Now for the renal side of the story

Content provided by the Faculty of the Harvard Medical School

Now for the renal side of the story

Prevention and early detection of kidney disease could save your life.

The kidneys get no respect. We talk of “lion hearts,” “leather lungs,” and even “iron stomachs,” but the kidneys go unheralded — that is, until they go wrong. The pair of bean-shaped organs go quietly about their complex business of cleansing the blood of waste products, dumping excess water, regulating hormone levels, adjusting blood pressure, and ordering new red blood cells. Only when their function is impaired do the kidneys attract real notice. Then suddenly they loom very large.

We need to pay closer attention to our kidneys. Experts say that 20 million Americans have some form of chronic kidney disease, including over 7 million with less than half the kidney function rate of a young adult. That’s considered “moderate” impairment. Severe impairment begins when the function level is less than 25% of the norm. When it falls below 10%–15%, end-stage renal disease — in other words, kidney failure — begins.

Diabetes is the primary diagnosis for nearly half of the people with kidney failure. High blood pressure is the underlying condition for another 30%. Although the number of new cases has increased each year for over two decades, the rate of increase has slowed. This is probably evidence that efforts to prevent the progression from chronic kidney disease to kidney failure are working. Currently, the only “cure” for kidney failure is a transplant. About 15,000 kidney transplants are performed each year in this country, but about 60,000 more Americans are on the waiting lists.

Master and recycler

Blood is filtered in the kidneys’ nephrons, but much of the water, salts, and metabolites are reabsorbed. By recycling in this way, the kidneys are master regulators of fluid and other levels.

But the grim fact is that most chronic kidney disease patients die from a heart attack or some other cardiovascular “event” before their kidneys ever give out. To some extent, lack of treatment is to blame. A number of studies have shown that many kidney patients don’t receive the heart medications or get the coronary procedures that would improve their chances of avoiding a dire cardiovascular event. Experts decry this “therapeutic nihilism” and are pushing doctors to treat kidney disease patients like they would other high-risk cardiovascular patients.

On the flip side, a number of studies suggest that kidney function tests might be a useful bellwether for heart attack patients, and perhaps for the general population. Renal blood vessels seem to be unusually sensitive to vascular problems, so declines in kidney function might be an early warning sign of cardiovascular woe. Moreover, “renal insufficiency,” as doctors call it, may accelerate cardiovascular disease because when your kidneys aren’t working right, levels of homocysteine and other substances that are hard on blood vessels and the heart tend to go up.

Kidney function tests

In early 2005, researchers at the National Institutes of Health, the Centers for Disease Control and Prevention, and the Johns Hopkins Bloomberg School of Public Health examined awareness of kidney disease among 4,101 adults by matching lab tests of their kidney function rates against their answers to the question: “Have you ever been told by a doctor or health care professional that you had weak or failing kidneys (excluding kidney stones, bladder infections, or incontinence)?” Fewer than 10% of those whose function rates were already “moderately impaired” remembered any such warning. Only those whose lab tests revealed severely decreased function knew about chronic kidney disease.

One problem may be that doctors depend too much on an older test of kidney function, says Dr. Thomas Hostetter, one of the study’s authors and the head of an education program at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The test measures the level of creatinine (pronounced cree-AT-i-nen), a normal muscle protein metabolite that isn’t harmful but serves as a marker of how fast the kidneys are running. The normal range for creatinine is 0.8 to 1.3 mg/dL, although that varies from lab to lab.

But normal can be misleading, says Dr. Hostetter, unless the numbers are plugged into a glomerular filtration rate (GFR) calculator, an equation that adjusts for a patient’s age, gender, and race. For the GFR, race is defined as African American or not, a reflection of alarming statistics that show African Americans progress to kidney failure four times faster than Americans of European descent. Knowing your GFR is your first step to kidney awareness, says Dr. Hostetter, who is promoting a free GFR calculator on the NIDDK’s National Kidney Disease Education Program Web site at www.nkdep.nih.gov. (To find the calculator, click through to the Health Professionals page of the Web site.) Many labs already perform the GFR calculation at no additional cost, although physicians must request it.

As you might expect, doctors also use urine tests to assess kidney function. Levels of a protein called albumin are often measured. Kidneys that aren’t working properly can’t separate albumin from normal waste products, so levels in the urine go up.

A test for older people

Even when the number is properly adjusted, creatinine levels may not be the best indicator of how well our kidneys are working, especially as we grow older, so doctors are looking for alternatives. One possibility is a protein in the blood called cystatin C, which is also filtered by the kidneys. Age, race, and other factors don’t seem to affect cystatin C levels as much as they do the level of creatinine. A study comparing cystatin C with creatinine testing was published in the May 19, 2005, New England Journal of Medicine. The researchers measured both proteins in about 4,600 healthy people ages 65 and over, and then kept tabs on them for about seven years. The cystatin C level turned out to be a stronger predictor than creatinine of overall mortality, and also of cardiovascular events. The FDA has approved a cystatin C test, but more research needs to be done before doctors know how to use it in day-to-day patient care.

Polycystic kidney disease

Polycystic kidney disease (PKD) has the dubious distinction of being the most common life-threatening genetic disorder in the world. It affects an estimated 600,000 Americans and 12.5 million people worldwide.

There are other cystic kidney disorders, but PKD’s signature is the formation of large, fluid-filled pockets in epithelial tissue. The kidneys swell and may eventually shut down altogether. When they are autopsied, PKD kidneys look like they are filled with golf balls.

Transplants are still the only cure. However, researchers think they may have figured out what goes wrong in PKD and how, someday, it might be put right.

The suspect was the cilium, a small hair-like structure that protrudes from the surface of many kinds of cells. Cilia are biological propulsion devices. Waving cilia are the oars of one-celled organisms like paramecia. Cilia in the human bronchial linings keep airways clear. But cilia in human kidneys don’t move and don’t seem to do much of anything. At best, kidney cell cilia were considered leftover evolutionary baggage like the appendix.

Then in 2003, researchers found a new use for the “useless” cilia in epithelial kidney cells. They seem to act as “mechano-sensory devices,” protruding into the narrow kidney tubes and sensing when to slam the brakes on cell growth.

The cilia connection was found by working backward from genetic studies of human families with PKD. That led to the identification of two PKD genes that produce polycystin proteins. But what these proteins actually did was a difficult question to answer in the hugely complex human genome, so researchers turned to animal models. The breakthrough came when PKD genes were identified in mice and fish. The PKD-like mutated genes produced defective cilia that, in effect, left the epithelial kidney cells without any brakes. The runaway cells kept on proliferating, piling up in the narrow tubes until they bloomed into massive cysts.

There’s still a long way to go before this discovery results in useful medications. In the meantime, researchers are looking to answer basic questions about the progression of PKD and about variations within the same inheritance pattern. They are also looking for ways to treat PKD’s most notorious symptom — hypertension. The HALT-PKD study is testing a drug “blockade” of the renin-angiotensin system that is the body’s blood pressure control mechanism. Patients will be given ACE inhibitors, ARBs (angiotensin II receptor blockers), and disease management techniques in various combinations to see if PKD progression can be slowed or even stopped.

Clogged filter

Glomerulonephritis is inflammation of the glomeruli, the tufts of capillaries in the kidneys that filter the blood. It’s the third leading cause of kidney failure in the United States.

Autoimmune disorders like lupus cause glomerulonephritis. Sometimes it develops after an infection (strep throat is the classic example). It’s not the infection itself that does the damage, but particles in the blood left over from fighting it off. They get trapped in the sieve-like glomeruli, so the glomeruli get inflamed. The course of the disease can be baffling: Acute but short-lived, sudden and rapidly progressive, or stubbornly chronic.

Corticosteroids are sometimes prescribed. High blood pressure is often a by-product of glomerulonephritis, so patients often take blood pressure medications and stick to low-salt diets.

What you can do

We tend to think of the kidneys as part of the urinary system, but they’re also cardiovascular organs. High blood pressure can be the start of a vicious cycle because the hormones that regulate blood pressure are partly under the kidneys control. Blood continually pounding against the walls of the tiny blood vessels in the organs’ filtering units (nephrons) upsets the balance of those hormones, so blood pressure goes up even more.

As for diabetes, it causes kidney trouble because high blood sugar is hard on blood vessels, and the lacy vessels in the kidneys seem to be especially vulnerable.

The good news is that we have some control over high blood pressure and diabetes. A good diet (eat those fruits and vegetables; avoid too much sodium) and exercise (why, of course!) reduce the chances of developing both conditions. Not putting on pounds helps, too. If all of this fails, many medications can help you keep high blood pressure and diabetes under control. And you’ll be doing your kidneys a favor in the process.

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Last updated:	August 21, 2006

Medical content reviewed by the Faculty of the Harvard Medical School. Harvard Health Publications, Copyright © 2007 by President and Fellows of Harvard College. All rights reserved. Used with permission of StayWell.

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