Diabetic nephropathy

Leading cause of end-stage renal disease worldwide.

One of the most common causes of proteinuria in patients with type two diabetes, particularly if diabetic retinopathy is also present.

A slowly progressive chronic disease associated with an increase of proteinuria and serum creatinine levels over a period of years.

 In diabetic glomerulosclerosis there is a thickening of the basement membrane, which can become up to 4-5 times thicker than normal. 


Chronic hyperglycemia leads to diabetic kidney disease which gradually develops over many years and has several interrelated stages, including reversible glomerular hyperfiltration, normal glomerular filtration, and normal microalbuminuria, declining glomerular filtration, and macro albuminuria, end stage renal disease.

In  type two diabetes, the hyperabsorption of glucose and sodium in the proximal renal tubules by SGLT2 causes afferent arteriolar vasodilation, which causes glomerular hyperfiltration, leading to glomerular information, fibrosis, and ultimately diabetic kidney disease.

The reduction of reabsorption of sodium increases the sodium concentration at the macula densa, the specialized cells in the distal renal tubules adjacent to the glomeruli.

Tubuloglomerular feedback activates  adenosine receptors constricting the afferent glomerular arterioles  reducing glomerular hyperfiltration and further renal damage.

There are two sodium-glucose co-transporters responsible for glucose reabsorption: SGLT1 and SGLT2.

Progressive chronic process that affects 20-40% of patients with diabetes mellitus.

In the US diabetes mellitus accounts for more than 44% of patients with end stage renal disease.

Ten billion dollars per year in annual medical expenditures.

Approximately 40% of 21 million diabetics will develop nephropathy.

High levels of plasma homocysteine associated with risk of developing DN.

In type one diabetes nephrotic-range proteinuria of greater than 3 1/2 g a day take several years to develop after the onset of the disease.

Similar process occurs in type two diabetes but that pattern is unreliable because vascular renal disease tends to be present.

Cumulative risk of renal failure after the onset of overt proteinuria is very similar among patients with either type of diabetes.

In a multicenter, randomized double blind, placebo controlled trial with vitamin B-folic acid, vitamin B6, and vitamin B12 in diabetic with Type I and Type II diabetes with diabetic nephropathy: high doses of vitamin B resulted in a greater decrease in GFR and increase in vascular events (Diabetic Intervention with Vitamins to Improve Nephropathy), despite significantly lowering plasma total homocysteine.

Prevalence in type 2 diabetes greater in blacks, Hispanics, and Asians.

Asians have the highest prevalence.

Strict control of hyperglycemia and hypertension can slow its progression and insulin resistance correlates with onset and severity of albuminuria.

The development and rate of renal deterioration is closely related to patient’s blood pressure and guidelines suggest that blood pressure in patients with diabetes and chronic kidney disease should be kept at 130/80 mmHg or less (Bakris GL et al).

Insulin resistance correlates with albuminuria even in normotensive patients who do not have diabetes.

Rapid development and progression of proteinuria is inconsistent with classic diabetic nephropathy, as is high levels of albuminuria.

Microalbuminuria a significant risk factor for the development of DN in type 2 diabetics.

Microalbuminuria is predictive of diabetic nephropathy and premature cardiovascular disease.

Intensive treatment in diabetics with microalbuminuria significantly decreases the development of DN (Steno-2 Study).

DN can be delayed by tight diabetic control, and such therapy should be employed in diabetics with normoalbuminuria (Tu S).

The renin-angiotensin system has been implicated in the deterioration of renal function in patients with DN and in patients with stage 3 or 4 chronic kidney disease with microalbuminuria on macro albuminuria.

ACE inhibitors and ARBs slow the worsening of GFR and lower the rate of albumin excretion in diabetes.

Combination therapy with ACE inhibitors and an ARB is associated with an increased risk of adverse events among patients with diabetic neuropathy (Fried LF et al).

In a meta-analysis of the 157 studies with 43,256 participants of patients with type two diabetes or chronic kidney disease comparing the impact of blood pressure lowering drugs including angiotensin-converting enzyme inhibitors , angiotensin receptor blockers, and endothelium inhibitors showed no drug therapy was more effective than placebo for decreasing death rates, risk of end-stage renal disease was significantly reduced after the treatment with ARBs and ACE inhibitors (Palmer SC et al).

In the Ongoing Telmisartan Alone and in the Combination with Ramipril Global Endpoint Trial (ONTARGET) a randomized study of combination therapy was associated with increased cardiovascular risk, no cardiovascular or renal benefits but increased risk of hyperkalemia and acute kidney injury requiring dialysis.

ACE inhibitors delay the onset of microalbuminuria in patients with type II diabetes, hypertension, normoalbuminuria, and normal renal function.

In the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study this agent (Benicar) was tested at 40 mg a day, compared with placebo in type II diabetics, with one of cardiovascular risk factor, normoalbuminuria , to seek a target blood pressure of less than 130/80 mm of mercury:Olmesartan was associated with delayed onset of microalbuminuria with 8.2% versus 9.8% in the placebo group, the time to onset of microalbuminuria was increased by 23%, fewer nonfatal cardiovascular events 3.6% versus 4.1% but a greater number of fatal cardiovascular events 0.7% versus 0.1% (Haller H et al.).

Podocyte-specific deficiency of insulin receptors leads to glomerular lesions that resemble diabetic nephropathy in the absence of hyperglycemia.

The podocyte is a specialized cell of the glomerulous which helps prevent proteinuria by regulating the actin cytoskeleton in their foot processes.

Insulin sensitizers may confer protection against diabetic nephropathy.

Empagliflozin showed a significant reduction in the development of worsening kidney function, defined as the composite of doubling of the serum creatinine level, an increase in albuminuria, initiation of renal replacement therapy, or death due to kidney disease.

Inhibitors of the renin-angiotensin system is superior to calcium channel blockers for the reduction of Albuminuria in the nephropathy  due to hypertension and diabetes mellitus: The net clinical benefit is small.

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