by George Taniwaki

Remember, World Kidney Day 2014 is coming soon. This year it is 13 Mar 2014 and the theme is “kidneys age, just like you.” This campaign, designed to raise awareness of kidney health is organized by the International Federation of Kidney Foundations and the International Society of Nephrologists and is sponsored by Danone Research.

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by George Taniwaki

This week’s issue of the New Engl J Med (subscription required) should be of special interest for those who follow kidney disease. The issue contains several articles on medical investigations into treatments and risk factors for  kidney disease along with related editorials. Unfortunately, most of the news is not good.

NewEnglJMed

However, there is an important lesson to gain from these studies. Scientific knowledge advances in two ways. First, is the knowledge gained by learning what works. There is the obvious clinical benefit of knowing what is the best treatment for a patient. But successful studies also point the direction for other researchers showing where they can expect the greatest promise for future investigation.

Yet failures are valuable learning experiences. Knowing what doesn’t work reduces the chance that doctors or patients will try the same therapy on their own. But an unsuccessful trial does not mean a line of research should be abandoned. Rather, a failure should teach us to look at root causes.

Every experiment or medical trial is expected to be successful (otherwise you should invest time and effort in a different project with a greater potential payoff). When it isn’t we are temporarily surprised. But that should lead to a new investigation as to why the trial did not work as intended. And that investigation will hopefully lead to new insights that can be added to the body of human knowledge.

Trial of ACE inhibitors and ARBs

In the first article, Linda Fried of the Univ. Pittsburgh School of Medicine and her coauthors examine the effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) on patients with type 2 diabetes who also have kidney disease. These two drugs are often prescribed for the treatment of hypertension and congestive heart failure.

For kidney patients, the use of these drugs was intended to slow the decline in glomerular filtration rate (GFR). Previous studies had shown that ACE inhibitors and ARBs could benefit patients who already showed signs of proteinuria (protein in the urine, a sign of kidney disease). The goal of this study was to see if prescribing ACE inhibitors and ARBs to kidney patients earlier could forestall the progress toward end-stage renal disease (ESRD).

Since the progress of kidney disease for a particular patient is uncertain and can take many years, this study required a large sample that would be willing to participate by taking a prescription drug (or a placebo) for a multiyear period.

As reported in the article, the trial was stopped after four years because of safety concerns. There were more adverse events  in the therapy group than in the placebo group. The most common problem was acute kidney injury with the next most common being hyperkalemia (high potassium levels in the blood that if untreated can cause irregular heart beat). Because the study was stopped early, we now know that the combination therapy of ACE inhibitors and ARBs can cause injury, but we don’t know if it can delay the onset of ESRD.

Trial of bardoxolone methyl

The next article (online first) by Dick de Zeeuw of the Univ. Groningen and coauthors summarizes the results of treating patients that have both type 2 diabetes and stage 4 kidney disease with bardoxolone methyl. This drug is an antioxidant that can taken orally and has been shown to reduce serum creatinine.

Similar to the ACE inhibitor and ARB study, the sample size was large and the test was intended to span several years. However, also like the other study, it was ended early due to safety concerns. Those in the therapy group had more adverse events than those in the placebo group. Those who received the treatment had significantly higher GFR (a good thing) but experienced higher rates of heart failure, nonfatal stroke, hospitalization for heart failure, and higher death rate from cardiovascular causes.

Off-label use of abatacept

Abatacept (sold under the trade name Orencia) is a protein that inhibits a molecule called B7-1 that activates T cells. It is approved for the treatment of rheumatoid arthritis. It is also in clinical trials for the treatment of multiple sclerosis, type 1 diabetes, and lupus. These are all autoimmune diseases.

Chih-Chuan Yu of Harvard Medical School and coauthors noted elevated levels of B7-1 in certain patients with proteinuric kidney disease,  including primary focal segmental glomerulosclerosis (FSGS). They conducted a series of in vitro studies (laboratory experiments) to show that abatacept would block the migration of podocytes (a type of kidney cell). They then recruited patients whose FSGS who did not respond to standard treatments. They selected four kidney transplant patients with rituximab-resistant recurrent FSGS and one patient with glucocorticoid-resistant primary FSGS. They treated all five with abatacept and all five patients experienced remission.

APOL1 risk variants

APOL1 is the gene that encodes the apolipoprotein L1, a component of HDL, also called good cholesterol. Although the exact purpose of APOL1 is not known, we do know that certain variants of APOL1, called G1 and G2, circulating in plasma can suppress Trypanosoma brucei, the parasite that causes sleeping sickness. We also know that these variants are associated with ESRD, though the mechanism isn’t known.

We know that the G1 and G2 variants are more common among African-Americans than in white/Caucasians. And we know that African-Americans have between 3 to 5 times the risk of ESRD than white/Caucasians even though the prevalence of earlier stages of kidney disease are roughly equal for both racial groups. Thus, the question is whether these variants of APOL1 are responsible for some of the difference between rates of ESRD among blacks and whites.

A paper by Afshin Parsa, et al., attempts to answer that question by looking at data from two studies, one called the African-American Study of Kidney Disease and Hypertension (AASK) and the other called Chronic Renal Insufficiency Cohort (CRIC). They find direct evidence that “APOL1 high-risk variants are associated with increased disease progression over the long-term.”

Data for the AASK patient group are shown in the table below. Some items to notice:

  1. There is very little difference in CKD incidence between the patients with no copies of the APOL1 risk variants and those with one copy. This indicates that the trait is recessive
  2. Even patients with no copies of the risk variants have high rates of CKD. This indicates there are more factors left to be discovered
  3. There is a high prevalence (23%) of patients with 2 copies of the risk variants within the African-American population
  4. The risk variants may explain only about 5% (= 23% * (58% – 35%)) of the difference in the incidence rate of ESRD between blacks and whites. Further, the association does not explain the cause of kidney disease in patients with two copies of the risk variants. It does however seems to rule out hypertension and diabetes, since the study controlled for these factors
All patients
Col %
CKD at end*
Col %

Row %
No copies of APOL1 risk variants 234   34%   83   29% 35%
1 copy of APOL1 risk variants 299   43% 112   39% 37%
2 copies of APOL1 risk variants 160   23%   93   35% 58%
TOTAL 693 100% 288 100% 42%

*Number with ESRD or doubling of serum creatinine by end of study

Conclusions

All four papers described above were the subject of editorials in this week’s issue of New Engl J Med. One written by Dr. Zeeuw, the lead author of the  bardoxolone methyl paper, points out that the failure of ACE inhibitor ARB therapies may indicate that “improvement in surrogate markers — lower blood pressure or less albuminuria — does not translate into risk reduction.” In fact he writes that it may go further and the use of these two measures as risk markers for “as therapeutic targets in our patients with type 2 diabetes” may be in doubt. He also promotes the use of “enrichment design” to select patients who are less likely to display an adverse event.

Another editorial by Jonathan Himmelfarb and Katherine Tuttle of the Univ. Washington School of Medicine (and the Kidney Research Institute) make three recommendations to improve the safety and likelihood of success for clinical trials. First, all researchers should make more preclinical data available so that others can conduct better preclinical analysis. Second, researchers should consider the possible off-target effects of a proposed agent and collect data before starting clinical trials. The development of organ on a chip may greatly help this. Finally, researchers should exercise caution whenever a drug has known side effects, for instance when a “drug for diabetic kidney disease increases, rather than decreases, the degree of albuminuria.”

In a third editorial, Börje Haraldsson of the Univ. Gothenburg says the work of Dr. Yu and his colleagues “may signal the start of a new era in the treatment of patients with proteinuric kidney disease.” Let us hope that is true. As we discover more about how the immune system works, how it interacts with its cellular and microbial environment, and how it can be modulated, treatment of many chronic conditions, cancer, and even old age may be affected.

by George Taniwaki

The year 2013 marks the 100th anniversary of the invention of hemodialysis, a life saving procedure to removing waste product from the blood of people with chronic kidney disease.

An experiment using animals is described in the May 1913 issue of Trans Assoc Amer Phys. The work was done by three doctors, John Abel, L.G. Rowntree, and B.B. Turner, all of Johns Hopkins Medical School.

TransAssocAmerPhys

A screenshot from the article describing the invention of hemodialysis. Image from Google books

From the archives of Scientific American Sept 1913 comes a description of the experiment. The article contains this quote from the Times of London:

A demonstration which excited great interest was that of Prof. [John Jacob] Abel of Baltimore. Prof. Abel presented a new and ingenious method of removing substances from the circulating blood, which can hardly fail to be of benefit in the study of some of the most complex problems. By means of a glass tube tied into the main artery of an anesthetized animal the blood is conducted through numerous celloidin tubes before being returned to the veins through a second glass tube. All diffusible substances circulating in the blood pass through the intervening layer of celloidin. In this way Prof. Abel has constructed what is practically an artificial kidney.

In their experiment Dr. Abel and his colleagues use a dialysis membrane made of celloidin. Celloidin is an early plastic made from nitrocellulose (cotton or wood pulp reacted with nitric acid). It was translucent and water-repellent. Films or tubes made from celloidin were water permeable, which made them good osmotic filters. However, celloidin was highly flammable and dangerous to work with.

Today, dialysis membrane tubing is made from rayon fiber (cellulose reacted with carbon disulfide and mixed with glycerin, then extruded through a spinneret to form a thread) or cellophane film (chemically similar to rayon, except that it is extruded through a slit to form a thin sheet).

by George Taniwaki

Patients with end-stage renal disease (ESRD) often wait many years for a transplant. There are currently over 85,000 people in the U.S. waiting for a kidney transplant and the number grows each year. The average wait time is over three years. The mortality rate for those with ESRD on dialysis is over 15% per year, meaning that almost half of the patients die and never get a transplant.

Eliminating the waiting list for kidney transplants is a complex problem. But I see four separate solutions. They are reduce the incidence rate of ESRD, increase the supply of deceased donor organs, increase the supply of live donor organs, and apply new technologies to enhance or replace human organs. These solutions are not mutually exclusive and should each be investigated and instituted by the appropriate organizations. In fact, I don’t believe any one of these solutions will eliminate the list on its own, and so possibly all of them will need to be pursued.

I will illustrate the various pieces of this problem with the four flow charts shown below and then discuss each of the four solution areas in future blog posts. The text in orange boxes represent actions that can be taken. The text in green boxes indicate the intended results of those actions.

Access to healthcare

For blog posts related to patient access to preventative care, patient education on treatment modalities, or dialysis treatment, see entries tagged with Access To Healthcare or Dialysis.

Note that in the right side of Figure 1, educating patients about the advantages of transplant therapy will increase the demand for transplants, which will make the waiting list longer if other steps are not taken to reduce the incidence of ESRD or increase the supply of organs.

KidneyFlowESRD

Figure 1. Actions that may reduce the incidence of ESRD (left) and increase demand for transplant therapy (right)

Deceased donor transplants

For blog posts related to deceased donor transplants, including patient evaluation and experience, see entries tagged with Deceased Donor.

KidneyFlowDeceasedTX

Figure 2. Actions that may increase supply of deceased donor kidneys

Live donor transplants

For blog posts related to live donor transplants, see entries tagged with Live Donor or Kidney Exchange. (For more on the live donor evaluation process, see entries tagged with Donor Story.)

KidneyFlowLiveTx

Figure 3. Actions that may increase supply of live donor kidneys

New technologies

For blog posts related to alternatives to current transplant therapy, see entries tagged with Artificial Organs, Stem Cells, and New Therapies.

KidneyFlowNewTech

Figure 4. New technologies that may someday replace standard transplant therapy

Disclosure note: I am a community member of the Organ Donation Legislative Workgroup in Washington state. I am also a volunteer for several organizations that provide healthcare services to patients with ESRD. However, the opinions in this blog post are my own and do not represent those of any group.

All images by George Taniwaki

[Update1: I modified Figure 3]

[Update2: I added links to tagged blog posts]

I happened upon a personal finance column that appeared in the New York Times April 1981. The story predicted that treatment of end-stage renal disease (ESRD) would soon become a serious financial and moral issue.

The article pointed out that in 1980, there were slightly over 62,000 patients on dialysis. The total annual cost to the federal government for treatment was $1 billion and climbing. (ESRD is the only disease covered under Medicare regardless of age.) Medicare covers 80% of the cost with the rest coming from private insurance or state Medicaid programs.

At the time, medical experts worried that by the end of the decade the number of ESRD patients could reach 90,000 with costs rising to $4 billion to $5 billion annually. (It’s not clear why a 50% growth in patients would lead to a 400% growth in cost, though the early 80s was a time of double-digit inflation.)

I did a bit of investigation, looking at data collected by the United Network for Organ Sharing (UNOS) and U.S. Renal Data System (USRDS) to find out what the actual outcomes were.

In 1989, there were 175,000 patients with ESRD, of which 130,000 were on dialysis and 45,000 with a functioning transplant. That’s nearly double the number predicted. The total cost of treatment was $4 billion which after adjustments indicates that per patient costs were rising about as fast as inflation. That’s a bit of a bargain since total medical costs rose significantly faster than inflation during that period.

So where are we today? In 2008 (the latest year data is available) there were 547,000 patients with ESRD, of which 382,000 were on dialysis and 165,000 with a functioning transplant. Total Medicare expenditures on ESRD were $27 billion, consuming about 6% of the total Medicare budget. The growth in kidney disease may have been a crisis in 1989. Today, it is an absolute financial disaster with an immeasurable human toll as patients on dialysis die waiting for transplants.

ERSDPrevalence

ESRD prevalence counts and prevalence rates in the U.S. Graphic from USRDS 2010 Annual Report

ESRDCosts

Medicare expenditures on ESRD, not adjusted for inflation. Graphic from USRDS 2010 Annual Report

****

Incidentally, the 1981 NY Times article said the best chance of reducing costs for dialysis was to encourage use of home dialysis which would reduce capital and labor costs for dialysis facilities. Home dialysis never became popular. The number of patients using peritoneal dialysis, the most common home treatment, has remained steady since the mid-1980s while the total number of ESRD patients has grown rapidly. Today only 5 percent of kidney patients choose it as their form of therapy.

The article also stated that few patients could be helped by transplantation therapy. Unknown to the author, the immunosuppressant drug cyclosporine would be released in 1983, making transplant from deceased donors and unrelated living donors possible. The number of transplants boomed. But as the data above shows, the number of kidney patients grew even faster, creating a waiting list that continues to grow to this day.

****
For another interesting historical note, see this May 2010 blog post.

The Dec 2010 issue of The Atlantic contains an investigative report by Robin Fields on dialysis quality and costs in the U.S. and how lessons learned can apply to national health care policy. The story also appears on ProPublica, which includes photos. It is a very good story, though it is unbalanced. (It’s the nature of investigative journalism.) In addition to reading the article, I encourage you to read the comments at the bottom of both versions of the article. I’ll address two points from the article below.

The dialysis business is big and concentrated but there are outliers

As reported in the Economist Apr 2010, the market for dialysis treatment is large. There are about 350,000 patients in the U.S. receiving dialysis therapy. The average cost of dialysis treatment is about $70,000 per patient per year. Further, it is highly concentrated, with one big buyer (called a monopsony) and two big suppliers (called an oligopoly).

In the U.S., the cost of dialysis care is covered mostly by Medicare, and the federal government spends about $24 billion per year, or about 85% of the total cost, which represents about 6% of Medicare’s total budget. End-stage renal disease is the only medical condition that Medicare covers regardless of age. Dialysis reimbursement is the single biggest Medicare cost category and is growing faster than overall medical costs.

There are two major manufacturers of dialysis equipment in the world, Fresenius of Germany and Gambro of Sweden. These manufacturers sell to dialysis service providers that tend to buy all their equipment from one provider or the other. In fact, there are now two major dialysis service providers in the U.S., both of which are for-profit enterprises. The largest is Fresenius Medical Care, a subsidiary of Fresenius and uses only Fresenius equipment. Next is DaVita, an independent company that acquired all of Gambro’s clinics and uses Gambro equipment. Between them, they operate about two-thirds of the 5,000 dialysis clinics in the U.S.

There are also many smaller regional clinic chains, many of which are not-for-profit. Not-for-profit organizations need not be any better run than for-profit ones. In fact, their clinics are often inefficient, poorly maintained, and less likely to used advanced technology. But some of them, like Northwest Kidney Centers in Washington are well run and have clean, comfortable, safe facilities. NKC operates 14 dialysis centers around Seattle, making it the biggest provider in the Puget Sound region. [Disclosure: I am a volunteer for Northwest Kidney Centers and have contributed to it.]

Reimbursement policy affects how dialysis treatment centers are run

Currently, Medicare reimburses dialysis providers a flat amount per patient plus pharmaceutical costs. This has led to several behaviors by the dialysis providers that are unintended, but should have been expected.

1) They use high blood flow rates through the dialysis machines. This reduces the time each patient is in the clinic, which means more patients can be handled per day and less technician labor is needed per patient. However, high blood flow rate causes low blood pressure in the patient during dialysis. This is correlated with higher rates of cardiac events and death.

2) They limit each patient to three visits per week and discourage home hemodialysis (which allows the patients to treat themselves more frequently). However, fewer visits are also correlated with higher rates of cardiac events and death.

3) They prescribe higher doses of drugs such as heparin and especially expensive ones like erythropoietin than dialysis centers in other countries. They also use more injectable drugs, which are more expensive than oral ones. Medication now accounts for one-quarter of the total cost of dialysis treatment.

Medicare will soon switch to bundled reimbursement of $230 per session (indexed for inflation) and institute a 2% bonus system under its Quality Incentive Program. This has been a very controversial change.

First, the change itself will reduce revenues for nearly all dialysis centers, putting even more pressure to reduce costs. In the U.S. there has been considerable pressure to consolidate and cut costs as Medicare keeps reimbursement rates low.

For examples of discretionary costs, consider the Northwest Kidney Centers. It runs kidney fairs to encourage the public to get tested for hypertension and diabetes to avoid end-stage kidney disease. It also works with nephrologists to encourage its most healthy patients to consider getting a kidney transplant. And it partners with the Univ. Washington Medical Center to support the Kidney Research Institute. All of these actions are good social policy, but are expensive, have little benefit to existing patients, and hopefully reduce the total number of patients needing its services in the future. Thus, they are all bad for the bottom line.

Second, even if improved quality reduces costs, the benefit may not reach the dialysis centers. Medicare may pay a small bonus to the dialysis center, but may keep most of the cost savings  for itself. For more on the perverse impact of improved quality on care provider profit, see this article in the Nov 2002 amednews.

Finally, Medicare plans to measure quality via blood tests rather than base it on medical outcomes. Blood tests have the advantage of being fast, cheap, and less prone to measurement errors than other tests. However, blood tests are not a reliable indicator of quality. Some better measures would be mortality rates and morbidity rates. But both are hard to measure and expensive to track. Blood tests may be easy to adjust to meet the QIP goal and may not be closely correlated with desired medical outcomes.

Bill Peckham, who is quoted in the article, is an expert on how bundled reimbursement will affect dialysis centers and their patients. Mr. Peckham is a patient and an advocate for Northwest Kidney Centers. You can read more at his blogs, Dialysis from the Sharp End of the Needle and Fix Dialysis.

In an Aug 2010 blog post, I discussed the prospects for regenerative medicine to alleviate the shortage of transplantable organs. Regenerative medicine usually starts with an organ obtained from deceased donors. But the organ itself isn’t used. Instead the cells are removed and the remaining scaffold is seeded with stem cells to create a new organ. Near the end of that blog post I mentioned that there was work being performed by David Hume and others at the Univ. of Michigan to produce an external device that could perform some of the endocrine functions of a kidney. It would supplement an external dialyzer to provide complete kidney function for a patient with end-stage renal disease.

Recently, Univ. California, San Francisco issued a press release stating that Shuvo Roy and other researchers in the Department of Bioengineering and Therapeutic Sciences have reduced the size of both devices by using a combination of micro-electromechanical systems (MEMS) and human kidney cells. Their prototype is about the size of a coffee cup, or similar in size to a kidney. They hope the device will be implantable, leading to a portable, artificial kidney. Much work remains and they don’t expect clinical trials to begin for another five to seven years. Yet, the promise is great. Such a device could help improve the medical outcomes and quality of life of all patients with ESRD, meaning both those waiting for a transplant and those who would otherwise receive dialysis therapy.

UCSFdialyzer

Artificial kidney. Video from UCSF

[Update: Replaced the cutaway view with a video.]