Month: March 2020

An Important Genetic Cause of Kidney Disease in Nigeria- APOL1 Mediated Kidney Disease


Ever wonder why so many people are falling victim to the problems of kidney failure in Nigeria and sub saharan Africa? Well, recent scientific advances show that the cause of this survival disadvantage in Africa is not only inherited from our parents but is part of our defensive response to overcome African sleeping sickness transmitted by the Tsetse fly. The genetic code to resist sleeping sickness that increases risk for kidney disease is called the APOL1 gene

The growing problem of kidney disease around the world and in West Africa in particular is alarming. A casual look at social media pages very often show people reaching out for help to deal with the catastrophic physical and financial burden of kidney failure. Many Nigerians know someone personally who has or is suffering from the burden of kidney disease.

What is the reason for this? Well, for decades, the common medical advice has been that high blood pressure, high blood sugar and lifestyle choices like high alcohol intake, smoking and taking toxic herbal medications and remedies are the major causes of kidney disease and kidney failure in Nigeria. However, recent medical advances in genetic testing and computational science in the last 20 years since the completion of the genome project have indicated that the cause of the plague of kidney disease in Nigeria and the broader sub saharan region is more complicated than just lifestyle choices or blood pressure. The cause seems to be in our cells and this cause has been part of our evolution as a people to survive against things in our environment that could kill us. What in our environment could kill us and make us have to adapt in such a way that we now suffer from kidney disease? Well, the answer has been linked to the story of our relationship with the Tsetse fly.

The Tsetse fly in Western and Sub Saharan Africa causes African sleeping sickness also called African trypanosomiasis. A bite from the tsetse fly releases the parasite into the blood that causes the disease. One of the first historical records of trypanosomiasis is by the famous Arabian geographer Abu Abdallah Yaqut (1179–1229). During his journey into Africa he found in the “Country of Gold” an underground village whose inhabitants and even their dogs were just skin and bones and asleep! The World Health Organization (WHO) in a 1998 report estimated the number of people infected to be about 300 000- likely an underestimation.

The Tsetse fly transmits a very serious and deadly disease called African trypanosomiasis or African sleeping sickness. The first stage of African sleeping sickness, known as the hemolymphatic phase, is characterized by fever, headaches, joint pains, and itching. Invasion of the circulatory and lymphatic systems by the parasites is associated with severe swelling of the lymph nodes, often to tremendous sizes. If left untreated, the disease overcomes the host’s defenses and can cause more extensive damage. The second phase of the disease, the neurological phase, begins when the parasite invades the brain and spinal cord. Disruption of the sleep cycle is a leading symptom of this stage and is the one that gave the disease the name ‘sleeping sickness.’ Infected individuals experience a disorganized and fragmented 24-hour rhythm of the sleep-wake cycle, resulting in daytime sleepiness and nighttime periods of wakefulness.

Human African Trypanosomiasis is causes by trypanosomes transmitted by the tsetse fly. The 2 main species of the parasite Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are most common in sub saharan Africa (B). The APOL1 gene is key to natural defenses to this infection and over time Africans have evolved even more effective gene variants to kill trypanosomes that resist the ancestral gene G0. These evolved gene variants are called G1 and G2 with a high prevalence in West Africa. You can see in the middle panel that Nigeria is ground zero and a hot spot for a high number of people with the G1 variant of APOL1.

So what has this history of the tsetse fly and African sleeping sickness got to do with kidney disease in Nigeria and other African countries? Well the story gets more interesting and the picture above tells part of the story where you can see an overlap in the occurrence of African sleeping sickness caused by trypanosomiasis with the defense against the illness. Simply speaking, we humans started competing with the tsetse fly. Over time, people affected by African sleeping sickness developed a resistance coded by a gene on chromosome 22 called the APOL1 gene. This gene produces a protein called APOL1 which circulates in the blood and is the tool the body uses to destroy the parasite injected into the body by the tsetse fly. Over hundreds of years the parasite evolved resistance to this ancestral APOL1 gene (G0) and in response humans developed even more effective APOL1 called G1 and G2 variants. People with G1 and G2 variants of the APOL1 gene are able to resist infection transmitted by the tsetse fly. Approximately 23-46% of Nigerians have 2 alleles with either G1 and/or G2 while approximately 60% of Nigerians have at least 1 of the 2 genetic variants of APOL1 that also confers resistance to the infection. However, this survival advantage for people with 2 genetic variants of the APOL1 gene has been found to be a 12 times higher risk for progressive kidney disease.

The burden of kidney disease and kidney failure is now so common that several celebrities- a past president, musicians, actors, journalists have succumbed to the complications of this truly devastating disease. We do not know if APOL1 was the cause of their kidney disease but the chances are high that it may have been involved based on emerging research findings

But why does having an APOL1 gene variant increase the risk for kidney disease? Well, that has taken some time to figure out and scientists first figured out how APOL1 kills the trypanosome parasite. Essentially, the parasite while feeding on nutrients in the blood takes in the APOL1. The APOL1 then binds to structures in the parasite causing it to swell up, burst and die. APOL1 protein is also produced in other tissues as well as part of the defense against sleeping sickness infection and most importantly it is produced in the kidney. In the kidney, a special cell called the podocyte that helps in filtering the blood is damaged whenever APOL1 is activated in the kidney. What can activate APOL1 production in the kidney? Anything that injures the kidney or makes it think it is under attack by the parasite transmitted by the tsetse fly. This activated APOL1 in the kidney then kills the podocyte cell in the kidney in very much the same way that it kills the parasite leading to damage to the kidney filtration system of the kidney and eventually to rapidly progressive kidney problems and kidney failure. In fact is has been documented that patients with 2 APOL1 gene variants with kidney disease progress 2-3 times faster to kidney failure than patients with only 1 or no gene variants for the APOL1 gene.

QUESTIONS

  1. Is there a test for APOL1 gene variants? The answer is yes. However, it is not easy to get by walking into any lab and it is only becoming more commonly available in places like the US. For now it is expensive.
  2. Does everyone with 2 APOL1 genetic variants develop kidney disease? The answer is No and we do not yet know why. However, we do know that something can happen in the life of people with 2 APOL1 gene variants like infection, taking toxins contained in many of our herbal medicines that can hurt the kidney or other health problems that triggers increased production of APOL1 and that leads to accelerated kidney injury.
  3. Does this mean that controlling blood pressure, body weight, blood sugar and avoiding excessive alcohol and smoking are no longer important? Absolutely not. These are still very important causes of kidney disease and can make the kidney disease in many of us who have 2 APOL1 gene variants progress much faster. So please continue to exercise, eat healthy, avoid excess alcohol, avoid smoking, get BP checks and take medication when prescribed.
  4. Can the risk for APOL1 mediated kidney disease be inherited? Yes. If only one parent has a risk gene, it may be inherited by offspring but people with only one gene variant do not appear to be at increased risk for kidney disease. If both parents have the genetic variants, then the children can inherit the genetic variants and be at risk. Remember not all people with 2 variants will develop kidney disease and we do not yet know why.
  5. Can APOL1 mediated kidney disease be treated? Well there are no specific treatments yet for this yet but efforts are under way in the US to develop treatments for this problem.