|
 |
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© American Diabetes Association ®, Inc., 2006
Prevention of Progression in Diabetic Nephropathy
 |
Abstract |
|---|
 Top Abstract IntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
In Brief
Diabetic nephropathy is the most common cause for end-stage renal disease and for patients entering into chronic dialysis care. It occurs in 25–40% of patients with diabetes. Risk factors include hyperglycemia, hypertension, genetic predisposition, glomerular hyperfiltration, proteinuria, the renal renin-angiotensin system, advanced glycation end-products, and possibly reduced nephron number and lipid disorders. Prevention of diabetic nephropathy is crucial. Tight control of diabetes, blood pressure treatment to systolic pressure of < 130 mmHg, reduction of proteinuria, and treatment with drugs that inhibit the renin-angiotensin system are all associated with prevention of or delay in progression of diabetic kidney injury.
|
Introduction |
|---|
|
TopAbstractIntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
A quarter of a century ago, C.E. Mogensen1 made the unique observation that lowering blood pressure in patients with type 1 diabetes and diabetic nephropathy reduced the rate of loss in kidney function. In that study of five insulin-dependent proteinuric men with long-standing diabetes, blood pressure was lowered with combinations of furosemide, prazosin, hydralazine, and ß-blockers. This observation presaged what has become a crucial intervention in diabetic nephropathy: that lowering systemic blood pressure has been repeatedly shown to alter the course of diabetic kidney disease. Great progress has been made in understanding some of the other mechanisms of this disorder and in delaying its clinical expression and preventing its progression.
The importance of diabetic nephropathy as a cause for patient morbidity and
mortality is well known. Diabetic nephropathy occurs in 
30% of people
with type 1 diabetes and 25–40% of people with type 2 diabetes, often
irrespective of glycemic control. Diabetic nephropathy is the single most
common cause of end-stage renal disease (ESRD) in the United States,
accounting for > 50% of new cases of renal failure. Patients who have
diabetes and reach ESRD have a poor prognosis because of high cardiovascular
events. Thus, early identification of patients who have diabetes and are at
high risk for nephropathy is mandatory in order to prevent the development or
progression of diabetic nephropathy.
This article will review what is known about the major mechanisms and risk factors promoting renal injury in diabetes and will summarize the evidence-based recommendations for preventing progression.
|
MECHANISMS OF RENAL INJURY IN DIABETES |
|---|
|
TopAbstractIntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
The mechanisms of renal injury in diabetes are listed in Table 1 and discussed in more detail in this section.
|
Hyperfiltration Injury
What is known about how renal disease develops and progresses has changed
in recent years. Previously, it was thought that kidney injury was simply the
result of various insults such as immune complexes, ischemia, toxins, or, in
the case of diabetes, some metabolic product (e.g., advanced glycoslyation end
products [AGEs]). Now, however, we know that progressive renal disease is
caused by the combination of an initial or ongoing injury and a final common
pathway of maladaptive response to that injury, a response that involves
changes in glomerular hemodynamics and the release of cytokines and vasoactive
hormones.
Research has shown that the following sequence of events leads to chronic kidney failure. Most renal diseases result from an initial injury that causes a loss of functioning nephrons. Each remaining nephron must then work harder, filtering more blood per minute to maintain homeostasis. To do this, the kidney secretes intrarenal vasoactive hormones, such as prostaglandin E2, that preferentially dilate afferent arterioles and other hormones, such as angiotensin and catecholamines, that constrict efferent arterioles. Each glomerulus therefore receives more blood at a higher pressure and therefore filters more fluid into tubules. This situation, called hyperfiltration, damages the glomerular capillary in subtle ways, produces mesangial cell and glomerular basement membrane injury, and stimulates release of cytokines. All of these effects can produce further relentless injury and scarring of the remaining nephrons with further nephron loss. In addition, most renal diseases are accompanied by systemic hypertension and proteinuria, both of which are thought to accentuate this ongoing maladaptive intrarenal response. Systemic hypertension, in the setting of a glomerulus with dilated afferent and constricted efferent arterioles and abnormal basement membrane permeability (the hyperfiltration state), causes even greater degrees of glomerular pressure and injury. Proteinuria results in increased proximal tubular protein uptake, which causes an inflammatory response in the interstitium.
Diabetic renal disease begins not with loss of nephrons, but rather with glomerular hyperfiltration and increased glomerular filtration rate (GFR). This hyperfiltration, which has been shown to be present in early phases of both type 1 and type 2 diabetes, may exist for several years.2,3 Several studies have shown that hyperfiltration is associated with the degree of hyperglycemia.
However, hyperfiltration does not always predict the future development of kidney injury in diabetes. In vulnerable patients destined for diabetic kidney disease, GFR begins to decrease as microalbuminuria appears. When overt proteinuria occurs, most individuals with diabetes have clinically decreased GFR. At this point in the course of diabetic kidney disease, loss in nephrons occurs, with the maladaptive events described above. Although the overall GFR is decreased, the glomerular filtration rate per nephron is increased, and hyperfiltration injury continues. This leads to further nephron loss, proteinuria, glomerular and interstitial scarring, and progressive renal failure.
Although diabetes is often accompanied by hyperglycemia, hypertension, and altered lipids, surprisingly, most individuals with type 1 or type 2 diabetes do not develop diabetic nephropathy. This suggests that other factors are involved.
Genetic Factors
It is clear that there are genetic factors in the risk for diabetic
nephropathy. Data from the Diabetes Control and Complications Trial
(DCCT)4 have shown
that up to 35% of patients develop diabetic nephropathy, regardless of their
level of glycemic control. Seaquist et
al.5 showed that
siblings of patients with type 1 diabetes who also have diabetes have a
fourfold greater chance of developing diabetic nephropathy. In African
Americans, Freedman et
al.6 have also shown
that ESRD is five times higher in relatives of patients with type 2 diabetes
with ESRD. Among diabetic Pima Indians, 14% of descendants of parents without
nephropathy develop diabetic nephropathy, whereas the incidence of nephropathy
is 23% if one parent had proteinuria and 46% if both parents had
nephropathy.7
These observations alone do not prove a genetic contribution for diabetic nephropathy but may illustrate a socioeconomic/cultural clustering. However, several investigators employing molecular genetic techniques have performed linkage analyses to explain the vulnerability for diabetic nephropathy. Thus far, evidence for linkage to diabetic nephropathy has been detected on chromosomes 3q, 10q, and 18q.8
Reduced Number of Nephrons
Several animal and human
studies9–11
have shown that reduced numbers of glomeruli at birth are associated with the
eventual development of hypertension or kidney disease. The suggestion is that
for individuals who start with a reduced number of nephrons, any subsequent
renal injury will render them more vulnerable to progressive nephropathy.
Diabetes in pregnant rats diminishes kidney weight and nephron number in their
offspring.12,13
This finding can be imitated by exposing pregnant rats to hyperglycemia at the
time fetal renal tissue is developing. If this is also true for humans,
hyperglycemia in pregnant women may predispose their children to both
hypertension and renal disease.
|
AGEs |
|---|
|
TopAbstractIntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
In the setting of diabetes and long-standing hyperglycemia, free amino groups of proteins are nonenzymatically modified by glucose and its metabolites to form Schiff bases that eventually lead to the formation of AGEs. AGEs may produce functional changes in the kidney by crosslinking with the glomerular basement membrane and other vascular membranes.14 AGE-binding proteins may also be involved. The best defined of these is the receptor for AGEs (RAGE).15 Binding of AGEs to RAGEs activates cell signaling mechanisms coupled to increased transforming growth factor ß (TGF-ß) and vascular endothelial growth factor (VEGF) expression, which are increased in diabetic nephropathy and are thought to contribute to diabetes complications.16,17
Several recent studies have shown that angiotensin receptor blockers (ARBs) and ACE inhibitors reduce AGEs and alter functioning of RAGEs.18,19 These effects suggest that these drugs provide renal protection by inhibiting the expression of TGF-ß and VEGF mediated by AGEs and RAGEs that leads to the endothelial injury and fibrosis that is so characteristic of diabetic nephropathy.
Hyperglycemia
The hyperglycemic state itself is known to be a significant risk factor for
diabetic nephropathy. Glycemic control in both type 1 and type 2 diabetes has
been associated with reduced appearance of diabetic nephropathy
(microalbuminuria).20,21
The reasons for this are likely multiple. At least two clinical observations
inform us about possible mechanisms.
The first is that the hyperglycemic state seems to sensitize the endothelium to injury from elevated blood pressure. In type 2 diabetes, lowering blood pressure, regardless of the type of agent used to do so, retards the onset and progression of diabetic nephropathy.22 In type 1 diabetes, Lurbe et al.23 have noted that an insufficient decline in nighttime blood pressure (nondipping) preceded the onset of microalbuminuria. The second observation is that successful pancreas transplant that results in normal insulin regulation and normoglycemia is associated with a reversal of the lesions of diabetic nephropathy.24
Proteinuria
Proteinuria accompanies most progressive renal diseases. Proteinuria,
either microalbuminuria or macroalbuminuria, accompanies diabetic nephropathy.
In general, the greater the proteinuria, the more likely the disease will
progress. Many have considered proteinuria as simply a marker of significant
renal injury. Recent
studies,25,26
however, suggest that the proteinuria itself may contribute to progression of
renal disease.
Any glomerular injury that increases the permeability of the glomerular basement membrane will allow plasma proteins to escape into the urine, resulting in proteinuria. Some of these proteins are ingested by proximal tubular cells, initiating an inflammatory response that contributes to interstitial scarring. Several investigators26–28 have shown that lisinopril and mycophenolate significantly reduce proteinuria-induced inflammatory injury as well as the rate of disease progression in normal rats with 1-5/6 nephrectomy (a procedure that reduces functioning kidney tissue to < 25% of normal). This information implies that any therapy, such as treatment with an ACE inhibitor or ARB, that reduces proteinuria may have a benefit beyond that brought about by reduction in blood pressure or alteration of glomerular hemodynamics.
Renal Renin-Angiotensin System
Past observations have shown that diabetes is a low-renin state, yet
diabetic nephropathy seems responsive to pharmacological blockade of the
renin-angiotensin system (RAS). It is now well appreciated that a local
(renal) RAS exists and is activated in diabetic individuals in the proximal
tubular epithelial
cells,29 mesangial
cells,30 and the
podocytes.31 It is
this intrarenal RAS that may explain the difference in dose-response curves
for blood pressure lowering and lowering of urinary protein excretion, namely,
that higher doses are needed for urinary protein lowering in experimental
animals and
humans.32
Systemic Hypertension
Of all of the mechanisms contributing to diabetic nephropathy, reduction of
blood pressure has been clearly shown to be an important and powerful
intervention. Multiple-treatment clinical trials in type 1 and type 2 diabetes
have confirmed that reducing blood pressure is associated with decreased
progression of diabetic nephropathy. In type 2 diabetes, blood pressure
lowering independent of the antihypertensive agent used retards onset and
progression of diabetic
nephropathy.22 In
animal models of diabetes, the degree and severity of diabetic nephropathy is
strongly linked to systemic blood pressure, being more marked in the obese
type 2 model than in the normotensive type 1 model (streptozotocin-induced
diabetes).33,34
In individuals with diabetes who have disordered autoregulation of the
microcirculation of the retina and kidney, systemic hypertension causes
barotrauma with endothelial injury.
Lipid Abnormalities
Patients with diabetes have a variety of disorders of plasma lipids. These
lipid abnormalities are known to contribute to cardiovascular risk. The role
of lipids in diabetic nephropathy is not clear. In animals with reduced
nephron number, dietary-induced hypercholesterolemia worsens glomerular
injury.35
Cholesterol-lowering drugs given to Zucker rats were associated with
attenuation of glomerular
lesions.36 Thus
far, a controlled trial to investigate whether lipid lowering will be
beneficial in diabetic nephropathy has not been reported.
|
TREATMENTS FOR REDUCING DIABETIC NEPHROPATHY |
|---|
|
TopAbstractIntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
From the above discussion, it is clear that diabetic nephropathy is the result of several contributing mechanisms, not all of which are operative in most individuals with diabetes. Clearly, prevention of diabetes is the surest way to prevent diabetic nephropathy. At this time, prevention of type 1 diabetes is not possible. Genetic factors in type 2 diabetes, if proven, are not yet modifiable. As will be reviewed below, aggressive treatment of patients with cardiovascular risk factors can reduce de novo type 2 diabetes. If hyperglycemia during embryonic development is shown to cause reduced nephron numbers in humans, prevention of hyperglycemia during pregnancy may be protective from future renal injury, but this deduction has not been tested.
At the moment, glycemic control, blood pressure lowering, and inhibition of the RAS are the major treatment strategies once diabetes is present (Table 2). What has research shown to guide our treatments?
|
Preventing the Onset of Diabetes
Several large
studies37–40
have solidly documented that both ACE inhibitors and ARBs lower the risk of de
novo type 2 diabetes. These studies were criticized because in some studies
ACE inhibition or ARB therapy was compared to diuretics or ß-blockers,
agents that could have increased the appearance of diabetes and thus made the
ACE inhibition or ARB agents appear more effective.
This issue was clearly resolved by the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.41 In this trial, the use of the ARB valsartan versus amlodipine clearly demonstrated a reduction in the appearance of type 2 diabetes. VALUE compared an ARB with amlodipine, which is not known to have any adverse effect on the development of diabetes. Pos-sible explanations for the favorable effect of inhibition of RAS on de novo diabetes comes from a study by Lau et al.42 showing that RAS is present in ß-cells of the pancreatic islets, that there is dose-dependent inhibition of glucose-stimulated insulin release by angiotensin 2, and that this suppression is completely reversed by pretreatment with the angiotensin type 1 receptor antagonist losartan but not by angiotensin type 2 receptor blockade.
Preventing the Appearance of Diabetic Nephropathy
Glycemic control
One of the earliest markers for diabetic nephropathy is microalbuminuria.
Because the presence of microalbuminuria is thought to be a manifestation of
renal and generalized endothelial injury and strongly predicts progressive
diabetic nephropathy and cardiovascular risk, preventing its development is
likely to be associated with prevention of progressive diabetic nephropathy
and possibly of cardiovascular disease. Hence, in diabetes, the appearance or
presence of microalbuminuria is used as an important indicator of effective
treatment intervention.
In type 1 and type 2 diabetes, the DCCT21 and the U.K. Prospective Diabetes Study (UKPDS)20, respectively, have shown a direct linear relationship between hyperglycemia and both the development (as evidenced by microalbuminuria) and progression of diabetic nephropathy (progression to macroalbuminuria or increasing serum creatinine) in patients who already have diabetes. Both studies showed that tight glycemic control was associated with a reduction in the appearance of microalbuminuria. In the latter trial, any decrease of hemoglobin A1c (A1C) by 1% was accompanied by a 37% decrease in the incidence rate of micro- or macroalbuminuria and retinal complications. These and many other observations have resulted in a recommendation from the American Diabetes Association (ADA) that renoprotective glycemic values are A1C < 7%, preprandial blood glucose 90–130 mg/dl, and postprandial peak < 180 mg/dl.43
The oral hypoglycemic drugs rosiglitazone and pioglitazone, both thiazolidinediones (TZDs), are used in the treatment of type 2 diabetes. These drugs are agonists of the peroxisome proliferator–activated receptors (PPARs). PPARs are nuclear hormone receptors and transcription factors. Three different subtypes have been identified. These have been found to be crucial factors in regulating diverse biological processes, including lipid metabolism, insulin sensitivity, and cell growth and differentiation.44
One of these subtypes, PPAR-
, is also present in glomerular
mesangial cells.45
When compared to oral hypoglycemic agents, including metformin, glyburide, and
glibenclamide, all antidiabetic TZDs exhibit similar glycemic control but also
seem to provide superior protection against diabetic
nephropathy.46–48
This protection is likely a result of the systemic effect on glycemic control
as well as a direct local renal effect on mesangial cell function, possibly
related to the unique actions of these drugs on PPAR-. Support for this
conclusion comes from studies in animal models of both type 1 and 2 diabetes,
wherein PPAR- agonists have been shown to improve diabetic
nephropathy.49–52
In summary, it appears that angiotensin blockade reduces the onset of diabetes in high-risk populations. Tight glycemic control in diabetic patients lessens the appearance and progression of diabetic nephropathy. PPAR agonists may provide additional protection against diabetic nephropathy beyond that attributed to glycemic control.
Blood pressure control
The EUCLID (Eurodiab Controlled Trial of Lisinopril in Insulin Dependent
Diabetes) study53
in type 1 diabetic subjects did not detect any difference in the appearance of
microalbuminuria in patients treated with lisinopril versus placebo. However,
in a study of 1,204 subjects with hypertension and nonalbuminuric type 2
diabetes, Ruggenenti et
al.54 compared
trandolapril alone, trandolapril plus verapamil, verapamil alone, and placebo
in preventing the appearance of microalbuminuria. Trandolapril alone and in
combination with verapamil were much more effective in preventing the
appearance of microalbuminuria than verapamil alone or placebo. This benefit
occurred even though the levels of blood pressure control achieved were
identical in all groups, suggesting that inhibition of the RAS provided
protection in addition to that resulting from lowering of blood pressure. The
Appropriate Blood Pressure Control in Diabetes (ABCD)
trial22 found
significant reduction in the development of microalbuminuria in normotensive
but not hypertensive type 2 diabetic patients treated to the same goal blood
pressure with either nisoldipine or enalapril.
In the UKPDS, tight blood pressure control did not reduce the development of microalbuminuria in type 2 diabetic subjects.55 In the Microalbuminuria Cardiovascular Renal Outcomes (MICRO)–Heart Outcomes Prevention Evaluation (HOPE) substudy56 there was no difference in the development of microalbuminuria between groups who received ramipril and placebo.
In summary, the above clinical trials do not clearly show that blood pressure control in type 1 diabetic patients lessens the appearance of microalbuminuria. In type 2 diabetes, at least two of the trials do indicate that lowering blood pressure is associated with reduction in the appearance of microalbuminuria, and they also suggest that this is best achieved with an angiotensin-inhibiting regimen that may provide protection beyond that resulting from blood pressure control alone.
Prevention of Progression in Diabetic Nephropathy
Several studies have clearly shown that in both type 1 and type 2 diabetic
patients who already have microalbuminuria, ACE inhibition is effective in
reducing renal progression. It has been proposed that the benefit is
independent of blood pressure. Nonetheless, in most studies of type 1
diabetes, the treatment has been compared to placebo, and there have been
slight but significant differences in blood
pressure.57 In the
MICRO-HOPE study56
of type 2 diabetic patients, microalbuminuric patients who received ramipril
had reduced progression rate to proteinuria. However, significant differences
existed in blood pressure between groups. In the ABCD
trial,58 aggressive
blood pressure control slowed progression to proteinuria in normotensive but
not hypertensive patients with type 2 diabetes.
In the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study,59 patients with microalbuminuria were protected from renal progression. Patients who received 300 mg of irbesartan daily for 24 months had a 70% risk reduction versus placebo, whereas the blood pressure achieved was basically identical. In addition, the patients who received high-dose irbesartan had a greater regression to normoalbuminuria (34%) than did the ones receiving 150 mg of irbesartan (24%) or placebo (21%). The Microalbuminuria Reduction With Valsartan (MARVAL) trial60 compared the effects of valsartan and amlodipine in 322 patients who had type 2 diabetes and microalbuminuria. After 24 weeks, patients treated with an ARB had a greater reduction in microalbuminuria and in regression to normoalbuminuria.
It is in patients with overt diabetic nephropathy (macroalbuminuria and abnormal GFR) that blood pressure reduction, usually with an ARB or ACE inhibitor, has dramatically improved the renal prognosis.
In patients with type 1 diabetes, ACE inhibition has been shown to reduce doubling of serum creatinine (DSC) reaching ESRD, and death: 409 patients with overt nephropathy were randomized to receive either captopril or placebo for 4 years. Captopril was associated with a 48% risk of DSC, which was thought to be independent of a small but significant difference in blood pressure between the groups.61
In type 2 diabetes, two large randomized long-term trials have shown that ARBs are effective in slowing progression of diabetic nephropathy. In the Reduction of Endpoints in NIDDM With the Angiotensin Antagonist Losartan (RENAAL) study,62 1,513 patients were randomized to either losartan or placebo (in addition to conventional therapy, excluding ACE inhibitors and ARBs) and followed for 3.4 years. Compared to the placebo group, patients who received losartan had a risk reduction of 25% for DSC and 28% for reaching ESRD. In the Irbesartan Diabetic Nephropathy Trial (IDNT),63 1,715 patients were randomized to receive irbesartan, amlodipine, or placebo (in addition to conventional therapy excluding ACE inhibitors, ARBs, and calcium channel blockers) and followed for 2.6 years. Irbesartantreated patients had a risk reduction for DSC of 33% compared to the placebo group and of 37% compared to the amlodipine group. Furthermore, both irbesartan and losartan were associated with greater reductions in albumin excretion rates than seen in other treatment groups. Overall, these studies have shown that nephroprotection with ACE inhibitors and ARBs occurs over and above what might be expected with reduction of blood pressure.
These studies have led the ADA to recommend the use of ARBs for the treatment of patients with type 2 diabetes, proteinuria, and microalbuminuria, whereas ACE inhibitors are indicated for patients with type 1 diabetes.43 We are still lacking large trials of ACE inhibition in type 2 diabetic patients with proteinuria and of ARBs in type 1 diabetes. Despite this lack of trial data, the National Kidney Foundation has recommended that either ARBs or ACE inhibitors be used for patients with diabetes regardless of the presence of hypertension.64 This recommendation is made because both classes of drugs interrupt the RAS, which is known to be an important mechanism in diabetic nephropathy. Furthermore, patient intolerance to one class of these drugs may be avoided by substituting the other class without losing the potential benefit of the RAS inhibition. Several small studies have suggested that combining ACE inhibitors and ARBs may afford even more protection or regression of diabetic nephropathy, but further large trials are needed.
|
SUMMARY |
|---|
|
TopAbstractIntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
Following are the key therapeutic strategies for diabetic nephropathy.
- Glycemic control to A1C < 7% reduces the appearance of diabetic kidney
disease.
- Blood pressure reduction to < 130/80 mmHg with ACE inhibitors or ARBs
reduces the appearance of diabetic nephropathy in type 2 diabetes but is not
proven to do so in type 1 diabetes.
- Slowing the progression of diabetic nephropathy has been demonstrated with
blood pressure lowering (to < 130/80mmHg) with ACE inhibition in type 1 and
type 2 diabetes and by ARB treatment in type 2 diabetes.
- The protective effect of ACE inhibition or ARB therapy has been shown to be
the result of both blood pressure reduction and direct drug effect.
- In patients with diabetic nephropathy and mild to moderate azotemia,
therapy with ACE inhibitors or ARBs may cause up to a 25%increase in serum
creatinine within 4 weeks of initiation of therapy. Increases in serum
potassium may also be seen. The rise in serum creatinine does not nullify the
protective effects of ACE inhibitor or ARB therapy. Serum potassium elevations
may be modified by a low-potassium diet and inclusion of diuretics in the
antihypertensive regimen.
|
Footnotes |
|---|
Phillip M. Hall, MD, is a consultant in the Department of Nephrology and Hypertension at the Cleveland Clinic Foundation in Cleveland, Ohio.
|
References |
|---|
|
TopAbstractIntroductionMECHANISMS OF RENAL INJURY...AGEsTREATMENTS FOR REDUCING DIABETIC...SUMMARYReferences |
|---|
-
1 Mogensen CE:
Antihypertensive treatment inhibiting the progression of diabetic nephropathy.
Acta Endocrinol (Suppl. 238):103
–108, 1980
2 Bangstad HJ, Osterby R, Rudberg S, Hartmann A, Brabrand K, Hanssen KF: Kidney function and glomerulopathy over 8 years in young patients with type I (insulin-dependent) diabetes mellitus and microalbuminuria. Diabetologia45 : 253–261,2002[Medline]
3 Nelson RG, Tan M, Beck GJ, Bennett PH, Knowler WC, Mitch WE, Blouch K, Myers BD: Changing glomerular filtration with progression from impaired glucose tolerance to type II diabetes mellitus. Diabetologia42 : 90–93,1999[Medline]
4 The DCCT Research Group: Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 47:1703 –1720, 1995[Medline]
5 Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320:1161 –1165, 1989[Abstract]
6 Freedman BI, Spray BJ, Tuttle AB, Buckalew VM Jr: The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis21 : 387–393,1993[Medline]
7 Pettitt DJ, Saad MF, Bennett PH, Nelson RG, Knowler WC: Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia33 : 438–443,1990[Medline]
8 Satko SG, Freedman BI, Moossavi S: Genetic factors in end-stage renal disease. Kidney Int (Suppl.) 94:S46 –S49, 2005
9 Fassi A, Sangalli F, Maffi R, Colombi F, Mohamed EI, Brenner BM, Remuzzi G, Remuzzi A: Progressive glomerular injury in the MWF rat is predicted by inborn nephron deficit. J Am Soc Nephrol 9:1399 –1406, 1998[Abstract]
10 Hakim RM, Goldszer RC, Brenner BM: Hypertension and proteinuria: long-term sequelae of uninephrectomy in humans. Kidney Int25 : 930–936,1984[Medline]
11 Keller G, Zimmer
G, Mall G, Ritz E, Amann K: Nephron number in patients with primary
hypertension. N Engl J Med 348:101
–108, 2003
12 Amri K, Freund N, Vilar J, Merlet-Benichou C, Lelievre-Pegorier M: Adverse effects of hyperglycemia on kidney development in rats: in vivo and in vitro studies. Diabetes 48:2240 –2245, 1999[Abstract]
13 Doublier S, Amri K, Seurin D, Moreau E, Merlet-Benichou C, Striker GE: Overexpression of human insulin-like growth factor binding protein-1 in the mouse leads to nephron deficit. Pediatr Res 49:660 –666, 2001[Medline]
14 Chen S, Cohen MP, Ziyadeh FN: Amadori-glycated albumin in diabetic nephropathy: pathophysiologic connections. Kidney Int (Suppl.)77 : S40–S44,2000
15 Neeper M, Schmidt
AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stem D, Shaw A: Cloning and
expression of a cell surface receptor for advanced glycosylation end products
of proteins. J Biol Chem 267:14998
–15004, 1992
16 Wendt T, Tanji N,
Guo J, Hudson BI, Bierhaus A, Ramasamy R, Arnold B, Nawroth PP, Yan SF,
D'Agati V, Schmidt AM: Glucose, glycation, and RAGE: implications for
amplification of cellular dysfunction in diabetic nephropathy. J Am
Soc Nephrol 14:1383
–1395, 2003
17 Wendt TM, Tanji N,
Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz
GS, Stein G, Bierhaus A, Liliensiek B, Arnold B, Nawroth PP, Stern DM, D'Agati
VD, Schmidt AM: RAGE drives the development of glomerulosclerosis and
implicates podocyte activation in the pathogenesis of diabetic nephropathy.
Am J Pathol 162:1123
–1137, 2003
18 Forbes JM, Cooper
ME, Thallas V, Burns WC, Thomas MC, Brammar GC, Lee F, Grant SL, Burrell LA,
Jerums G, Osicka TM: Reduction of the accumulation of advanced glycation end
products by ACE inhibition in experimental diabetic nephropathy.
Diabetes 51:3274
–3282, 2002
19 Forbes JM, Thorpe
SR, Thallas-Bonke V, Pete J, Thomas MC, Deemer ER, Bassal S, El Osta A, Long
DM, Panagiotopoulos S, Jerums G, Osicka TM, Cooper ME: Modulation of soluble
receptor for advanced glycation end products by angiotensin-converting
enzyme-1 inhibition in diabetic nephropathy. J Am Soc
Nephrol 16:2363
–2372, 2005
20 UKPDS Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837 –853, 1998[Medline]
21 The DCCT Research Group: The effect of
intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N
Engl J Med 329:977
–986, 1993
22 Schrier RW, Estacio RO, Esler A, Mehler P: Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 61:1086 –1097, 2002[Medline]
23 Lurbe E, Redon J,
Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D: Increase in nocturnal
blood pressure and progression to microalbuminuria in type 1 diabetes.
N Engl J Med 347:797
–805, 2002
24 Fioretto P,
Steffes MW, Sutherland DE, Goetz FC, Mauer M: Reversal of lesions of diabetic
nephropathy after pancreas transplantation. N Engl J
Med 339:69
–75, 1998
25 Eddy AA: Interstitial nephritis induced by protein-overload proteinuria. Am J Pathol 135:719 –733, 1998
26 Remuzzi G, Bertani T: Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int 38:384 –394, 1990[Medline]
27 Romero F, Rodriguez-Iturbe B, Parra G, Gonzalez L, Herrera-Acosta J, Tapia E: Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int55 : 945–955,1999[Medline]
28 Abbate M, Zoja C,
Rottoli D, Corna D, Perico N, Bertani T, Remuzzi G: Antiproteinuric therapy
while preventing the abnormal protein traffic in proximal tubule abrogates
protein- and complement-dependent interstitial inflammation in experimental
renal disease. J Am Soc Nephrol10
: 804–813,1999
29 Zhang SL, Filep JG, Hohman TC, Tang SS, Ingelfinger JR, Chan JS: Molecular mechanisms of glucose action on angiotensinogen gene expression in rat proximal tubular cells. Kidney Int 55:454 –644, 1999[Medline]
30 Vidotti DB,
Casarini DE, Cristovam PC, Leite CA, Schor N, Boim MA: High glucose
concentration stimulates intracellular renin activity and angiotensin II
generation in rat mesangial cells. Am J Physiol Renal
Physiol 286:F1039
–F1045, 2004
31 Durvasula RV, Petermann AT, Hiromura K, Blonski M, Pippin J, Mundel P, Pichler R, Griffin S, Clouser WG, Shankland SJ: Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int65 : 30–39,2004[Medline]
32 Weinberg MS, Weinberg AJ, Zappe DH: Effectively targeting the renin-angiotensin-aldosterone system in cardiovascular and renal disease: rationale for using angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors. J Renin Angiotensin Aldosterone Sys1 : 217–233,2000
33 Gross ML, Ritz E, Schoof A, Adamczak M, Koch A, Tulp O, Parkman A, El Shakmak A, Szabo A, Amann K: Comparison of renal morphology in the streptozotocin and the SHR/N-cp models of diabetes. Lab Invest84 : 452–464,2003
34 Gross ML, Ritz E, Schoof A, Helmke B, Parkman A, Tulp O, Munter K, Amann K: Renal damage in the SHR/N-cp type 2 diabetes model: comparison of an angiotensin-converting enzyme inhibitor and endothelin receptor blocker. Lab Invest83 : 1267–1277,2003[Medline]
35 Kasiske BL, O'Donnell MP, Schmitz PG, Kim Y, Keane WF: Renal injury of diet-induced hypercholesterolemia in rats. Kidney Int37 : 880–891,1990[Medline]
36 Kasiske BL, O'Donnell MP, Cleary MP, Keane WF: Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney Int33 : 667–672,1988 [erratum Kidney Int 33:1216, 1988][Medline]
37 ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group: The Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): major
outcomes in high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blocker vs
diuretic. JAMA 288:2981
–2997, 2002
38 Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients (STOP) with Hypertension-2 study. Lancet354 : 1751–1756,1999[Medline]
39 Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet359 : 995–1003,2002[Medline]
40 Yusuf S, Gerstein
H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, Zinman B: Ramipril and the
development of diabetes. JAMA286
: 1882–1885,2001
41 Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet363 : 2022–2031,2004[Medline]
42 Lau T, Carlsson PO, Leung PS: Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia47 : 240–248,2004[Medline]
43 Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, Steffes MW: Nephropathy in diabetes. Diabetes Care27 (Suppl. 1): S79–S83,2004[Medline]
44 Guan Y: Peroxisome
proliferator-activated receptor family and its relationship to renal
complications of the metabolic syndrome. J Am Soc
Nephrol 15:2801
–2815, 2004
45 Ruan XZ, Moorhead
JF, Fernando R, Wheeler DC, Powis SH, Varghese Z: PPAR agonists protect
mesangial cells from interleukin 1beta-induced intracellular lipid
accumulation by activating the ABCA1 cholesterol efflux pathway. J
Am Soc Nephrol 14:593
–600, 2003
46 Nakamura T, Ushiyama C, Shimada N, Hayashi K, Ebihara I, Koide H: Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients. J Diabetes Complications 14:250 –254, 2000[Medline]
47 Imano E, Kanda T, Nakatani Y, Nishida T, Arai K, Motomura M, Kajimoto Y, Yamasaki Y, Hori M: Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care 21:2135 –2139 1998[Abstract]
48 Wolffenbuttel BH, Gomis R, Squatrito S, Jones NP, Patwardhan RN: Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabet Med17 : 40–47,2000[Medline]
49 Baylis C,
Atzpodien EA, Freshour G, Engels K: Peroxisome proliferator-activated receptor
[gamma] agonist provides superior renal protection versus
angiotensin-converting enzyme inhibition in a rat model of type 2 diabetes
with obesity. J Pharmacol Exp Ther307
: 854–860,2003
50 Buckingham RE, Al-Barazanji KA, Toseland CD, Slaughter M, Connor SC, West A, Bond B, Turner NC, Clapham JC: Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes7 : 1326–1334,1998
51 Fujii M, Takemura R, Yamaguchi M, Hasegawa G, Shigeta H, Nakano K, Kondo M: Troglitazone (CS-045) ameliorates albuminuria in streptozotocin-induced diabetic rats. Metabolism 46:981 –983, 1997[Medline]
52 Isshiki K, Haneda M, Koya D, Maeda S, Sugimoto T, Kikkawa R: Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. Diabetes49 : 1022–1032,2000[Abstract]
53 The EUCLID Study Group: Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 349:1787 –1792, 1997[Medline]
54 Ruggenenti P,
Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G,
Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R,
Dodesini AR, Remuzzi G: Bergamo Nephrologic Diabetes Complications Trial
(BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes.
N Engl J Med 351:1941
–1951, 2004
55 The UKPDS Group: Tight blood pressure
control and risk of macrovascular and microvascular complications in type 2
diabetes: UKPDS 38. BMJ 317:703
–713, 1998
56 Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet355 : 253–259,2000[Medline]
57 ACE Inhibitors in Diabetic Nephropathy Trialist
Group: Should all patients with type 1 diabetes mellitus and
microalbuminuria receive angiotensin-converting enzyme inhibitors? A
meta-analysis of individual patient data. Ann Intern
Med 134:370
–379, 2001
58 Schrier RW, Estacio RO, Esler A, Mehler P: Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 61:1086 –1097, 2002[Medline]
59 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 345:870
–878, 2001
60 Viberti G.
Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study
Investigators: Microalbuminuria reduction with valsartan in patients with type
2 diabetes mellitus: a blood pressure-independent effect.
Circulation 106:672
–678, 2002
61 Lewis EJ,
Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group: The effect
of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
N Engl J Med 329:1456
–1462, 1993
62 Brenner BM, Cooper
ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang
Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in
patients with type 2 diabetes and nephropathy. N Engl J
Med 345:861
–869, 2001
63 Lewis EJ,
Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde
R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. N
Engl J Med 345:851
–860, 2001
64 Kidney Disease Outcomes Quality Initiative (K/DOQI): K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 43 (Suppl. 1):S1 –S290, 2004[Medline]
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
Related Article:
- Hypertension in Diabetes: Controlling a Critical Comorbid Condition
- Samuel L. Abbate
Diabetes Spectr 2006 19: 17.[Extract] [Full Text] [PDF]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |