Management of Diabetic Nephropathy

Managing diabetic nephropathy
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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. 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.

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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: A study by Ueno indicated that in patients with type 2 diabetes with hyperuricemia, kidney function significantly improves when serum urate levels are reduced below 6.

A meta-analysis examining the effects of dietary protein restriction 0. 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. When nephropathy is advanced, the diet should reflect the need for phosphorus and potassium restriction, with the use of phosphate binders.

Pharmacologic Treatment of Diabetic Nephropathy

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. Dietary salt reduction may help slow progression of kidney disease in both type 1 and type 2 diabetes. 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. Avoidance of potentially nephrotoxic substances such as nonsteroidal anti-inflammatory medications and aminoglycosides.

Early detection and optimal management of diabetes, especially in the setting of family history of diabetes. 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.

To see complete information on the conditions below, please go to the main article by clicking on the title:. Renal complications of diabetic nephropathy include increased risk of urinary tract infections, which may be further increased with the use of SGLT2 inhibitors. For example, type 4 hyperkalemic, low—anion gap renal tubular acidosis is more common in patients with type 2 DM, especially those with moderate renal insufficiency, and is associated with decreased ammoniagenesis.

It has also been noted that kidney stones may be more common in patients with type 2 DM, as well as metabolic syndrome. A low urine pH primarily favors uric acid stone formation; studies have found that female patients with type 2 DM, especially, have strikingly higher rates of uric acid stones.

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Recent advances in managing and understanding diabetic nephropathy. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Is obesity a major cause of chronic kidney disease?. Adv Ren Replace Ther. Glomerular hyperfiltration in the prediction of nephropathy in IDDM: Odegaard JI, Chawla A. Connecting type 1 and type 2 diabetes through innate immunity. Cold Spring Harb Perspect Med.

Role of growth factors in diabetic kidney disease. Mediators of diabetic renal disease: J Am Soc Nephrol. The association of folic acid deficiency and diabetic nephropathy in patients with type 2 diabetes mellitus. Temporal trends in the prevalence of diabetic kidney disease in the United States. An autopsy study suggests that diabetic nephropathy is underdiagnosed. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians.

Risk for ESRD in type 1 diabetes remains high despite renoprotection. Risk Factors for Diabetic Nephropathy. Choroidal thickness alterations in diabetic nephropathy patients with early or no diabetic retinopathy. Glomerular filtration rate estimation in patients with type 2 diabetes: Variability in glycated albumin levels predicts the progression of diabetic nephropathy.

Pathologic classification of diabetic nephropathy. Novel therapies of diabetic nephropathy. Curr Opin Nephrol Hypertens. Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst Rev. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. 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.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease.

Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Effect of renal impairment on the pharmacokinetics of exenatide. Br J Clin Pharmacol. Mild renal impairment and the efficacy and safety of liraglutide. The effect of blood pressure intervention on renal function in insulin-dependent diabetes.

Therapeutic inhibition of the renin angiotensin aldosterone system. Expert Opin Ther Pat. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD.

Clin J Am Soc Nephrol. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes VITAL study: Avosentan reduces albumin excretion in diabetics with macroalbuminuria. Daudon M, Jungers P. Type 2 diabetes increases the risk for uric acid stones. Cancer risk in patients with diabetic nephropathy: Fan JZ, Wang R. Non-diabetic renal diseases in patients with type 2 diabetes: J Clin Med Res. Diabetic retinopathy may predict the renal outcomes of patients with diabetic nephropathy.

A Latent Class Analysis. Early diabetic nephropathy in type 1 diabetes: Curr Opin Endocrinol Diabetes Obes. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes Received salary from Medscape for employment. George R Aronoff, MD is a member of the following medical societies: Sign Up It's Free!

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If you log out, you will be required to enter your username and password the next time you visit. Share Email Print Feedback Close. A recent meta-analysis confirms that hyperfiltration is associated with the future risk of developing DN. Blunting the profibrotic effects of angiotensin II may also be a significant factor in the benefits observed with these agents. The classic natural history of DN is described as a stepwise progression from a hyperfiltration phase via incipient nephropathy with microalbuminuria to overt nephropathy with persistent dipstick positive proteinuria, followed by progressive CKD, finally reaching ESRD.

Typical histopathological changes include glomerular basement membrane thickening, mesangial matrix expansion, development of Kimmelstiel Wilson nodules and arteriolar hyaline thickening. The natural history is predominantly based on follow-up of patients with T1DM.

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Clinical trials have shown that it is possible to alter the natural history of DN by targeting multiple risk factors eg achieving tight glycaemic control, aggressive treatment of hypertension and the use of ACEIs and ARBs. The trial concluded that the proportion of patients with T2DM who develop microalbuminuria is substantial, with one-quarter affected within 10 years of diabetes diagnosis.

Fewer patients develop macroalbuminuria, but the death rate in those who do exceeds the rate of progression to worse nephropathy. Annual transition rates through stages of nephropathy to death from any cause, as described in the UK Prospective Diabetes Study. Adapted from Ref 6 with permission from Macmillan Publishers Ltd: The higher mortality is largely attributed to an increased risk of cardiovascular disease. DM, CKD and microalbuminuria are all independently associated with an increased risk of cardiovascular disease.

Having all three significantly increases mortality risk. Annual screening for microalbuminuria is recommended for patients with T2DM from the time of diagnosis as the duration of their diabetes will be unknown. For patients with T1DM, annual microalbuminuria screening is recommended from five years after diagnosis.

A reduction in protein excretion to below 0. Excellent glycaemic control can prevent the onset of microalbuminuria, reverse glomerular hypertrophy and hyperfiltration, and stabilise or decrease proteinuria in those with established DN. Intensive therapy to near-normal glycaemia can reduce the onset or progression of DN even in those with previous poor glycaemic control.

Methods for HbA 1c measurement are affected by renal failure, leading to falsely elevated levels. However, in those patients with advanced CKD other factors contribute to decrease in measured HbA 1c , leading to an underestimate of glycaemic control, for example reduced red blood cell life span, recent transfusion, iron deficiency, accelerated erythropoiesis due to administration of erythropoietin and metabolic acidosis.

CKD is associated with insulin resistance, but the half-life of insulin increases as renal failure progresses and patients may need a reduction in total insulin dose, particularly those with reduced appetite associated with uraemia.

Approach Considerations

ACE inhibition has been shown to delay the development of diabetic nephropathy. Another feature of diabetic patients is the persistent elevation of endothelin level. The dissociated Nrf2 translocates to the nucleus where it triggers the genes encoding the antioxidant and detoxifying molecules, thus activating their transcription. These agents should only be used in combination with an ACE inhibitor and should not be used in patients with a recent coronary event. The source of dietary protein should also be considered.

Oral hypoglycaemic drug therapy can also be challenging in diabetic patients with advanced CKD. Metformin is used with caution in people with CKD because of the associated risk of lactic acidosis. Second-generation sulphonylureas are the agent of choice, but may also require dose reduction due to increased drug half-life. Benefits of RAAS blockade include reduction in intraglomerular pressure and hyperfiltration, antifibrotic effects and endothelial stabilisation.

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Several issues are key in the medical care of patients with diabetic nephropathy. These include glycemic control, management of hypertension. Diabetic nephropathy is the single most common cause of end-stage renal disease in the western world and is associated with greatly increased cardiovascular.

In patients with microalbuminuria or hypertension at all stages of nephropathy, an ACEI or ARB should be considered and uptitrated to achieve BP and proteinuria targets. Patients should be told to stop these drugs during any episodes of dehydration, intercurrent illness or exposure to radiocontrast. Compared with monotherapy, combined therapy can produce a greater reduction in protein excretion. Nevertheless, the recent ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trail ONTARGET study reported that combining an ACEI and ARB in patients with vascular disease or high-risk diabetes, but without heart failure, did not reduce the risk of the primary outcome death from cardiovascular causes, myocardial infarction, stroke or hospitalisation for heart failure but increased the risk of hypotensive symptoms, syncope, hyperkalaemia, and renal failure requiring dialysis.

Most patients with DN require multiple drugs to achieve BP goals. In those with volume overload, a diuretic will help enhance the antiproteinuric effects of RAAS blockade. Addition of calcium channel blockers can help to achieve BP targets.

For those who remain proteinuric, a non-dihydropyridine agent such as diltiazem may reduce intraglomerular pressure and proteinuria. A pooled analysis of nine major clinical trials of DN 12 confirmed that lower mean arterial pressures are directly correlated with reduction in the annual loss of GFR.

Simultaneous targeting of multiple clinically modifiable risk factors for DN has proved to be a successful prevention strategy. Prolonged follow-up of the STENO Diabetes Centre STENO-2 study participants demonstrated that intensive intervention with multiple drug combinations and behaviour modification in at-risk patients with T2DM had sustained beneficial effects with respect to DN, vascular complications and cardiovascular and all-cause mortality. Various other novel agents for the treatment of DN and reduction in proteinuria are currently being investigated including fibrates, fish oils, vitamin D analogues and peroxisome proliferated activated receptor-gamma agonists.

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Another renal diagnosis should be considered if retinopathy is absent in T1DM or if there is sudden onset of nephrotic range proteinuria, haematuria or rapidly declining renal function. Timely referral for those approaching ESRD is imperative to ensure adequate individual planning for renal replacement therapy: The earliest sign of DN is the development of microalbuminuria which is associated with a significant risk of both progressive renal failure and premature death from cardiovascular disease.

User Name Password Sign In. In this window In a new window. Previous Section Next Section. Glycaemic control Excellent glycaemic control can prevent the onset of microalbuminuria, reverse glomerular hypertrophy and hyperfiltration, and stabilise or decrease proteinuria in those with established DN. Novel agents Various other novel agents for the treatment of DN and reduction in proteinuria are currently being investigated including fibrates, fish oils, vitamin D analogues and peroxisome proliferated activated receptor-gamma agonists.

Annual data report Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: BMJ ;