Kidney Disease; Alport Syndrome

Subject: Science
Type: Problem Solution Essay
Pages: 9
Word count: 2261
Topics: Biology, Disease, Genetics, Health, Medicine, Nursing
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Abstract

Alport syndrome (AS) is a condition characterized by diminished kidney function that result to Kidney disease. The affected victims have hematuria and experience hearing problems and eye abnormalities. It is an inherited disorder that affects the basement membranes, the membranes mostly affected is the glomeruli involving type IV collagen. It is a renal disease that affects males and females with more severity to the males. AS has become a public health concern for many reasons as will be discussed. Several organizations in conjunction with the government have come up with measures to try and cure the AS. They have allocated financial resources to the research on the congenital nephritis. But what has been achieved so far in finding the cure? The project provides problem statement, solution, evaluation and future actions on AS.

Problem

Cecil A Alport was the first individual to shed light on Alport syndrome (AS). He described a generation from a family with deafness and hereditary nephritis that was seen three generations. In 1961, the name Alport syndrome came to exist after numerous researches had been done on the truth of the existence of the hereditary syndrome (Mahajan &et al., 2003). Alport Syndrome is a heterogeneous syndrome that is caused by a defect in the X chromosome, particularly in the subunit of the a5 type IV collagen. In some rare cases, the AS is caused by a defect in the a4 and a3 subunits (Coville, 1997). The subunits are components of the glomerulus, retina, cornea and cochlea’s basement membranes with the a5 being the major component. Patients with AS have the basement membranes of their eyes, kidneys, and ears degenerating with time.  To the eyes, the degeneration causes lenticular opacities, corneal ulcers, and anterior lenticonus.  Ears begin to experience deafness due to the effect on the sensory nerves. The kidneys are mostly affected due to the replacement of the a5 subunits by a1 and a2 subunit. The replacement causes the kidney to go through stages of thinning, then thickening, division and finally the manifestation of urinary failure which progresses to severe renal failure (Coville, 1997). There are three types of AS:

  • X-linked AS (XLAS) is common affecting 85% of total patients with AS. It  occurs when COL 4 A5 gene mutate
  • Autosomal recessive AS (ARAS) caused when COL 4 A3 genes mutate. It occurs to offspring whose parents are closely related, maybe cousins or siblings. It affects both the male and female offspring.
  • Autosomal dominant AS (ADAS) caused when COL 4 A3 and COL4 A4 genes mutate.  It affects patents of both sexes equally. It is a rare AS.

AS is the second leading inherited disease linked to renal failure. It is also the leading inherited nephritis. Its severity is more in males than females.  In the United States, 3% of children are estimated to have AS while 0.2% of adults have end-stage renal disease (ESRD). The percentage of those with ESRD in Europe is 0.6 %( Mahajan, 2003)

AS normally progresses to renal failure among its patients.  It is estimated that 90%of patients born with AS will have ESRD by the time they are 40 years with 75% having a renal failure by 30 years. The males with XLAS become deaf by 40 years. 

The main diagnostic criteria for AS is by looking at the family generation. The symptoms that justify the existence of AS in the family include eye anomalies, progressive deafness and nephritis. The patients can be taken through ultrasound tests, renal biopsy with inclusion of genetic mutation tests (O’Meara, 2006)

Why is AS a concern?

Alport Syndrome is a concern because despite its severity in patients, there are no clinical trials of treating it.  Treatment to slow down the progression of AS to renal failure has not been found yet. There have been hopes to patients through kidney transplant which has proven successful and helpful; however not all patients benefit from the transplant.  5-10% of patients develop anti-glomerular basement syndrome after the transplant due to the defective a5 chain (Kashtan, 1996). The chain destroys the new kidney.  Though research on the genetic therapies for AS is still ongoing, researchers report having more questions than answers on the AS gene.  Many characteristics of Alport Syndrome have not been explained and hence have remained a field for investigation for a long time.

Why I chose Alport Syndrome

Alport Syndrome has been part of my family for two generation. I have lost two of my uncles to the disease. One of the uncles died of renal failure in composition with heart failure. The other one, my maternal uncle died of renal failure after turning deaf and blind. My two sisters are normal after undergoing ophthalmological examination. Last year, my eye examination revealed 25/60 and 20/60 in the left and right eye respectively. This year, there was a drop in the eye examination results. I am worried about my eyesight and the future of my generation. I therefore chose to study this topic knowing how important it is to me. Cultural factors affecting the cure of AS is mainly ignorance by family members on the disease

Solution

Several organizations have come forward to help intercede and attempt to “cure” the existing problem. Finances have been allocated to the research of medication to the AS.  Some organizations help with the early-identification of AS for early intervention. Some of the organizations include:

The International Society of Nephrology

In 1997, the International society published an article with the title Alport syndrome be treated by gene therapy (Tryggvason, 1997). The aim of the article was to present the research they had done on the possibility of AS to be treated by gene therapy. They based their research on the advancement that had been made on molecular gene research. According to the organization, they saw the gene therapy as the only possibility to treating AS. Gene therapy has not been used as means for treating human diseases. But for this case, since AS attacks the renal glomeruli, which is a part of the kidney, gene therapy could be easily possible. The kidney is a separate organ with its own circulatory system; gene therapy can easily be done on it. The half-life of collagen type IV is also a factor (Tryggvason, 1997).

The organization however has raised many questions on the success of its research. The following are some of the questions:

  • Can gene transfer be made to the epithelial and endothelial cells?
  • Will the transferred genes be long-lasting?

The half-life of type IV collagen is estimated to be half a year. Questions arise whereby if the patient undergoes gene therapy, does it mean that after 6 months they will need another gene therapy? The surgical implications of the therapy to the patient would be adverse.

  • Will the transferred gene be incorporated normally into the renal glomeruli? Or will it cause an uncontrolled reaction to the kidney?
  • Can the new, corrected type IV collagen be assimilated into the renal glomeruli and is to function as before?

The organization is facilitating its research by using animal models for their experiments. One of the animals they use is the Samoyed dog.  Experiments on the dogs with the AS are still underway. The organization still has hope that one-day gene therapy will become a possible treatment for the AS.

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In 2014, the International Workshop on Alport Syndrome was held in Oxford, the UK for three days. The workshop had been held annually for five years and brought together people from four continents. The theme of the workshop was “Shining a Light on Alport Syndrome”. Through the concert, biologists, physicians and scientists got to interact with families and patients with AS. The workshop has achieved the following:

  • They have availed gene testing to more countries and increased number of families. Through this, the cost of testing is expected to decrease.
  • They have developed a database for patients and families so that they can meet to share experiences and shed knowledge on AS
  • They have devised several methods for identifying mutations. They have the “next generation sequencing” (NGS) lab test methods. The methods have advanced from lab tests to clinical methods.

The workshop discussed that possibility that AS could be cured by the restored production of healthy type IV collagen protein. This, they anticipate could halt the progression of AS to renal failure. It is also unfortunate the workshop is still relying on researches on gene therapy.

The European Registry is playing a bigger role in its own capacity towards the cure of AS. They have created a patient registry to store information. AS is a rare and has several mutations, having patients’ information in one place will help in the testing of treatment and clinical trials. Currently, 3000 patients have been registered in the 6 databases in different continents.

Alport Syndrome Treatments and Outcomes Registry (ASTOR) were created by the University of Minnesota’s Department of Pediatrics for the purpose of enrolling patients with AS and families with the history of the syndrome. The information will be used to conduct research on potential treatment of AS.  They also provide patients with updated information on AS and the on-going research.

There has been researching by EARLY PROTECT on the theory that early therapy on AS delay the progression to renal failure and improves the patient’s lifespan (Gross, 2012). The project began in 2012 with patients with early stages of AS. 80 patients between 18 months and 24 years were used for the trial. The results from the 3-year trial period are yet to be uncovered and will become the basis for much research

Financial Resources

Research for Alport Syndrome requires heavy funding considering the weight of the matter. It is almost a century since the disease was uncovered but no known sure treatment has been realized. There is a need for finances to facilitate clinical trials, laboratory equipment, physicians, biologists and many more sectors. The following are some of the organizations that have come forward to help with the funding:

In 2015, The Alport Syndrome Foundation (ASF), Pedersen Family, Kidney Foundation of Canada (KFOC) Research Funding Program awarded two research firms an equivalent of $176, 000 to facilitate projects on AS (ASF, 2015). The firms awarded are Dr. James Scholey of the University of Toronto which received $100,000 for a whole year to facilitate research on Drug Repurposing for the Treatment of Experimental Alport Syndrome (ASF, 2015). The study was intended to target gene expression patterns using a drug called vorinostat. The experimental animal was the mice of which they are to determine if vorinostat in conjunction with ACE inhibitors prolongs the patients’ life. The foundation has been a major funder to most researches on AS.

Dr. Jeffrey Miner of Washington University was awarded $76,500 for an equal one year. The research was focused on WISE Antibody as a Treatment for Alport Syndrome (ASF, 2015). The study was meant to test the contributions of two antibodies in inhibiting quick progression of AS to renal failure (ASF, 2015).

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Evaluation

The major longtime success that organizations, biologists, physicists and geneticists long to achieve are finding the cure for Alport Syndrome. The cure that has seen many researchers interested in the research on gene therapy. Therefore, the success that everyone looks forward to is the possible use of gene therapy to cure AS. Currently, there is no treatment for the disease (Greenberg & Chung, 2005). However, the treatment given by physicians aims at slowing the progression of the disease and its effect on the kidney. Some of the technique the progression of the kidney disease is by using angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. Also, patients can wear hearing protection to modulate ambient sounds. However, the significant damage it causes to vision cannot be corrected (Greenberg & Chung, 2005). There are several factors that have affected the success and they include:

  • Failed trials: Several experiments have been done with different trial animals but none has yielded the expected results. This however has not stopped researchers from going on with the research.
  • Different mutations of AS: AS has different forms each with different morphological and genetic characteristics. The many mutations have made the treatment of AS harder since each patient has to undergo a trial to proceed with the treatment.
  • The rareness of AS: Though severe, AS is rare, getting the right trials, finances and support has proven to be hard since it only affects a small percentage of individuals worldwide.

Recommendations

I recommend the following to be done in the addressing of Alport Syndrome;

  • Allocation of more resources to its research, this involves financial and manpower. The inclusion of more funds and people interested in finding the cure would help in fastening the discovery of AS treatment
  • Government Involvement: From my research, there is little involvement of the government in the AS treatment research. I therefore, wish that the government, with all its ability would direct some attention to AS. Private organizations, on their own, may not achieve much.
  • Awareness of the existence of the syndrome should be made. The existence of Autosomal recessive AS (ARAS) caused by marriage by close relatives necessitates the need to discourage such marriages. Early detection of the disease can also be aided by awareness.

Conclusion

Alport Syndrome is a hereditary disease leading to blindness, deafness and kidney failure. The only available cure, for now, is kidney transplant which is not 100% effective. The future treatment lies with gene therapy. Extensive researches are being made within many laboratories to explore the possibilities of using gene therapy. If the experiments become successful, Alport Syndrome treatment will be possible someday.

Did you like this sample?
  1. ASF, 2015. Announcing funding for alport syndrome research. The Alport Syndrome Foundation (ASF), Pedersen Family, Kidney Foundation of Canada (KFOC). 
  2. Colville DJ, Savige J. Alport syndrome-a review of ocular manifestations. Ophthalmic Genet 1997; 18 (4): 161-73.
  3. Greenberg, A., & Cheung, A. K. (2005). Primer on kidney diseases. Philadelphia, PA: Saunders. 
  4. Gross, O., Friede, T., Hilgers, R., Görlitz, A., Gavénis, K., Ahmed, R., & Dürr, U. (2012). Safety and efficacy of the ACE-inhibitor ramipril in alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN pediatrics, 2012.
  5. Kashtan, C. E., & Michael, A. F. (1996). Alport syndrome. Kidney international, 50(5), 1445-1463.
  6. Mahajan, S. K., Sud, S., Sood, B. R., Patil, R. K., Prashar, N., & Prashar, B. S. (2003). Alport syndrome. J Indian Acad clin Med, 4, 337-9.
  7. O’Meara YM, Brady HR, Brenner BM. Glomerulopathies associated with multi–system diseases. In: Braunwald E, Fauci AS, Kasper DL et al. (Eds). Harrison’s Principles of Internal Medicine, 15th Ed. New York, McGraw-Hill 2001; 2: 1596.
  8. Tryggvason, K., Heikkilä, P., Pettersson, E., Tibell, A., & Thorner, P. (1997). Can Alport syndrome be treated by gene therapy?. Kidney international, 51(5), 1493-1499.
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