Diabetic nephropathy

Diabetic nephropathy (DN), also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Protein loss in the urine due to damage to the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) and result in the nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2</small>  to less than 15, at which point the patient is said to have end-stage kidney disease (ESKD). It usually is slowly progressive over years.

Pathophysiologic abnormalities in DN begin with long-standing poorly controlled blood glucose levels. This is followed by multiple changes in the filtration units of the kidneys, the nephrons. (There are normally about 750,000–1.5 million nephrons in each adult kidney). Initially, there is constriction of the efferent arterioles and dilation of afferent arterioles, with resulting glomerular capillary hypertension and hyperfiltration; this gradually changes to hypofiltration over time. Concurrently, there are changes within the glomerulus itself: these include a thickening of the basement membrane, a widening of the slit membranes of the podocytes, an increase in the number of mesangial cells, and an increase in mesangial matrix. This matrix invades the glomerular capillaries and produces deposits called Kimmelstiel-Wilson nodules. The mesangial cells and matrix can progressively expand and consume the entire glomerulus, shutting off filtration.

The status of DN may be monitored by measuring two values: the amount of protein in the urine - proteinuria; and a blood test called the serum creatinine. The amount of the proteinuria reflects the degree of damage to any still-functioning glomeruli. The value of the serum creatinine can be used to calculate the estimated glomerular filtration rate (eGFR), which reflects the percentage of glomeruli which are no longer filtering the blood.  Treatment with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), which dilates the arteriole exiting the glomerulus, thus reducing the blood pressure within the glomerular capillaries, which may slow (but not stop) progression of the disease. Three classes of diabetes medications – GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors – are also thought to slow the progression of diabetic nephropathy.

Diabetic nephropathy is the most common cause of ESKD and is a serious complication that affects approximately one quarter of adults with diabetes in the United States. Affected individuals with end-stage kidney disease often require hemodialysis and eventually kidney transplantation to replace the failed kidney function. Diabetic nephropathy is associated with an increased risk of death in general, particularly from cardiovascular disease.

Signs and symptoms
The onset of symptoms is 5 to 10 years after the disease begins.  A usual first symptom is frequent urination at night: nocturia. Other symptoms include tiredness, headaches, a general feeling of illness, nausea, vomiting, frequent daytime urination, lack of appetite, itchy skin, and leg swelling.

Risk factors
The incidence of diabetic nephropathy is higher in people with diabetes that have one or more of the following conditions:
 Poor control of blood glucose
 Uncontrolled high blood pressure
 Type 1 diabetes mellitus, with onset before age 20
 Past or current cigarette use
 A family history of diabetic nephropathy

Pathophysiology
 
The pathophysiology of the glomerulus in DN can best be understood by considering the three involved cells as a unit: the endothelial cell, the podocyte, and the mesangial cell. These cells are in physical contact with one another at various locations within the glomerulus; they also communicate with one another chemically at a distance. All three cells are abnormal in DN.

Diabetes causes a number of changes to the body's metabolism and blood circulation, which likely combine to produce excess reactive oxygen species (chemically reactive molecules containing oxygen). These changes damage the kidney's glomeruli (networks of tiny blood vessels), which leads to the hallmark feature of albumin in the urine (called albuminuria). As diabetic nephropathy progresses, a structure in the glomeruli known as the glomerular filtration barrier (GFB) is increasingly damaged. This barrier is composed of three layers including the fenestrated endothelium, the glomerular basement membrane, and the epithelial podocytes. The GFB is responsible for the highly selective filtration of blood entering the kidney's glomeruli and normally only allows the passage of water, small molecules, and very small proteins (albumin does not pass through the intact GFB). Damage to the glomerular basement membrane allows proteins in the blood to leak through, leading to proteinuria. Deposition of abnormally large amounts of mesangial matrix causes periodic-acid schiff positive nodules called Kimmelstiel–Wilson nodules.

High blood sugar, which leads to formation of advanced glycation end products;  and cytokines have also been implicated as mechanisms for the development of diabetic nephropathy.

Diagnosis

Staging
To stage the degree of damage in this (and any) kidney disease, the serum creatinine is determined and used to calculate the estimated glomerular filtration rate (eGFR). Normal eGFR is equal to or greater than 90ml/min/1.73 m2.

Treatment 
The goals of treatment are to slow the progression of kidney damage and control related complications. The main treatment, once proteinuria is established, is ACE inhibitor medications, which usually reduce proteinuria levels and slow the progression of diabetic nephropathy. Other issues that are important in the management of this condition include control of high blood pressure and blood sugar levels (see diabetes management), as well as the reduction of dietary salt intake.

Prognosis
Diabetic nephropathy in type 2 diabetes can be more difficult to predict because the onset of diabetes is not usually well established. Without intervention, 20–40 percent of patients with type 2 diabetes/microalbuminuria, will evolve to macroalbuminuria.

Diabetic nephropathy is the most common cause of end-stage kidney disease, which may require hemodialysis or even kidney transplantation. It is associated with an increased risk of death in general, particularly from cardiovascular disease.

Epidemiology 
In the U.S., diabetic nephropathy affected an estimated 6.9 million people during 2005–2008. The number of people with diabetes and consequently diabetic nephropathy is expected to rise substantially by the year 2050.

See also 
 Diabetic diet
 Hyperbaric medicine
 Nephrology

References

Further reading

External links 

Category:Kidney diseases
Category:Vascular diseases
Category:Diabetes