Hypertrophy of the Kidney (part 2) With Pictures!

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.

Hypertrophy of the Kidney (Part 1)

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.

Palette Cleanser: 18 of the Most Interesting Kidney Facts I Could Find

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!)

Possible Drug Treatment for BK Virus Nephropathy (Part 1)

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:

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:

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

Data and Statistics for the Previous Post

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.

How Immunosuppressants Have Evolved

It has been requested that I do a post on the differences between early immunosuppressive agents and the ones that we currently use. One way to compare these differences in terms that most people are familiar with is likening the immunosuppressive agents to antibiotics. In the same way that separate classes of antibiotics disrupt bacteria multiplication through different mechanisms, these agents each intervene with specific functions of differing cells within the immune response. One of my earlier posts shows how several induction agents either prevented the antigen presenting cell from communicating with the T-cell or directly interfere with the response of the T-cell itself. Early exploration and differentiation of these agents was mainly focused on finding different mechanisms of action, searching for one which had the fewest number of collateral effects. Relating back to the my timeline of maintenance and induction agents, the main difference between earlier agents and ones that are used now lies in side effects (generally lesser with newer medication) and potency (how much it curbs immune response per a given dosage).

A higher strength agent is not, however, always the most desirable to use. One particular article which compares the the incidence of BK viremia (BK Virus presence in the bloodstream) and BK viruria (presence in the urine, which implies a strong presence in the kidney) of two different maintenance agents shows the risk of using the stronger agent. The study included 629 patients of various backgrounds who were randomly assigned a immunosuppressive regimen of either Tacrolimus (the most widely used and more powerful agent) or Cyclosporine (relatively weaker). Though the study did not go further and explore whether one drug has a higher rate of developing BK nephropathy (the actual damage to the kidney) it can be safely assumed that higher rates of viremia correlate with higher rates of nephropathy. The study showed significant difference in the rates of BK Viremia between the two agents.