Diabetic Nephropathy

Back

Background

Diabetic nephropathy is a clinical syndrome characterized by the following:

Proteinuria was first recognized in diabetes mellitus in the late 18th century. In the 1930s, Kimmelstiel and Wilson described the classic lesions of nodular glomerulosclerosis in diabetes associated with proteinuria and hypertension. (See Pathophysiology.)

By the 1950s, kidney disease was clearly recognized as a common complication of diabetes, with as many as 50% of patients with diabetes of more than 20 years having this complication. (See Epidemiology.)

Currently, diabetic nephropathy is the leading cause of chronic kidney disease in the United States and other Western societies. It is also one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes. Diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States. (See Prognosis.)

Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients may have physical findings associated with long-standing diabetes mellitus. (See Clinical Presentation.)

Good evidence suggests that early treatment delays or prevents the onset of diabetic nephropathy or diabetic kidney disease. (See Treatment and Management.)

Regular outpatient follow-up is key in managing diabetic nephropathy successfully. (See Long-term Monitoring.)

Recently, attention has been called to atypical presentations of diabetic nephropathy with dissociation of proteinuria from reduced kidney function. Also noted is that microalbuminuria is not always predictive of diabetic nephropathy.[1] Nevertheless, a majority of the cases of diabetic nephropathy presents with proteinuria, which progressively gets worse as the disease progresses, and is almost uniformly associated with hypertension.

Go to Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2 for more complete information on these topics.

Pathophysiology

Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins. Second, thickening of the glomerular basement membrane (GBM) occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). These different histologic patterns appear to have similar prognostic significance.

The key change in diabetic glomerulopathy is augmentation of extracellular matrix. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix. The image below is a simple schema for the pathogenesis of diabetic nephropathy.


View Image

Simple schema for the pathogenesis of diabetic nephropathy.

Light microscopy findings show an increase in the solid spaces of the tuft, most frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction) material (diffuse diabetic glomerulopathy). Large acellular accumulations also may be observed within these areas. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules.

Immunofluorescence microscopy may reveal deposition of albumin, immunoglobulins, fibrin, and other plasma proteins along the GBM in a linear pattern, most likely as a result of exudation from the blood vessels, but this is not immunopathogenetic or diagnostic and does not imply an immunologic pathophysiology. The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia and hypertensive arteriosclerosis.

Electron microscopy provides a more detailed definition of the structures involved. In advanced disease, the mesangial regions occupy a large proportion of the tuft, with prominent matrix content. Further, the basement membrane in the capillary walls (ie, the peripheral basement membrane) is thicker than normal.

The severity of diabetic glomerulopathy is estimated by the thickness of the peripheral basement membrane and mesangium and matrix expressed as a fraction of appropriate spaces (eg, volume fraction of mesangium/glomerulus, matrix/mesangium, or matrix/glomerulus).

The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).

In addition to the renal hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing glomerular filtration rate [GFR]) generally develop systemic hypertension. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature.

Evidence suggests that hypertension associated with obesity, metabolic syndrome, and diabetes may play an important role in the pathogenesis of diabetic nephropathy. Central obesity, metabolic syndrome, and diabetes lead to increased blood pressure.

Central obesity induces hypertension initially by increasing renal tubular reabsorption of sodium and causing a hypertensive shift of renal-pressure natriuresis through multiple mechanisms, including activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as physical compression of the kidneys.[2] Hypertension, along with increases in intraglomerular capillary pressure and the metabolic abnormalities (eg, dyslipidemia, hyperglycemia) likely interact to accelerate renal injury.

Similar to obesity-associated glomerular hyperfiltration, renal vasodilation, increases in the glomerular filtration rate and intraglomerular capillary pressure, and increased blood pressure also are characteristics of diabetic nephropathy.[3] Increased systolic blood pressure further exacerbates the disease progression to proteinuria and a decline in the glomerular filtration rate, leading to end-stage kidney disease.

Etiology

The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycosylation products, and activation of cytokines. Many investigators now agree that diabetes is an autoimmune disorder, with overlapping pathophysiologies contributing to both type 1 and type 2 diabetes; and recent research highlights the pivotal role of innate immunity (toll-like receptors) and regulatory T-cells (Treg).[4]

Glycemic control reflects the balance between dietary intake and gluconeogenesis and tissue uptake or utilization through storage as glycogen or fat and oxidation. This balance is regulated by insulin production from the β cells in the pancreas. Insulin regulates serum glucose through its actions on liver, skeletal muscle, and fat tissue. When there is insulin resistance, insulin cannot suppress hepatic gluconeogenesis, which leads to hyperglycemia. Simultaneously, insulin resistance in the adipose tissue and skeletal muscle leads to increased lipolysis, causing hyperlipidemia in addition to hyperglycemia.

Evidence suggests that when there is insulin resistance, the pancreas is forced to increase its insulin output, which stresses the β cells, eventually resulting in β-cell exhaustion. The high blood glucose levels and high levels of saturated fatty acids create an inflammatory medium, resulting in activation of the innate immune system, which results in activation of the nuclear transcription factors-kappa B (NF-κB), and release of inflammatory mediators, including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α, promoting systemic insulin resistance and β-cell damage as a result of autoimmune insulitis.

The consequent insulin resistance further leads to high glucose levels, along with high serum levels of free fatty acids and IL-1, leading to glucotoxicity, lipotoxicity, and IL-1 toxicity, resulting in apoptotic β-cell death.

Hyperglycemia also increases the expression of transforming growth factor-β (TGF-β) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF-β and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy.[5, 6] Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes.[7]

Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes.

It has been argued that the genetic predisposition to diabetes that is so frequent in Western societies, and even more so in minorities, reflects the fact that in the past, insulin resistance conferred a survival advantage (the so-called thrifty genotype hypothesis).

Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. However, definitive genetic markers have yet to be identified. More recently, the role of epigenetic factors, especially micro-RNAs, has appeared as another contributing mechanism.[8]

Epidemiology

Since the 1950s, kidney disease has been clearly recognized as a common complication of diabetes mellitus (DM), with as many as 50% of patients with DM of more than 20 years’ duration having this complication.

United States statistics

Diabetic nephropathy rarely develops before 10 years’ duration of type 1 DM (also known as insulin-dependent diabetes mellitus [IDDM]). Approximately 3% of newly diagnosed patients with type 2 DM (also known as non–insulin-dependent diabetes mellitus [NIDDM]) have overt nephropathy. The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-20 years, after which the rate progressively declines.

The risk for the development of diabetic nephropathy is low in a normoalbuminuric patient with diabetes’ duration of greater than 30 years. Patients who have no proteinuria after 20-25 years have a risk of developing overt renal disease of only approximately 1% per year.

In terms of diabetic kidney disease in the United States, the prevalence increased from 1988-2008 in proportion to the prevalence of diabetes.[9] Among people with diabetes, the prevalence of diabetic kidney disease remained stable.

International statistics

Striking epidemiologic differences exist even among European countries. In some European countries, particularly Germany, the proportion of patients admitted for renal replacement therapy exceeds the figures reported from the United States. In Heidelberg (southwest Germany), 59% of patients admitted for renal replacement therapy in 1995 had diabetes and 90% of those had type 2 DM. An increase in end-stage renal disease (ESRD) from type 2 DM has been noted even in countries with notoriously low incidences of type 2 DM, such as Denmark and Australia. Exact incidence and prevalence from Asia are not readily available.

Sex distribution for diabetic nephropathy

Diabetic nephropathy affects males and females equally.

Age distribution for diabetic nephropathy

Diabetic nephropathy rarely develops before 10 years’ duration of type 1 DM. The peak incidence (3%/y) is usually found in persons who have had diabetes for 10-20 years. The mean age of patients who reach end-stage kidney disease is about 60 years. Although in general, the incidence of diabetic kidney disease is higher among elderly persons who have had type 2 diabetes for a longer generation, the role of age in the development of diabetic kidney disease is unclear. In Pima Indians with type 2 diabetes, the onset of diabetes at a younger age was associated with a higher risk of progression to end-stage kidney disease.[10]

Prevalence of diabetic nephropathy by race

The severity and incidence of diabetic nephropathy are especially great in blacks (the frequency being 3- to 6-fold higher than it is in whites), Mexican Americans, and Pima Indians with type 2 DM. The relatively high frequency of the condition in these genetically disparate populations suggests that socioeconomic factors, such as diet, poor control of hyperglycemia, hypertension, and obesity, have a primary role in the development of diabetic nephropathy. It also indicates that familial clustering may be occurring in these populations.

By age 20 years, as many as half of all Pima Indians with diabetes have developed diabetic nephropathy, with 15% of these individuals having progressed to ESRD.

Prognosis

Diabetic nephropathy accounts for significant morbidity and mortality.

Proteinuria is a predictor of morbidity and mortality. (See Workup.) The overall prevalence of microalbuminuria and macroalbuminuria in both types of diabetes is approximately 30-35%. Microalbuminuria independently predicts cardiovascular morbidity, and microalbuminuria and macroalbuminuria increase mortality from any cause in diabetes mellitus. Microalbuminuria is also associated with increased risk of coronary and peripheral vascular disease and death from cardiovascular disease in the general nondiabetic population.

Patients in whom proteinuria did not develop have a low and stable relative mortality rate, whereas patients with proteinuria have a 40-fold higher relative mortality rate. Patients with type 1 DM and proteinuria have the characteristic bell-shaped relationship between diabetes duration/age and relative mortality, with maximal relative mortality in the age interval of 34-38 years (as reported in 110 females and 80 males).

ESRD is the major cause of death, accounting for 59-66% of deaths in patients with type 1 DM and nephropathy. In a prospective study in Germany, the 5-year survival rate was less than 10% in the elderly population with type 2 DM and no more than 40% in the younger population with type 1 DM.

The cumulative incidence of ESRD in patients with proteinuria and type 1 DM is 50% 10 years after the onset of proteinuria, compared with 3-11% 10 years after the onset of proteinuria in European patients with type 2 DM.

A study by Rosolowsky et al found that despite renoprotective treatment, including transplantation and dialysis, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD.[11]

Although both type 1 and type 2 DM lead to ESRD, the great majority of patients are those with type 2 diabetes. The fraction of patients with type 1 DM who develop renal failure seems to have declined over the past several decades. However, 20-40% still have this complication. On the other hand, only 10-20% of patients with type 2 DM develop uremia due to diabetes. Their nearly equal contribution to the total number of patients with diabetes who develop kidney failure results from the higher prevalence of type 2 DM (5- to 10-fold).

Cardiovascular disease is also a major cause of death (15-25%) in persons with nephropathy and type 1 DM, despite their relatively young age at death.

Patient Education

Patient education is key in trying to prevent diabetic nephropathy. Appropriate education, follow-up, and regular doctor visits are important in prevention and early recognition and management of diabetic nephropathy.

For excellent patient education resources, visit eMedicineHealth’s Diabetes Center. In addition, see eMedicineHealth’s patient education article Diabetes Mellitus.

For further information, see Mayo Clinic - Kidney Transplant Information.

History

Diabetic nephropathy should be considered in patients who have diabetes mellitus (DM) and a history of one or more of the following:

Physical Examination

Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients may have physical findings associated with long-standing diabetes mellitus, such as the following:

Almost all patients with nephropathy and type 1 DM demonstrate signs of diabetic microvascular disease, such as retinopathy and neuropathy.[12] Clinical detection of the retinopathy is easy, and in these patients the condition typically precedes the onset of overt nephropathy. The converse is not true. Only a minority of patients with advanced retinopathy have histologic changes in the glomeruli and increased protein excretion that is at least in the microalbuminuric range, and most have little or no renal disease (as assessed by renal biopsy and protein excretion).

Patients with type 2 DM who have marked proteinuria and retinopathy typically have diabetic nephropathy, while those persons who do not have retinopathy frequently exhibit nondiabetic glomerular disease.

To see complete information on the conditions below, please go to the main article by clicking on the title:

Approach Considerations

Diabetic nephropathy is characterized by the following:

The rate of decline in the GFR in various stages of type 1 and type 2 diabetes is shown in the image below.


View Image

Rate of decline in glomerular filtration rate in various stages of type 1 and type 2 diabetes.

Whether cystatin C or creatinine-based calculation of GFR is the most sensitive measure for assessing early decline in renal function in patients with type 2 diabetes who have mild-to-moderate chronic kidney disease is controversial. The two methods were compared in a cohort of 448 patients with type 2 diabetes. Creatinine-based calculation was found to be more accurate than cystatin-C, which confirms the current practice in diabetes literature of reporting estimated GFR primarily by creatinine decrements and the modification of diet in renal disease (MDRD) calculation.[13]

Urinalysis

A 24-hour urinalysis for urea, creatinine, and protein is extremely useful in quantifying protein losses and estimating the GFR. Typically, the urinalysis results from a patient with established diabetic nephropathy show proteinuria varying from 150 mg/dL to greater than 300 mg/dL, glucosuria, and occasional hyaline casts.

Microalbuminuria is defined as albumin excretion of more than 20 μg/min or an albumin-to-creatinine ratio (µg/g) of greater than 30. This phase indicastes incipient diabetic nephropathy and calls for aggressive management, at which stage the disease may be potentially reversible (ie, microalbuminuria can regress). (See the image below.)


View Image

Screening for and prevention of the progression of microalbuminuria in diabetes mellitus. (ACE-I stands for angiotensin-converting enzyme inhibitor)

Perform microscopic urinalysis to help rule out a potentially nephritic picture, which may lead to a workup to rule out other primary glomerulopathies, especially in the setting of rapidly deteriorating renal function (eg, rapidly progressive glomerulonephritis). In general, onset of overt proteinuria with less than 5 years of the onset of diabetes, an active urine sediment with dysmorphic red cells and casts, or an abrupt decline in kidney function suggests a nondiabetic etiology of the kidney disease.

Blood Tests

Blood tests, including calculation of GFR (by various formulas, such as the MDRD formula), are helpful in monitoring for the progression of kidney disease and in assessing its stage.

Serum and Urinary Electrophoresis

Serum and urinary electrophoresis is performed mainly to help exclude multiple myeloma (in the appropriate setting) and to classify the proteinuria (which is predominantly glomerular in diabetic nephropathy).

Renal Ultrasonography

Observe for kidney size, which is usually normal to increased in the initial stages and, later, decreased or shrunken with chronic renal disease. Rule out obstruction. Perform echogenicity studies for chronic renal disease.

Renal Biopsy

Renal biopsy is not routinely indicated in all cases of diabetic nephropathy, especially in persons with a typical history and a progression typical of the disease. It is indicated if the diagnosis is in doubt, if other kidney disease is suggested, or if atypical features are present.

Histologic Findings

The following three major histologic changes occur in the glomeruli of persons with diabetic nephropathy:

These different histologic patterns appear to have similar prognostic significance.

Staging

See the image below regarding the developmental stages in the natural history of diabetic nephropathy.


View Image

Stages in the development of diabetic nephropathy.

Approach Considerations

Several issues are key in the medical care of patients with diabetic nephropathy.[14, 15] These include glycemic control, management of hypertension, and reducing dietary salt intake and phosphorus and potassium restriction in advanced cases.

A meta-analysis from the Cochrane Database shows a large fall in blood pressure with salt restriction, similar to that of single-drug therapy.[16] All diabetics should consider reducing salt intake at least to less than 5-6 g/d, in keeping with current recommendations for the general population, and may benefit from lowering salt intake to even lower levels. Reducing dietary salt intake may help slow progression of diabetic kidney disease. Renal replacement therapy may be necessary in patients with end-stage renal disease (ESRD).

A 2012 post-hoc analysis of the data merged from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial and the Irbesartan Diabetic Nephropathy Trial (IDNT) in 1177 patients demonstrated that a low-sodium diet (24-h urinary sodium/creatinine ratio (mmol/g) < 121) enhanced the renoprotective and cardioprotective effect of angiotensin receptor blockers (losartan or irbesartan) in type 2 diabetic patients with nephropathy. Compared with higher sodium intake groups, the patients in the low-sodium group had better renal (by 43%) and cardiovascular (by 37%) outcomes. These improved outcomes in the low-sodium group underscore the importance of recent calls for population-wide intervention to reduce dietary salt intake, particularly in patients with diabetes and nephropathy treated with angiotensin receptor blockers.[17]

Glycemic Control

In persons with either type 1 or type 2 diabetes mellitus (DM), hyperglycemia has been shown to be a major determinant of the progression of diabetic nephropathy. The evidence is best reported for type 1 DM.

It has been shown that intensive therapy can partially reverse glomerular hypertrophy and hyperfiltration, delay the development of microalbuminuria, and stabilize or even reverse microalbuminuria.

Results from pancreatic transplant recipients in whom true euglycemia is restored suggest that strict glycemic and metabolic control may slow the progression rate of progressive renal injury even after overt dipstick-positive proteinuria has developed.

In the Diabetes Control and Complications Trial, reduction in microvascular complications was of a smaller magnitude in patients with type 2 DM receiving intensive insulin therapy than in patients with type 1 DM.[18] In an outcome and cost-effective analysis of the United Kingdom Prospective Diabetes Study (UKPDS), the authors concluded that intensive blood glucose control in patients with type 2 DM significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications.[19]

Newer agents in diabetic patients with kidney disease

Dipeptidyl peptidase inhibitors

The dipeptidyl peptidase (DPP)–4 inhibitors (ie, gliptins) are a new class of antidiabetic agents that can be used in type 2 diabetes. These agents include sitagliptin, saxagliptin, linagliptin, and alogliptin, and they decrease the breakdown of the incretin hormones such as glucagonlike peptide 1 (GLP-1). GLP-1 is secreted by the GI tract in response to food intake and leads to insulin secretion in a glucose-dependent manner, while also decreasing glucagon release. GLP-1 also slows gastric emptying.

Sitagliptin was the first available DPP-4 inhibitor. Approximately 80% of sitagliptin is cleared by the kidney; therefore, the standard dose of 100 mg daily should be reduced in patients with reduced glomerular filtration rates (GFRs). With an estimated GFR (eGFR) of 30 or greater to less than 50 mL/min/1.73 m2, the recommended dose is 50 mg once daily, and with an eGFR less than 30 mL/min/1.73 m2, a dose of 25 mg once daily is advised.[20]

The starting dose for saxagliptin is 2.5-5 mg daily in patients with an eGFR greater than 50 mL/min, but dose adjustment is recommended in patients with an eGFR of 50 mL/min/1.73 m2 or less to 2.5 mg daily.

Alogliptin also requires a dose reduction from 25 mg daily to 12.5 mg daily in patients with an eGFR of less than 60 mL/min/1.73 m2 and to 6.25 mg daily if the eGFR is less than 30 mL/min/1.73 m2.

In contrast, only the kidney clears a small amount of linagliptin; thus, no dose adjustment is necessary in patients with a reduced GFR.[21]

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors (acarbose, miglitol) decrease the breakdown of oligosaccharides and disaccharides in the small intestine, slowing the absorption of glucose after a meal. The major adverse effects are bloating, flatulence, and abdominal cramping.

Acarbose is minimally absorbed, with less than 2% of the drug and active metabolites present in the urine. However, in patients with reduced renal function, serum levels of acarbose and metabolites are significantly higher. Miglitol has greater systemic absorption with greater than 95% renal excretion. It is recommended that miglitol be avoided if the GFR is less than 25 mL/min/1.73 m2.[22] These drugs have not been studied in patients with advanced kidney disease, and their use should be avoided in this population.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

There are several SGLT2 inhibitors under development or consideration by the US Food and Drug Administration (FDA), and canagliflozin (Invokana) is the first SGLT2 inhibitor approved for use in the United States. Canagliflozin inhibits renal glucose absorption in the proximal tubule, the site in the kidney where approximately 90% of glucose reabsorption occurs. This leads to increased excretion of glucose in the urine, which may help subjects lose up to 5 kg of weight over a year. The decreased glucose reabsorption is also accompanied by increased urinary excretion of sodium, which, in turn, may help with further blood pressure lowering, which could be an advantage in patients with diabetic kidney disease and hypertension.

At this time, the maximum dose in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 is 100 mg once daily and it is not recommended in patients with an eGFR of less than 45 mL/min/1.73 m2. Increased glucosuria is believed to increase the risk of urinary tract infections, especially candidal infections, and more frequently in women.[23]

Glucagonlike peptide-1 (GLP-1) receptor agonistsor incretin mimetics

The GLP-1 agonists exenatide (Byetta) and liraglutide (Victoza) are also known as injectable incretin mimetics. These drugs enhance central satiety and reduce appetite, thus helping with weight loss. These drugs promote insulin release, delay glucagon release, and slow gastric emptying and are less likely to cause hypoglycemia. There is some concern, however, about safety, as they may cause pancreatitis. Exenatide clearance is GFR dependent and is reduced at low GFRs.[24]

Although disputed, there are cases of acute renal failure associated with exenatide, and it is recommended to be used with caution in patients with a GFR of 30-50 mL/min and not be used at all if the eGFR is less than 30 mL/min. Liraglutide is not metabolized by the kidney, and no dose adjustment is necessary in patients with a decreased GFR, including ESRD, although data in this population are limited.[25] Cases of acute renal failure and worsening of chronic renal impairment have been reported with liraglutide, and the manufacturer advises caution in initiating or increasing the dose in patients with kidney disease.

Amylin analogs

Amylin is a 37-amino acid peptide co-secreted by β cells with insulin and is deficient in diabetes. Its levels parallel insulin levels, and its actions are complementary to insulin in regulating plasma glucose concentration. Amylin slows gastric emptying, reduces postprandial glucagon, and can suppress appetite.

Pramlintide (Symlin) is the only available amylin analog; it is given as an injection along with insulin therapy at meals. Dose adjustments for pramlintide are not required in the presence of mild-to-moderate renal disease, but there are no data on its use in end-stage kidney disease.[26]

Management of Hypertension

In general, antihypertensive therapy, irrespective of the agent used, slows the development of diabetic glomerulopathy. Mogensen showed that antihypertensive treatment attenuates the rate of decline in renal function in patients who have type 1 DM, hypertension, and proteinuria.[27] This is particularly significant when lowering of systemic blood pressure is accompanied with concomitant lessening of glomerular capillary pressure.

Careful blood pressure control is needed to prevent the progression of diabetic nephropathy and other complications; however the optimal lower limit for systolic blood pressure is unclear.[28] In the UKPDS, a 12% risk reduction in diabetic complications was found with each 10 mm Hg drop in systolic pressure, the lowest risk being associated with a systolic pressure below 120 mm Hg.[19]

Angiotensin-converting enzyme inhibitors

From a therapeutic standpoint, preventing the progression of kidney disease is better achieved with a nonglycemic intervention, such as treatment with angiotensin-converting enzyme (ACE) inhibitors, which confer superior long-term protection even in comparison with triple therapy with reserpine, hydralazine, and hydrochlorothiazide or a calcium channel blocker (nifedipine).

Long-term treatment with ACE inhibitors, usually combined with diuretics, reduces blood pressure and albuminuria and protects kidney function in patients with hypertension, type 1 DM, and nephropathy. Beneficial effects on kidney function have also been reported in patients with normotension, type 1 DM, and nephropathy.

ACE inhibition has been shown to delay the development of diabetic nephropathy. In the ACE inhibition arm of a large trial, only 7% of patients with microalbuminuria experienced progression to overt nephropathy; however, in the placebo-treated group, 21% of patients experienced progression to overt nephropathy. The beneficial effect of ACE inhibition on preventing progression from microalbuminuria to overt diabetic nephropathy is long-lasting (8 y) and is associated with the preservation of a normal glomerular filtration rate (GFR).

The impact of ACE inhibition in patients with microalbuminuric type 2 DM has also been evaluated. Treatment with an ACE inhibitor for 12 months has significantly reduced mean arterial blood pressure and the urinary albumin excretion rate in type 2 DM patients who have microalbuminuria.

In a study of normotensive patients with microalbuminuric type 2 DM who received enalapril or placebo for 5 years, 12% of those in the actively treated group experienced diabetic nephropathy, with a rate of decline in kidney function of 13%, and 42% of those in the placebo group experienced nephropathy.

Meta-analysis has shown that ACE inhibitors are superior to beta-blockers, diuretics, and calcium channel blockers in reducing urinary albumin excretion in normotensive and hypertensive type 1 and type 2 DM patients. This superiority is pronounced in the normotensive state, whereas it is diminished progressively with progressive blood pressure reduction. Reduced glomerular capillary hydraulic pressure in combination with diminished size- and charge-selective properties of the glomerular capillary membrane are the most likely mechanisms involved in the antiproteinuric effect of ACE inhibitors.

The antiproteinuric effect of ACE inhibition in patients with diabetic nephropathy varies considerably. Individual differences in the renin-angiotensin system (RAS) may influence this variation. A potential role may exist for an insertion/deletion polymorphism of the ACE gene on this early antiproteinuric responsiveness in young patients with hypertension and type 1 DM who have developed diabetic nephropathy.

In addition to beneficial cardiovascular effects, ACE inhibition has also been demonstrated to have a significant beneficial effect on the progression of diabetic retinopathy and on the development of proliferative retinopathy.

Angiotensin receptor blockers for renin-angiotensin system inhibition

RAS inhibition is effective in treating type 1 and type 2 diabetic nephropathy.[29] It is important to consider type 2 diabetic nephropathy separately from type 1, as there are significant differences between them. Both are characterized by the appearance of microalbuminuria, which leads to overt proteinuria and progressive loss of GFR. A series of renal biopsy samples from patients with type 2 DM and proteinuria revealed that a significant proportion of these patients had glomerular lesions other than the classic lesions associated with type 1 diabetic nephropathy.

ACE inhibitors reduce the risk of progression of overt type 1 diabetic nephropathy to end-stage renal disease (ESRD) and in type 1 patients with microalbuminuria to overt nephropathy. Although ACE inhibition improves glomerular permeability in patients with type 1 DM as assessed by dextran clearances, it does not do so in patients with type 2 DM. Furthermore, the superior effect of blockade of the RAS has been difficult to prove.

Two studies (the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] Study and the Irbesartan Diabetic Nephropathy Trial [IDNT]) demonstrated that angiotensin II receptor blockers (ARBs) are superior to conventional therapy and amlodipine in slowing the progression of overt nephropathy.

These trials were performed with ARBs and not ACE inhibitors. This raised the question as to whether such beneficial results in patients with type 2 DM would be seen with ACE inhibitors as well. Unfortunately, a large head-to-head comparison of ACE inhibitors and ARBs is unlikely to be made.

The choice between an ARB and an ACE inhibitor is made more difficult by the results of the Microalbuminuria-Heart Outcomes Prevention Evaluation (MICRO-HOPE) Trial, in which ramipril reduced the risk for myocardial infarction, stroke, or cardiovascular death by 26% after 2 years. Perhaps the more interesting question is whether the combination of an ACE inhibitor and an ARB is more effective than either drug alone. One meta-analysis showed that ACEI + ARB reduced 24-hour proteinuria to a greater extent than ACEI alone. However, this benefit was associated with small effects on GFR, serum creatinine, potassium, and blood pressure.[30]

A study by Imai et al determined that combined treatment with ACE inhibitors and ARBs significantly decreased blood pressure, proteinuria, and rate of change of reciprocal serum creatinine; however, higher cardiovascular death was reported among the olmesartan-treated patients compared with placebo. Major adverse cardiovascular events and all–cause data were similar between the 2 groups. Hyperkalemia was more frequent in the olmesartan–treated group than in the placebo group. These findings confirm previous studies that combined therapy for patients with diabetic nephropathy may improve short-term biomarkers but is not associated with improvement in long-term hard endpoints.[31]

However, the recent Nephron-D trial, which evaluated the effect of adding losartan, an ARB, to the ACE inhibitor lisinopril on albumin-to-creatinine ratio in 1448 patients with type 2 diabetes was stopped early because of safety concerns. Combination therapy significantly increased the risk of hyperkalemia and acute kidney injury.[32] Thus, the combination should be avoided as a strategy to reduce proteinuria with the hope of slowing progression of diabetic nephropathy, and should be reserved for individual situations in which optimal control of blood pressure may require it. Until further studies shed additional light, for antiproteinuric effect, the addition of an aldosterone antagonist (ie, spironolactone) may be more effective.

Direct renin inhibitors

In a small double-blind, randomized, crossover trial, Persson et al observed the combination of aliskiren and irbesartan to be more antiproteinuric in type 2 diabetes mellitus than was monotherapy with either drug.[33] This study assessed the effect of aliskiren, a direct renin inhibitor, on proteinuria in patients with type 2 DM (n = 26) and compared the effect with that of placebo, irbesartan (an ARB), and the combination of aliskiren and irbesartan.

Patients were assigned to four 2-month treatments in random order. Monotherapy with either aliskiren or irbesartan significantly improved albuminuria when compared with placebo. Combination therapy with aliskiren and irbesartan reduced albuminuria by 71%, more than did either monotherapy (aliskiren monotherapy 48%; irbesartan monotherapy 58%).

Research suggests that vitamin D may have a role in renin inhibition and that vitamin D supplementation may be useful in reducing proteinuria in patients with diabetic nephropathy. Patients with diabetic nephropathy with stage 3 chronic kidney disease (eGFR 59 – 30 mL/min/1.73 m2) or more advanced stages should be evaluated for their vitamin D and parathyroid hormone status as recommended by the National Kidney Foundation- Kidney Disease Dialysis Outcomes Quality Initiative (NKF-KDOQI).[34] If vitamin D levels are low, patients should be given vitamin D supplementation. One randomized controlled trial suggested that vitamin D supplementation may reduce proteinuria in patients with diabetic nephropathy.[35, 36]

Endothelin Antagonist Therapy

Endothelin antagonists have demonstrated antifibrotic, anti-inflammatory, and antiproteinuric effects in experimental studies.

A randomized, placebo-controlled, double-blind, parallel-design, dosage-range study on the effect of the endothelin-A antagonist avosentan on urinary albumin excretion rate in 286 patients with diabetic nephropathy, macroalbuminuria, and a blood pressure of < 180/110 mm Hg found that all dosages of avosentan, administered in addition to standard treatment with an ACE inhibitor or an ARB, reduced the mean relative urinary albumin excretion rate (-16.3% to -29.9%, relative to baseline).[37]

Renal Replacement Therapy

As for any other patient with ESRD, diabetic patients with ESRD can be offered renal replacement therapy. Carefully explain the therapeutic options and modalities of renal replacement therapy to patients, their partners, and their families in an early stage of renal failure. In chronically ill patients with diabetes, this tends to be much more important than in those renal patients who do not have diabetes.

In patients with diabetic nephropathy, starting at a creatinine clearance or estimated GFR of 10-15 mL/min is wise. In diabetic patients, starting earlier is useful when hypervolemia renders blood pressure uncontrollable, when the patient experiences anorexia and cachexia or other uremic symptoms, and when severe vomiting is the combined result of uremia and gastroparesis.

In principle, diabetic patients who require renal replacement therapy have the following 4 options:

Peritoneal dialysis and hemodialysis

Dialysis treatment partially reverses insulin resistance so that insulin requirements are often reduced. Adequate control of glycemia is important to prevent hyperglycemia-induced thirst, which can lead to volume overload and hyperkalemia. Proper attention must be given to optimizing nutrition, correcting anemia, controlling hypertension and hyperlipidemia, and modifying associated cardiovascular risk factors.

Regarding peritoneal dialysis, in a recently completed study, female patients with diabetes mellitus had a better outcome in the first 3 years of requiring renal replacement therapy when they chose peritoneal dialysis over hemodialysis. This positive effect did not continue beyond 3 years.

Kidney transplantation and kidney-pancreas transplantation

Except in patients with severe macroangiopathic complications, renal transplantation should be considered a first-line objective because it offers the best degree of medical rehabilitation in patients with uremia and diabetes. This option must be discussed early on with the patient and his or her family. Transplantation even before dialysis (preemptive transplantation) is becoming increasingly popular in some centers.

Renal transplantation is generally restricted to younger patients with type 1 DM; this may not be completely justified because good results have also been achieved in patients with type 2 DM if high-risk patients with macrovascular disease are excluded. Because of higher cardiovascular mortality, long-term survival of patients with diabetes with renal allografts is definitely inferior to that of those without diabetes.

The major rationale for combined kidney and pancreas transplantation is the increased quality of life and, probably, (controversial) halting or even reversing diabetic complications. Transplantation of the more immunogenic pancreas appears to have a higher risk of biopsy-proven acute kidney graft rejection episodes, but the 1-year graft and patient survival rates are not different from those in patients who had kidney transplantation alone.

In patients with type 1 DM, pancreas transplantation is the only treatment that consistently achieves insulin independence. Recently, successful reports of islet cell transplantation have been presented.

Indications for pancreas transplantation in nonuremic patients have not been established. Generally, it is offered to patients with extremely brittle diabetes and documented episodes of hypoglycemia without preceding symptoms. In patients with type 1 DM and renal insufficiency, the following 2 options exist: (1) simultaneous kidney and pancreas transplantation and (2) first kidney and then pancreas transplantation (the latter is usually performed when patients receive a live donor graft).

Dietary Changes

A meta-analysis examining the effects of dietary protein restriction (0.5-0.85 g/kg/d) in diabetic patients suggested a beneficial effect on the GFR, creatinine clearance, and albuminuria. However, a large, long-term prospective study is needed to establish the safety, efficacy, and compliance with protein restriction in diabetic patients with nephropathy. Limitations include ensuring compliance by patients.

The American Diabetic Association suggests diets of various energy intake (caloric values), depending on the patient. With advancing renal disease, protein restriction of as much as 0.8-1 g/kg/d may retard the progression of nephropathy.

When nephropathy is advanced, the diet should reflect the need for phosphorus and potassium restriction, with the use of phosphate binders.

A meta-analysis from the Cochrane Renal Group revealed that dietary salt reduction significantly reduced blood pressure (BP) in individuals with type 1 or type 2 diabetes.[38] These findings, along with other evidence relating salt intake to BP and albuminuria in hypertensive and normotensive patients, make a strong case for a reduction in salt intake among patients with diabetes. The recommendation for the general population in public health guidelines is less than 5-6 g/d. Dietary salt reduction may help slow progression of kidney disease in both type 1 and type 2 diabetes.

Restriction of Activity

No restriction in activity is necessary for persons with diabetic nephropathy, unless warranted by other associated complications of diabetes, such as associated coronary disease or peripheral vascular disease.

Measures for Prevention of Diabetic Nephropathy

Efforts should be made to modify and/or treat associated risk factors such as hyperlipidemia, smoking, and hypertension.

Specific goals for prevention include the following:

Long-Term Monitoring

Regular outpatient follow-up is key in managing diabetic nephropathy successfully. Regular annual urinalysis is recommended for screening for microalbuminuria (see the image below). Ensuring optimal glucose control, optimizing blood pressure, and screening for other associated complications of diabetes (eg, retinopathy, diabetic foot, cardiovascular disease) are also crucial.


View Image

Screening for and prevention of the progression of microalbuminuria in diabetes mellitus. (ACE-I stands for angiotensin-converting enzyme inhibitor)

To see complete information on the conditions below, please go to the main article by clicking on the title:

Medication Summary

Major therapeutic interventions include near-normal blood glucose control, antihypertensive treatment, and restriction of dietary proteins.[14] Drug classes employed include hormones (ie, insulin), sulfonylureas, biguanides, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blocking agents, calcium channel blockers, and diuretics.

Insulin regular human (Novolin, Humulin)

Clinical Context:  The structure of insulin was established in 1960, leading to complete synthesis by 1963. Human insulin was approved by the US Food and Drug Administration (FDA) in 1982. Bovine, porcine, and recombinant human insulin preparations are currently available for use in diabetes treatment worldwide; however, insulin derived from bovine tissue is no longer available in the US market as of 1999 because of FDA concerns over transmission of bovine spongiform encephalopathy. Regular insulin has a rapid onset of action of 0.5-1 hours and duration of action of 4-6 hours. The peak effects are seen within 2-4 hours.

Insulin aspart (NovoLog)

Clinical Context:  Insulin aspart has a short onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin aspart is FDA approved for use in insulin pumps.

Insulin glulisine (Apidra)

Clinical Context:  Insulin glulisine has a rapid onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin glulisine is FDA approved for use in insulin pumps.

Insulin lispro (Humalog)

Clinical Context:  Insulin lispro has a rapid onset of action of 5-15 minutes and a short duration of action of 4 hours.

Insulin Glargine (Lantus)

Clinical Context:  Insulin glargine is a long-acting insulin that has an onset of action of 4-8 hours and a duration of action of 24 hours. The peak effects occur within 16-18 hours.

Insulin NPH (Humulin N, Novolin N)

Clinical Context:  Insulin NPH is an intermediate-acting insulin that has an onset of action of 3-4 hours and a duration of action of 16-24 hours. The peak effect of insulin NPH occurs within 8-14 hours.

Class Summary

Hormones stimulate proper use of glucose by cells and reduce blood sugar levels. Based on their duration of action, several types of insulin are available.

Chlorpropamide (Diabinese)

Clinical Context:  Chlorpropamide is a first-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Tolazamide (Tolinase)

Clinical Context:  Tolazamide is a first-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Tolbutamide (Orinase)

Clinical Context:  Tolbutamide is a first-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Glyburide (DiaBeta, Micronase)

Clinical Context:  Glyburide is a second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Glipizide (Glucotrol)

Clinical Context:  Glipizide is a second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Class Summary

Sulfonylureas act primarily by stimulating release of insulin from beta cells. Extrapancreatic actions include increasing the number of insulin receptors and enhancing insulin-mediated glucose transport independent of increased insulin binding. The use of oral agents has decreased because more emphasis is placed on better control as a means of slowing the development of late complications.

Sulfonylureas are indicated for some patients with relatively mild disease. Commonly used sulfonylureas include chlorpropamide, tolazamide, tolbutamide, glyburide, and glipizide.

Metformin (Glucophage)

Clinical Context:  Metformin reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in peripheral tissues (muscle and adipocytes). It is a major drug used in obesity and type 2 DM. In contrast to sulfonylureas, metformin does not cause hypoglycemia.

Class Summary

Biguanides are useful in patients with type 2 diabetes mellitus (DM) who are not responsive to diet and exercise. They are usually added as an adjunctive agent in patients whose disease is not controlled by maximal doses of sulfonylureas. Occasionally, they may be prescribed as monotherapy in diabetic patients who are obese.

Pioglitazone (Actos)

Clinical Context:  Pioglitazone improves target cell response to insulin without increasing insulin secretion from the pancreas. It decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, liver and adipose tissue.

Rosiglitazone (Avandia)

Clinical Context:  Rosiglitazone is used to treat type 2 diabetes associated with insulin resistance and has an effect on the stimulation of glucose uptake in skeletal muscle and adipose tissue.

Class Summary

Thiazolidinedione derivatives are active only in the presence of insulin. They are approved for use in patients who are obese, have type 2 DM, and whose diabetes is poorly controlled on insulin. Some physicians administer thiazolidinedione derivatives as add-on agents in patients with type 2 DM who are on maximal doses of other oral agents.

Captopril (Capoten)

Clinical Context:  Captopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Enalapril (Vasotec)

Clinical Context:  Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion.

Lisinopril (Zestril, Prinivil)

Clinical Context:  Lisinopril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion

Class Summary

All of these agents except fosinopril are excreted primarily by the kidney. They have similar actions and adverse effects, including severe hypotension, acute renal failure (especially in bilateral renal artery stenosis), hyperkalemia, dry cough (sometimes accompanied by wheezing), and angioedema. Cough and angioedema are believed to be mediated by bradykinin.[14]

Losartan (Cozaar)

Clinical Context:  Losartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema.

Valsartan (Diovan)

Clinical Context:  Valsartan produces direct antagonism of angiotensin II receptors. It may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Irbesartan (Avapro)

Clinical Context:  Irbesartan is used to treat diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/d) in patients with type 2 diabetes and hypertension. It reduces the rate nephropathy progression. It blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor.

Class Summary

ARBs are specific and selective angiotensin II receptor antagonists.[14] Compared with ACE inhibitors, ARBs are associated with a lower incidence of drug-induced cough, rash, and/or taste disturbances.

Metoprolol (Lopressor)

Clinical Context:  Metoprolol is used to treat hypertension. It is a beta-adrenergic blocking agent that affects blood pressure via multiple mechanisms. Actions include negative a chronotropic effect that decreases the heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the CNS, and suppression of renin release from the kidneys. During intravenous administration, carefully monitor blood pressure, heart rate, and ECG.

Atenolol (Tenormin)

Clinical Context:  Atenolol is used to treat hypertension. It selectively blocks beta1-receptors, with little or no affect on beta 2 types. It is also used to improve and preserve hemodynamic status by acting on myocardial contractility, reducing congestion, and decreasing myocardial energy expenditure.

Labetalol (Trandate)

Clinical Context:  Labetalol is a beta-adrenergic blocking agent that reduces blood pressure via multiple mechanisms. Actions include a negative chronotropic effect that decreases the heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, a reduction of sympathetic outflow from the CNS, and suppression of renin release from the kidneys.

Class Summary

Beta-adrenergic blocking agents affect blood pressure via multiple mechanisms. Actions include a negative chronotropic effect that decreases heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the central nervous system, and suppression of renin release from kidneys.

Diltiazem (Cardizem)

Clinical Context:  Diltiazem is a nondihydropyridine calcium channel blocker. It relaxes the vascular smooth muscle, causing a decrease in peripheral vascular resistance and leading to antihypertensive effects.

Verapamil (Calan, Covera-HS)

Clinical Context:  Verapamil is a nondihydropyridine calcium channel blocker. It inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes.

Nifedipine (Adalat)

Clinical Context:  Nifedipine is a dihydropyridine calcium channel blocker. It relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. In addition, it decreases peripheral resistance, systemic blood pressure, and afterload.

Amlodipine (Norvasc)

Clinical Context:  Amlodipine is a dihydropyridine calcium channel blockers that has antianginal and antihypertensive effects. It inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle.

Class Summary

Calcium channel blockers inhibit the influx of extracellular calcium across myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits contractile processes of myocardial smooth muscle cells, resulting in dilation of coronary and systemic arteries and improved oxygen delivery to myocardial tissue. In addition, total peripheral resistance, systemic blood pressure, and afterload are decreased.

Calcium channel blockers provide control of hypertension associated with less impairment of function of the ischemic kidney. Calcium channel blockers may have beneficial long-term effects, but this remains uncertain. During depolarization, these agents inhibit calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. Amlodipine is longer acting.

Furosemide (Lasix)

Clinical Context:  Furosemide is a loop diuretic that increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. It increases renal blood flow without increasing the filtration rate. The onset of action generally is within 1 hour. It increases potassium, sodium, calcium, and magnesium excretion.

Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide)

Clinical Context:  This is a thiazide diuretic that inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions. Diuretics are used only as an as an adjunct to other medications.

Bumetanide (Bumex)

Clinical Context:  Bumetanide increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.

Class Summary

Furosemide and bumetanide are loop diuretics that appear primarily to inhibit reabsorption of sodium and chloride in the ascending limb of the loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Following administration, renal vasodilation occurs, renal vascular resistance decreases, and renal blood flow is enhanced.

Hydrochlorothiazide is a thiazide diuretic that inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water and potassium and hydrogen ions.

Aliskiren (Tekturna)

Clinical Context:  Aliskiren is a direct renin inhibitor that decreases plasma renin activity and inhibits the conversion of angiotensinogen to angiotensin I (as a result, also decreasing angiotensin II) and thereby disrupts the renin-angiotensin-aldosterone system feedback loop. It is indicated for hypertension as monotherapy or in combination with other antihypertensive drugs.

Class Summary

This is the newest class of antihypertensive drugs. They act by disrupting the renin-angiotensin-aldosterone system feedback loop.

Sitagliptin (Januvia)

Clinical Context:  Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Sitagliptin is indicated for diabetes type 2 as monotherapy or combined with metformin or a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist (eg, thiazolidinediones).

Linagliptin (Tradjenta)

Clinical Context:  Linagliptin increases and prolongs incretin hormone activity, which are inactivated by DPP-4 enzyme Incretins regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic β cells and reducing glucagon secretion from pancreatic α cells.

Saxagliptin (Onglyza)

Clinical Context:  Saxagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM.

Alogliptin (Nesina)

Clinical Context:  Alogliptin slows inactivation of incretin hormones (eg, GLP-1, GIP), thereby reducing fasting and postprandial glucose concentrations in a glucose-dependent manner

Class Summary

The dipeptidyl peptidase (DPP)–4 inhibitors (ie, gliptins) are a new class of antidiabetic agents that can be used in type 2 diabetes. They decrease the breakdown of the incretin hormones, such as glucagonlike peptide 1 (GLP-1). GLP-1 is secreted by the GI tract in response to food intake and leads to insulin secretion in a glucose-dependent manner, while also decreasing glucagon release. GLP-1 also slows gastric emptying.

Acarbose (Precose)

Clinical Context:  Acarbose delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. It inhibits the metabolism of sucrose to glucose and fructose.

Miglitol (Glyset)

Clinical Context:  Miglitol delays glucose absorption in the small intestine and lowers postprandial hyperglycemia.

Class Summary

Alpha-glucosidase inhibitors decrease the breakdown of oligosaccharides and disaccharides in the small intestine, slowing the absorption of glucose after a meal.

Canagliflozin (Invokana)

Clinical Context:  Canagliflozin is a selective sodium-glucose transporter-2 (SGLT2) inhibitor. SGLT-2 inhibition lowers the renal glucose threshold (ie, the plasma glucose concentration that exceeds the maximum glucose reabsorption capacity of the kidney); lowering the renal glucose threshold results in increased urinary glucose excretion.

Class Summary

Agents in this category inhibit renal glucose absorption in the proximal tubule, the site in the kidney where approximately 90% of glucose reabsorption occurs. This leads to increased excretion of glucose in the urine.

Exenatide (Bydureon, Byetta)

Clinical Context:  Exenatide is an incretin mimetic agent that mimics glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. It improves glycemic control in patients with type 2 DM by enhancing glucose-dependent insulin secretion by pancreatic βcells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The drug's 39–amino acid sequence partially overlaps that of the human incretin, GLP-1. It is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin or a sulfonylurea but have not achieved glycemic control.

Liraglutide (Victoza)

Clinical Context:  Liraglutide is an incretin mimetic analog of human GLP-1; it acts as a GLP-1 receptor agonist to increase insulin secretion in the presence of elevated blood glucose; it delays gastric emptying to decrease postprandial glucose, and it also decreases glucagon secretion.

Class Summary

These drugs act in the satiety center and reduce appetite, thus helping with weight loss. These drugs promote insulin release, delay glucagon release, and slow gastric emptying and are less likely to cause hypoglycemia.

Pramlintide (SymlinPen 120, SymlinPen 60)

Clinical Context:  Pramlintide is a synthetic analog of human amylin, a naturally occurring hormone made in pancreas βcells. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake due to centrally mediated appetite modulation. It is indicated to treat type 1 or type 2 diabetes in combination with insulin. It is administered before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. Pramlintide helps achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, Hgb A1C levels) compared with insulin alone. Additionally, less insulin use and reduction in body weight is also observed.

Class Summary

These agents are amylin analogs; amylin is co-secreted by βcells with insulin and is deficient in diabetes. Its levels parallel insulin levels, and its actions are complementary to insulin in regulating plasma glucose concentration. Amylin slows gastric emptying, reduces postprandial glucagon, and can suppress appetite.

Author

Vecihi Batuman, MD, FACP, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

Coauthor(s)

Anjana S Soman, MD, Staff Physician, Department of Pathology, Quest Diagnostics

Disclosure: Nothing to disclose.

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Disclosure: Renal Ventures Ownership interest Other

Sandeep S Soman, MBBS, MD, DNB, Senior Staff Physician, Department of Internal Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Chief Editor

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Additional Contributors

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Sreepada TK Rao, MD, FACP Professor, Department of Medicine, State University of New York Downstate Medical Center

Sreepada TK Rao, MD, FACP is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology

Disclosure: Nothing to disclose.

References

  1. Ekinci EI, Jerums G, Skene A, Crammer P, Power D, Cheong KY. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care. Nov 2013;36(11):3620-6. [View Abstract]
  2. Hall JE, Henegar JR, Dwyer TM, Liu J, Da Silva AA, Kuo JJ. Is obesity a major cause of chronic kidney disease?. Adv Ren Replace Ther. Jan 2004;11(1):41-54. [View Abstract]
  3. Yip JW, Jones SL, Wiseman MJ, Hill C, Viberti G. Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes. Dec 1996;45(12):1729-33. [View Abstract]
  4. Odegaard JI, Chawla A. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb Perspect Med. Mar 2012;2(3):a007724. [View Abstract]
  5. Chiarelli F, Gaspari S, Marcovecchio ML. Role of growth factors in diabetic kidney disease. Horm Metab Res. Aug 2009;41(8):585-93. [View Abstract]
  6. Rask-Madsen C, King GL. Kidney complications: factors that protect the diabetic vasculature. Nat Med. Jan 2010;16(1):40-1. [View Abstract]
  7. Ziyadeh FN. Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J Am Soc Nephrol. Jan 2004;15 Suppl 1:S55-7. [View Abstract]
  8. Deshpande SD, Putta S, Wang M, Lai JY, Bitzer M, Nelson RG. Transforming growth factor-ß-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy. Diabetes. Sep 2013;62(9):3151-62. [View Abstract]
  9. de Boer IH, Rue TC, Hall YN, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. Jun 22 2011;305(24):2532-9. [View Abstract]
  10. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. Jul 26 2006;296(4):421-6. [View Abstract]
  11. Rosolowsky ET, Skupien J, Smiles AM, et al. Risk for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol. Mar 2011;22(3):545-53. [View Abstract]
  12. Kostadaras A. Risk Factors for Diabetic Nephropathy. Astoria Hypertension Clinic. Available at http://www.kidneydoctor.com/dm.htm
  13. Iliadis F, Didangelos T, Ntemka A, et al. Glomerular filtration rate estimation in patients with type 2 diabetes: creatinine- or cystatin C-based equations?. Diabetologia. Dec 2011;54(12):2987-94. [View Abstract]
  14. Shlipak M. Diabetic nephropathy. Clin Evid (Online). Jan 14 2009;2009:[View Abstract]
  15. Burney BO, Kalaitzidis RG, Bakris GL. Novel therapies of diabetic nephropathy. Curr Opin Nephrol Hypertens. Mar 2009;18(2):107-11. [View Abstract]
  16. Suckling RJ, He FJ, Macgregor GA. Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst Rev. Dec 8 2010;12:CD006763. [View Abstract]
  17. Heerspink HJ, Holtkamp FA, Parving HH, Navis GJ, Lewis JB, Ritz E, et al. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int. Mar 21 2012;[View Abstract]
  18. Diabetes Control and Complications Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int. Jun 1995;47(6):1703-20. [View Abstract]
  19. UK Prospective Diabetes Study 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). UK Prospective Diabetes Study (UKPDS) Group. Lancet. Sep 12 1998;352(9131):837-53. [View Abstract]
  20. Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. Jul 2007;30(7):1862-4. [View Abstract]
  21. Scheen AJ. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol. May 2013;9(5):529-50. [View Abstract]
  22. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial. Sep-Oct 2004;17(5):365-70. [View Abstract]
  23. Lamos EM, Younk LM, Davis SN. Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. Jun 2013;9(6):763-75. [View Abstract]
  24. Linnebjerg H, Kothare PA, Park S, Mace K, Reddy S, Mitchell M. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. Sep 2007;64(3):317-27. [View Abstract]
  25. Davidson JA, Brett J, Falahati A, Scott D. Mild renal impairment and the efficacy and safety of liraglutide. Endocr Pract. May-Jun 2011;17(3):345-55. [View Abstract]
  26. Young A. Clinical studies. Adv Pharmacol. 2005;52:289-320. [View Abstract]
  27. Mogensen CE. The effect of blood pressure intervention on renal function in insulin-dependent diabetes. Diabete Metab. 1989;15(5 Pt 2):343-51. [View Abstract]
  28. Diabetes Guidelines. Royal Free Hampstead NHS Trust. Available at http://royalfree.org.uk/default.aspx?top_nav_id=1&sel_left_nav=25&tab_id=403. Accessed 7/2/09.
  29. Laight DW. Therapeutic inhibition of the renin angiotensin aldosterone system. Expert Opin Ther Pat. Jun 2009;19(6):753-9. [View Abstract]
  30. Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis. Diabet Med. May 2007;24(5):486-93. [View Abstract]
  31. Imai E, Chan JC, Ito S, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. Dec 2011;54(12):2978-2986. [View Abstract]
  32. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. Nov 14 2013;369(20):1892-903. [View Abstract]
  33. [Best Evidence] Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, et al. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care. Oct 2009;32(10):1873-9. [View Abstract]
  34. National Kidney Foundation. NKF-KDOQI Guidelines. Available at http://www.kidney.org/professionals/kdoqi/guidelines.cfm
  35. Agarwal R. Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol. Sep 2009;4(9):1523-8. [View Abstract]
  36. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. Nov 6 2010;376(9752):1543-51. [View Abstract]
  37. [Best Evidence] Wenzel RR, Littke T, Kuranoff S, Jürgens C, Bruck H, Ritz E, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol. Mar 2009;20(3):655-64. [View Abstract]
  38. Suckling RJ, He FJ, Macgregor GA. Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst Rev. Dec 8 2010;12:CD006763. [View Abstract]

Simple schema for the pathogenesis of diabetic nephropathy.

Rate of decline in glomerular filtration rate in various stages of type 1 and type 2 diabetes.

Screening for and prevention of the progression of microalbuminuria in diabetes mellitus. (ACE-I stands for angiotensin-converting enzyme inhibitor)

Stages in the development of diabetic nephropathy.

Screening for and prevention of the progression of microalbuminuria in diabetes mellitus. (ACE-I stands for angiotensin-converting enzyme inhibitor)

Rate of decline in glomerular filtration rate in various stages of type 1 and type 2 diabetes.

Simple schema for the pathogenesis of diabetic nephropathy.

Screening for and prevention of the progression of microalbuminuria in diabetes mellitus. (ACE-I stands for angiotensin-converting enzyme inhibitor)

Stages in the development of diabetic nephropathy.