Sunday, May 1, 2016
Though my daily routine at my internship did not lend itself very well to being described on a blog as it was largely reading journals, taking down data, and analyzing the said data I am glad to have been able to share what I learned along the way with those of you on my blog. I would like to thank all of the BASIS faculty members (as well as my external advisor) who helped us along the way with our projects and I would also like to congratulate all of the other seniors finishing up their projects. This has been an incredible learning experience, not just on my particular topic, but on what research actually entails, how to present my findings in a way that's meaningful, and also how to adhere to a schedule (still working on this last point). All of the projects being done here at BASIS are amazing and I am excited to see everyone present this coming week. As for what will happen on the blog, I plan on posting my research materials and some data on the second page and a copy of my presentation (for those who can't see it for some reason want to see it again). There may also be some surprise posts in the future, so if you're interested stay posted.
The final and most widely used agent used as a therapy against the BK virus is Leflunomide. Leflunomide is an immunosuppressive agent which is known to block dihydroorotate dehydrogenase, tyrosine kinase, and pyrimidine synthesis. It is licensed for treatment of rheumatoid arthritis and has been used in combination with immunosuppression reduction in the treatment of BK virus-associated diseases. It has modest in vitro activity, however, much like some of the other drugs discussed previously in vivo data is both scarce and sometimes conflicting. What is known is that it can serve the dual purpose of both an antiviral as well as an immunosuppressant in high enough doses (higher than those generally given for rheumatoid arthritis). The other main benefit of Leflunomide which makes it one of the most promising candidates as a therapy to fight the BK virus is its oral bioavailability and its relatively low nephrotoxicity. The factor which limits its dosage is damage to the liver (the same also being true for Dayquil and cough syrup).
Thursday, April 28, 2016
In a 2009 study, compensatory renal enlargement was assessed in 19 adult patients who either had a nephrectomy (the removal of a nephron, 17 cases) or developed a functionless kidney following obstruction (two cases). Hypertrophy of the healthy kidney was quantified by comparing renal size on urography (X-ray after the injection of radiographic contrast material) before and after removal or destruction of the diseased kidney. 40% of the patients within the study showed compensatory enlargement, including (most surprisingly) two patients in their sixties. The average increase in length was 3% and the maximum increase in length was 9%. The results of the study showed that compensatory enlargement occurs during both adulthood and childhood. This contrasts with the initial belief that compensatory enlargement occurred only during childhood. The increase in kidney size is, however, significantly larger if the destruction or removal occurred earlier in life. The study also showed that the presence of a hypertrophied adult kidney over 17 cm in length usually indicates that the contralateral renal disease was present in childhood (affecting both the destroyed kidney as well as the previously healthy one). In summary, the kidney has a mechanism (though it is limited) to be able to compensate for both loss of nephrons, as well as a reduction in nephron efficiency, regardless of the cause. Bringing this back around towards my focus in this project, it shows that even if the tubular atrophy and interstitial fibrosis caused by BK virus nephropathy (see post on BK Virus Nephropathy) can never be repaired, by stopping or slowing the progression of the disease, the kidney can take steps to bring itself closer to its original functionality. The irreversibility of the damage still highlights the need for close monitoring of transplant patients’ grafts as well as preventatively creating the most balanced immunosuppressive regimen for the patient.
When most people discuss plasticity it's most often with respect to the brain. Neuroplasticity is the trait of the brain where it can change its functional structures to fit a new need by forming new neural connections. An example would be how after a brain injury during which damage was sustained to the parts of the brain which handle speech, the tasks of the damaged portions can be taken up by other regions of the brain. It is even possible that functionality will return to normal or at least improve. The kidney, unfortunately, does not behave the same way.
Kidney damage can rarely ever be reversed and the progression of chronic kidney disease can really only ever be slowed down, not stopped. In addition to this, at around the age of 40 the kidney begins to lose functional nephrons (they become obsolescent nephrons), renal plasma (due to the absorption of obsolescent nephrons), and have an overall decrease in the glomerular filtration rate (GFR). While the list of things that can harm or reduce its functionality is incredibly expansive the kidney does, however, have a mechanism for dealing managing those factors that is somewhat similar to plasticity in the brain.
The reason people can live normal lives past the age of 50 is because of compensatory hypertrophy. Hypertrophy is defined as the increase in the volume of an organ or tissue due to the enlargement of its component cells. With respect to the kidney, this means that nephrons in a sense swell up in order to be able to filter more more blood, thus compensating (for the most part) for nephron reduction due to old age. This process is seen to occur most strikingly in patients who have lost all (or nearly all) function in one of their kidneys.
Wednesday, April 27, 2016
In the midst of many blogposts regarding many of the more technical aspects of my project, I wanted to include at least one post showing some fun characteristics of the kidney.
1. Each individual kidney consists of at least 1 million and up to 2 million nephrons.
Nephrons are nothing are the very tiny filters shown above which eliminate waste materials.
2. Within a single hour, kidneys receive around 120 pints of blood.
3. Despite accounting for only 0.5% of body weight almost 25% of the blood pumped by the heart goes to the kidneys.
4. Once a person reaches the age of 40, the number of functional nephrons present in each kidney start falling at a rate of 1% a year.
5. Despite the decline in the number of functional nephrons in kidneys after the age of 40, kidneys continue to function normally because the remaining nephrons enlarge to handle the increased flow (called hypertrophy).
6. If the nephrons in both kidneys are taken out and placed end to end horizontally, they will cover a distance of 16 kilometers.
7. If one kidney is taken away and the functional capacity of the other kidney is reduced to just 75%, it can still sustain life!
8. Another essential function kidneys perform is maintaining a constant amount of fluid in the body and so the entire blood supply in the body gets filtered around 400 times in a day through the kidneys.
9. If the blood pressure in kidneys fall, they start sending out signals to the rest of the body. As a result of these signals vasoconstriction occurs and pressure can return to normal.
10. Kidneys can also detect if the oxygen content of the blood falls. Once the kidneys sense a lack of oxygen, they secrete a hormone which triggers an increased production of red blood cells.
11. Some children are born with only one kidney. For them, the single kidney eventually grows to the extent where its weight is equal to the combined weight of two kidneys.
12. Excessive milk can cause kidney stones (my greatest fear).
13. Malfunctioning kidneys can lead to the development of anemia.
14. High blood pressure and diabetes can both lead to failure of kidneys (See my post about risk factors during transplant!)
15. The first ever kidney transplant was conducted by Yuri Voronoy, a Russian surgeon in 1933. The transplant failed.
16. The first ever successful kidney transplant was conducted by Dr. Joseph E. Murray in December 1954. The transplant was between two identical twins and took place in at Peter Bent Brigham Hospital, MA.
17. Nearly 700 million people globally (which nearly 10% of global adult population) suffer from some kind of kidney problem/damage. This leads or millions of premature deaths both from kidney disease as well as the related induced cardiovascular diseases.18. Nearly 1.5 million globally go through kidney transplant or kidney dialysis (why dealing with BK Virus related issues is significant!)
Tuesday, April 26, 2016
As I have stated in previous posts, the only therapy for BK nephropathy is immunosuppressive reduction, however, this also puts the patient at risk for graft rejection.
At the moment there are several non FDA approved drugs which show promise in counteracting the BK virus. So far they are approved for treatment of several DNA viruses such as Herpes simplex, CMV, Hepatitis. All of these drugs act by inhibiting DNA polymerases effectively halting viral replication.
Each of the following paragraphs will be brief descriptions the specific drugs that may in the future be used for treatment.
Cidofovir stops viral replication by inhibiting the viral DNA polymerase. Cidofovir is currently approved for the treatment of CMV-induced retinitis in HIV-infected patients. The CMV virus is very similar to the BK virus in that it is widespread among the population and those infected remain largely asymptomatic. This drug treats inflammation of the retina caused by CMV when the patient's immune system is weakened by HIV. So far Cidofovir has shown in vitro (outside of the body; petri dishes) activity against the BK virus; however, there are conflicting reports of in vivo activity. Cidofovir has so far been used to treat patients with both BK-related hemorrhagic cystitis and CMV infection. It was found to reduce both CMV replication and the level of BK viruria, and resulted in clinical improvement. Low dose Cidofovir treatment has been used in bone marrow transplants with positive clinical outcomes and decreased viruria and viremia in 84% and 47% of the patients respectively. There are, however, also reports claiming the deleterious effects of reduced renal function and increased viral load in Cidofovir-treated BKVAN patients. Cidofovir also has limited treatment potential in renal transplant patients due to its nephrotoxicity as well as its limited oral bioavailability. The variable and the conflicting results of Cidofovir treatment show the need for randomized clinical drug trials.
CMX001 is a slightly better alternative to Cidofovir in that it is orally delivered and has reduced nephrotoxicity. It is also able to inhibit BK Virus replication much more rapidly and with a longer-lasting effect. This compound was tested in renal transplant and BMT recipients but the results of this clinical study were not yet available at the time this review was written.
As a fun fact this compounds full name of all individual elements in this compound are
phosphoric acid; [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl) ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester; hexadecyloxypropyl cidofovir
Tuesday, April 12, 2016
My previous post gave the final result of the study, but not any of the hard numbers that give it credence. I hope to address that here.
The study (conducted over a 1 year interval) showed that by 3 months, the rates of viremia and viruria in both the Tac-arm and the CsA-arm had increased by nearly the same amount, 10% and 14% with CsA having the larger percentage. At 6 months something interesting occurred the two rates diverging and reversing, with the Tac-arm having 16.3% Viremia and CsA having 10.6%. This trend was shown continuing at the 12 month mark (Tac-12.1%, CsA-4.8%).
This therefore shows the significantly increased risk of developing BK nephropathy when given high potency agents. This should not, however, be interpreted to mean that CsA’s benefits automatically outweigh its costs. Weaker immunosuppression runs the higher risk of having the body inflict damage to the graft. What should be taken away from this study is the importance of balance. Finding the balance between the risk of developing BK related issues and the risk of an immune response for each individual person remains the ultimate goal for maximizing kidney graft longevity and thus bettering the life of the patient.
Attached above is a picture showing the graphed trends (%) for BK Viruria (left) and BK Viremia (right) over the one year interval with Cyclosporine being the solid point line and Tacrolimus being hollow.