Tag: HIVAN

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HIV and the Kidney

HIV and the Kidney (Keynote, PDF)

 

  • Updated April 2013
  • The lecture was about one hour.
  • The section on APOL1 is rough.
  • I would like a slide describing the transgenic mouse model studies by Klotman that showed that transcription of nef and pol are central to the disease.
  • I need some notes on why I have 2 graphs on slide 16.
  • Add some highlights to table in slide 23.
  • Loved how slide 26 and 27 worked.
  • I think there might be better data on steroids in HIV. Slide 51.
  • Need to flush out IRIS and DILS from slide 67
  • Add comment on adefovir slide mentioning that the hep B dose is a sixth of the anti-HIV dose

 

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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.
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HIV and the Kidney

Gave a lecture to the ID faculty and fellows today. That was the fourth lecture in 2 weeks. Done running the lecture gauntlet.

Excellent website on HIV from the UCSF: HIV InSite Knowledge base

I though my lecture’s section on HIVAN Therapy was little light here is InSite’s monolog on therapy for HIVAN:

Clinical Course and Treatment

In the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, the U.S. Department of Health and Human Services now includes a diagnosis of HIVAN as an indication for ART, regardless of CD4 count.(94) Other treatment options that may influence the course of HIVAN include angiotensin-converting enzyme inhibitors (ACEIs) and corticosteroids administered before dialysis or kidney transplantation.

Antiretroviral Therapy

The original case reports of HIVAN described a rapid and inexorable progression to ESRD over a period of weeks to months.(2-4) However, after highly active ART came into use, several dramatic reports of renal recovery among these patients emerged in the medical literature. In one study, a patient with HIVAN and dialysis-dependent renal failure became dialysis free after 15 weeks of ART. Repeat renal biopsy revealed significant histologic recovery from fibrosis with only infrequent glomeruli showing mild collapse and minimal fibrosis.(65) Since then, a growing number of studies has helped establish ART as a first-line treatment for HIVAN.

The effect of ART on kidney disease progression has been characterized primarily by observational studies. A cohort of 53 patients with biopsy-proven HIVAN from the Johns Hopkins renal clinic was found to have better renal survival when treated with ART compared with patients who did not receive ART (adjusted hazard ratio: 0.30; 95% CI: 0.09-0.98).(95) In a retrospective study of 19 patients with a clinical diagnosis of HIVAN, after median follow-up of 16.6 months, the use of protease inhibitors was significantly associated with a slowing of the decline in creatinine clearance.(96)

In the Strategies for Management of Antiretroviral Therapy (SMART) study, 5,472 HIV-infected patients who had a CD4 count of >350 cells/µL were randomly assigned to continuous or episodic use of ART and were followed for a mean period of 16 months. Investigators found that, compared with continuous ART, planned treatment interruptions guided by CD4 counts significantly increased the risk of fatal or nonfatal ESRD (hazard ratio: 4.5; 95% CI: 1.0-20.9) in the treatment interruption arm. Although this study was not statistically powered to detect a difference in renal outcomes, the high incidence of ESRD in the treatment interruption group suggests that continuous therapy with antiretroviral medications is a key factor in preventing and slowing progression of kidney disease.(97)

Angiotensin-Converting Enzyme Inhibitors

Both ACEIs and angiotensin II receptor blockade have inhibited the development and progression of HIVAN in animal models.(98-100) Two prospective studies support the use of ACEI for the treatment of HIVAN. In a case-control study of 18 patients with HIVAN prior to the advent of ART, 9 were treated with captopril, and matched with 9 controls.(101) The captopril-treated group had improved renal survival, defined as time to ESRD, compared with controls (mean renal survival: 156 ± 71 days vs 37 ± 5 days; p < .002). In a single-center, prospective cohort study of 44 patients with HIVAN, 28 patients received fosinopril 10 mg/day, and 16 patients who refused treatment were followed as controls over 5.1 years.(102) The median renal survival of treated patients was 16.0 months, with only 1 patient developing ESRD. All untreated patients rapidly progressed to ESRD over a median period of 4.9 months. Despite the limitations of these studies, they suggest that ACEIs may be beneficial in curbing progression of HIVAN, and this class of drugs is a reasonable first choice as an antihypertensive agent for patients with HIVAN.

Steroids

Evidence supporting the use of steroids for the treatment of HIVAN is also based on observational data.(95,103,104) In a single-center cohort study, 20 patients with HIVAN were prospectively enrolled to receive treatment with corticosteroids. Most patients (17 of 20) manifested improvements in kidney function and significant reductions in 24-hour urinary protein excretion. After steroid therapy, mean rates of protein loss declined from 9.1 ± 1.8 g per day to 3.2 ± 0.6 g per day (p < .005).(105) Another study of steroid therapy employed a control group and found similar results with no increased risk of infection in the steroid group.(104) Although these studies were generally limited by their nonrandomized designs, based on this evidence, steroids are considered second-line therapy for patients with HIVAN. The use of steroids should be considered for patients with a documented rapid deterioration in kidney function despite ART.