A 2-h nephropathy (10); it is also associated with increased transcrip- value Ն 200 mg/dl (11.1 mmol/L) is diagnostic of diabetes. tion of genes involved in the genesis of glomerulosclerosis The agreement between ADA and WHO criteria is not satis- (29), at least in . Consequently, MA is evidence factory. Many individuals diagnosed with diabetes on the basis of existing nephropathy, not a predictor of future nephropathy. of WHO criteria would be missed by ADA criteria (22). The The association between glomerular lesions and MA is less oral provides, in addition, prognostic pronounced in type 2 diabetes (25). Fioretto et al. (25) found an information and identifies individuals with the greatest attrib- overall relation, but some patients failed to have MA despite utable risk of cardiovascular events and death (22,23). Glucose glomerulosclerosis and conversely approximately 30% of mi- tolerance is influenced by renal dysfunction and by medication croalbuminuric type 2 diabetic patients had structurally normal (24). We recommend oral glucose tolerance tests in high-risk glomeruli. The known correlation of MA to cardiovascular populations (Table 1) even when the fasting plasma glucose events (27) may be explained by the fact that the generalized concentration is normal. microvascular and macrovascular complications in type 2 di- abetes are also found in the kidney, making MA a mirror of the Heterogeneity of Renal Involvement in Type 2 Diabetes generalized vascular pathology. There is experimental evi- Structural damage to the kidney in diabetes mellitus is dence for a role of AngII in reducing nephrin expression in the usually, but not uniformly (25), reflected by slit diaphragm of podocytes (30), thus explaining the BP- (MA), i.e., elevated urinary albumin excretion (30 to 300 mg/d) independent beneficial effect of angiotensin receptor blockers in 24-h urine collections or 20 to 200 ␮g/min or ␮g/ml in spot on MA in type 2 diabetic patients (31). The appears urine samples. Some consensus recommendations advise to also to be a key player in the progression of renal disease. correct urinary albumin in spot urine for concentra- Kidney biopsies in Pima Indians with type 2 diabetes and MA tion (albumin/creatinine ratio 2.5 to 25 mg albumin/mmol showed increased glomerular and mesangial volumes, while creatinine) and some to use even separate cutoffs for male and subjects with overt exhibited broadening of podo- female patients. Because albumin excretion shows high day- cyte foot processes and reduced numbers of podocytes (32). to-day variability (VC 30%), MA should be diagnosed only if Podocyte loss is also found in experimental models of diabetes two of three samples on different days test positive in the (33) and in patients with type 1 (34) as well as type 2 diabetes (35) and progressive nephropathy. The dogma of MA as a specific reflection of disturbed glomerular permselectivity has Table 1. Risk factors for impaired glucose tolerance or recently come under critique, however, because disturbances of latent type 2 diabetes proximal tubular reabsorption of albumin have been shown to be a major component of in experimental models ● Overweight (36) and in diabetic patients (37). ● Treatment-resistent hypertension Several studies in microalbuminuric patients with type 2 ● High-risk population (African American, Hispanic diabetes (25,38) documented that the morphology is much American, Asian American, Native American, Pacific more heterogeneous than in microalbuminuric type 1 diabetic Islander) patients. This contrasts with the observations in frankly pro- ● Triglycerides Ն 250 mg/dl and/or HDL cholesterol Յ 35 teinuric type 2 diabetic patients with impaired renal function in mg/dl whom one uniformly finds diabetic glomerulosclerosis (39). ● Women who have delivered a large baby (Ͼ 4 kg) or It was previously thought (40) that MA is uniformly asso- have had ciated with a decrease in GFR. In contrast, more recent studies ● Endocrine disease (e.g., acromegaly, Cushing syndrome, (41) showed that this is true mainly for the subgroup of patients hyperthyroidism) exhibiting typical lesions of diabetic . An Aus- ● Normal plasma fasting glucose but known hyperglycemia tralian group even identified a subgroup of patients with type in the past 2 diabetes and progressive decrease of creatinine clearance 1398 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 1396–1405, 2003 despite no increase in albuminuria (42). Unfortunately there is threshold was found for any of the microvascular complica- no information on the underlying renal morphology. tions above normal glucose levels (HbA1c Ͼ 6.2%). It has In contrast to type 1 diabetic patients in whom marked therefore been concluded that the lower the HbA1c value, the diabetic glomerulosclerosis is almost uniformly associated better. Enthusiasm has to be tempered, however, by the con- with , the latter is found only in approxi- sideration that tight control increases the risk of . mately 70% of patients according to the IDNT study (43). It is, Although the risk of hypoglycemia is less in type 2 diabetes, it however, a powerful predictor of an adverse renal prognosis does exist in patients with impaired renal function. Neverthe- (44). less, even there, a target value of Ͻ 7.0 HbA1c should be There have been reports that one often finds “minimal reached. change” lesions in proteinuric type 2 diabetic patients by light A cornerstone of glycemic control is lifestyle modification microscopy (45), but it is not perfectly clear whether this (54), although the efficacy of this measure diminishes as type constellation reflects early diabetes-related podocyte damage 2 diabetes progresses. In most patients, ancillary drug treat- that escapes diagnosis by light microscopy. It has also been ment is necessary and the question arises: does the drug that is claimed that is more frequent in diabetic used for glycemic control matter and does renal function affect compared with nondiabetic patients. This has been found in dosing and efficacy of the hypoglycemic agents? Table 3 neither our autopsy series (46) nor a review of world literature summarizes some important data on currently available oral by Olsen and Mogensen (47). Suggested indications for renal hypoglycemic agents. There is an increasing tendency in type biopsy are summarized in Table 2. 2 diabetic patients to aim for tight glycemic control by adopt- ing a regime of multiple daily insulin injections (55) to achieve Control of Glycemia target HbA1c values Ͻ 7%. This is particularly true in the Control of glycemia in type 2 diabetic patients with nephrop- difficult to control type 2 diabetic with impaired renal function. athy represents some peculiar aspects. Why should one aim for Insulin treatment is obligatory when the patient has intercurrent optimal glycemic control? Today there is no longer any doubt problems such as severe infection or surgery. With the excep- that tight glycemic control prevents the onset or progression of tion of and glimepirid, most sulfonylurea com- diabetic nephropathy in type 2 diabetic patients (48,49) as it pounds (or their active metabolites) accumulate in patients with does in type 1 diabetic patients. In the past, it had been thought reduced renal function and may then cause prolonged episodes that once clinically manifest nephropathy had developed, a of hypoglycemia. The insulin-sensitizing agent metformin point of no return was reached beyond which tight glycemic should not be given at all to patients with reduced renal control failed to prevent the further decline in renal function. function, e.g., serum creatinine Ͼ 1.3 mg/dl, because of the Nevertheless recent studies from the Steno Hospital showed risk of life-threatening lactic acidosis (56). Meformin should that glycemic control had some, although less pronounced also be discontinued before surgery and administration of compared with tight BP control, effect on the rate of progres- contrast media. The alpha-glucosidase inhibitor acarbose and sion (50). The most impressive evidence for the role of hyper- related compounds cause gastrointestinal side effects at a high glycemia, so far only in type 1 diabetic patients, comes from rate. They interfere with postprandial hyperglycemia; for this observations on patients with isolated transplants in reason, they reduce the risk that diabetes develops in patients whom delayed reversal of glomerulosclerosis was achieved by with impaired glucose tolerance (57). In patients with estab- prolonged normoglycemia (51). Furthermore, glycemic control lished diabetes, it has only a limited impact on HbA1c. The affects survival. Wu et al. (52) found that type 2 diabetic new glinides augment postprandial glucose-induced insulin patients with poor glycemic control in the last 6 mo before the secretion and abrogate postprandial hyperglycemic peaks. In- start of dialysis had much worse survival than patients with sulin sensitisers (glitazones) stimulate the PPR-␦ receptor. good glycemic control, and this is also true in type 2 diabetic These drugs are fascinating on theoretical grounds, but no data patients on dialysis (53). on long-term safety and efficacy are available in patients with In the United Kingdom Perspective Study UKPDS (49) no renal failure. Glitazones do not accumulate in renal failure.

Table 2. Indications for renal biopsy in albuminuric patients Control of Dyslipidemia with type 2 diabetes Even when patients with type 2 diabetes do not have a history of coronary heart disease, the risk of cardiovascular ● Nephritic sediment (dysmorphic erythrocytes, death is higher by a factor of 4 (58). The risk becomes abysmal acanthocytes, numerous casts, particularly composed of when diabetic patients are in ESRD or on dialysis (2,59). This red cells) has led to the recommendation (60) that in type 2 diabetic ● History of nondiabetic renal disease patients, LDL cholesterol concentrations should be lowered to ● Fast increase in proteinuria (over weeks) values Ͻ 100 mg/dl irrespective of the presence or absence of ● Proteinuria Ͼ 5 g/24 h CHD. In these patients, because of their high coronary risk, one ● Albuminuria in the absence of retinopathy should consider treatment with statins as the equivalent of ● Decrease in renal function in the absence of proteinuria primary coronary prophylaxis. Apart from its effect on CHD, ● Fast decline of renal function without obvious explanation dyslipidemia may also contribute to the progression of diabetic J Am Soc Nephrol 14: 1396–1405, 2003 DN in Type 2 Diabetes Prevention and Patient Management 1399

Table 3. Drugs to treat hyperglycemia in type 2 diabetes and potential problems in patients with diabetic nephropathy

Sulfonylureas Accumulate in renal failure with the exception of glimepiride and gliquidone, prolonged hypoglycemia possible. Meglitinides Dose reduction for repaglinide in renal failure. Inhibitors of glucosidase (acarbose, miglizol) Modest reduction in HbA1c (0.5%). Glitazones Only licensed for combination therapy. Some compounds of this novel class exhibit liver toxicity. May aggravate and heart failure. Insulin Insulin is degraded, amongst others, by the kidney and reduced renal function necessitates dose-reduction. Long-acting insulins should be used with particular care because of risk of hypoglycemia. Ongoing discussion on the safety-profile on insulin analogs. nephropathy, but only limited information on this point is pertension may predispose to the development of diabetic available. nephropathy. Strojek et al. (67) noted that BP values were Patients with type 2 diabetes have a complex lipid pattern significantly higher in offspring of parents with type 2 diabetes (and this is even more pronounced if patients have diabetic compared with those without diabetic nephropathy. Pre-dia- nephropathy) with elevated triglycerides, decreased HDL con- betic individuals with impaired glucose tolerance frequently centrations, and a concentration of LDL cholesterol that is not have hypertension as one facet of the metabolic syndrome. In significantly different from nondiabetic individuals. Neverthe- Pima Indians such pre-diabetic hypertension has been shown to less, there is an excess of small dense LDL particles that are be a predictor of diabetic nephropathy (5 yrs after onset of highly atherogenic. In contrast to type 1 diabetes, optimal diabetes) (68). At the time when type 2 diabetes had been treatment of glycemia does not normalize dyslipidemia, and diagnosed but acute hyperglycemia had been reversed, abnor- this is presumably explained by the fact that even in the mal ambulatory BP values (Ͼ 130/80 mmHg) or an abnormal absence of hyperglycemia, pre-diabetic patients with impaired circadian BP profile (Ͻ 15% nighttime decrease) was noted in glucose tolerance exhibit this pattern of dyslipidemia as one 80% of the patients (15). Apparently, an inappropriate decrease facet of the metabolic syndrome. of nighttime BP early on is somehow related to the onset of There is now clear evidence for benefit from treatment with nephropathy, as recently also shown in type 1 diabetes by statins. In the Heart Protection Study (61), diabetic patients Lurbe et al. (69). In type 2 diabetic patients, it is also a with CHD benefited from treatment with simvastatin as much powerful predictor of cardiovascular death, increasing the risk as nondiabetics. In the WOSCOP study (West of Scotland by a factor of 20 (70). It is also related to the risk of progres- Coronary Prevention Study), pravastatin therapy in nondiabetic sion to dialysis dependency. Even when diabetic patients are patients even led to a 30% reduction in the hazard of devel- normotensive at baseline, an excessive BP increase may be oping type 2 diabetes (62), but this observation has not been observed during exercise. consistently confirmed. The beneficial effect of statins on CV Non-proteinuric type 2 diabetic patients who subsequently events may be mediated, at least in part, through improved develop overt proteinuria and diabetic nephropathy have higher endothelial cell dysfunction (63). Whether statins are also BP values (71), as shown in Table 4. effective in type 2 diabetic patients with ESRD requires further The pulsatile BP profile in type 2 diabetes is strongly influ- studies. Because of some unique aspects of atherogenesis in enced by reduced aortic compliance causing higher peak sys- renal failure and the potential role of nonclassical risk factors, tolic and lower end-diastolic pressures at any given mean this problem is currently being investigated in a controlled trial arterial pressure. As a result, the BP amplitude is increased. In on dialysed type 2 diabetic patients (64). such patients, systolic BP is often elevated despite normal Increased triglyceride concentrations would a priori be a diastolic BP values (isolated systolic hypertension). In this good indication for fibrates. Indeed, in diabetic subjects, gem- context, it is notable that systolic BP is the strongest predictor fibrozil reduced the incidence of cardiovascular events by more of progression, , and CV events (72). In diabetic pa- than 20% (65) and fenofibrate also reduced progression of tients with ESRD, a high pulse wave velocity as a surrogate coronary lesions (66). Nevertheless, the use of fibrates has not marker for reduced vascular compliance significantly predicted become popular in renal failure patients because of the risk of mortality (73). rhabdomyolysis, particularly when fibrates are used that are Although the type 2 diabetic patient is usually hypertensive partially eliminated by renal excretion. before the onset of nephropathy, nephropathy aggravates the severity of hypertension. It would be beyond the scope of this Hypertension in Type 2 Diabetes article to discuss the mechanisms through which renal dysfunc- Hypertension — Pathogenesis. Hypertension plays a ma- tion affects BP: mainly sodium retention, inappropriate activity jor role in the onset and progression of diabetic nephropathy as of the renin angiotensin system (RAS), sympathetic overactiv- well as in the development of macrovascular lesions. There has ity, and impaired endothelial cell-dependent vasodilatation been some recent evidence that genetic predisposition to hy- (72). Because these pathomechanisms have consequences for 1400 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 1396–1405, 2003

Table 4. Hypertension preceding manifest nephropathy in type 2 diabetic patients (reference 71)a

Postprandial Blood Glucose (mg/dl) Systolic BP (mmHg) Frequency of Hypertension

Later development of proteinuria (n ϭ 63) 208 164 70% (139 to 295) (105 to 215) No development of proteinuria (n ϭ 63) 199 149 (104 to 272) (122 to 183) 43%

a Data given as median and range.

the selection of antihypertensive agents, it is for instance Table 5. Prevention of the onset of diabetic nephropathy important that at similar levels of GFR diabetic patients are consistently more hypervolemic than nondiabetic patients (74), ● Achieve normotension as low as tolerated with a therapy underlining the importance of reduced dietary salt intake and regimen including an angiotensin converting enzyme diuretic treatment in the antihypertensive management of dia- (ACE)-inhibitor or AT1-receptor antagonist betic patients with nephropathy. A low sodium diet potentiates ● Salt restriction (Ͻ 6 g/d), recommended protein intake the antihypertensive and antiproteinuric effect of AT-1 recep- (0.8 to 1.0 g ϫ kgϪ1 body weight) tor antagonists in type 2 diabetes (75). An average daily intake ● Good control of hyperglycemia (target HbA1c Ͻ 7.0) of6gofNaCl is recommended by the ADA (76). ● Cessation of smoking The role of excessive activity of the RAS, at least of the ● Administration of statins? local system in the kidney, and of the sympathetic system ● Weight loss (if obese), light regularly aerobic exercise explains why pharmacologic blockade of the RAS and sympa- ● No use of minor analgesics thetic system is so effective. ● Avoidance of nephrotoxic medications (contrast media, Hypertension is a potent predictor of microvascular (renal antibiotics, nonsteroidals) and retinal) and cardiovascular (coronary, cerebrovascular, pe- ripheral artery disease) complications of diabetes. Coexistance of hypertension and hyperglycemia dramatically and synergis- tically increases the risk of these complications (for review, see onset of type 2 diabetes; it also increases the risk of develop- reference 77). It appears that hyperglycemia “sensitizes” the ment of microalbuminuria and further progression of diabetic vascular system to the complications of hypertension. It is nephropathy in type 2 diabetic patients (82). This is true even beyond the scope of this review to discuss the cardiovascular when patients are on ACE inhibitors and have achieved ade- benefit derived from lowering BP in type 2 diabetic patients, quate BP control (83). Consequently, nephrologists should not but this has clearly been documented in the UKPDS (78) and remain passive, but constantly point out the adverse effects of Hypertension Optimal Treatment (HOT) studies (79). The jus- smoking to their patients. Behavioral therapies combined with tification for such provocatively low target BP, the safety of nicotine strips, antidepressants (84), and in the future possibly which had been hotly contested in the past, is reinforced by the nicotine vaccines (85) should be considered. results of the Prospective Studies Collaboration (80) that, even It is not yet definitely established whether antihypertensive in nondiabetic individuals, the lowest cardiovascular risk is treatment and particularly pharmacologic blockade of the RAS seen at systolic pressures of 120 mmHg. prevent the onset of diabetic nephropathy, although some data are very suggestive indeed (86,87). This point has become Prevention of the Onset of Diabetic Nephropathy largely academic, however, because according to the results of A certain consensus has been reached with respect to the the HOPE and LIFE studies even non-microalbuminuric type 2 recommendations for prevention and retardation of progression diabetic patients should be managed with ACE inhibitors or of diabetic nephropathy. We refer particularly to the updated angiotensin receptor blockers to prevent cardiovascular events. Clinical Practice Recommendations of the American Diabetes Although there are no controlled data, there is little doubt Association (81). that obesity is a potent renal risk factor (88) and this is true in Table 5 summarizes the relevant information with respect to type 2 diabetes as well. prevention. A group in Kumamoto documented that intensified The results of the observational EURODIAB trial show that insulin treatment prevented onset and progression of diabetic excessive protein intake is correlated to the degree of mi- microvascular complications, including nephropathy, in type 2 croalbuminuria (89), but there is little hard evidence for a diabetic patients (48). Similarly, the UKPDS found that inten- beneficial effect of dietary intervention. In later stages of sified glycemic control achieving an average HbA1c of 7% diabetic nephropathy, protein intake seems to affect CV end- decreased the overall rate of microvascular complications (ret- points, but paradoxically not the rate of progression (90). The inopathy and nephropathy) by 25% irrespective how near- ADA recommends a protein intake of 0.8 to 1.0 g/kg body normoglycemia was achieved (49). weight per day for patients with type 2 diabetes with mi- There is no doubt that smoking increases not only the risk of croalbuminuria and 0.8 g/kg body weight per d in individuals J Am Soc Nephrol 14: 1396–1405, 2003 DN in Type 2 Diabetes Prevention and Patient Management 1401 with overt nephropathy (76). When recommending low-protein (103,104), including a study documenting benefit on renal diets, it is indispensable to guarantee adequate intake of calo- histology (105). Attempts at achieving these BP targets must ries (30 to 35 kcal/kg per day) to maintain good nutritional be tempered by the observation that in the IDNT trial (101) the status, especially in patients with preterminal renal failure who renal risk increased progressively as BP in the orthostatic are at risk of catabolism (91). Close follow-up of these patients position was lower, possibly because of injury from intermit- is recommended to avoid malnutrition. The danger of malnu- tent renal underperfusion potentially explained by reduced trition is illustrated by the fact that in dialysis patients low body ischemia tolerance of the diabetic kidney (106). mass index predicts poor survival (92). The discussion about the relative priorities in the selec- Various analgesics have an adverse influence on progres- tion of antihypertensive agents is largely academic, at least sion, and a recent study from Sweden showed that even acet- in the opinion of the authors. To achieve the above target BP aminophen and aspirin dose-dependently increased the risk of values, we and others need an average of four to five chronic renal failure (93). antihypertensive agents, including ACE inhibitors or angio- tensin receptor blockers, diuretics, beta-blockers, and cal- Prevention of Progression cium channel blockers (CCB). Particularly concerning CCB, Monitoring of type 2 diabetic patients for microalbuminuria there has been much discussion whether they are safe with at least once per year is recommended. Microalbuminuria in respect to cardiovascular (107) and renal prognosis (108). type 2 diabetic patients is not as potent a renal risk predictor as CCB are a heterogenous group, and even different galenic in type 1 diabetic patients, but it is certainly the best available preparations, e.g., of short and long acting dihydropyridines, tool to identify patients in need of intensified treatment (94). have different effects (109). In one study, an excess fre- To prevent progression in microalbuminuric or proteinuric quency of myocardial infarctions was found in nephropathic patients, it is important to adopt an integrated approach, com- diabetic patients (107), but in the ALLHAT study (110), prising tight antihypertensive control, including pharmacologic there was no indication for excess risk in type 2 diabetes, blockade of the RAS by ACE inhibitors or angiotensin receptor and the SYSTEUR data even showed that the relative (per- blockers, intensified glycemic control, cessation of smoking, cent) benefit with respect to CV events derived from CCB body weight reduction when appropriate (91), and dietary was greater in diabetic patients (111). Although amlodipine sodium restriction. As shown in Table 6, the loss of GFR was was shown to accelerate the loss of GFR in proteinuric significantly less in type 2 diabetic patients receiving such patients with impaired renal function in the AASK study integrated structured treatment in a diabetes clinic compared (108), this does not mean that CCB are generally contrain- wth patients managed by private physicians (95–97). A recent dicated in proteinuric patients with renal disease (109). 4-yr randomized controlled trial confirmed that changes in Amlodipine did not increase the renal risk compared with lifestyle can be implemented in type 2 diabetic patients with placebo in the IDNT trial (43). Ruggenenti et al. (112) had appropriate education and close follow-up (98). Early involve- also shown that in proteinuric patients with impaired renal ment of the nephrologist in such a treatment program is desir- function, proteinuria, and loss of GFR were on average able, and there is consensus that the best management of these higher in patients on CCB, but this was no longer the case patients is a multidisciplinary approach. when patients concomitantly received ACE inhibitors and When balancing the relative importance of these measures, it had mean arterial pressure values well below 100 mmHg. goes without saying that lowering of BP presumably to target Consequently, CCB are excellent partners in the multi-drug values of at least 120/70 mmHg is the single most important approach to control hypertension in type 2 diabetes, but the measure, as recently documented by the Appropriate BP Con- first medication should be a drug interfering with the acti- trol in Diabetes (ABCD) trial (99). Nevertheless there is also vated RAS. recent evidence for additional BP-independent renoprotection by angiotensin receptor blocking agents and advanced New Therapies on the Horizon? (100,101) and early nephropathy of type 2 diabetes (31,102). In Although the renal risk in diabetic nephropathy can be less rigorous trials, similar renoprotection, in part BP-indepen- reduced by 20 to 40% (IDNT and RENAAL), the fact remains dent, has previously also been shown for ACE inhibitors that 70% still progress, justifying attempts to develop novel

Table 6. The impact of intensified multifactorial intervention in patients with type 2 diabetes (reference 95)

Changes in parameters

HbA1c (%) Total Cholesterol (mmol/l) Urinary Albumin (mg/24 h) GFR (ml/min per 1.73 m2)

Standard treatment (n ϭ 76) 0.2 Ϫ 0.2 ϩ 10 Ϫ13 Ϯ 1.9 Ϯ 1.3 (Ϫ26 to 110) Ϯ 15 Intensified treatment (n ϭ 73) Ϫ 0.8 Ϫ 0.6 Ϫ 22 Ϫ 11 Ϯ 1.6 Ϯ 0.9 (Ϫ51 to 18) Ϯ 20 P 0.0001 0.0002 0.0002 NS 1402 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 1396–1405, 2003 therapeutic approaches. Many such treatments work well in 9. Brownlee M: Biochemistry and molecular biology of diabetic animals (interference with TGF-␤-expression, blocking the complications. Nature 414: 813–820, 2001 effect of AGE, antioxidative therapy), but the clinical effects of 10. Mogensen CE: Microalbuminuria, and diabetic experimental approaches are, at best, limited. Some innovative renal disease: Origin and development of ideas. Diabetologia 42: strategies have been clinically tested on small numbers of 263–285, 1999 11. Wolf G, Thaiss F: Hyperglycaemia-pathophysiological aspects at patients. As an example, the glycosaminoglycan sulodexide the cellular level. 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