By Stephen Z. Fadem, MD, FACP

Chronic kidney disease (CKD) is a condition where kidney damage leads to a progressive deterioration in kidney function. It has many causes, and regardless of the original disease or condition, it can result in kidney failure. Most of the time, however, it does not progress to kidney failure. This may happen because secondary conditions that accompany CKD overcome the patient who dies of a cardiovascular event. Along with advancing disease, CKD is an independent risk factor for cardiovascular disease. Unfortunately, many people who have kidney disease will experience a cardiac event or stroke before they ever reach the stage where dialysis is necessary.

In the last several years, there have been many clinical trials, the results of which have guided us to help prepare patients and greatly delay the progression of disease. The incentives to prevent kidney disease are great, for in its final stages, dialysis or a kidney transplant is necessary.

What can be done to either delay the progression of disease or, in many instances, prevent it? This brief overview will list ten steps that, in cooperation with your physician, you can follow to help slow advancing disease. The earlier one starts, the better the chances of helping preserve kidney function and reducing cardiovascular disease morbidity.

1. Treat the Underlying Condition

Several general diseases, such as lupus erythematosus or vasculitis (inflammation of a blood or lymph vessel), can cause kidney disease. Early management may stop the disease before progression advances. Diabetes and hypertension, which are discussed later in this article, can also be aggressively treated with positive outcomes.

Glomerulonephritis (inflammation of the kidney filter) may also be the original condition, and early attention may bring the disease into remission. Diseases of blood vessels that feed the kidney may cause ischemic kidney, and may respond to intervention or surgery. If ignored, infections, urologic disorders and tubulointerstitial disease can also harm the kidney. The best management plan is for your doctor to perform a thorough diagnostic evaluation, determine the cause of kidney disease, and then commence with appropriate therapy whenever possible.

2. Blood Pressure Control

According to the National Heart, Lung, and Blood Institute (NHLBI), 65 million Americans have hypertension. The Centers for Disease Control (CDC) reports 25 percent of the general population, and more than 40 percent of African Americans, have high blood pressure. Less than half of patients diagnosed with hypertension were being treated and only a quarter had blood pressures below 140/90 mm Hg.¹ This is concerning because in major longitudinal studies of kidney disease, both in the U.S. and in Europe, hypertension was inextricably linked with kidney disease. High blood pressure not only causes kidney disease, but is caused by it.

It is a physical property of our blood vessels that they can only contain so much fluid before the pressure against the sides of the vessels stimulates long-term damage to blood vessel walls. Once this occurs, the walls thicken and become inelastic. It is the elasticity of the walls that acts as a shock absorber, buffering the effect of our heart, a mighty pump, on target organs such as the brain and kidney. Furthermore, stiff, narrowed and inelastic vessels increase the force in which the heart needs to pump, which ultimately damages the heart. It is no surprise that 74 percent of kidney disease patients who undergo dialysis treatments also have heart damage.^{2 & 3}

There have been many studies that link high blood pressure and kidney disease, and also numerous clinical trials that demonstrate that tight blood pressure control can reduce progression of kidney disease. The National Kidney Foundation published the K/DOQI Clinical Practice Guidelines for the management of high blood pressure with kidney disease. The current recommendation is that blood pressure be kept below 130/80. In African Americans and individuals with proteinuria, the recommendation is to keep the systolic blood pressure as low as 110.⁴

3. Using an ACE Inhibitor or ARB

Meanwhile, as kidney disease progresses, the number of filters in the kidney decreases. When the pressure is distributed among a diminished number of filters, the pressure on each filter rises. This pressure is associated with enlargement of the filter and puts into place a chain reaction that damages the elements of the filter, which causes further damage and even more pressure on the few surviving filters. Given this picture, it makes sense that if there was a medicine that could reduce pressure against the filter, perhaps by dilating the blood vessels that take blood away from the filter (efferent arteriole), kidney function could be preserved. There are such medicines – angiotensin receptor blockers (ARBs).

Initial studies by Lewis⁵ have demonstrated that an angiotensin converting enzyme (ACE) inhibitor would reduce the doubling time of creatinine (a marker of disease progression) in type I diabetics. This study was later extended.⁶ In 2001, two independent trials appeared in the same issue of the New England Journal of Medicine,^{7, 8} and showed ARBs were effective in reducing the doubling time of creatinine in type II diabetics. Studies have also shown that not just for diabetes, but regardless of the cause, ACE inhibitors and ARBs reduce the progression of advancing disease.

4. Reducing Proteinuria

Not only is pressure associated with worsening kidney function, but also the passage of protein across a membrane. We can measure how much protein passes across the membrane – proteinuria. In the past, 24-hour urine specimens were collected. But it is just as accurate and much more convenient to simply perform a urine ratio of protein, or better, a type of protein known as albumin and creatinine (there’s that marker again). The angio-tensin blockers have the effect of lowering proteinuria independent of their blood pressure lowering effect. Thus, we can analyze the use of an ACE inhibitor, ARB or the combination of both to reduce proteinuria and likewise reduce the progression of disease.⁹

5. Controlling Diabetes

In 1993, a large clinical trial by the Diabetes Control and Compli-cations Trial Research Group (DCCT) was published that looked at differences in treating diabetes with conventional therapy and intensive therapy. Intensive therapy of 1,441 patients followed for a mean of 6.5 years demonstrated that maintaining the blood glucose levels close to normal reduced the development of diabetic retinopathy (the serious eye condition that accompanies diabetes), the development of neuropathy and albuminuria.¹⁰

6. Controlling Excess Body Mass

Once on dialysis, the body mass index (BMI) is not associated with a higher mortality rate, but in patients undergoing a transplant evaluation, it is associated with more progressive heart lesions. In predialysis patients, and certainly in the general population, obesity, (BMI more than 30) is associated with a variety of problems ranging from diabetes, hypertension, increased cardiovascular events, and a higher cancer rate. Currently, we are enduring an epidemic of obesity and consequently have a growing incidence of diabetes. Diabetes is a major cause of kidney disease. Although it is a paradoxical survival factor in end-stage renal disease (ESRD), in the CKD population it is an independent risk factor for disease development and progression.¹¹

7. Exercising

Inflammation is associated with CKD and may be helped with physical exercise training. In animal studies, voluntary running, as opposed to forced running, lessened the progression of disease.¹² In patients already on dialysis, exercising for one hour, twice a week, for three months lowered arterial stiffness, which offers a beneficial effect on the heart. It is inconclusive whether or not exercise programs will protect kidney function. However, if it is deemed safe by your physician, low impact exercise for 20 to 30 minutes a day may be beneficial. It is certain to improve the quality of life and well-being.

8. Controlling Lipids

Although cholesterol and triglyceride disorders, known as dyslipidemias, have been associated with kidney disease, it is still uncertain whether lipid-lowering therapy will protect the kidneys. In patients with ESRD, elevated cholesterol levels have not been associated with higher mortality rates in their predialysis counterparts. Other mechanisms may play a more predominant role in ESRD. Furthermore, a large clinical trial in Europe, soon to be published, did not show that atorvastatin changed the mortality rate in dialysis patients. Another large clinical trial, the Study of Heart and Renal Protection (SHARP) is ongoing. It will study 9,000 CKD patients with no known cardiac disease to see if lipid lowering agents will protect the heart and kidneys.

9. Refraining from Cigarette Smoking

Cigarette smoking has been associated with CKD progression, particularly by damaging small arteries. However, the responsible mechanisms for nicotine-induced kidney damage are unknown. Current and former smokers have a higher risk for proteinuria. There is evidence that proteinuria associated with smoking is irreversible, though it is possible that quitting might prevent further progressive disease. A second reason to stop cigarette smoking is that nicotine accelerates the progression of atherosclerosis. A trial started several years ago in Framingham, Mass., has demonstrated this. When the results of the DCCT (mentioned earlier) were reexamined, tobacco users consumed more fat, cholesterol and alcohol, and elevated the ratio of LDL to HDL (the bad to the good) cholesterol.¹³

10. Avoiding Drugs Known to Damage the Kidneys

Several medications are associated with the progression of CKD. In addition, since many medications are metabolized and excreted by the kidneys, decreased function leads to accumulation of pharmaceutical metabolic waste. This can be toxic to the kidney and other target organs. Many drugs used each day can promote kidney disease, even over-the-counter medicines. Non-steroidal, anti-inflammatory drugs such as ibuprofen and naproxen, have been associated with a type of kidney disease known as interstitial nephritis. Kidney patients should check with their doctors before starting any medication that they are not certain of, and to understand whether the drug is metabolized by the kidneys or liver. In drugs metabolized by the liver, secondary metabolites may accumulate and “clog” the enzyme systems that break down drugs. This promotes toxicity. Some drugs metabolized by liver enzymes can cause fatal cardiac rhythm disturbances if the enzyme system is overburdened and toxins are allowed to accumulate.¹⁴

Summary

Patients with kidney disease have many options to help slow its progression. These often require a major alignment in ones lifestyle, and as a secondary advantage, cardiovascular complications may be reduced. For some events, there is evidence confirmed by large clinical trials. For others, clinical trials may only be forthcoming for patients with kidney disease and we must look at the large trials that have been performed in the general population.

A tremendous effort is required to initiate and maintain a major lifestyle change, and it requires a great deal of trust that what one is attempting to accomplish will be of benefit. These resources should be of value to those seeking evidence and consensus from the clinical studies that have been performed in recent years.

References:

1. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995; 25(3):305-13.

2. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int 1995; 47(3):884-90.

3. Goodkin DA, Young EW, Kurokawa K, Prutz K-G, Levin NW. Mortality among hemodialysis patients in Europe, Japan, and the United States: case-mix effects. Am J Kidney Dis 2004; 44(5 Suppl 3):16-21.

4. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43(5 Suppl 1):1-290.

5. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329(20):1456-62.

6. Wilmer WA, Hebert LA, Lewis EJ, et al. Remission of nephrotic syndrome in type 1 diabetes: long-term follow-up of patients in the Captopril Study. Am J Kidney Dis 1999;34(2):308-14.

7. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345(12):851-60.

8. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12):861-9.

9. Remuzzi G, Chiurchiu C, Ruggenenti P. Proteinuria predicting outcome in renal disease: nondiabetic nephropathies (REIN). Kidney Int Suppl 2004(92):90-6.

10. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329(14):977-86.

11. Wiggins KJ, Johnson DW. The influence of obesity on the development and survival outcomes of chronic kidney disease. Adv Chronic Kidney Dis 2005;12(1):49-55.

12. Loupal G, Url A, Skalicky M, Viidik A. Physical exercise retards the development of chronic nephropathy in the ageing rat as efficiently as food restriction does. Gerontology 2005; 51(2):83-93.

13. Cundiff DK. Diet and tobacco use: analysis of data from the diabetic control and complications trial, a randomized study. MedGenMed 2002; 4(1):2.

14. Aronoff G, Brater DC, Schrier R, Bennett WM. Use of drugs in patients with renal insufficiency. Workshop report. Blood Purif 1994;12(1):14-9.

Stephen Z. Fadem, MD, FACP, serves as a vice president of the AAKP National Board of Directors and is a member of the AAKP Medical Advisory Board. He is a practicing nephrologist in Houston.

This article originally appeared in the September/October 2005 issue of Kidney Beginnings: The Magazine, Vol. 4, No. 3.

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