1. Diabetic Nephropathy
This presentation will provide an overview of the natural history of diabetic nephropathy, treatment and prevention of diabetic nephropathy, and treatment options for end-stage renal disease (ESRD).

2. Diabetic Nephropathy
Over 40% of new cases of end-stage renal disease (ESRD) are attributed to diabetes.
In 2001, 41,312 people with diabetes began treatment for end-stage renal disease.
In 2001, it cost $22.8 billion in public and private funds to treat patients with kidney failure.
Minorities experience higher than average rates of nephropathy and kidney disease
Diabetes is the most common cause of kidney failure, accounting for more than 40% of new cases. Treatment for end stage renal disease is expensive; in 2001 it cost the United States over $22 billion to treat patients with kidney failure. Dialysis, one form of treatment for kidney failure, can relieve the symptoms of kidney disease, but over time the damaged kidneys will continue to contribute to problems such as heart disease, bone disease, arthritis, nerve damage, infertility, and malnutrition. Kidney transplant, another treatment alternative, may prove to be a more permanent solution to kidney disease for some patients. However, transplantation has its own risks including the risk of surgery, the risk of organ rejection, and the risk of infection and other complications from immunosuppressant drugs.
The best course of action is to prevent kidney disease from developing in the first place. Minorities with diabetes have an even greater challenge in preventing kidney disease, since African Americans, Hispanics, and American Indians experience higher rates of kidney disease than Caucasians.

3. Five Stages of Kidney Disease
Stage 1: Hyperfiltration, or an increase in glomerular filtration rate (GFR) occurs. Kidneys increase in size.
Stage 2: Glomeruli begin to show damage and microalbuminurea occurs.
Stage 3: Albumin excretion rate (AER) exceeds 200 micrograms/minute, and blood levels of creatinine and urea-nitrogen rise. Blood pressure may rise during this stage.
We can describe 5 stages or phases of diabetic nephropathy. In the first phase, the kidney is enlarged and GFR is elevated. It is not until the second stage of kidney disease development that clinical evidence of disease begins to show in the form of microalbuminurea when loss of albumin exceeds 30mg/day or 20 micrograms/min. Blood pressure usually begins to rise about the same time that microalbuminurea occurs. Individuals with type 1 and type 2 diabetes may remain at stage two for many years with good control of blood glucose and blood pressure.
During stage three, loss of albumin and other proteins exceeds 300 mg/day or 200 micrograms/minute. When this occurs, the patient is diagnosed as having clinical albuminuria. During this stage the kidneys also demonstrate an inability to adequately filter wastes from the blood, and creatinine and urea-nitrogen blood levels begin to rise.

4. Five Stages of Kidney Disease (con’t.)
Stage 4: GFR decreases to less than 75 ml/min, large amounts of protein pass into the urine, and high blood pressure almost always occurs. Levels of creatinine and urea-nitrogen in the blood rise further.
Stage 5: Kidney failure, or end stage renal disease (ESRD). GFR is less than 10 ml/min. The average length of time to progress from Stage 1 to Stage 4 kidney disease is 17 years for a person with type 1 diabetes. The average length of time to progress to Stage 5, kidney failure, is 23 years.
Stage four nephropathy is also known as "advanced clinical nephropathy". A decrease in GFR signals that the patient is progressing to kidney failure. If an increase in blood pressure was not evident in prior stages, it is usually evident at this time.
The final phase is stage five kidney disease, also known as kidney failure or end-stage renal disease. The glomeruli function at low levels and patients in this phase require dialysis or transplantation to survive.

5. Screening for Diabetic Nephropathy
This slide outlines recommended nephropathy screening guidelines for patients with diabetes.
Blood pressure should be monitored at each office visit and adults with diabetes should strive to maintain a blood pressure of less than 130mmHG systolic and 80mmHG diastolic. Patients with very high blood pressure (>180mmHg systolic), should be encouraged to lower their blood pressure slowly. Lowering blood pressure has been shown to delay the progression from microalbuminuria ( mg/day or micrograms/min) to macroalbuminuria (>300 mg/day or >200 micrograms/min).
Because it is possible for type 2 patients to have had diabetes for some time before being diagnosed, a urinalysis should be performed at diagnosis for these patients. Type 1 patients are usually diagnosed at or near onset of disease, therefore screening for urinary albumin can begin 5 years post-diagnosis.
There are three methods used when screening a patient for microalbuminuria:
1) Measurement of the albumin-creatinine ratio in a random spot collection;
2) 24-hour collection with creatinine, allowing the simultaneous measurement of creatinine clearance; and
3) timed collection (4 hours or overnight).
The preferred method is measurement of the albumin-creatinine ratio in a random spot collection. The 24-hour collection and timed collection are rarely necessary to perform, however at least two of the three tests should show elevated levels of urinary albumin before a patient is diagnosed as having microalbuminuria.
1American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004

6. Treatment of Diabetic Nephropathy
Hypertension Control - Goal: lower blood pressure to <130/80 mmHg
Antihypertensive agents
Angiotensin-converting enzyme (ACE) inhibitors
captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipril
Angiotensin receptor blocker (ARB) therapy
candesartan cilexetil, irbesartan, losartan potassium, telmisartan, valsartan, esprosartan
Beta-blockers
Nephropathy can be successfully treated during its early stages by lowering blood pressure and making lifestyle and dietary changes.
Hypertension control is key in preventing the progression of diabetic nephropathy, and the goal for all patients with diabetes is to maintain a blood pressure of <130/80 mmHg. ACE inhibitors have been shown to not only reduce blood pressure but also reduce microalbuminuria. Therefore, ACE inhibitors can be used in normotensive type 1 patients who present with microalbuminuria. In type 2 patients with hypertension and microalbuminuria (Stage 2 kidney disease), ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria (Stage 3 kidney disease). Finally, in type 2 patients with macroalbuminuria, hypertension, and renal insufficiency (serum creatinine >1.5mg/dL), ARBs are known to delay the progression to end stage renal disease.
Beta-blockers are another treatment option and, although the UKPDS did not show a difference in effectiveness between beta-blockers and ACE inhibitors in lowering blood pressure or microalbuminuria, ACE inhibitors continue to be the drug of choice because some studies have shown that they can slow the rate of progression of nephropathy more than other antihypertensive agents. Beta-blockers or non-DCCBs should be considered when patients cannot tolerate ACE inhibitors or ARBs. Many patients need two or more agents to adequately control blood pressure.
ACE inhibitors are contraindicated during pregnancy, and patients taking ACE inhibitors or ARBs should be monitored for hyperkalemia.
Because microalbuminuria is a marker of increased cardiovascular disease risk, lifestyle modifications including weight loss, exercise, and reduction of dietary salt and alcohol are recommended to reduce the chances of a CVD event.

7. Treatment of Diabetic Nephropathy (cont.)
Glycemic Control
Preprandial plasma glucose mg/dl
A1C <7.0%
Peak postprandial plasma glucose <180 mg/dl
Self-monitoring of blood glucose (SMBG)
Medical Nutrition Therapy
Restrict dietary protein to RDA of 0.8 g/kg body weight per day
Glycemic control has been shown to delay the progression of diabetic nephropathy. ADA recommendations state that adults with diabetes should strive to maintain an A1C of <7.0%, preprandial plasma glucose of mg/dl ( mmol/L), and peak postprandial plasma glucose of <180 mg/dl (<10.0 mmol/L). Components of a successful glycemic control plan include: self-monitoring of blood glucose (SMBG), performing an A1C test at least two times each year for patients who meet treatment goals and quarterly in patients who do not, and individualized medical nutrition therapy (MNT). The UKPDS, DCCT, and Minnesota Medical school Trial have shown that intensive management of blood glucose can be helpful to patients in preventing the progression to kidney disease.
Protein restriction has been shown to prevent the decline in GFR in some patients. Current ADA guidelines recommend that patients with nephropathy restrict their dietary protein intake to the adult Recommended Daily Allowance (RDA) which equals ~10% of daily calories. Further restriction to 0.6g/kg body weight per day may be useful, however patients should follow a low-protein diet developed by a registered dietition to prevent nutrition deficiency.

8. Treatment of End-Stage Renal Disease (ESRD)
There are three primary treatment options for individuals who experience ESRD:
1. Hemodialysis
2. Peritoneal Dialysis
3. Kidney Transplantation
There are currently three treatment options available to patients who experience kidney failure: Hemodialysis, peritoneal dialysis, and kidney transplantation. Although kidney transplantation is a serious operation, it offers patients with kidney failure their best opportunity for survival. For patients who choose dialysis, approximately one third are still alive after five years of treatment vs. a possible 90% survival rate for individuals who receive a kidney from a living relative. The next part of this presentation will review the procedures, risks and complications associated with each of these options.

9. Hemodialysis Procedure
A fistula or graft is created to access the bloodstream
Wastes, excess water, and salt are removed from blood using a dialyzer
Hemodialysis required approx. 3 times per week, each treatment lasting 3-5 hrs
Can be performed at a medical facility or at home with appropriate patient training
Hemodialysis filters wastes from the body by using a dialyzer to filter harmful wastes, excess salt and water from the blood.
Blood is drawn out and returned to the body through an access that is created prior to beginning dialysis treatment. A surgeon may create a fistula from the patients own blood vessels, or they may create a graft. When a fistula is used, an artery in the forearm is connected directly to a vein. Increased blood flow to the vein causes the vein to grow stronger and larger so that it can be used for multiple needle insertions. This is the preferred type of access and may take up to several weeks to be ready for use.
Creating a graft is another way to access the bloodstream. In this process a synthetic tube is used to connect an artery to a vein. A graft can be used right away, however patients with a graft are more likely to experience clotting or infection vs. patients with a fistula.
If kidney disease has progressed quickly or has gone undiagnosed, the patient and physician may not have the luxury of creating a permanent access before beginning hemodialysis. In this case a catheter inserted into the neck, chest, or leg may be used as a temporary access.
Hemodialysis is usually needed three times each week and is normally performed at a dialysis center, but in some cases can be performed at home with appropriate patient and family/caregiver training.

10. Hemodialysis (cont.) Hemodialysis Diet Complications
Monitor protein intake
Limit potassium intake
Limit fluid intake
Avoid salt
Limit phosphorus intake
Complications
Infection at access site
Clotting, poor blood flow
Hypotension
Patients on hemodialysis should eat balanced amounts of high-protein food and limit the amount of potassium in their diets. These patients should also limit fluid intake, since water can build up quickly in the body when kidneys are not functioning properly and cause heart problems and high blood pressure. Salt should also be avoided because it causes thirst and fluid retention. Finally, excess phosphorus can cause calcium to be pulled from the bones and can cause arthritis.
The most common problems with hemodialysis involve the access site and include infection and blockage from clotting. Other problems can be caused by the rapid changes in the body's chemical balance during treatment. A sudden drop in blood pressure is a common side effect, as are muscle cramps.

11. Peritoneal Dialysis Procedure
Dialysis solution is transported into the abdomen through a permanent catheter where it draws wastes and excess water from peritoneal blood vessels. The solution is then drained from the abdomen.
Three Types of Peritoneal Dialysis
Continuous Ambulatory Peritoneal Dialysis (CAPD)
Continuous Cycler-Assisted Peritoneal Dialysis (CCPD)
Combination CAPD and CCPD
Peritoneal dialysis removes wastes, excess water and chemicals from the body using the peritoneal membrane as a filter. Dialysis solution travels through a catheter into the abdomen, where wastes are drawn from the peritoneal membrane into the dialysis solution. After several hours the solution is drained from the abdomen and another exchange is begun.
There are three types of peritoneal dialysis. The most common type is CAPD, where dialysis solution remains in the abdomen for a dwell time of 4-6 hours, is drained and the process repeated. With CAPD the patients blood is continuously being cleaned.
A second type of peritoneal dialysis is CCPD. This method uses a cycler to fill and empty the abdomen 3-5 times during the night while the patient sleeps. In the morning an exchange occurs with a dwell time that lasts the entire day.
Some patients and physicians may find that a combination of CAPD and CCPD work best for their needs. For example, patients may use a cycler at night but also perform an exchange during the day. This may work best for patients over 175 pounds or for those whose peritoneums filter wastes slowly. Both types of peritoneal dialysis are usually performed by the patient alone without the help of a health professional or caregiver.

12. Peritoneal Dialysis (cont.)
Peritoneal Dialysis Diet
Limit salt and fluid intake
Consume more protein
Some potassium restrictions
Reduce caloric intake
Complications
Peritonitis
Patients on peritoneal dialysis should limit their salt and fluid intake to prevent water retention and blood pressure problems. However, fluid intake usually does not have to be as limited as with hemodialysis. A dietitian should be consulted to help the patient develop a meal plan with appropriate protein and potassium restrictions. Caloric intake should be monitored since the dialysis solution contains calories that may cause patients to gain weight.
The primary complication with peritoneal dialysis is peritonitis due to contamination of the catheter.

13. Kidney Transplant Procedure
A cadaveric kidney or kidney from a related or non-related living donor is surgically placed into the lower abdomen.
Three factors must be taken into consideration to determine kidney/recipient match:
Blood type
Human leukocyte antigens (HLAs)
Cross-matching antigens
The final method of treatment for patients with end-stage renal disease is kidney transplantation. Survival rates are highest among patients who receive a kidney from a living relative (up to 90% after five years) vs. a cadaver (80.6% after five years).2
Three factors must be taken into consideration when matching donor kidneys with potential recipients: blood type, HLA, and cross-matching antigens. The recipient blood type must match the donor blood type; this is the most important matching factor. Human leukocyte antigens (HLAs) do not have to be a complete match, however receiving a kidney from a relative provides a lower chance of rejection. Finally, a cross-match is done to determine if there is a reaction between the donor and recipient; if there is no reaction the transplant can take place.

14. Kidney Transplant (cont.)
Kidney Transplant Diet
Reduce caloric intake
Reduce salt intake
Complications/Risk Factors
Rejection
Immunosuppressant side effects
Benefits
No need for dialysis
fewer dietary restrictions
higher chance of living longer
Calories must be monitored to prevent excess weight gain, and sodium intake must be reduced to prevent hypertension.
Organ rejection and side effects from immunosuppressant therapy are the most common complications of organ transplantation. Immunosuppresants can cause infections, and diminished immunity over time can cause cancer. These drugs can also cause bone marrow suppression resulting in decreased numbers of RBCs, WBCs and platelets.
Some of the benefits of transplantation include:
Dialysis can be discontinued
The diet for patients who receive a transplant is less restrictive than for those on dialysis.
Patients who undergo a successful matching process and surgery have a greater chance of living a longer life (90% five-year survival rate with a living donor compared to approx. 32% five-year survival rate for those on dialysis).2
A word on pancreas transplants: A recenty study (JAMA, 2003) has indicated that, for patients with functioning kidneys, survival rates of patients who receive pancreas-only transplants are worse than the survival rates of patients who manage their diabetes with conventional therapy (insulin, diet, etc.). Therefore, the decision to have a pancreas-only transplant should be very carefully considered by both the patient and physician. Because of the lower survival rates seen with pancreas-only transplants, and because a pancreas transplanted along with a kidney is less likely to fail than a pancreas transplanted alone, pancreas transplants are nearly always done only in people with type 1 diabetes who are getting or already have a transplanted kidney.

15. How Can You Prevent Diabetic Kidney Disease?
Maintain blood pressure <130/80 mm/Hg
Maintain preprandial plasma glucose mg/dl
Maintain postprandial plasma glucose <180 mg/dl
Maintain A1C <7.0%
The steps that can be taken to prevent diabetic kidney disease are similar to the ones that are used to treat patients once they are diagnosed with microalbuminuria: maintain blood pressure below 130/80 mmHg and maintain glycemic control according to ADA guidelines. Helping patients to achieve good control of blood pressure and blood glucose levels will help significantly in delaying progression to diabetic kidney disease.

16. References
American Diabetes Association: Nephropathy in Diabetes (Position
Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004
National Kidney and Urologic Diseases Information Clearinghouse.
Kidney Disease of Diabetes. Bethesda, MD: National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health (NIH), DHHS; 2003.
United States Renal Data System. USRDS 2003 Annual Data
Report. Bethesda, MD: National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health (NIH), DHHS;
2003.
DeFronzo RA: Diabetic nephropathy: etiologic and therapeutic
considerations. Diabetes Reviews 3: , 1995
Kidney Failure: Choosing a Treatment That’s Right For You.
Bethesda, MD: National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health (NIH), DHHS; 2003.