Diabetic nephropathy is typically defined by either macroalbuminuria — that is, a urinary albumin excretion of greater than 300 mg in a 24-hour collection — or by abnormal renal function as represented by an abnormality in serum creatinine, calculated creatinine clearance, or glomerular filtration rate (GFR). The common progression from microalbuminuria to overt nephropathy has led many to consider microalbuminuria to define early or incipient nephropathy. Renal disease is suspected to be secondary to diabetes in the clinical setting of long-standing diabetes. This is supported by the history of diabetic retinopathy, particularly in type I diabetics, where there is a strong correlation. Clinically, diabetic nephropathy is characterized by a progressive increase in proteinuria and decline in GFR, hypertension, and a high risk of cardiovascular morbidity and mortality.

The natural history of diabetic nephropathy is a process that progresses gradually over years. Early diabetes is heralded by glomerular hyperfiltration and an increase in GFR. This is thought to be related to increased cell growth and expansion in the kidney, possibly mediated by hyperglycemia itself. Microalbuminuria typically occurs after 5 years in type I diabetes. Overt nephropathy, with urinary protein excretion greater than 300 mg/day, often develops after 10 to 15 years. ESRD develops in 50% of type I diabetics, with overt nephropathy within 10 years' time.

Type II diabetes has a more variable course. Patients often present at diagnosis with microalbuminuria because of delays in diagnosis and other factors affecting protein excretion. Fewer patients with microalbuminuria progress to advanced renal disease. Without intervention, approximately 30% progress to overt nephropathy, and after 20 years of nephropathy, approximately 20% develop ESRD. Because of the high prevalence of type II compared to type I diabetes, however, the majority of diabetics on dialysis are type II diabetics (Table 1).

In the United States, approximately 17 million people, or 6.2% of the population, are estimated to have diabetes, with a growing incidence. Roughly one third of this population is estimated to be undiagnosed with type II diabetes. The prevalence of diabetes is higher in certain racial and ethnic groups, affecting approximately 13% of African Americans, 10.2% of Hispanics, and 15.1% of Native Americans, primarily with type II diabetes. Approximately 20% to 30% of all diabetics will develop evidence of nephropathy, although a higher percentage of type I patients progresses to ESRD.

Ongoing research has led to further understanding of the complex pathophysiology in diabetic nephropathy. Increased glomerular capillary pressure occurs early in diabetes and is associated with hyperfiltration at the glomerulus. The glomerular mesangium expands, initially by cell proliferation and then by cell hypertrophy. Increased mesangial stretch and pressure can stimulate this expansion, as can high glucose levels. Mediators of proliferation and expansion include platelet-derived growth factor and transforming growth factor-ß (TGF-ß). TGF-ß is particularly important in the mediation of expansion and later fibrosis via the stimulation of collagen and fibronectin.

Glucose can bind irreversibly to proteins in the kidney and circulation to form so-called advanced glycosylation end products (AGEs). AGEs can form complex crosslinks over years of hyperglycemia and can contribute to renal damage by stimulation of growth and fibrotic factors via receptors for AGEs.

Angiotensin II (ATII) itself contributes to the progression of diabetic nephropathy. ATII is stimulated in diabetes despite the high-volume state typically seen with the disease, and intra-renal ATII is typically high, even in the face of lower systemic concentrations. ATII preferentially constricts the efferent arteriole in the glomerulus, leading to higher glomerular capillary pressures. In addition to its hemodynamic effects, ATII also stimulates renal growth and fibrosis through ATII type 1 receptors, which secondarily upregulate TGF-ß and other growth factors.

Diabetic nephropathy is also an inflammatory process with evidence of macrophage infiltration in glomeruli with early diabetic sclerosis. There is upregulation of monocyte chemoattractant protein-1 (MCP-1) in diabetes, which stimulates macrophage infiltration both in the glomeruli and in the renal interstitium. Macrophages enter from the circulation and release inflammatory mediators and cytokines. MCP-1 is stimulated by ATII and can be down-regulated by renin-angiotensin blockade in experimental models.

Tubulointerstitial fibrosis is seen in advanced stages of diabetic nephropathy and is a better predictor of renal failure than glomerular sclerosis. Hyperglycemia, ATII, TGF-ß, and likely proteinuria itself all play a role in stimulating this fibrosis. There is an epithelial-mesenchymal transition that takes place in the tubules, with proximal tubular cell conversion to fibroblast-like cells. These cells can then migrate into the interstitium and produce collagen and fibronectin.

Thus, early expansion and proliferation, with high glomerular pressures and hyperglycemia, herald the development of diabetic nephropathy. After years of expansion, fibrosis begins to develop as TGF-ß upregulation leads to secondary collagen and fibronectin production. Inflammatory cells cause cellular damage and scarring through release of cytokines and oxygen radicals, and ultimately renal cells themselves may transform into fibroblasts and cause late tubulointerstitial fibrosis.

It is not uncommon to find micro- or macroalbuminuria in a type II diabetic at or soon after the initial diagnosis of diabetes. This may be because the patient has had undiagnosed diabetes for many years, or it may relate to the contributions of hypertension or other processes that may cause proteinuria independently of diabetes, such as small-vessel atherosclerosis. Microalbuminuria is now recognized as an independent cardiac risk factor even in the absence of diabetes. Screening for microalbuminuria in non-diabetics may have important implications for cardiac risk, and should lead to instituting some of the same therapies used in diabetic nephropathy (Table 2).

Frequently the question is raised as to whether proteinuria is from diabetes or from a primary renal disease. Suspicion may arise in patients with significant proteinuria without a long history of diabetes, or without other signs of end-organ damage such as retinopathy or neuropathy. While the presence of retinopathy supports a diabetic source of proteinuria, the lack of diabetic retinopathy does not rule out diabetic nephropathy, particularly in type II diabetics. Patients with diabetes can develop nephrotic-range proteinuria (greater than 3.5 grams/24 hours), but typically only after long-standing diabetes. A bland urine sediment supports the diagnosis of diabetes, although it is not uncommon to have some microscopic hematuria with advanced diabetic nephropathy. The presentation of an acute nephrotic syndrome, rapidly rising urinary protein, or rapidly declining GFR should lead to the consideration of renal biopsy. The finding of red cell or white cell casts in the urine should also make one consider a biopsy.

Often a patient will present without available history and may be frankly nephrotic in the face of longstanding diabetes. In cases of uncertainty like this it is not wrong to consider a renal biopsy, since the finding of a primary glomerular disease could potentially change the course of management.

In screening for diabetic nephropathy, we recommend early testing for glucose intolerance and diabetes to identify patients who are at risk for developing microalbuminuria, particularly if they have other risks for type II diabetes such as hypertension, lipid abnormalities, or central obesity. As stated above, approximately one-third of type II diabetics are thought to be undiagnosed. Once the diagnosis of diabetes has been made, we routinely check urinary protein only to guide therapy and prognosis. We often do not wait to see microalbuminuria before instituting therapy with angiotensin blockade, especially if patients are not at goal for blood pressure.

Glycemic Control
One keystone in the prevention and management of diabetic nephropathy is tight glycemic control. In the Diabetes Control and Complications Trial, type I diabetics were randomized to intensive or conventional insulin treatments and followed for an average of 6.5 years.¹ Average hemoglobin A1c (HbA1c) values were 7.2% versus 9.2%. There was a 39% risk reduction in the development of microalbuminuria and a 54% reduction in development of macroalbuminuria in the intensive treatment group. Glycemic control in type II diabetics was also studied in the UK Prospective Diabetes Study (UKPDS).² 3,867 patients with newly diagnosed type II diabetes were randomized to oral or insulin therapy versus dietary control and followed for 11 years. The difference in HbA1c was 7.0% versus 7.9%. After 9 years, there was a significant risk reduction in the intensive group, with a relative risk of 0.76 for the development of microalbuminuria. Finally, the complete correction of hyperglycemia with pancreatic transplant in type I diabetics has led to a dramatic resolution in glomerular and tubular expansion and fibrosis over time.³ With a drop in HbA1c from an average of 8.7% to 5.5% in eight transplanted patients, there was a significant reduction in basement membrane thickening and mesangial expansion on repeat biopsies over time. Even glomerular sclerosis appeared to resolve, showing that renal fibrosis may be reversible, although it took 10 years after transplant to see these significant changes.

Treatment of Blood Pressure
Control of blood pressure is the other keystone in prevention and treatment. Blood pressure control is critical in slowing the natural history of diabetic nephropathy in both type I and type II diabetics. Parving et al studied 12 type I diabetics and treated hypertension before angiotensin inhibitors were available.⁴ Using metoprolol, hydralazine, and diuretics, patients with macroalbuminuria and declining GFR were treated to reduce mean arterial pressure from 120 to under 105 mm Hg. An initial decline in GFR was noted in most patients immediately after blood pressure lowering. However, 2-year subsequent follow-up showed a slowing in the rate of reduction of GFR from an average of 0.91 ml/min/month to 0.39 ml/min/month, with significant preservation of GFR above that expected from pretreatment measurements. The initial drop in GFR illustrated a functional or hemodynamic effect of antihypertensive treatment, which does not lead to permanent renal damage but rather to renal preservation. A recent review has recommended maintaining antihypertensive therapy in renal disease even if therapy causes some hemodynamic drop in GFR, providing there is a stabilization in creatinine with an increase of less than 30% of baseline.⁵

Blood pressure control has also been shown to reduce the risk of diabetic complications in type II diabetics. The UKPDS studied 1,148 hypertensive patients who had recently been diagnosed with type II diabetes.⁶ Patients were assigned to tight blood pressure control, achieving a mean level of 144/82 mm Hg, or less tight control, with a mean pressure of 154/81 mm Hg. After a median follow-up of 8.4 years, there was significant reduction in risk of death related to diabetes, stroke, and microvascular disease in the tight control group. There was no difference in outcomes within the tight control group in patients assigned to either atenolol or captopril, although captopril was dosed only twice daily at 25-50 mg/dose.

The importance of blood pressure control, no matter what agent is used, cannot be emphasized enough in diabetes, both for slowing progression of nephropathy and for preventing cardiovascular morbidity and mortality. Currently, the recommendation from the most recent Joint National Committee guidelines is that blood pressure in diabetics be reduced to less than 130/80 mm Hg.⁷ Some studies of hypertension treatment in diabetics have shown benefit with lowering blood pressure even further. For example, in the Hypertension Optimal Treatment trial, diabetics with a target diastolic pressure of 80 mm Hg had half of the cardiovascular events seen in patients with a target of 90 mm Hg.⁸ Furthermore, the Modification of Diet in Renal Disease Study found value in further reduction in a diverse group of patients with renal disease and proteinuria.⁹ In patients with 24-hour urinary protein greater than 1 gram, a blood pressure at or below 125/75 was shown to slow the decline in GFR. Based on the above data, we recommend a target blood pressure of < 130/80 in all diabetics, with a further goal of 125-130/75-80 in diabetics with macroalbuminuria (Table 3). These blood pressure goals may seem difficult to accomplish in some patients, but within clinical trials preset goals have been consistently achieved. It is important for clinicians and patients to be aware early on that three or more agents may be required to achieve the blood pressure goal, and these agents will likely be needed long term.

It is important to emphasize that diuretics are extremely beneficial adjuncts in blood pressure control and are often missing in patients who are not close to meeting blood pressure goals. Diuretics are first-line agents for many hypertensives, and we routinely add a diuretic as a second-line agent after angiotensin blockade in diabetics. Thiazide diuretics work well even at low dosages for patients with normal renal function. For example, just 12.5 to 25 mg/day of hydrochlorothiazide is often effective. When GFR is below 60, we often institute loop diuretics for a better natriuretic effect. Short-acting loops such as furosemide work better when dosed at least twice daily to avoid rebound sodium retention.

Angiotensin II Blocking Agents
Specific use of agents that block the renin-angiotensin system appears to be particularly beneficial in the prevention or slowing of progression of diabetic nephropathy. ATII can increase glomerular capillary pressure by preferentially constricting the renal efferent arteriole. ATII also stimulates renal cell growth and fibrosis independent of hemodynamic effects. Even with blood pressure at goal and without microalbuminuria, we consider initiation of low dosages of angiotensin blocking agents, with titration up as tolerated. Other antihypertensives may not offer this antiproliferative effect and may cause adverse hemodynamic effects. For example, the calcium channel blockers, in particular the dihydropyridines, cause afferent dilation and thus may increase glomerular capillary pressure. Dihydropyridines may best be reserved as third- or fourth-line agents in patients with diabetes, only after angiotensin blockade and diuretics have already been instituted.

The benefits of angiotensin converting enzyme inhibitors (ACEIs) were shown by the Collaborative Study Group using captopril compared with placebo in 409 patients with type I diabetes and macroalbuminuria.¹⁰ Patients with a creatinine greater than 1.5 mg/dl had a significant reduction in risk of doubling serum creatinine and of the composite of death, dialysis, or transplantation when treated with captopril, even after controlling for changes in blood pressure. Second, a substudy of the Heart Outcomes Prevention Evaluation (HOPE) looked at 3,577 patients age 55 or older with diabetes and randomized to ramipril 10 mg/day or placebo.¹¹ All patients had at least one other cardiac risk factor in addition to diabetes, including lipid abnormalities, hypertension, microalbuminuria, or current smoking. Patients with dipstick-positive proteinuria and overt nephropathy were excluded, as were patients with congestive heart failure. The ramipril group had a reduction in blood pressure of 2.5 mm Hg systolic and 1 mm Hg diastolic. When corrected for blood pressure, there was a significant reduction in risk of stroke and cardiovascular morbidity and mortality. There was also a relative risk reduction of 24% in the progression to diabetic nephropathy in all patients, although this was not controlled for the minor change in blood pressure. In subgroup analysis, the diabetics who had significant benefit were those who already had either coronary disease or microalbuminuria.

Angiotensin receptor blockers (ARBs) have also shown renal protection recently in type II diabetics. Two studies looking at the prevention of progression in patients with microalbuminuria have recently been published.^12,13 Both irbesartan and valsartan were shown to lower albumin excretion and prevent development of diabetic nephropathy, even when controlling for changes in blood pressure. The effects of irbesartan appeared to be dosage dependent, with greater protection at 300 mg/day versus 150 mg/day. The study using valsartan did not stratify for dosage, and the average dosage was 122 mg/day. Two trials of ARBs in patients with overt diabetic nephropathy have also shown a decline in rate of progression of disease.^14,15 Both studies showed a slowing in the rate of progression to doubling of creatinine or to ESRD using irbesartan titrated to 300 mg/day or losartan at an average dosage of 85.5 mg/day. The benefit in both studies was impressive, although importantly the treatment only decreased the rate of progression of disease but did not halt it. The average patient had a delay in progression to ESRD of about 2 years.

Angiotensin blockade should be started early and may have its greatest benefit in prevention or reversal of early kidney disease. Extrapolating from nondiabetic renal disease, the Ramipril Efficacy in Nephropathy trial demonstrated that even patients with very mild renal disease and high GFR benefited from ACE inhibition.¹⁶ Patients with GFR ranging from 51.7 to 100.9 and averaging 71.1 were shown to have similar slowing in reduction of GFR over time with ramipril as patients with lower GFR. There may even be some reversal of kidney disease early on with angiotensin blockade. In both trials of irbesartan and valsartan in type II diabetics with microalbuminuria, a significant percentage of treated patients had albumin excretion decrease into the normal range. Irbesartan at 300 mg/day led to a 34% incidence of normalization of protein excretion compared to 21% in the placebo group. Similarly, valsartan treatment led to an approximately 30% normalization compared to 14.5% in the placebo group. Early treatment is important to prevent and possibly even reverse diabetic nephropathy.

The combination of an ACEI and an ARB has been tried in one study.¹⁷ Lisinopril 20 mg/day and candesartan 16 mg/day were given individually and then in combination in patients with type II diabetes, hypertension, and microalbuminuria. Any patient with a diastolic blood pressure less than 80 mm Hg was not eligible to receive the combination, thus excluding one-quarter of the original participants. In the remaining patients receiving the combination, there was a further lowering in blood pressure and in urinary protein excretion compared to either agent alone, and the treatment was well tolerated.

We recommend attempting to maximize angiotensin blockade as much as patients will tolerate, especially given the dosage-related benefits shown in some studies. The benefit of using an ACEI/ARB combination over a higher dosage of a single agent alone has not been proven, but regardless of the agent used, more seems to be better. If the maximal dosage of one agent has been achieved, it is certainly reasonable to introduce the second agent. Some are recommending adding an ARB to an ACEI once a moderate dosage of the ACEI is achieved. There may be ATII formation independent of ACE, and blocking the receptor should block this ATII activity. Angiotensin blockade may reach a threshold above which further benefit will not be gained, and animal studies at supramaximal dosages of ACEIs and ARBs show incomplete blockage of TGF-ß. However, many patients are underdosed and could gain more benefit from maximal therapy.

At this point it is difficult to recommend one type of ARB over another for initial treatment in diabetics. There are ample data supporting ACEIs for type I diabetics. Based on data from the HOPE trial, it would seem acceptable to also choose an ACEI in type II diabetics with coronary artery disease, although beta-blockers remain first line agents. Similarly, in patients with congestive heart failure, trials of ARBs are in progress but ACEIs remain first-line agents. Patients with type II diabetes and either microalbuminuria or overt nephropathy but no known cardiac disease should probably receive an ARB as first-line treatment based on recent data reviewed above (Table 3).

It is important to treat with angiotensin blockade even in patients with baseline renal insufficiency. Even patients with a high serum creatinine are candidates for angiotensin blockade, although patients need close follow-up with cautious titration. As stated above, GFR often drops some at initiation of therapy, and close monitoring of renal function should take place within a week or two of starting medication. Providing there is a bump of no more than 30% in serum creatinine and it remains stable, therapy may be continued.⁵

ACEIs and ARBs are generally both very well tolerated. However, attempting to institute and titrate either agent must be done while monitoring for side effects such as symptomatically low blood pressure or hyperkalemia. We often tolerate a potassium level in the mid-five range if it remains stable, just as we tolerate a mild, stable bump in serum creatinine. Patients should be monitored for hyperkalemia within 1 week of starting or changing the dosage of either agent, and should be counseled on limiting potassium in the diet. Diuretics such as thiazides or loop diuretics are often useful and necessary adjunctive treatments for blood pressure control, and can have the added benefit of offsetting a rise in serum potassium. The side effect of cough secondary to bradykinin accumulation with an ACEI may necessitate conversion to an ARB. Whether bradykinins themselves have any benefit in hypertension or heart disease is debated.

Rarely, severe, life-threatening angioedema can occur with either ACEIs or ARBs. This side effect has been reported even months or years after starting an ACEI. The incidence of angioedema appears to be less frequent with ARBs. In a patient with history of ACEI-induced angioedema, an ARB may be started cautiously at a low dosage if there is a strong indication such as diabetes and microalbuminuria, but should probably be held if there is no abnormal urinary albumin excretion.¹⁸ ACEIs and ARBs are also both contraindicated in pregnancy, and should be used with caution in women of childbearing potential.

Dietary Changes
A common question from patients and primary care providers is whether the reduction of dietary protein is beneficial in diabetic nephropathy. Many animal studies of glomerulopathies have shown reduction in decline in renal function by restricting dietary protein. The data in humans remain inconclusive, however. We currently counsel patients to avoid protein supplements such as protein shakes or powders, but do not otherwise restrict protein from the diet. Others recommend a restriction of 0.8 g/kg/day in patients with overt nephropathy, or even 0.6 g/kg/day in the face of a falling GFR.

It is important to maintain a low-sodium diet in diabetic nephropathy. Many diabetics with renal disease are salt sensitive, and minimizing salt intake can help in reaching blood pressure goals, with secondary benefits of decreased stroke risk, regression of left ventricular hypertrophy, and reduction in proteinuria. We advocate a low-sodium diet of equal or less than 2.3 grams (5.8 grams of NaCl) or 100 mEq daily in patients with diabetes and either hypertension or any degree of proteinuria.

Avoidance of Nephrotoxins
It is important to avoid nephrotoxic agents if possible in patients with diabetic nephropathy. Nonsteroidal antiinflammatory drugs (NSAIDs) can cause a significant drop in GFR in patients with diabetic nephropathy, particularly when used with angiotensin-blocking agents. Daily low-dosage aspirin is safe in diabetics, and the cardiac benefits greatly outweigh any risk. However, aspirin at higher dosages and other NSAIDs should be avoided if possible. Cyclooxygenase 2 (COX-2) inhibitors are similar to other NSAIDs in their potential for renal toxicity.

Radiocontrast media are also particularly nephrotoxic in diabetics. Even with normal serum creatinine, patients with diabetes and proteinuria should be volume loaded with normal saline 12 hours before and after exposure to contrast if possible. Diuretics should be temporarily discontinued, and hyperglycemia should be controlled. Other agents such as dopamine-like agonists and acetylcysteine may help prevent contrast nephropathy in diabetics but require further study.

Other Pharmacologic Agents
There are other classes of agents currently under study for diabetic nephropathy that may show hope for the future. Aldosterone receptor antagonists decrease proteinuria further in patients with diabetes on ACE inhibitors.¹⁹ Eplerenone, a new aldosterone blocking agent, has recently been approved by the Food and Drug Administration. It is similar to spironolactone but lacks the sex steroid side effects such as impotence and gynecomastia. It is currently under study in diabetics with proteinuria who are already being treated with ACEIs. One side effect that must be monitored is hyperkalemia, which may be increased with this combination.

HMG coenzyme-A reductase inhibitors, or statins, are also being studied. There are already recommendations for tight lipid control in diabetics because of the high cardiac risk in these patients. Statins may have additional unique benefits independent of lipid lowering. In animal models of diabetic nephropathy, statin treatment blocks intracellular signaling and decreases the mRNA expression of TGF-ß.²⁰

Agents that directly inhibit or degrade TGF-ß or inhibit AGEs have shown success in animals and are being developed for clinical human trials. One such agent, currently known as ALT-711, breaks crosslinks in AGE complexes. It has been shown to improve vascular endothelial function in diabetes and may have promise in diabetic nephropathy.²¹

Nephrology Referral
Referral to a nephrologist should be considered if the GFR is steadily declining or is already below 60-70 ml/min. Challenges in blood pressure control, hyperkalemia, or rising creatinine on angiotensin blockade may also prompt a referral. We consider it appropriate to refer a patient in any situation where the primary physician feels he or she needs additional input or assistance with management of diabetic nephropathy.

Prevention and treatment of diabetic nephropathy consist of tight glucose control and tight blood pressure control, starting with angiotensin blockade but often adding multiple agents as necessary to meet blood pressure goals. Avoidance of nephrotoxins is important. Other measures such as lipid control, smoking cessation, weight loss, and exercise modulate cardiac risk and may also inhibit the progression of renal disease itself. Future treatments may target and even reverse lesions in advanced diabetic nephropathy. For now, however, early aggressive treatment is most effective in the prevention of renal failure. Therefore, screening for diabetes and for glucose intolerance early on is important, and initiating aggressive treatment at or before the onset of microalbuminuria is the best strategy.

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