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.

JOURNAL CLUB: Kidney allograft nephrectomy can improve survival.

An interesting article would like to share with you:
Transplant Nephrectomy Improves Survival following a Failed Renal Allograft , Juan Carlos Ayus et al. J Am Soc Nephrol 21: 374–380, 2010.

There are a growing number of patients returning to dialysis after a failed kidney transplant; the prevalence and incidence of ESRD are projected to increase substantially in the US during the next several decades. Approximately 2000 patients annually enter dialysis in the United States after allograft failure (10% of the population initiating dialysis) and only approximately 15% undergo repeat transplantation. Thus, optimal treatment of the large majority of these patients who do not receive repeat kidney transplantation is a challenging problem risk for death after renal allograft failure is an underappreciated problem.

This study is a large, retrospective cohort of patients returning to dialysis after failed kidney transplant. It shows close to 32% decrease in relative risk of death from any reason in those patients who had allograft nephrectomy after starting on dialysis.
Theories mentioned in previous literature explaining why keeping the allograft in situ increase death are:
1-The presence of a failed allograft at dialysis initiation is associated with anemia and hypoalbuminemia—predictors of poor outcomes among dialysis patients.
2-Chronically rejected renal allograft is a nidus of immunoreactivity that causes chronic inflammation-a major CVD risk.
3-Continued use of Immunosuppressants which has increase risk – CVD/infections.

So why don’t we perform allograft nephrectomy for all failed allograft as standard of care for all patients retaining to dialysis?
It’s shown in previous studies that allograft nephrectomy has a negative impact on the Percent Panel Reactive Antibodies, with a significant rise in the PRA post nephrecotmy persistently, which can theoretically decrease the chance of having a matching donor if future transplant is considered!
Also, not to ignore the fact that these patients are high risk; and allograft nephrectomy carries high morbidity and mortality rate which can go up into 20-30% of cases.
Overall, allograft nephrectomy should always be considered, especially for those who can tolerate the surgery and have no future plan for a repeated transplant. We still need prospective randomized controlled trials regarding this issue and its’ affect on the PRA.

TOPIC DISCUSSION: Nutrition

If you wanted to know that the prescribed protein restricted diet is adhered to by your CKD patient, how would you go about figuring that out?

Concepts:
1- Nitrogen Balance = Nitrogen Intake - Urea Nitrogen Appearance Rate (i.e. 24hr urine urea nitrogen if in steady state) - Non Urea Nitrogen

2- Non Urea Nitrogen = 0.031g Nitrogen/kg body weight

3- If Nitrogen Balance = 0, then Nitrogen Intake = Urea Nitrogen Appearance Rate + Non Urea Nitrogen

Take the result (g Nitrogen/day) and multiple by 6.25 (since 16% protein in Nitrogen) to get g protein

Use these concepts for PD patients as well, where you take 24hour urine V x random urea Nitrogen (or 24hour urine Nitrogen if available) and add to dialysate volume and urea concentration of dialysate.

Fun with numbers!

TOPIC DISCUSSION: Drugs and Cyclosporine

Cyclosporine is metabolized by the  hepatic cytochrome P450 family of enzymes and excreted into the bile.  
Drugs that induce CYP3A4 decrease the levels of cyclosporine.  Examples of these include carbamazepine, nafcillin, nevirapine, phenobarbital, and phenytoin. Drugs that inhibit CYP3A4 may increase the levels of cyclosporine.  Examples of these include antifungals( azoles), doxycycline, erythromycin, isoniazid, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. 
Cyclosporine may increase the levels of CVP3A4 substrates.  Examples of substrates include benzodiazepines, calcium channel blockers, mirtazapine, sildenafil, venlafaxine and believe it or not- tacrolimus.


courtesy: http://www.medicalpearls.com/

IN THE NEWS- NSF and Kidney Transplantation

A recent study in AJT March 2010 issue evaluated what happens to patients after they get a kidney transplant in terms of their nephrogenic systemic fibrosis disease. They studied 17 patients retrospectively.
Nine of 11 transplanted patients had NSF pre transplant and 2 had post transplant DGF and then NSF.
6 dialysis patients with NSF were also studied. They followed these patients for 35 months for post transplant patients and 9 months for dialysis patients.  Baseline GFR for transplant patients were 42ml.min.
NSF only improved in 55% of transplant patients and 50% of non transplanted patients. Of the 6 patients of the 11 total transplanted patients, 4 had partial remission and 2 had complete remission of NSF.
It seems that they summarize that transplant or no transplant, 50% had some remission of NSF. So it doesn't seem that transplantation changed outcomes for their NSF.
This is important as this is the largest study of NSF in transplant patients I found so far. Hopefully a more prospective study might be more helpful. In general, i  think we are going to see less and less of this disease as we are avoiding gadolinium based MRIs in many of our CKD and post transplant CKD patients.

Bowel Transplantations, not enough!

Interestingly, just read in AJT that bowel transplantations are not happening as much as they should.
The AJT report summarizes some of the reasons why.
1. Experience of Physicians and surgeons taking care of these patients
2. Knowledge gap and some physicians even not knowing this option exists.
3. TPN might be a better options in some viewpoints
4. There are not enough recipients
5. Some physicians consider this an experimental procedure.

As a Nephrologists, I think that its fascinating that the field of transplantation and immunology has come this far and hopefully in future, bowel transplantation might become a more standard of care option for patients with intestinal failure.

Horseshoe Kidney

Horseshoe Kidney

The Online Transplant Center: New Agents for renal transplantation

The Online Transplant Center: New Agents for renal transplantation

CLINICAL CASE 8

In distal tubular cells, this transmembrane protein can break off and circulate as a hormone to alter FGF receptor so that FGF23 can fit right in, " In Greece, she spins the thread of life"?

PTH	1 (5%)
Klotho	15 (83%)
GALNT3	1 (5%)
TRPV5	1 (5%)

The correct answer is Klotho, nice job everyone. TRPV5 is expressed in renal pithelial cells, where it plays an important role in the reabsorption of calcium and loss of TRPV5 in mice leads to hypercalciuria and hyperparathyroidism and bone disease. Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphetemia, inappropriate elevation in 1,25 Vitamin D and painful hyperostosis.  It has been shown that this is due to an inactivating mutations in GALNT3, encoding UDP-N-acetyl alpha D galactosamine polypeptide N acetylgalactosaminyltransferase 3. Some suggests that this protein's genetic alteration can lead to low levels of FGF-23.
Klotho, in Greek mythology spun the thread of life. In the kidney world, klotho is a membrane protein that is expressed in distal kidney tubules, choroid plexus and parathyroid gland. This protein breaks off and circulates as a hormone. It increases FGF23 and it stabalizes TPRV5 so calcium is transported into distal tubular cells. It's role in altering FGF receptor so that FGF23 can bind with great affinity is where it has gained its fame. Its important to learn the actions of FGF-23 as its become a hormone that might be playing a key role in bone metabolism in kidney disease. FGF23 promotes renal phosphate excretion and inhibits 1-alpha hydroxylation of vitamin D in the kidney and increases klotho levels and decreases pTh expresion and secretion. So if you had FGF-23 over expression: you would have hypophosphetemia, osteomalacia,and low 1,25 Vitamin D levels. In contrasts, FGF-23 knockouts would have hyperphosphetemia,high vitamin 1,25 D levels,tumor calcinosis and low klotho levels. When you have klotho knockout, you get hyperphos, high Vitamin 1,25 , early aging calcification, and high FGF-23. 

So basically, phosphate and vitamin D levels can turn FGF23 and klotho to the direction they need to go. Calicum plays a role as well in differentiating it from when pth overrides FGF-23 expression. 

In setting of hypocalcemia and hyperphos, and low Vitamin D:- pth dominates

In setting of hypercalcemia and hyperphos and low Vitamin D:- FGF-23 dominates

The link below from is a great review of the topic using pictures.

The references are listed at the end of the course. A lot still has to be 

clarified in this topic. How this will be used for treatment or monitoring

bone disease, no one really knows yet.

History of Nephrology: The first randomised controlled trial in dialysis

History of Nephrology: The first randomised controlled trial in dialysis

Common Sense vs. Evidence-based Medicine

Common Sense vs. Evidence-based Medicine

TOPIC DISCUSSION: DIFFERENT TYPES OF PROTEINURIA

We see proteinuria all the time. What are the different types of proteinuria? Here is a list of different types of proteinuria from a recent article in Kidney International.


1. Glomerular Proteinuria:- usually loss of albumin and higher molecular weight proteins
2. Tubular Proteinturia:- b2 microglobulin and loss of low molecular weight protein
3. Overflow Proteinuria:- usually seen in myeloma or paraproteinemias that lead to an overflow and loss in the urine due to overproduction.
4. Post exercise:- transient and benign and can be as high as 10gm
5. Post prandial:- very transient and its due to insulin action on the podocytes
6. Infection associated:- by Toll receptors. like we see in urinary tract infections perhaps. maybe its a response to clear the infection?

New Agents for renal transplantation

Nature reviews Nephrology has a nice review on the new drugs that have been recently tried and are upcoming for the treatment of rejection or for induction.
To name and summarize a few:-
1. Alafacept  which targets Cd2 is a fusion protein that will delete activated T cells only( apoptosis method)
2. Belatacept which targets Cd80 and cd86 is also a fusion protein and can inhibit the second signal to activate T cells.
3. Sotrastaurin is a protein kinase C target and inhibits it to decrease T cell activation.
4. CP-690,550 is a JAK-3 inhibitor.
5. Eculizimab is a C5 inhibitor and inactivates complement cascade, very good use in ab mediated rejection
6. Bortezomib is a NFkB target and can deplete plasma cells and helps in plasma cell rich ab mediated rejection.
For an excellent summary, look at Figure 1 in the review article in Nature Nephrology.

TOPIC DISCUSSION: Renal Artery Stenosis

A recent review in Nature Nephrology, one of my favorite journals talks about the recent trials and overall summary of the diagnosis and treatment of renal artery stenosis.  What I loved about the article is an overall summation of all studies that is noted in table 2. In Box 1, they also list other causes of renal artery stenosis that we often forget to look for:- fibromuscular dysplasia, arterititis( PAN, Takayasu), Tuberous Sclerosis, vascular Ehlers Danlos Syndrome, Renal artery spasm, etc.

Basically, this review article concludes that atherosclerotic renal artery stenosis should be aimed at prolonging the period that is free from cardiovascular or renal events.  Age and age related risk factors, vascular disease, hypertension, renal function and kidney size all are determining factors of how patients should be treated.
Patients with FMD should be treated more aggresively with stenting as angioplasty has a better blood pressure outcome in FMD than atherosclerotic RAS.  but again, each case has to be taken on an individual basis, based on age and other co morbid factors.

Image courtesy: vascularweb.com

TOPIC DISCUSSION: THE WWW and the NEPHROLOGIST

As we are seeing an emergence of websites that are educational and patient friendly in the field of nephrology, a good summary can be found on the above linked article.
I was surprised to see some of these articles. Its good that we have the websites as such that are either physician developed or patient or organization developed. What we have to monitor and wonder in the future is what is the content on these websites. Is it evidence based? Is it just opinions ( like some of our blogs) and Is it violating patient privacy laws? These are real questions that will come up in the near future as we move into the field of
E-Nephrology. Take a look at this NEJM editorial for an excellent commentary by prominent bloggers.

My personal favorite Teaching related nephrology websites are:
www.ukidney.com
www.nephrologyondemand.com
www.nephron.com

My personal favorite online dictionary and community patient friendly website is
www.medpedia.com

Other good references:
http://www.ncbi.nlm.nih.gov/pubmed/18155112
image source: http://www.blue-inc-solutions.co.uk/web/images/www.jpg

IN THE NEWS- Hyperkalemia treatment in trouble

A recent paper in JASN questions the use of kayexalate and resins for treatment of hyperkalemia.

Sodium polystyrene sulfonate (SPS), an ion-exchange resin designed to bind potassium in the colon, was approved in 1958 as a treatment for hyperkalemia by the US Food and Drug Administration. Recently, there have been cases of colonic necrosis when used in concomitant with sorbitol and especially if used in the PR form.  The authors give a clinical commentary in JASN based on unpublished data at their institution and find no convincing evidence that SPS increases fecal potassium losses in experimental animals or humans and no
evidence that adding sorbitol to the resin increases its effectiveness as a treatment for hyperkalemia. There is growing concern, however, that suspensions of SPS in sorbitol can be harmful. They think its not a wise choice of drug to use for hyperkalemia.

Besides this commentary, there is one paper from 1998 that questioned this( listed below). There are two questions that arise.
1. Are resins really good and do they bind K and help in treatment of hyperkalemia?
2. Is the colonic side effect more due to sorbitol or due to the resin itself?


When first used, resin therapy was approved by FDA after few uncontrolled studies. Initially, the resins were not bound to sorbitol. Due to constipation side effects, it was started to be stocked with sorbitol. More recent data call the safety of the 33% sorbitol formulation into question. A study published in 2009 described 11 new cases of colonic necrosis associated with SPS in sorbitol, four of them fatal,
identified over 9 years in a single center. So things are now coming to question!


I think that at this point, before large studies condemn the use of resins, historic use of this drug and success in seeing that it drops the K level, its a good drug to use. This brings the entire point of evidence based medicine vs experience in question as usual again. I think that some senior nephrologists might question this theory of resins not working. I think it will be an interesting debate and lets see what comes out of it.

Any thoughts!

Other references:
http://www.ncbi.nlm.nih.gov/sites/entrez
http://www.ncbi.nlm.nih.gov/pubmed/9773794
http://www.ncbi.nlm.nih.gov/pubmed/2817643
http://www.ncbi.nlm.nih.gov/pubmed/8990142
image courtesy: rxlist.com

IN THE NEWS ---> ACUTE KIDNEY INJURY

Current issue of CJASN has two papers:
1. Urine Netrin as an early predictor of AKI in cardiac surgery patients
2. Urine Sediment Score as a predictor of AKI and how severe it will be, using the AKIN criteria.

Two more contenders to the already growing list of Kim-1, NgAl, perforin, granzyme B, cystatin C.
So far, creatinine is the best marker we have. Hoping these above studies and markers being studied will eventually change the way we look at the renal disease. We are in a  need for a "troponin" for the kidney.

CONSULT ROUNDS: SIADH and Escitalopram ( lexapro)

Lets talk about a case of Na of 110 and seizure. Medications involved are  mephobarbiturate and escitalopram( recent in last 2 years). The exam is consistent with euvolemia and you make a diagnosis of SIADH.  Neuro status improves after receiving hypertonic saline and furosemide in the first 24 hours.
The Na corrects by 10Meq in the first 24 hours and another 20 meq by 36 hours.  A little too rapid.
The urine output had just picked up. As a result, desmopression was administed and D5W to bring the Na down by 5Meq in 48 hours.

Discussion points..

Would you attribute SIADH to lexapro?
What do you do when there is overcorrection?

CONSULT ROUNDS: Clinical dilemma in Nephrogenic Diabetis Insipidus

In a case with Nephrogenic diabetes insipidus with Stage 4 CKD; both secondary to Lithium
I suppose lithium associated CKD reduces no of AVP2 channels with persisting NDI long after lithium therapy..

I know that Amiloride is the drug of choice for Lithium associated NDI while pt is on lithium therapy..
Once someone is off lithium, can HCTZ should be used instead.
but would it be effective at this GFR??.. probably not..
what do you think

CONSULT ROUNDS: Metformin toxicity, Lactic Acidosis, and dialysis

What is the role of dialysis in Metformin associated Lactic acidosis?

Review of literature about metformin associated severe L lactic acidosis ( MALA):
Lactic Acidosis: Lactate is generated from pyruvate with lactate dehydrogenase as a catalyst. Lactic acidosis results when:
1) lactate production exceeds consumption This occurs when tissue hypoperfusion or hypoxia ( Type A or fast LA).
2) compromised lactate metabolism without hypoxia, which is frequently termed type B (slow) lactic acidosis. Biguanides may inhibit oxidative metabolism and thus increase the concentration of NADH, reduce gluconeogenesis, and suppress the gastrointestinal absorption of glucose.

Metformin-associated lactic acidosis is a rare but serious complication of biguanide treatment associated with high mortality. Population-based studies have estimated a rate of 0.02–0.09 cases of LA in metformin users per 1000 patient-years, but results vary. Risk is higher in patients with renal failure, heart and liver failure.

Management includes supportive care including fluid resuscitation, mantaining tissue oxygenation, IV bicarbonate therapy for severe acidosis and hemodialysis or CVVHDF.
There are mostly case reports of severe lactic acidosis due to metformin toxicity succesfully treated with CRRT. One study looked at metformin levels before and after dialysis and showed that sequential measurements of metformin levels during HD were consistent with a bicompartmental elimination pattern. A cumulative HD duration of 15 hours was associated with the return of metformin level to the therapeutic normal range. Available data suggest prolonged HD is required to correct metformin overdose.

Of interest, only initial PT activity ( measure of liver function) is independently associated with mortality and degree of lactic acidosis or metformin levels has no effect on survival.

Some Reviews:
Lactic Acidosis Update for Critical Care Clinicians FRIEDRICH C. LUFT J Am Soc Nephrol 12:S15-S19, 2001

Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern? Gudmundsdottir H, Aksnes H, Heldal K, Krogh A, Froyshov S, Rudberg N, Os I.Clin Nephrol. 2006 Nov;66(5):380-5.

Metformin-associated lactic acidosis: A prognostic and therapeutic study Seidowsky, Alexandre MD Critical Care Medicine: July 2009 - Volume 37 - Issue 7 - pp 2191-2196

Metformin-associated lactic acidosis treated with continuous renal replacement therapy.
Alivanis P, Giannikouris I, Paliuras C, Arvanitis A, Volanaki M, Zervos A. Clin Ther. 2006 Mar;28(3):396-400.

Sigrun Friesecke, Peter Abel, Matthias Kraft, Andreas Gerner, and Soeren RungeCombined renal replacement therapy for severe metformin-induced lactic acidosisNephrol. Dial. Transplant., July 2006; 21: 2038 - 2039.

CLINICAL CASE 7

What is the most common renal biopsy finding in patients with primary Sjorgen's Syndrome?

FSGS	2 (16%)
Minimal Change Disease	1 (8%)
Chronic Tubularinterstitial Disease	9 (75%)
Mesangioproliferative Glomerulonephritis	0 (0%)

Correct. Most common finding in Sjorgen's Syndrome(SS) is Chronic TI disease.

A case series in CJASN 2009 supports chronic TIN as the predominant kidney biopsy finding in patients with renal involvement from SS but also illustrates diverse glomerular lesions.  Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in SS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for SS

because it may affect management and renal outcome. Other small cases found in that series included FSGS, Minimal Change, MPGN and membranous as well. Distal RTA is another clinical finding that is fairly common in SS patients.

References:

Tu WH, Shearn MA, Lee JC, Hopper J Jr: Interstitial nephritis in Sjogren’s syndrome. Ann Intern Med 69: 1163–1170, 1968

http://www.ncbi.nlm.nih.gov/pubmed/18465457

http://cjasn.asnjournals.org/cgi/content/full/4/9/1423

IN THE NEWS- HgA1C for Diabetes Diagnosis. How about for the CKD and transplant patients?

A recent study is recommending using HgA1C now as a diagnostic tool for DM. The recommendations suggest that when A1C is >6.5%, confirmed with repeat testing, a diagnosis can be suspected of DM.
I think this is a great idea and hopefully we can pick up more cases of DM earlier in this case.
However, an editorial in JASN brings up some good points in setting of CKD and transplant patients?
1. Anemia of kidney disease and how does that affect the HgA1C, in the setting of treatment with erythropoetin stimulating agents? How does that alter the diagnostic criteria?
2. Does the state of uremia alter the HgA1c?
3. Can this test be used in ESRD and dialysis patients at all due to increased inflammatory state and on going blood loss?
4. Post transplant - can HgA1c predict onset of NODAT? Perhaps using pre transplant values can predict NODAT? who knows?
Good things to consider and study in years to come as HgA1c becomes a more standard of care for diagnosis of DM.
Please see the following link:
http://www.medscape.com/viewarticle/704021
Image source: http://mset.rst2.edu/msn/s/soper_m/sget650/module3/newa1c.jpg

KIDNEY DONORS have Good Long term survival

A recent paper in JAMA suggests that living donors live normal lives and have good long term survival. Live donors were drawn from a registry and donors between 1984 and 2009 were studied.  A matched cohort of non donors was used for comparison.  Surgical mortality was 3.1per 10,000 donors and did not change during the last 15 years. The long term mortality risk was no higher in live donors than randomly matched participants matched with age and comorbidities.  The median follow up was only 6.3 years, which is long but is it too short for a donor? That we don't know. Physiologic changes do happen in patients when they donate to the other kidney. These findings suggest that epidiemiologically there is no major difference in outcomes to other non donors in the community.
This is one of the largest studies of donors and takes a long period into consideration. It also has a good sample size. Shorter follow up is a major limitation, besides it being a retrospective evaluation.

At least from this study and the recent one in NEJM linked below, long term outcomes of kidney donors are excellent.

TOPIC DISCUSSION: VEGF Nephropathology

Vascular endothelial Growth factor is a fascinating molecule that has now entered the field of nephrology in the last decade. It's implications are very important in many diseases.  Tight control of this molecule might be important for podocyte development and function as we are learning.
A nice resource and an article that everyone should read is linked above.  In this paper, the authors show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease within two weeks that looked like renal TMA and pre elampsia like. Homozygous deletion of VEGF-A in glomeruli resulted in premature death of the mice and finally  overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy.


So basically to say it in simple terms: Too little VEGF or inhibition of VEGF leads to pre eclampsia like biopsy findings or thrombotic microangiopathy like findings( this has been shown independently in pre eclamptic patients as well and also in patients who are on chemotherapy agents that are anti VEGF agents:- bevacizumab,sunitinib, sorafinib and so forth)
Too much VEGF is noted in collapsing FSGS. 
So there are two different spectrum of glomerular diseases that are seen with extremes of VEGF
( one with blood less glomeruli and the other with a collapsing glomeruli)


Very fascinating: Worth reviewing the Nephropathology of VEGF 
Image source: biooncology.com
Other good references:


http://www.ncbi.nlm.nih.gov/pubmed/18337603
http://www.ncbi.nlm.nih.gov/pubmed/19909254
http://www.ncbi.nlm.nih.gov/pubmed/19909248

TOPIC DISCUSSION: Post Transplant Collapsing FSGS, what role does ischemia play?

A case report of three cases in AJKD this month reports de-novo post transplant collapsing glomerulopathy(PTCG). Rare cases of de novo collapsing glomerulopathy have been reported during the post-transplant course and, in some instances, have been associated with renal graft vascular lesions. This finding raises the important question of whether ischemia could induce podocyte transdifferentiation, a hypothesis supported by evidence of hypoxia-inducible factor–dependent podocyte proliferation in HIV-associated nephropathy.This paper nicely shows the immuno-staining of those patients and positive for VEGF at the podocytic injury suggesting that hypoxia induced increased hypoxia inducible factor is leading to increased VEGF for their survival that ultimately leads to the collapse. Other causes that are commonly associated with Collapsing Glomerulapthy are pamidronate use, interferon use, use of sirolimus, parvovirus B19 virus, CMV infection, Renal artery stenosis, SLE, lymphoma, and recently even use of depakote and dilantin. HIV was negative in all patients? It was unclear if parvo virus was checked as post transplant parvo virus B19 cases of collapsing GN has been noted.

It is a devastating disease and something to keep in the differential diagnosis even post transplant in nephrotic range proteinuria.  Ischemia likely from chronic rejection, chronic calcineurin use might be the culprits.

The same causes that lead to Collapsing FSGS in the non transplanted kidney, should also be ruled out in the transplanted kidney. The important major difference is the ischemia as a cause might be more evident in transplanted kidney.

Image courtesy: design milk

Other references:-

http://www.abstracts2view.com/asn/view.php?nu=ASN09L1_2723a

http://www.ncbi.nlm.nih.gov/pubmed/16705026

http://journals.lww.com/transplantjournal/Abstract/1998/05150/De_Novo_Collapsing_Glomerulopathy_in_Renal.9.aspx

Post Transplant Collapsing FSGS: Is it really all Ischemia?

A case report of three cases in AJKD this month reports de-novo post transplant collapsing glomerulopathy(PTCG). Rare cases of de novo collapsing glomerulopathy have been reported during the post-transplant course and, in some instances, have been associated with renal graft vascular lesions. This finding raises the important question of whether ischemia could induce podocyte transdifferentiation, a hypothesis supported by evidence of hypoxia-inducible factor–dependent podocyte proliferation in HIV-associated nephropathy.This paper nicely shows the immuno-staining of those patients and positive for VEGF at the podocytic injury suggesting that hypoxia induced increased hypoxia inducible factor is leading to increased VEGF for their survival that ultimately leads to the collapse. Other causes that are commonly associated with Collapsing Glomerulapthy are pamidronate use, interferon use, use of sirolimus, parvovirus B19 virus, CMV infection, Renal artery stenosis, SLE, lymphoma, and recently even use of depakote and dilantin. HIV was negative in all patients? It was unclear if parvo virus was checked as post transplant parvo virus B19 cases of collapsing GN has been noted.
It is a devastating disease and something to keep in the differential diagnosis even post transplant in nephrotic range proteinuria.  Ischemia likely from chronic rejection, chronic calcineurin use might be the culprits.
The same causes that lead to Collapsing FSGS in the non transplanted kidney, should also be ruled out in the transplanted kidney. The important major difference is the ischemia as a cause might be more evident in transplanted kidney.
An abstract at ASN showed similar findings as well.


Other references:-
http://www.abstracts2view.com/asn/view.php?nu=ASN09L1_2723a
http://www.ncbi.nlm.nih.gov/pubmed/16705026
http://journals.lww.com/transplantjournal/Abstract/
1998/05150/De_Novo_Collapsing_Glomerulopathy_in_Renal.9.aspx

CLINICAL CASE 6

What is the most sensitive test for detection of paraproteinemia?

A.Serum protein electropheresis (SPEP)	1 (5%)
B.Serum immunofixation	3 (15%)
C.Serum free light chains	2 (10%)
D.Serum free light chains + immunofixation	14 (70%)

Yes. That is correct. Most of you got it right. I think its about time that everyone starts using serum free light chains not only for detection but also for follow up in some of the paraproteinemia patients. The serum immunoglobulin-free light chain (FLC) assay measures levels of free  and  immunoglobulin light chains. Based on the Hematology Associations. there are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity( just serum free light chains and immunofixation is good enough and you can rule out a lot of your paraproteinemias), and negates the need for 24-h urine studies for diagnoses. 

Just for context, a serum immunofixation might detect 50 fold increase in a specific light chain, the serum free light chains assay detects even a 10 fold increase; hence making it very sensitive test.

Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL Amyloidosis, oligosecretory myeloma and many patients who had previously been deemed to have non-secretory myeloma. In AL Amyloidosis patients, serial FLC measurements outperform PEL and immunofixation. In myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. 

Check out the above linked reference for further reading.

For excellent reading:  Read  the Kidney in Plasma Cell Dyscrasias

The links below are also helpful:-

http://www.mayoclinicproceedings.com/content/81/12/1575.full

http://myeloma.org/pdfs/UnderstandingFreeLight.pdf