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.

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