CLINICAL CASE 9

Urine AQP2 excretion is increased by dehhydration	2 (10%)
Urinary AQP2 is augmented in SIADH	4 (21%)
The predominant aquaporin in the proximal tubule is AQP1	1 (5%)
AQP2 is predominantly found in the S3 segment of the proximal tubules	6 (31%)
V2 receptor antagonists can be used to treat X linked congenital Nephrogenic Diabetes Insipidus	6 (31%)

Which statement above is false?

Tough question. It seems like it was between the last two choices.  Aquaporins in renal diseases and physiology are important to know about. A nice review was recently published in Nature

Review Nephrology, please all read. Its an exceptional review.  
***The AQP we really care most about is AQP2, the water channel found in the urinary surface of the principal cells of the collecting duct. Hence answer 4 is the right answer as that statement is false.

***The most prominent aqp in the s3 segment of the proximal tubule is aqp7 and in general Aqp1 is the most abundant in the proximal tubule. Aqp3 and 4 are also found on principal cells but in the basolateral

side.  

***The AQP2 is the one that is effected the most in all causes of Diabetes Insipidus(DI). Few recent studies have shown that urinary AQP2 excretion can give a clue of what is the WATER 

status of our patients.  It is associated with ADH activity indirectly.  
***You want more water to be absorbed in hypernatremic and severe dehydration sates and hence there will be more production and movement of AQP2 channels in the apical membrane in those instances and hence increased urinary production of them as well.  
So dehydration increases AQP2 in the urine and hydration decreases it. Augmentation of AQP2 is also found in SIADH and hence more water is absorbed and compounds the problem. Even in CHF patients, AQP2 activity is enchanced. 

***The last statement is interesting and its true. Most patients with congenital X-linked nephrogenic DI have defective V2 vasopressin receptors 

that are unable to properly fold intracellularly and, as a consequence, correctly transfer to the cell surface. In in vitro systems, the administration of selective, cell permeable nonpeptide 

V2 and V1a receptor antagonists were able to rescue mutant V2 receptors by promoting their proper folding and maturation . This resulted in the expression of functional cell surface V2 receptors.

lIn a pilot study, a nonpeptide V1a receptor antagonist was administered to five men with nephrogenic 

DI (each with one of three identified mutations in the V2 gene that codes for the V2 receptor)

lThis resulted in an increase in urine osmolality from a mean of 100 to 150 mosm/kg, and reductions in urine volume from 12 to 8 L/day and in water intake from 11 to 7 L/day.

lMost aquaporin-2 mutations associated with nephrogenic DI also result in proteins being retained in the intracellular space

lResearch to find chaperone-like molecules to help direct these proteins to the cell surface is ongoing.

The Online Transplant Center: Post transplant MPGN

The Online Transplant Center: Post transplant MPGN

Post transplant MPGN

A nice recent paper in Kidney International April 2010 edition talks about the examination of MPGN post transplant at a single center.  Few interesting observations they noted:- They found that the risk of recurrence was increased most with patients who had pre transplant low complement levels and elevated monoclonal proteins.  The 29 patients they studied, 5 lost their graft and 2 patients remained on plasmapheresis.  The recurrence rate was low but was important to note few clinical key points.

What does this mean? MPGN is a tough diagnosis to make in my opinion. They ruled out all DDD and fibrillary patients from their study. They did include rare causes like Rheumatoid Arthritis but "clinically" all secondary causes were ruled out. That's my concern as MPGN is one disease that has found to have so many secondary causes.  From infectious to autoimmune diseases, you name it and it can cause MPGN.  Now recently, there has been some suggestion that paraproteins can be related to cause of primary MPGN.  Again, we cannot call it primary if we have found a secondary cause. MPGN like pattern of injury can be seen in TMA, Autoimmune diseases and paraproteinemias. If those are all negative, and there are deposits, perhaps its primary. Also, in post transplant- its even tougher, as immune mediated changes can lead to an MPGN like pattern on the biopsy, CNI induced chronic TMA can look like MPGN as well and transplant glomerulopathy is basically an MPGN pattern of injury. First we need to differential pattern of injury from primary MPGN.
Regardless, the two great points that come up are:
Should we screen everyone with MGPN regularly with complements and if they are low, then their risk post transplant recurrence is high?
Should we screen everyone prior to transplant with serum free light chain assays and if they are present:- not transplant them or consider a bone marrow prior to transplant?
No clear answers but this study raises these important questions!!

TOPIC DISCUSSION: PCO2, which one is better?

Ever wonder what Pc02 represents and which one is better? We use Pc02 as a maker of the buffering system for the H+ load in our body.
Which Pco2( arterial, venous, capillary or skeletal muscle venous) is the most accurate in predicting how our buffering is working?
Arterial Pc02 is what the brain PCo2 is closest to. Its the minimum requirement for the cells to function. The PC02 in the venous blood will be higher as it has been through cells and there was the process of extration of oxygen in hence PC02 will increase.
The capillary Pc02 is going to be higher then the arterial one as again , you are closer to cells that will use Oxygen and Co2 production is higher.  The capillary PCo2 reveals the buffer system has operated efficiently in the vast majority of the intracelleular and extraceullar compartments.
But the PCo2 in the skeletal muscles (venous) is of most importance. Since these are heavily used areas of the body, the HCo3 production is the most in these areas and if there is a place where the buffer system can be tested, it is this compartment.  PC02 hence either in the brachial or femoral veins would be best Pc02 to check for the maximum buffering our body can do.

So for instance in a state of shock, the ECF is contracted and each cell is extracted the maximum oxygen you can.  In that circumstance, the venous pc02 will be higher than arterial pc02 but the venous skeletal muscle will be even higher.  The goal of the hydration then should be to not have more than 10mmHg difference in the skeletal venous PCo2 and arterial Pco2.
In other words, the skeletal muscle venous PC02 is an excellent marker of volume status.

The book Fluid , Electrolytes, and Acid base physiology by Halperin, Kamel and Goldstein has more details on this topic.

Image Quiz- Answers

What is it called?

The correct answer is Hollenhurst Plaque. A Hollenhorst plaque is a cholesterol emboli that is seen in a blood vessel of the retina. This is also seen in post cath patients in the kidney.The phenomenon is named after Dr. Robert Hollenhorst, an ophthalmologist in 1961.  

CONSULT ROUNDS: METHANOL and the EYE?

Methanol toxicity increases formic acid and causes an anion gap and osmolar gap and classic optic findings.
WHY the eye and not other organs like liver, other small vessels? anyone ever wondered? Even as little as 10ml can destroy the optic nerve.
Methanol is a CNS depressant and can cause same effects as alcohol. It also gets metabolised to formic acid via formaldehyde in a process by an enzyme called alcohol dehydrogenase in the liver.
Formic acid can inhibit mitocondrial cytochrome c oxidase leading to hypoxia and anerobic changes leading to acidosis.

The eye has Vitamin A and needs it for functioning. Apparently Vitamin A is metabolized by alcohol dehydrogenase ( the same enzyme), since there is a place for that enzyme there, its possible that the optic nerve becomes a target for methanol's toxication. and not other organs specifically.

CONSULT ROUNDS: ACID BASE

What we learned! When you deal with an acid base problem
Keep the three golden rules in mind!

1. Is their consistency of the HCO3 and Ph, so check with the equation ( H & H)
    H+ = 24 PC02/ HCo3.  Once you have confirmed internal consistency, move to next step
2. Is there an Anion Gap? Always check for this even if the main disorder is alkalosis as THERE IS ALWAYS SOMETHING HIDING IN the GAP.
3. Look for compensation

This is a simplistic view but in the big picture will help. we all know there are other equations that come in to play and we need to go ahead and figure out how much compensation and so forth, but the hardest ABG to figure out is a triple acid base one and the above 3 things will make it systematic for you.