eMedicine Specialties > Nephrology > The Kidney in Systemic Diseases

Diabetic Nephropathy: Treatment & Medication

Author: Sandeep S Soman, MBBS, MD, DNB, Senior Staff Physician, Department of Internal Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital
Coauthor(s): Anjana S Soman, MD, Staff Physician, Department of Pathology, Quest Diagnostics
Contributor Information and Disclosures

Updated: Jul 2, 2009

Treatment

Medical Care

Several issues are key in the medical care of patients with diabetic nephropathy.^3,4

• Glycemic control
  • In persons with either IDDM or NIDDM, hyperglycemia has been shown to be a major determinant of the progression of diabetic nephropathy. The evidence is best reported for type 1 diabetes mellitus.
  • It has been shown that intensive therapy can partially reverse glomerular hypertrophy and hyperfiltration, delay the development of microalbuminuria, and stabilize or even decrease protein levels in patients with microalbuminuria.
  • Results from pancreatic transplant recipients in which 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 type 2 diabetes, reduction in microvascular complications in patients receiving intensive insulin therapy was of a smaller magnitude than in patients with type 1 diabetes in the Diabetes Control and Complications Trial. 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 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications.
• Antihypertensive treatment
  • Mogensen showed that antihypertensive treatment attenuates the rate of decline in renal function in patients who have IDDM, hypertension, and proteinuria. This is particularly significant when lowering of systemic blood pressure is accompanied with concomitant lessening of glomerular capillary pressure.
  • In general, antihypertensive therapy, irrespective of the agent used, slows the development of diabetic glomerulopathy. 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.⁵
    
    In the UKPDS, a 12% risk reduction in diabetic complications (P <0.001) was found with each 10 mm Hg drop in systolic pressure, the lowest risk being associated with a systolic pressure below 120 mm Hg. However, ACE inhibitors confer superior long-term protection even in comparison with triple therapy with reserpine, hydralazine, and hydrochlorothiazide or a calcium (Ca⁺) channel blocker (nifedipine).
    
    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.
  • ACE inhibition delays 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 GFR.
  • The impact of ACE inhibition in patients with microalbuminuric NIDDM 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 NIDDM patients who have microalbuminuria.
  • Normotensive patients with microalbuminuric NIDDM received enalapril or placebo for 5 years. Of the patients, 12% in the actively treated group experienced diabetic nephropathy, with a rate of decline in kidney function of 13%, and 42% of the patients receiving placebo experienced nephropathy.
  • From a therapeutic standpoint, preventing the progression of kidney disease is better achieved with a nonglycemic intervention, such as treatment with ACE inhibition. 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 IDDM who have developed diabetic nephropathy.
  • Long-term treatment with ACE inhibitors, usually combined with diuretics, reduces blood pressure and albuminuria and protects kidney function in patients with hypertension, IDDM, and nephropathy. Beneficial effects on kidney function have also been reported in patients with normotension, IDDM, and 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 IDDM and NIDDM 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.
• RAS inhibition is effective in treating type 1 and type 2 diabetic nephropathy.⁶ ACE-I reduces the risk of progression of overt type 1 diabetic nephropathy to ESRD and in type 1 patients with microalbuminuria to overt nephropathy.
  • 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 diabetes 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-I, which improves glomerular permeability in patients with type 1 diabetes as assessed by dextran clearances, do not do so in patients with type 2 diabetes. 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 (ARB) are superior to conventional therapy and amlodipine in slowing the progression of overt nephropathy.
  • These trials were performed with ARB and not ACE-I. This raised the question as to whether such beneficial results in patients with type 2 diabetes would be seen with ACE-I as well. Unfortunately, a large head-to-head comparison of ACE-I and ARB is unlikely to be made.
  • The choice between an ARB and an ACE-I 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 ACE-I and ARB is more effective than either drug alone. Studies are ongoing to address this issue.
• Endothelin antagonists have demonstrated antifibrotic, anti-inflammatory, and antiproteinuric effects in experimental studies. Wenzel et al conducted a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study on the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate in 286 patients with diabetic nephropathy, macroalbuminuria, and a blood pressure of <180/110 mm Hg.⁷ All dosages of avosentan, administered in addition to standard ACE inhibitor/ARB treatment, were found to reduce the mean relative urinary albumin excretion rate (-16.3% to -29.9%, relative to baseline) in the study's patients.
• Dietary protein intake: 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 in the patients.
• Specific therapies: This includes modification and/or treatment of associated risk factors such as hyperlipidemia, smoking, and hypertension.
• Renal replacement therapies
  • As for any other patient with ESRD, diabetic patients with ESRD can be offered hemodialysis, peritoneal dialysis, kidney transplantation, or combined kidney-pancreas transplantation.
  • In patients with uremia of any cause, starting at a creatinine clearance 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.
  • 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 principle, diabetic patients who require renal replacement therapy have the following 4 options:
    • Refusal of further treatment for uremia, leading to a progressive decline in general health and ultimately leading to death
    • Peritoneal dialysis (eg, machine-assisted intermittent peritoneal dialysis, continuous ambulatory peritoneal dialysis, continuous cyclic peritoneal dialysis)
    • Hemodialysis (eg, facility hemodialysis, home hemodialysis)
    • Renal transplantation (eg, cadaver donor kidney, living related-donor kidney, living unrelated-donor kidney [emotionally related donor], living unrelated-donor kidney [unrelated by family or emotionally; the so-called altruistic donor], pancreas plus kidney 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. 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.
  • 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
  • Kidney transplantation offers the best medical rehabilitation in patients with uremia and diabetes.
  • Renal transplantation is generally restricted to younger patients with IDDM; this may not be completely justified because good results have also been achieved in patients with NIDDM 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.
  • In patients with IDDM, pancreas transplantation is the only treatment that consistently induces 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 IDDM 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).
  • 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.
  • The major rationale for combined kidney and pancreas transplantation is the increased quality of life and, probably, (controversial) halting or even reversing diabetic complications.

Surgical Care

• Surgical care in diabetic nephropathy is usually limited to the management of associated complications such as diabetic foot ulcers or peripheral vascular disease.
• Early creation of a surgical arteriovenous fistula or a graft is also an important part of the pre-ESRD related to diabetic nephropathy, as in any other renal disease.
• Other surgical aspects of diabetic nephropathy treatment are discussed in renal replacement therapies in Medical Care and kidney transplantation and kidney-pancreas transplantation in Medical Care.

Diet

• 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.

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.

Medication

Major therapeutic interventions include near-normal blood glucose control, antihypertensive treatment, and restriction of dietary proteins.³

Hormones

Stimulate proper use of glucose by cells and reduce blood sugar levels.

Insulin (Novolin, Humulin)

Structure of insulin was established in 1960, leading to complete synthesis by 1963. Human insulin approved by FDA in 1982. Bovine, porcine, and recombinant human insulin preparations currently available for use in diabetes worldwide; however, insulin derived from bovine tissue is no longer on US market as of 1999 because of FDA concerns over transmission of bovine spongiform encephalopathy. Based on their duration of action, several types of insulin are available.
Regular insulin: Onset of action begins approximately 30 min after SC administration and lasts 8-12 h. Maximal effects observed in 1-3 h.
Buffered regular insulin: Pharmacokinetics are identical to regular insulin administered SC. For SC use only.
Insulin lispro or insulin aspart: Have a more rapid onset of glucose-lowering activity and earlier peak glucose-lowering effect after SC administration. Reach peak plasma concentrations slightly faster (30-90 min) than regular insulin (60-120 min) when given SC.
Semi-Lente insulin (prompt insulin zinc susp): Rapid acting with onset of action of 1-1.5 h following SC administration, with peak effects occurring from 5-10 h.
Intermediate-acting NPH insulin (isophane insulin susp): Onset of action of 1-1.5 h following SC administration and duration of approximately 24 h.
Lente insulin (insulin zinc susp): Onset of action of 2-4 h and duration of approximately 24 h following SC administration.
Long-acting ultra-Lente insulin (extended insulin zinc susp): Long-acting insulin. Onset of action usually occurs within 4 h, with peak activity 10-30 h after SC administration. Duration typically longer than 36 h.
In many cases, more than one type of insulin preparation is administered in order to achieve the desired clinical effect. Dosage must be individualized to obtain optimal recommended glucose levels.

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. Use of oral agents has decreased because more emphasis is placed on better control as a means of slowing the development of late complications. Indicated for some patients with relatively mild disease. Commonly used sulfonylureas include chlorpropamide, tolbutamide, glyburide, and glipizide.

Chlorpropamide (Diabinese)

First-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Tolazamide (Tolinase)

First-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Tolbutamide (Orinase)

First-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Glyburide (DiaBeta, Micronase)

Second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Glipizide (Glucotrol)

Second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Biguanides

Useful in patients with NIDDM who are not responsive to diet and exercise. Usually added as an adjunctive agent in patients whose disease is not controlled by maximal doses of sulfonylureas. Occasionally, may be prescribed as monotherapy in diabetic patients who are obese.

Metformin (Glucophage)

Reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in peripheral tissues (muscle and adipocytes). Major drug used in obesity and type 2 diabetes. In contrast to sulfonylureas, does not cause hypoglycemia.

Thiazolidinedione derivatives

Only active in presence of insulin. Approved for use in patients who are obese, have NIDDM, and whose diabetes is poorly controlled on insulin. Administered by some physicians as an add-on agent in patients with NIDDM who are on maximal doses of other oral agents.

Pioglitazone (Actos)

Improves target cell response to insulin without increasing insulin secretion from pancreas. Decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, liver and adipose tissue.

Angiotensin-converting enzyme inhibitors

All except fosinopril are excreted primarily by the kidney. 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.³

Captopril (Capoten)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Enalapril (Vasotec)

Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Lisinopril (Monopril)

Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Angiotensin receptor blockers

Specific and selective angiotensin II receptor antagonists.³ Compared with ACE inhibitors, ARBs are associated with a lower incidence of drug-induced cough, rash, and/or taste disturbances.

Losartan (Cozaar), valsartan (Diovan)

For patients unable to tolerate ACE inhibitors. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors. Do not affect response to bradykinin and are less likely to be associated with cough and angioedema.

Beta-adrenergic blocking agents

Affect blood pressure via multiple mechanisms. Actions include negative chronotropic effect that decreases heart rate at rest and after exercise, negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from CNS, and suppression of renin release from kidneys.

Metoprolol (Lopressor), atenolol (Tenormin), labetalol (Normodyne)

During IV administration, carefully monitor blood pressure, heart rate, and ECG.

Calcium channel blockers

Inhibit influx of extracellular calcium across myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. 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.

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.

Diltiazem (Cardizem), verapamil (Calan, Covera), nifedipine (Adalat, Procardia)

Also include amlodipine (Norvasc). During depolarization, inhibit calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. Amlodipine is longer acting.

Diuretics

Furosemide and bumetanide are loop diuretics that appear primarily to inhibit reabsorption of sodium and chloride in ascending limb of 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.

Furosemide (Lasix), hydrochlorothiazide (Microzide, HydroDIURIL)

Also include bumetanide (Bumex). Diuretics are used only as an adjunct to other medications.

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