Kidney Week is facing an existential crisis

Painting faced an existential crisis with the invention of photography. The platonic ideal of making a picture that fully represented reality was made meaningless by the invention of photography. The goal of painting pivoted from realism to impressionism, surrealism and subsequent movements. Painting faced its crisis by changing the definition of what it strived for. And to be clear artists that spent their career mastering realism didn’t cover to the new movement. New artists came along to fill those niche that had growth and potential despite photography.

Medical education is facing a change in the way students digest it.

Go to a pre-clinical lecture at any medical school in the US and you can find yourself a seat. It doesn’t matter the size of the lecture hall or the size of the med school class, students don’t go to class. Lectures are videotaped and can be streamed. Students gravitate to the most efficient way for them to learn and surprise, it is not sitting in lectures watching slideshows. If the students likes slide shows they will watch it at double speed with the PowerPoint open in front of them, available for them to make notes. It is nothing like the lectures I attended in med school.

Slideshows are tired, allow and inefficient. Students are routing around them. Good for them. I love that students are finding ways to learn in ways most efficient to each individual’s mind.

ASN’s problem is that Kidney Week is slideshow-learning. Selling slideshow-learning to millenials who don’t go to slideshows even when they paid tens of thouands of dollars is going to be like selling sand in the Mojave.

ASN has to make like 19th-century painting and pivot to a different platonic ideal.

What do I mean?

I mean a Shark Tank with real money on the line

I mean TED-like talks

I mean an American Idol-like competition for the best educational lectures.

Have educators around the country compete to make the best lecture on the same subject. Have them compete with the finals at Kidney Week. Rotate the subject every year, but make it a fundamental lecture that everyone needs to give:

  • Acid-base
  • Hyponatremia
  • CKD
  • AKI
  • Dialysis for the internist

Pathology lecture that uses microscopes rather than slides


Biopsy training with cadavers

Ultrasound training with patients

A recreational run

With pre- and post- sodium levels and AKI biomarkers

Cooking classes

Panel discussions with patients


ASN is using a fifty year old model of what makes a medical meeting and if they don’t adapt there will be fewer and fewer, and older and older, people attending.┬áThe ER and critical care crew have layed the blue print with SMACC, nephrology should be the first specialty to follow it down the rabbit hole.

ASN Renal Week day 4: APOL1 the best medical science story of 2010

The Renal Fellow network may have ranked APOL1 as the fourth biggest story of 2010 but I think it is actually the best story in all of medicine, not just nephrology.

When I went to ASN Renal Week I stayed at Castle Marne, an idiosynchratic bed and breakfast about a mile and a half from the conference center. The other people staying at the Castle were a rogues gallery of interesting conference participants.

One of the breakfast crew was David J. Friedman, the second author on the Science paper blowing the lid off of APOL1.

The APOL1 story begins in 2008 with the discovery of MYH9. Scientists were doing whole genome analysis to find a genetic explanation for the excess renal risk African Americans face. This excess risk is seen in the dialysis population, where African Americans are over represented. This is particularly true in patients with ESRD due to hypertension. African Americans represent 13% of the U.S. population but represent 48% of the patients on dialysis due to hypertension (HA-ESRD).
Data from USRDS and US Census
The two other places that the increased renal risk of African Americans is seen is in FSGS and HIV associated nephropathy (HIVAN). FSGS is 5 times more likely in young African American males than in age-matched Caucasians. HIVAN is nearly unheard of among people of European ancestry. The only cause renal failure more specific to black patients than HIVAN is sickle cell nephropathy.
The genetic locus 22q13.1 was found to convey phenomenal excess risk of FSGS. The excess risk was 400-700% (OR5-8). In whole genome analysis, researchers are delighted to find odds ratios of 1.1-1.2. Finding ORs of this magnitude is nearly unheard of. Poking around the genetic neighborhood, the researchers found a likely genetic target, MYH9. 
MYH9 codes for an intra-cellular myoglobin. MYH9 was an especially appealing candidate gene because it is expressed in podocytes and mutations of the gene had previously been found to be associated with glomerular pathology. Quickly MYH9 was declared the genetic explanation for excess risk of renal disease among African Americans and the scientific nephrology community geared up to crack every mystery related to MYH9. 
It was the gene that launched a 1,000 RO1s.
The NIH and NIDDK sponsored symposia to get scientists up to speed with breakthrough discovery
Unfortunately, no one was able to find the specific genetic mutation that led to these renal complications. From the discussion of the original paper:

A limitation of our study is that we have not yet identified the causal sequence variation in MYH9 that is associated with FSGS

Then in August 2010, David Friedman and his team identified APOL1 as the gene that actually was associated with FSGS, HA-ESRD and HIVAN. The association was discovered after new genetic material was made available in the 1000 Genomes Project, a public database of genetic information from individuals around the world including a number of Africans.

APOL1 lives just to the centromere side of MYH9. Friedman et al showed a tighter association with APOL1 than MYH9 and when they controlled for APOL1, MYH9 was no longer significantly associated with renal disease.

As the scientific community began to feel the rumbles of truth emerge about MYH9 and APOL1, researchers hitching their wagon to MYH9, prayed they were funded before the NIH scorers realized that MYH9 was the wrong gene. Scientists with research proposals on MYH9 that were too late would have to rewrite the grant to focus on the new target, APOL1.

Friedman’s team didn’t just identify APOL1 they told a fascinating story involving parasitology, evolution and human migration.

In 2003 APOL1 was identified as the genetic source for an immunity factor which protected people from African sleeping sickness. 95% of African sleeping sickness (I refuse to use the 3-letter acronym) is caused by Trypanosoma brucei gambiense.

Trypanosomes cause the mortal disease African Sleeping Sickness

Trypanosome lytic factor (TLF) protected humans from sleeping sickness until Trypanosoma brucei rhodesiense and gambiense evolved a protein, Serum Resistance Associate Protein, that deactivated TLF. This adaoptive response by the trypanosome made humans susceptible to infection. This was the state until about 10,000 years ago when variants of APOL1 appeared and restored the protective action of TLF and made the carrier of even a single copy immune to African sleeping sickness.

These genetic variants of APOL1 appeared in Africa 10,000 years ago, but much of the human race had already left Africa to spread across six continents. Additionally, regions that did not have the Tze Tze fly didn’t have trypanosomes and hence didn’t have selective pressure for the APOL1 variants. In regions endemic to Tze Tze fly, the selective pressure for these mutations was immense. In the U.S. 30% of African Americans carry APOL1. Heterozygotes are immune to trypanosomes and may have a modest increase in the risk of HA-ESRD (OR 1.26, no risk for FSGS) . Homozygotes for APOL1 are equally immune to trypanosomes but unluckily have a sky high risk of renal disease.

So APOL1 behaves like sickle cell anemia and malaria. Heterozygotes are immune but homozygotes suffer from  devastating disease. Balanced polymorphism.

The last twist is the mystery of HIVAN in Africa. HIVAN is found in western, Sub-Saharan Africa. Eastern Africa has a lower rate of HIVAN than would be expected. This data comes from cohort studies done in Kenya and Ethiopia. The risk of HIVAN is associated with APOL1. The Tze Tze fly is not endemic to Eastern Africa, hence no trypanosomes, so no selective pressure for APOL1, so few people are homozygotes for the variant of APOL1 that predisposes to HIVAN.

This story was one of many that were batted around the breakfast table at Castle Marne and served to show that I found the perfect place to stay during ASN Renal Week.

Renal Revascularization: The Astral Trial

One of the important studies released at Renal Week 2008 was the ASTRAL Trial (Angioplasty and STent for Renal Artery Lesions). This is the largest trial ever done on renal angioplasty. This seems like one my constant battles with cardiologists. I get a consult a month regarding whether patients should get a renal agioplasty done. I am almost always fighting against this based on prior information which showed marginal improvements in blood pressure control with the therapy and no change in the level of kidney function. However this data was questionable due to a high cross-over rate (i.e. 22 of the 28 patients initially randomized to drug therapy alone underwent angioplasty after 3 months).
This shows that the 806 patients randomized to ASTRAL dwarves all of the previous work on the subject. (source)

ASTRAL was billed as the definitive study to determine if angioplasty and stent preserved renal function, improved blood pressure, prevented hospitalizations, or reduced CV mortality. Patients were followed for 27 months. The enrolled cohort is representative of that are typical candidates for renal revascularization. Here are the graphs from the Investigator Newsletter:


The bulk of patients had moderately severe renal disease. It is important that they did not select patients too late in the disease where revascularization may be too late to save the kidney. Similarly you wouldn’t wat to intervene too early where the splay between the groups may take longer than 27 months to materialize.

The average GFR was 40 mL/min.

Of note: if you just looked at patients with an initial GFR<25, size="4">Length

The fact that the affected kidney size was pretty good goes against the potential criticism that they were revascularizing too late after permanent infarction and scarring has ocured.

Most of the patients had severe stenosis, a high grade that if found during a diagnostic angiogram would be followed by an intervention.

  • 93% of interventions included use of a stent.
  • The mean stenosis was 76%

At follow-up, no difference in creatinine, blood pressure, time to first renal event, or mortality (p = ns for all outcomes)

The authors emphasized that there was no benefit for the entire cohort but they feel that the therapy is likely helpful for some subset of the population. I agree, like every nephrologist, I have seen patients have dramatic improvements in renal function following angioplasty for RAS. With the immense ASTRAL database it will be exciting to see if the authors can tease out which subgroups benefit from this technology.

Despite having seen multiple patients benefit from renal artery angioplasty I have remained a skeptic of the technology. Part of this comes from the older flawed and small trials and partly due to the ineffectiveness of cardiac angioplasty to help patients except in regards to reducing angina (a condition that doesn’t have a renal analog) or in patients having an active infarct.