17 Diabetic Nephropathy

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From: Contemporary Cardiology: Diabetes and Cardiovascular Disease, Second Edition Edited by: M. T. Johnstone and A. Veves © Humana Press Inc., Totowa, NJ

17 Diabetic Nephropathy

Richard J. Solomon, ^MD and Bijan Roshan, ^MD

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INTRODUCTION

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in the United States, accounting for nearly 40% of incident ESRD (1). Diabetes mellitus (DM) is also an independent and strong risk factor for ESRD ascribed to causes other than diabetes (2), such as hypertension, pyelonephritis, and other forms of glomerulopathies that can lead to chronic renal disease. Here we focus mainly on diabetic nephropathy as a major microvascular complication of both type 1 and type 2 diabetes.

Between 35% and 57% of type 1 diabetics (3–5) and 25% and 46% of type 2 patients with long-lasting diabetes (4,6), develop clinically detectable nephropathy, indicated by proteinuria and/or renal insufficiency. In fact, the prevalence of proteinuria is the same in both types of diabetes, after adjustment for differences in diabetes duration (4,7).

Crossectional studies indicate that 20% of type 2 DM have microalbuminuria, many at the time diabetes is diagnosed. The prevalence increases to nearly 50% in those with advanced retinopathy (8). Approximately 2–3% of patients with type 2 diabetes progress to overt proteinuria yearly (9).

PATHOGENESIS

Recent large-scale intervention trials have provided compelling evidence for the role

of hyperglycemia in the development and progression of nephropathy in type 1 and type

2 diabetes (10,11). However the fact that only a proportion of individuals with diabetes

develop nephropathy suggests that factors other than the hyperglycemic environment are

involved in the pathogenesis of nephropathy. Genetic, ethnic, and familial factors may

also play significant roles in the development of nephropathy. In the Diabetes Control and

Complications Trial (DCCT) primary prevention cohort of type 1 patients without retin-

opathy, no familial concordance for development of diabetic retinopathy was found,

whereas for nephropathy significant correlation was found (12). On the other hand, analysis of the severity of nephropathy did not generally show familial correlation, although for the severity of retinopathy it was significant (12).

Recent investigations have identified a number of candidate gene polymorphism that may contribute to diabetic nephropathy. The angiotensin-converting enzyme (ACE) gene variant with a deletion (D) of a 287 base pair sequence is one such polymorphism.

This gene-deletion polymorphism is associated with elevated circulating and tissue ac- tivity of ACE (13) and increased risk of left ventricular hypertrophy (14), ischemic heart disease (15), and lacunar cerebrovascular accident (16). A number of studies have found a positive association between the differential display phenotype and the prevalence and rate of progression of nephropathy (17–19). Kunz and his colleagues in their meta- analysis conclude that diabetic nephropathy is not associated with the presence of the ACE-D allele in Caucasians with type I and type II diabetes, whereas the risk for neph- ropathy seemed to increase by 50% to 70% in type II Asian diabetics (20). Additionally, the T allele of the AGT gene M235T polymorphism has been associated with increased risk of nephropathy (21) whereas the A14 allele of the NOS2 promoter has been associ- ated with a decreased risk (22).

Another basis for genetic/familial clustering of diabetic nephropathy is an increase in vitro sodium-lithium (Na-Li) countertransport activity, a biochemical marker of increased sodium reabsorptive capacity of the kidneys. Increased Na-Li countertransport activity has been found in some groups of patients with essential hypertension (23). Abnormali- ties of this membrane countertransport system, which has an inheritable component (24), have been found to be associated with diabetic nephropathy (25,26) and to predict the development of microalbuminuria in type 1 diabetes (27). Recently, increased Na-Li countertransport has been identified with a splicing variant of the NHE1 exchanger that alters its affinity for lithium and eliminates its sensitivity to amiloride (28).

How hyperglycemia causes nephropathy is multifactorial and is related to the stages of nephropathy.

Nephropathy Staging

Mogensen and his colleagues have developed a staging classification for the evolution of diabetic nephropathy (29–32) (Table 1). This staging pattern is more heterogeneous and possibly the pathogenesis is more complex in type 2 (33), but overall similar patterns are seen in both type 1 and 2 patients (34).

Early after diagnosis of diabetes in both type 1 (35,36) and type 2 (37,38), glomerular filtration rate (GFR) increases. Nephromegaly and glomerular hypertrophy (36,39) accom- pany this glomerular hyperfiltration. More pronounced reduction in afferent compared to efferent arteriolar resistance may lead to elevated plasma flow in diabetics resulting in an increased GFR (36). Additionally, total capillary surface area increases in early dia- betics (39) and both elevated renal plasma flow and increased capillary surface area (that in turn increases glomerular ultrafiltration coefficient) contribute to increased GFR.

Hyperglycemia may directly increase the production of vasodilatory prostaglandins that can contribute to renal hyperperfusion, intraglomerular hypertension, and hyperfiltration.

In experimental models, such as the streptozotocin-induced diabetic rat, glomeuli show

increased production of vasodilatory prostaglandins (40). Nitric oxide (NO) and atrial

natriuretic peptide (ANP) are other vasodilator candidates for inducing hemodynamic

changes leading to diabetic hyperfiltration. Elevated levels of ANP have been demon-

strated in diabetic rats (41), and a specific ANP receptor antagonist is capable of reducing

hyperfiltration in this experimental model (42). Increased endothelial NO synthase mRNA (43) and increased sensitivity of peripheral and renal vascular circulation to endothelium-derived NO has also been found in experimental models (44). Reversal of hyperfiltration with NO inhibition in experimental diabetes (44,45) indicates the potential importance of this mediator of diabetic hyperfiltration.

Indirectly, hyperglycemia may induce renal afferent vasodilation through activation of the tubuloglomerular feedback mechanism (46). The increased filtration of glucose stimulates sodium reabsorption in the proximal tubules via Na-glucose transporters. This diminishes the amount of sodium reaching the early distal nephron in which the macula densa resides. The reduced sodium delivery to the macula densa results in a vasodilatory signal to the afferent arteriole supplying that nephron. The signal is mediated by NO and perhaps prostaglandins. The net effect is a decrease in afferent arteriole resistance and increase in renal blood flow (47).

These metabolic and hemodynamic derangements may contribute to the initial struc- tural changes in the early stages of diabetic nephropathy. Stretching of glomerular cap- illaries and mesangial cells as a result of glomerular hypertension, may be involved in increased basement membrane thickening and mesangial matrix formation, mediated by increased tissue production of angiotensin II. This is a potent promoter of increased local synthesis of transforming growth factor (TGF)-G. Changes in the level of TGF-G (48) and increased release of TGF-G (by glomerular endothelial, epithelial, and mesangial cells) may cause mesangial hypertrophy (49). Increased and deranged production of basement membrane (BM) proteins, such as type IV collagen and fibronectin may contribute to structural changes. The effects of angiotensin II (Ang II) and glucose may be mediated by increased oxidative stress. Increased production of superoxide from endothelial nico- tinamide adenine dinucleotide phosphate (NADPH) occurs as a result of both increased

Table 1

Staging System for Diabetic Nephropathy

Stage 1 The earliest observation in development of nephropathy is an increase of up to 50% in the glomerular filtration rate (GFR). This is often present at diagnosis of diabetes and is frequently associated with increased kidney size and enlarged glomeruli.

Stage 2 Hyperfiltration may decrease to near normal levels of GFR and thickening of the glomerular capillary basement membrane (BM) is found histologically. Blood pressure and albumin excretion remain in normal range and clinically nephropathy remains undetectable at this stage.

Stage 3 Development of microalbuminuria (20–200 μg/minute or 30–300 mg/24 hours, not detectable by routine urine dipsticks) occurs after 6 to 15 years. Thickening of BM increases and mesangial matrix expansion appears. Incipient increases in blood pressure are seen in type 1. Type 2 diabetics may have hypertension even before development of nephropathy because of the genetic association of essential hypertension with type 2 diabetes. GFR may still be supranormal but declining.

Stage 4 Overt diabetic nephropathy and macroalbuminuria (>200 μg/minute or >300 mg/24 hours, that is detectable by routine dipsticks) with further development of structural changes. Usually takes 15 to 25 years to develop after appearance of diabetes mellitus.

Increasing hypertension and more rapid fall in GFR (usually 10 mL/minute/year) without treatment are prominent features.

Stage 5 End-stage renal disease (ESRD) (usually 25–30 years after diagnosis) with glomerular

closure and resultant decrease in proteinuria.

Ang II and hyperglycemia. The superoxide ion can activate nuclear factor (NF)PB and induce a number of profibrotic genes including TGF-G and fibronectin (43). Superoxide also scavenges NO, reducing its availability and leading to the formation of peroxynitrite.

Peroxynitrite in turn oxidizes lipids and tyrosine residues.

Later in the course of diabetic nephropathy, hyperfiltration decreases and for many years the renal injury remains clinically undetectable with normal renal function and normal albumin secretion. In patients who later develop overt diabetic nephropathy, structural injury gradually becomes more prominent. Development of microalbuminuria is the earliest clinical sign to the presence of renal injury in diabetes. Both histological evidence of injury and increased mRNAs for profibrotic mediators are observed at this stage (50). Still at this stage patients have normal or supranormal GFR. Other factors that cause urinary microalbuminuria, e.g., decompensated heart failure, acute febrile illness, urinary tract infection, metabolic decompensation, high-protein intake, heavy exercise (51), and poorly controlled essential hypertension (52) should not be confused with true diabetic microalbuminuria (51). For this reason, microalbuminuria measurements should be performed when control of these confounding conditions has been achieved and repeated measurements confirm the microalbuminuria is a persistent abnormality. Devel- opment of microalbuminuria is a strong predictor of progression to chronic renal insuffi- ciency and ESRD in type 1 diabetes (29–32,53). However, microalbuminuria at this stage can “regress” in association with glycemic control, normal levels of blood pressure (BP), cholesterol, and triglycerides (54). This highlights the importance of screening early in the course of diabetes. In type 2, possibly the presence of essential hypertension and other comorbid confounding conditions, makes microalbuminuria a less strong predictive fac- tor for the presence and progression of diabetic nephropathy (34,35).

Prolonged hyperglycemia can also cause nonenzymatic glycosylation of proteins and lipids (advanced glycosylation end-products [AGEs]) (56). As in other diabetic vascular complications, accumulation of AGEs in diabetic vasculature is believed to play an important role in pathogenesis of nephropathy (56,57). Interaction of AGEs with a recep- tor on endothelial cells can cause increased expression of vascular cell adhesion mol- ecule-1 (58), increased vascular permeability (59) and increased production of reactive oxygen species (60).

Long-term hyperglycemia can also increase the activity of another glucose-dependent pathway, the polyol pathway, which leads to accumulation of sorbitol in cells including the kidney and vasculature. This, in turn, depletes intracellular myoinositol, which inter- feres with cellular metabolism (61).

Hyperglycemia also increases the activity of protein kinase C in diabetic rat glomeruli (62). Hyperglycemia, perhaps through increased Ang II, upregulates plasminogen acti- vator inhibitor type-1 (PAI-1) activity. PAI-1 inhibits not only fibrinolysis but proteoly- sis of extracellular matrix (ECM) (63,64). This latter effects compounds the ECM accumulation resulting from increased production (vide supra) (65).

Correlation of Microvascular Changes to Functional Tests and Screening for Nephropathy

Unfortunately, there is not a good test to identify the patients at the earliest stages (1

and 2). GFR measurements are notoriously inaccurate in the outpatient clinical setting

and elevated levels must be confirmed and adjusted for body surface area. On the other

hand, a normal GFR may indicate either the absence of hyperfiltration or decline in GFR

after initial hyperfiltration and progression to overt nephropathy (stage 2).

Other measurements in these early stages are also problematic. In a study of 36 type 1 diabetic adolescents without macroalbuminuria, Berg and associates found that an increased filtration fraction ([FF] = GFR/effective renal plasma flow) was predictive of structural changes including BM thickening and increased mesangial matrix (66). They used clearance of inulin and para-amino hippuric acid during water diuresis to determine the GFR and effective renal plasma flow for calculating FF. They also found a direct correlation between epithelial foot process width and the log of urinary albumin excre- tion. Even if this correlation could be established by other studies, longitudinal determi- nation of FF would be needed for developing temporal comparisons. Finally, such measurements are too complicated for routine clinical practice. Likewise, measurement of Na-Li countertransport activity, or determination of the ACE gene polymorphism or mRNA levels of profibrotic cytokines in renal tissue to stratify diabetic patients at risk for development of nephropathy is impractical at present.

The earliest clinical marker of diabetic nephropathy in both types 1 and 2 is the presence of microalbuminuria (vide supra). The presence of microalbuminuria identifies high-risk patients that will benefit from the therapeutic measures described below.

Thus, several protocols exist for screening of diabetic patients for development of microalbuminuria. Table 2 summarizes the World Health Organization (51) and the National Kidney Foundation (67) screening recommendations for urinary albumin ex- cretion (UAE):

It should be noted that not all albuminuric/proteinuria type 2 DM individuals have diabetic nephropathy. Other renal diseases have been found in 10% to 24% of these individuals (68,69) and 50% of those without retinopathy (70). This is an important consideration because the rate of progression of renal disease in diabetes is generally greater than that seen with the other glomerulonephritides found in these patients (71).

The presence of other causes of renal disease might necessitate specific therapies and interventions.

TREATMENTS TO PREVENT OR DELAY PROGRESSION OF NEPHROPATHY

Long-term observational studies of cohorts of type 1 and type 2 DM have identified an number of modifiable promoters of nephropathy. These include arterial pressure, glucose control, serum cholesterol, and urinary protein (72). A number of randomized prospective trials have documented the beneficial effects of targeting these promoters for both primary and secondary prevention of nephropathy.

Table 2

Recommendation for Screening for Microalbuminuria

World Health Organization Urinary albumin excretion at least yearly for all patients with type 1 of more than 5 years duration and age above 12, and all patients with type 2 at the diagnosis until age 70. If abnormal it should be confirmed by repeat testing and repeated every 6 months.

National Kidney Foundation At least a yearly urine albumin/creatinine ratio in first morning

urine (or random urine). Positive result should be confirmed.

Glycemic Control

The DCCT, United Kingdom Prospective Diabetes Study (UKPDS), (33) and Kumamoto trial (11,73,74) provide strong evidence in favor of the role of intensive glycemic control in preventing and decreasing the progression of diabetic nephropathy in type 1 and type 2 DM respectively. In the DCCT, intensive insulin therapy was asso- ciated with a 40% decrease in the incidence of new microalbuminuria (10). In other observational studies, the lowest A1c levels were associated with the lowest incidence of developing microalbuminuria (7). In the UKPDS, sulphonylureas and insulin produce equally good results with regards to diabetic microvascular complications (11). The incidence of new microalbuminuria was decreased 34% with intensive control that resulted in a 1% lower A1c (11). Progression from microalbuminuria to proteinuria was also diminished in type 1 diabetes (10) and the longer follow-up data from Epidemiology of Diabetes Interventions and Complications show that the early control of glycemia may have long-lasting benefits on the rate of development of microvascular complications (75). Even in individuals with established nephropathy, observational studies suggest that the rate of loss of renal function is reduced in the presence of better glycemic control (72,76) although little effect was seen in some series (77).

The use of thiazolidinedione (TZD) agents may also be of particular benefit in treating nephropathy. In a recent report, TZD compounds completely prevented the high-glu- cose-induced TGF-Gpromoter activity and elevation of c-Fos nuclear transcription factor (78). Such actions might be expected to downregulate fibrosis and this has also been observed in animal studies. Activation of peroxisome proliferators-activated receptor-L decreases type I collagen mRNA and protein (79). Thus, is seems intriguing that TZDs may halt progression of nephropathy by mechanisms other than their hypoglycemic effect.

Smoking

Cigarette smoking, apart from its detrimental effects on macrovascular disease, has been implicated in progression of diabetic nephropathy in both types of diabetes in several studies (80–82). With smoking cessation, the risk of progression of diabetic nephropathy can be reduced (83).

Hypertension

The relationship between diabetes and hypertension has been discussed in detail in another chapter in this book. We focus on the role of hypertension in the pathogenesis of diabetic nephropathy and its importance as a target of therapy. More than two decades ago Mogensen showed that control of hypertension slows the progression of nephropathy (84). BP control per se can reduce the amount of proteinuria in both types (30,31,85) and almost all antihypertensive medications can reduce proteinuria as a result of their BP- lowering effect. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high BP, emphasizes the need for aggressive treatment of hypertension in the presence of diabetes, with an antihypertensive target of less than 130/80 mmHg (86). Despite this consensus, less than one-third of patients with diabetes achieve these BP targets (87). ACE inhibitors and angiotensin receptor blockers (ARBs) have an added effect on proteinuria that we will discuss later in more details.

The effect of many antihypertensive drugs in decreasing proteinuria and halting

the progression of diabetic nephropathy has been compared to ACE inhibitors.

Nondihydropyridine calcium channel blockers (CCBs), verapamil and diltiazem, have been reported to have a beneficial effect comparable to that of ACE inhibitors (88,89).

Short-acting dihydropyridine CCBs, on the other hand, do not have any added effect on proteinuria (90,91). Although, slow-release or long-acting newer dihydropyridines may reduce proteinuria (92,93), this needs further confirmation in larger trials. In the UKPDS, target BP control to less than 140/90 with either captopril or atenolol, in type 2 diabetes was equally effective in preventing macroalbuminuria and/or doubling of serum creati- nine concentration (94).

Effects of ACE Inhibitors, ARBs, and Treatments Other Than Glycemic and Blood Pressure Control

ACE inhibitors and ARBs have an additional favorable effect on glomerular hemody- namics and proteinuria that are independent of BP changes (95–99). In contrast, reduc- tions in proteinuria from other antihypertensive agents could be entirely explained by changes in BP. Even in normotensive diabetics with microalbuminuria or overt pro- teinuria, ACE inhibitors can decrease the rate of decline in GFR in both type 1 and 2 patients (100,101). The fact that ACE inhibitors can reduce the progression of microalbuminuria to macroalbuminuria in type 1 (102) and type 2 (101) patients and ARBs reduce progression in type 2 patients (96–99) underscores their efficacy at earlier stages of clinical nephropathy and provides an opportunity to halt the progression to ESRD (stage 5). Finally and perhaps most importantly, these agents reduce mortality in the more advanced stages of nephropathy (99,103). Thus, ACE inhibitors and ARBs have become the gold-standard treatment in diabetic patients with any stage of nephropathy.

Based on evidence from clinical trials, the American Diabetes Association has recom- mended ACE inhibitors for type 1 patients with nephropathy and ARBs for type 2 patients with nephropathy (104). The dose required for the maximum antiproteinuric effect is generally greater than that for maximum antihypertensive effect. Some investigators have found that doses even greater than those approved by the Food and Drug Admin- istration for BP control still have increasing antiproteinuric effects (104a).

The complex pathophysiology of hypertension in diabetic nephropathy usually demands two or more drugs for aggressive control of hypertension. The choice of a diuretic, CCB, G-blocker, or other antihypertensive agent is influenced by co-morbidities present in the individual patients. A diuretic will usually be needed in the presence of even mild reduc-

Table 3

Effect of Intensive Glycemic Control on Development of New Microalbuminuria (Primary Prevention) or Progression From Microalbuminuria to Proteinuria (Secondary Prevention)

in Types 1 and 2 Diabetes

Study Years Diabetes mellitus Primary Secondary

(reference) N follow-up type Treatment –A1C prevention prevention

DCCT (10) 1441 9 1 Insulin 2% 39% 54%

Kumamoto (74) 110 8 2 Insulin 2% 74% 60%

UKPDS (11) 4209 9 2 Various 1% 24% N/A

DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study;

N/A: not applicable.

tions in GFR and should be accompanied by sodium restriction. Sodium restriction can potentiate the BP-lowering effects of most antihypertensive medications. In diabetic animals, salt restriction also reduced the hyperfiltration, albuminuria, and the kidney weight (105). Salt restriction in man also improves the antiproteinuric effect of ACE inhibitors (106).

Proteinuria

Numerous studies have documented that the amount of proteinuria is the best single predictor of disease progression (107). Filtered proteins are taken up into proximal tubule cells in which they undergo degradation in lysosomes. This process when over-loaded generates profibrotic cytokines that accelerates nephron loss. Furthermore, the magni- tude of the reduction in proteinuria with therapy is a predictor of renal preservation (107a). For any degree of BP reduction, proteinuria is reduced more by ACE inhibitors and ARBs than other classes of antihypertensives. ACE inhibitors and ARBs reduce proteinuria through mechanisms independent of their BP-lowering effects. Tissue Ang II modulates the proteins comprising the slit diaphragm of the glomerular capillary wall.

By affecting the distribution of nephrin (108) and other slit diaphragm proteins, the integrity of the slit diaphragm to macromolecules is maintained. Additionally, Ang II upregulates cytokines involved in the profibrotic process. These include TGF-G, fibronec- tin, and PAI-1 (109). These cytokine effects may be mediated by increased oxygen radicals generated in response to Ang II effects on endothelial NADPH (43).

The central role of the renin–angiotensin–aldosterone system in the pathogenesis of diabetic nephropathy has led to efforts to more completely inhibit this system. Trials in nondiabetic (110) and diabetic renal disease (111–113) with combinations of ACE inhibi- tors and ARBs have shown enhanced antiproteinuric effects. The addition of an inhibitor of aldosterone has also provided enhanced antiproteinuric effects (114).

Dietary Interventions

Dietary protein restriction and its effect on progression of diabetic nephropathy has been a subject of controversy (as it is in nondiabetic renal disease). In the Modification of Diet in Renal Disease (MDRD) study a clear-cut benefit was not shown by protein restriction (115). Although this was the largest prospective trial studying the effect of protein restriction, no patient in MDRD had type 1 diabetes and only 3% of the patients had type 2 diabetes. Furthermore, during the study few patients developed renal failure.

In a rat model of diabetic nephropathy, protein restriction reduces hyperfiltration, intraglomerular pressure, and the rate of progression of renal disease (116). In a recent meta-analysis of five smaller studies including type 1 diabetic patients, protein restriction ranging from 0.5 to 0.85 g/kg significantly reduced the rate of decline in GFR or creati- nine clearance or the increase in UAE (117). For type 2 diabetic nephropathy, compelling data is not available. At this time, a protein restriction of 0.8 g/kg for patients with evidence of nephropathy seems reasonable (118) and safe.

Dyslipidemia is common in both types of diabetes. The National Cholesterol Educa-

tion Program advocates more aggressive control of cholesterol in diabetic patients with

a target low-density lipoprotein of less than 100 mg/dL (119). Dyslipidemia not only

contributes to devastating macrovascular changes, but also is a risk factor for nephropa-

thy (120,121). Studies have shown the effect of correction of dyslipidemia with

gemfibrozil (122) and lovastatin (123) in retarding the progression of diabetic nephropa-

thy. A meta-analysis of 13 prospective controlled trials in patients with different types of chronic kidney disease has shown lipid reduction may preserve GFR and decrease pro- teinuria (124). A large multicenter trial (Scottish Heart and Arterial Risk Prevention) is underway to further explore this aspect of therapy.

CONCLUSION

Nephropathy is a major microvascular complication of diabetes and in both types of diabetes it goes through similar pathophysiologic stages. Microalbuminuria is the earliest clinical marker for the presence of nephropathy, although it is a late manifestation of the pathophysiological process. Microalbuminuria is also a strong risk factor for develop- ment of macrovascular complications.

Tight glycemic control, aggressive BP control, use of ACE inhibitors and ARBs, smoking cessation, protein and salt restriction, and aggressive treatment of dyslipidemia can slow the progression of nephropathy to ESRD. An aggressive approach to the multiple risk factors for diabetic nephropathy can significantly reduce the risk of progression (125).

REFERENCES

1. System USRD. USRDS 2002 Annual Data Report. Bethesda, MD, National Institutes of Health, 2002.

2. Brancati FL, Whelton PK, Randall BL, Neaton JD, Stamler J, Klag MJ. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. JAMA 1997;278:2069–

2074.

3. Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T. Diabetic nephropathy in Type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983;25:496–501.

4. Hasslacher C, Ritz E, Wahl P, Michael C. Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 1989;4:859–863.

5. Rossing P, Rossing K, Jacobsen P, Parving HH. Unchanged incidence of diabetic nephropathy in IDDM patients. Diabetes 1995;44:739–743.

6. Ballard DJ, Humphrey LL, Melton L Jr, et al. Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota. Diabetes 1988;37:405–412.

7. Stephenson JM, Kenny S, Stevens LK, Fuller JH, Lee E. Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes. Diabet Med 1995;12:149–155.

8. Delcourt C, Villatte-Cathelineau B, Vauzzelle-Kervroedan F, Papoz L. Clinical correlates of advanced retinopthy in type II diabetes patients: implications for screening. J Clin Epidemiol 1996;49:679–685.

9. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225–232.

10. The effect of intensive treatment of diabetes on the development and progression of long-term compli- cations in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977–986.

11. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–853.

12. Clustering of long-term complications in families with diabetes in the diabetes control and complica- tions trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997;46:1829–

1839.

13. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymor- phism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343–1346.

14. Shunkert H, Hense HW, Holmer SR, et al. Association between a deletion polymorphism of the angio- tensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 1994;330:1634–1638.

15. Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641–644.

16. Markus HS, Barley J, Lunt R, et al. Angiotensin-converting enzyme gene deletion polymorphism. A new risk factor for lacunar stroke but not carotid atheroma. Stroke 1995;26:1329–1333.

17. Fujisawa T, Ikegami H, Kawaguchi Y, et al. Meta-analysis of association of insertion/deletion polymor- phism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy. Diabetologia 1998;41:47–53.

18. Kimura H, Gejyo F, Suzuki Y, Suzuki S, Miyazaki R, Arakawa M. Polymorphisms of angiotensin converting enzyme and plasminogen activator inhibitor-1 genes in diabetes and macroangiopathy.

Kidney Int 1998;54:1659–1669.

19. Yoshida H, Kuriyama S, Atsumi Y, et al. Angiotensin I converting enzyme gene polymorphism in non- insulin dependent diabetes mellitus. Kidney Int 1996;50:657–664.

20. Kunz R BJ, Fritsche L, Ringel J, Sharma, AM. Association between the angiotensin-converting enzyme- insertion/deletion polymorphism and diabetic nephropathy: methodologic appraisal and systemic re- view. J Am Soc Nephrol 1998;9:1653–1663.

21. Rogus JJ, Moczulski D, Freire MV, Yang Y, Warram JH, Krolewski AS. Diabetic nephropathy is associ- ated with AGT polymorphism T235: results of family-based study. Hypertension 1998;31:627–631.

22. Johannesen J, Tarnow L, Parving HH, Nerup J, Pociot F. CCTTT-repeat polymorphism in the human NOS2-promoter confers low-risk of diabetic nephropathy in type 1 diabetic patients. Diabetes Care 2000;23:560–562.

23. Canessa M, Adragna N, Solomon HS, Connolly TM, Tosteson DC. Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N Engl J Med 1980;302:772–776.

24. Hasstedt SJ, Wu LL, Ash KO, Kuida H, Williams RR. Hypertension and sodium-lithium countertransport in Utah pedigrees: evidence for major-locus inheritance. Am J Hum Genet 1988;43:14–22.

25. Krolewski AS, Canessa M, Warram JH, et al. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 1988;318:140–145.

26. Rutherford PA, Thomas TH, Carr SJ, Taylor R, Wilkinson R. Changes in erythrocyte sodium-lithium countertransport kinetics in diabetic nephropathy. Clin Sci (Lond) 1992;82:301–307.

27. Monciotti CG, Semplicini A, Morocutti A, et al. Elevated sodium-lithium countertransport activity in eryth- rocytes is predictive of the development of microalbuminuria in IDDM. Diabetologia 1997;40:654–661.

28. Zerbini G, Maestroni A, Breviario D, Mangili R, Casari G. Alternative splicing of NHEZ-1 mediates Na- Li countertranport and associates with activity rate. Diabetes 2003;52:1511–1518.

29. Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 1983;32 Suppl 2:64–78.

30. Mogensen CE, Hansen KW, Osterby R, Damsgaard EM. Blood pressure elevation versus abnormal albu- minuria in the genesis and prediction of renal disease in diabetes. Diabetes Care 1992;15:1192–1204.

31. Mogensen CE. Systemic blood pressure and glomerular leakage with particular reference to diabetes and hypertension. J Intern Med 1994;235:297–316.

32. Mogensen CE. How to protect the kidney in diabetic patients: with special reference to IDDM. Diabetes 1997;46 Suppl 2:S104–S111.

33. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria.

Diabetologia 1996;39:1569–1576.

34. Nelson RG, Bennett PH, Beck GJ, et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996;335:1636–1642.

35. Ditzel J, Junker K. Abnormal glomerular filtration rate, renal plasma flow, and renal protein excretion in recent and short-term diabetics. Br Med J 1972;2:13–19.

36. Mogensen CE, Andersen MJ. Increased kidney size and glomerular filtration rate in untreated juvenile diabetes: normalization by insulin-treatment. Diabetologia 1975;11:221–224.

37. Myers BD, Nelson RG, Williams GW, et al. Glomerular function in Pima Indians with noninsulin- dependent diabetes mellitus of recent onset. J Clin Invest 1991;88:524–530.

38. Nowack R, Raum E, Blum W, Ritz E. Renal hemodynamics in recent-onset type II diabetes. Am J Kidney Dis 1992;20:342–347.

39. Kroustrup JP, Gundersen HJ, Osterby R. Glomerular size and structure in diabetes mellitus. III. Early enlargement of the capillary surface. Diabetologia 1977;13:207–210.

40. Schambelan M, Blake S, Sraer J, Bens M, Nivez MP, Wahbe F. Increased prostaglandin production by glomeruli isolated from rats with streptozotocin-induced diabetes mellitus. J Clin Invest 1985;75:404–412.

41. Ortola FV, Ballermann BJ, Anderson S, Mendez RE, Brenner BM. Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. J Clin Invest 1987;80:670–674.

42. Zhang PL, Mackenzie HS, Troy JL, Brenner BM. Effects of an atrial natriuretic peptide receptor antago- nist on glomerular hyperfiltration in diabetic rats. J Am Soc Nephrol 1994;4:1564–1570.

43. Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS. Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int 2002;61:186–194.

44. Komers R, Allen TJ, Cooper ME. Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes. Diabetes 1994;43:1190–1197.

45. Tolinns J, Schultz, PJ, Raji L, et al. Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO. Am J Physiol 1993;265:F886-F895.

46. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus. J Am Soc Nephrol 1999;10:2569–2576.

47. Vallon V, Blantz RC, Thomson S. Glomerular hyperfiltration and the salt paradox in early Type 1 diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol 2003;14:530–537.

48. Yasuda T, Kondo S, Homma T, et al. Mechanisms for accumulation of extracellular matrix in rat mesangial cells in response to stretch/relaxation. J Am Soc Nephrol 1994;5:834 (abstr).

49. Rocco MV, Chen Y, Goldfarb S, Ziyadeh FN. Elevated glucose stimulates TGF-beta gene expression and bioactivity in proximal tubule. Kidney Int 1992;41:107–114.

50. Adler SG, Kang SW, Feld S, et al. Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy. Kidney Int 2001;60:2330–2336.

51. Prevention of diabetes mellitus. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1994;844:1–100.

52. Parving HH, Mogensen CE, Jensen HA, Evrin PE. Increased urinary albumin-excretion rate in benign essential hypertension. Lancet 1974;1:1190–1192.

53. Almdal T, Norgaard K, Feldt-Rasmussen B, Deckert T. The predictive value of microalbuminuria in IDDM. A five-year follow-up study. Diabetes Care 1994;17:120–125.

54. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in Type 1 diabetes. N Engl J Med 2003;348:2285–2293.

55. Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984;310:356–360.

56. Brownlee M, Cerami A, Valssara H. Advanced glycosylation endproducts in tissue and biochemical basis of diabetic complications. N Engl J Med 1988;318:1315–1320.

57. Brownlee M, Cerami A, Vlassara H. Advanced products of nonenzymatic glycosylation and the patho- genesis of diabetic vascular disease. Diabetes Metab Rev 1988;4:437–451.

58. Schmidt AM, Hori O, Chen JX, et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endot- helial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 1995;96:1395–1403.

59. Wautier JL, Zoukourian C, Chappey O, et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in dia- betic rats. J Clin Invest 1996;97:238–243.

60. Vlasara H. The AGE-receptor in the pathogenesis of diabetic complications. Diabetes Metab Res Rev 2001;17:436–443.

61. Greene DA, Lattimer SA, Sima AA. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987;316:599–606.

62. Cravan PA, DeRubertis FR. Protein kinase C is activated in glomeruli from streptozotocin diabetic rats.

Possible mediation by glucose. J Clin Invest 1989;83:1667–1675.

63. Bastard JP, Pieroni L, Hainque B. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Diabetes Metab Res Rev 2000;16:192–201.

64. Fogo AB, Vaughan DE. Compound interest: ACE and PAI-1 polymorphisms and risk of thrombosis and fibrosis. Kidney Int 1998;54 1765–1766.

65. Paueksakon P, Revelo MP, Ma LJ, Marcantoni C, Fogo AV. Microangiopathic injury and augmented PAI-1 in human diabetic nephropathy. Kidney Int 2002;61:2142–2148.

66. Berg UB, Torbjornsdotter TB, Jaremko G, Thalme B. Kidney morphological changes in relation to long- term renal function and metabolic control in adolescents with IDDM. Diabetologia 1998;41:1047–1056.

67. Bennett PH, Haffner S, Kasiske BL, et al. Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 1995;25:107–112.

68. Schwartz MM, Lewis EJ, Leonard-Matin T, Breyer-Lewis J, Battle D. Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy. Nephrol Dial Transplant 1998;13:2547–2552.

69. Parving HH, Gall MA, Skott P, et al. Prevalence and cause of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 1992;41:758–762.

70. Ruggenenti P, Remuzzi A. The diagnosis of renal involvement in non-insulin-dependent diabetes mel- litus. Curr Opin Nephrol Hypertens 1997;6:141–145.

71. Christensen PK, Gall M, Parving HH. Course of glomerular filtration rate in albuminuric type 2 diabetic patients with and without diabetic glomerulopathy. Diabetes Care 2000;23:B14-B20.

72. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Progression of diabetic nephropathy. Kidney Int 2001;59:702–709.

73. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Diabetes Control and Complication Research Group. Kidney Int 1995;47:1703–1720.

74. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23 (suppl 2):B21-B29.

75. Writing team for the Diabetes Control and Complication Trial. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002;287:2563–2569.

76. Mulec H, Blohme G, Grande B, Bjorck S. The effect of metabolic control on rate of decline in renal function in insulin-dependent diabetes mellitus with overt diabetic nephropathy. Nephrol Dial Trans- plant 1998;13:651–655.

77. Parving HH. Renoprotection in diabetes: genetic and non-genetic risk factors and treatment. Diabetologia 1998;41:745–759.

78. Weigert C, Brodbeck K, Bierhaus A, Haring HU, Schleicher ED. C-fos-driven transcriptional activation of transforming growth factor beta-1: inhibition of high glucose-induced promoter activity by thiazolidinediones. Biochem Biophys Res Commun 2003;304:301–307.

79. Zheng F, Fornoni A, Elliot SJ, et al. Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPAR-gamma activation. Am J Physiol 2002;282:F639–648.

80. Christiansen JS. Cigarette smoking and prevalence of microangiopathy in juvenile-onset insulin-depen- dent diabetes mellitus. Diabetes Care 1978;1:146–149.

81. Chase HP, Garg SK, Marshall G, et al. Cigarette smoking increases the risk of albuminuria among subjects with type I diabetes. JAMA 1991;265:614–617.

82. Biesenbach G, Grafinger P, Janko O, Zazgornik J. Influence of cigarette-smoking on the progression of clinical diabetic nephropathy in type 2 diabetic patients. Clin Nephrol 1997;48:146–150.

83. Ritz E, Ogata H, Orth SR. Smoking: a factor promoting onset and progression of diabetic nephropathy.

Diabetes Metab 2000;26 (Suppl 4):S54-S63.

84. Mogensen CE. Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scand J Clin Lab Invest 1976;36:383–388.

85. Parving HH, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PA. Effect of antihyper- tensive treatment on kidney function in diabetic nephropathy. Br Med J (Clin Res Ed) 1987;294:1443–

1447.

86. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:2560–2572.

87. McFarlane SI, Jacober SJ, Winer N, et al. Control of cardiovascular risk factors in patients with diabetes and hypertension at urban academic medical centers. Diabetes Care 2002;25:718–723.

88. Bakris GL. Effects of diltiazem or lisinopril on massive proteinuria associated with diabetes mellitus.

Ann Intern Med 1990;112:707–708.

89. Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med 1990;113:987–988.

90. Abbott K, Smith A, Bakris GL. Effects of dihydropyridine calcium antagonists on albuminuria in patients with diabetes. J Clin Pharmacol 1996;36:274–279.

91. Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int 1998;54:889–896.

92. Crepaldi G, Carta Q, Deferrari G, et al. Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure. The Italian Microalbuminuria Study Group in IDDM. Diabetes Care 1998;21:104–110.

93. Sumida Y, Yano Y, Murata K, et al. Effect of the calcium channel blocker nilvadipine on urinary albumin excretion in hypertensive microalbuminuric patients with non-insulin-dependent diabetes mellitus. J Int Med Res 1997;25:117–126.

94. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317:713–720.

95. Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118:129–138.

96. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002;106:672–678.

97. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–878.

98. Lewis EJ, Hunsicker LC, Clark WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860.

99. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869.

100. Parving HH, Hommel E, Damkjaer Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ 1989;299:533–536.

101. Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-convert- ing enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med 1996;156:286–289.

102. Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 1994;271:275–279.

103. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibi- tion on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329:1456–1462.

104. American Diabetes Association: Diabetic nephropathy (position statement). Diabetes Care 2003;26 (Suppl 1):S94-S98.

104a. Weinberg AJ, Zappe DH, Ashton M, Weinberg MS. Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study. Am J Nephrol 2004;

24(3):340–345.

105. Allen TJ, Waldron MJ, Casley D, Jerums G, Cooper ME. Salt restriction reduces hyperfiltration, renal enlargement, and albuminuria in experimental diabetes. Diabetes 1997;46:19–24.

106. Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D. Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989;36:272–279.

107. Breyer JA, Bain RP, Evans JK, et al. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. Kidney Int 1996;1996:1651–1658.

107a. de Zeeuw D, Remuzzi G, Darving HH, Keane WF, Zhang Z, Shahinfar S. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65(6):2309–2320.

108. Benigni A, Tomasoni S, Gagliardini E, et al. Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis. J Am Soc Nephrol 2001;12:941–948.

109. Wolf G, Ziyadeh FN. The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 1997;29:153–163.

110. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angio- tensin II receptro blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlled trial. Lancet 2003;361:117–124.

111. Kuriyama S, Tomonari H, Tokudome G. Antiproteinuric effects of combined antihypertensive thera- pies in patients with overt type 2 diabetic nephropathy. Hypertens Res 2002;25:849–855.

112. Jacobsen P, Andersen S, Jensen BR, Parving HH. Additive effect of ACE inhibition and angiotensin II receptor blockade in type 1 diabetes with diabetic nephropathy. J Am Soc Nephrol 2003;14:992–

999.

113. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin- angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent dia- betes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440–1444.

114. Sato A, Hayashi K, Naruse M, Saruto T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 2003;41:64–68.

115. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994;330:877–884.

116. Zatz R, Meyer TW, Rennke HG, Brenner BM. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A 1985;82:5963–5967.

117. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med 1996;124:

627–632.

118. Franz MJ, Horton ES, Sr, Bantle JP, et al. Nutrition principles for the management of diabetes and related complications. Diabetes Care 1994;17:490–518.

119. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of high blood cholesterol in adults. JAMA 2001;285:2486–2497.

120. Krolewski AS, Warram JH, Christlieb AR. Hypercholesterolemia—a determinant of renal function loss and deaths in IDDM patients with nephropathy. Kidney Int Suppl 1994;45:S125–131.

121. Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med 1998;158:998–1004.

122. Smulders YM, van Eeden AE, Stehouwer CD, Weijers RN, Slaats EH, Silberbusch J. Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-depen- dent diabetes mellitus? Eur J Clin Invest 1997;27:997–1002.

123. Lam KS, Cheng IK, Janus ED, Pang RW. Cholesterol-lowering therapy may retard the progression of diabetic nephropathy. Diabetologia 1995;38:604–609.

124. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta- analysis. Kidney Int 2001;59:260–269.

125. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH. Multifactorial intervention and cardiovascular diseae in patients with type 2 diabetes. N Engl J Med 2003;348:383–393.