Diabetic nephropathy

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Overview
Diabetic nephropathy (nephropatia diabetica), also known as Kimmelstiel-Wilson syndrome and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and nodular glomerulosclerosis. It is due to longstanding diabetes mellitus, and is a prime cause for dialysis in many Western countries.

History
The syndrome was discovered by British physician Clifford Wilson (1906-1997) and Germany-born American physician Paul Kimmelstiel (1900-1970) and was published for the first time in 1936.

Epidemiology
The syndrome can be seen in patients with chronic diabetes (15 years or more after onset), so patients are usually of older age (between 50 and 70 years old). The disease is progressive and may cause death two or three years after the initial lesions, and is more frequent in men. Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage kidney disease in the United States. People with both type 1 and type 2 diabetes are at risk. The risk is higher if blood-glucose levels are poorly controlled. Further, once nephropathy develops, the greatest rate of progression is seen in patients with poor control of their blood pressure. Also people with high cholesterol level in their blood have much more risk than others.

Etiopathology
The earliest detectable change in the course of diabetic nephropathy is a thickening in the glomerulus. At this stage, the kidney may start allowing more serum albumin (plasma protein) than normal in the urine (albuminuria), and this can be detected by sensitive medical tests for albumin. This stage is called "microalbuminuria". It can appear 5 to 10 years before other symptoms develop. As diabetic nephropathy progresses, increasing numbers of glomeruli are destroyed by nodular glomerulosclerosis. Now the amounts of albumin being excreted in the urine increases, and may be detected by ordinary urinalysis techniques. At this stage, a kidney biopsy clearly shows diabetic nephropathy.

Signs and symptoms
Kidney failure provoked by glomerulosclerosis leads to fluid filtration deficits and other disorders of kidney function. There is an increase in blood pressure (hypertension) and of fluid retention in the body (oedema). Other complications may be arteriosclerosis of the renal artery and proteinuria (nephrotic syndrome).

Throughout its early course, diabetic nephropathy has no symptoms. They develop in late stages and may be a result of excretion of high amounts of protein in the urine or due to renal failure:


 * oedema: swelling, usually around the eyes in the mornings; later, general body swelling may result, such as swelling of the legs
 * foamy appearance or excessive frothing of the urine
 * unintentional weight gain (from fluid accumulation)
 * anorexia (poor appetite)
 * nausea and vomiting
 * malaise (general ill feeling)
 * fatigue
 * headache
 * frequent hiccups
 * generalized itching

The first laboratory abnormality is a positive microalbuminuria test. Most often, the diagnosis is suspected when a routine urinalysis of a person with diabetes shows too much protein in the urine (proteinuria). The urinalysis may also show glucose in the urine, especially if blood glucose is poorly controlled. Serum creatinine and BUN may increase as kidney damage progresses.

A kidney biopsy confirms the diagnosis, although it is not always necessary if the case is straightforward, with a documented progression of proteinuria over time and presence of diabetic retinopathy on examination of the retina of the eyes.

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 drugs, which usually reduces proteinuria levels and slows the progression of diabetic nephropathy. Several effects of the ACEIs that may contribute to renal protection have been related to the association of rise in Kinins which is also responsible for some of the side effects associated with ACEIs therapy such as dry cough. The renal protection effect is related to the antihypertensive effects in normal and hypertensive patients, renal vasodilatation resulting in increased renal blood flow and dilatation of the efferent arterioles. Many studies have shown that related drugs, angiotensin receptor blockers (ARBs), have a similar benefit. In fact, a combination may be best.

Blood-glucose levels should be closely monitored and controlled. This may slow the progression of the disorder, especially in the very early ("microalbuminuria") stages. Medications to manage diabetes include oral hypoglycemic agents and insulin injections. As kidney failure progresses, less insulin is excreted, so smaller doses may be needed to control glucose levels.

The diet may be modified to help control blood-sugar levels. Modification of protein intake can effect hemodynamic and nonhemodynamic injury. High blood pressure should be aggressively treated with antihypertensive medications, in order to reduce the risks of kidney, eye, and blood vessel damage in the body. It is also very important to control lipid levels, maintain a healthy weight, and engage in regular physical activity.

Patients with diabetic nephropathy should avoid taking the following drugs:


 * Contrast agents containing iodine
 * Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, or COX-2 inhibitors like Celebrex, because they may injure the weakened kidney.

Urinary tract and other infections are common and can be treated with appropriate antibiotics.

Dialysis may be necessary once end-stage renal disease develops. At this stage, a kidney transplantation must be considered. Another option for type 1 diabetes patients is a combined kidney-pancreas transplant.

C-peptide, a by-product of insulin production, may provide new hope for patients sufering from diabetic nephropathy.

Prognosis
Diabetic nephropathy continues to get gradually worse. Complications of chronic kidney failure are more likely to occur earlier, and progress more rapidly, when it is caused by diabetes than other causes. Even after initiation of dialysis or after transplantation, people with diabetes tend to do worse than those without diabetes.

Complications
Possible complications include:


 * hypoglycemia (from decreased excretion of insulin)
 * rapidly progressing chronic kidney failure
 * end-stage kidney disease
 * hyperkalemia
 * severe hypertension
 * complications of hemodialysis
 * complications of kidney transplant
 * coexistence of other diabetes complications
 * peritonitis (if peritoneal dialysis used)
 * increased infections

Additional Resource

 * Kimmelstiel P, Wilson C. Benign and malignant hypertension and nephrosclerosis. A clinical and pathological study. Am J Pathol 1936;12:45-48.