Pediatrics Grand rounds continue , the last one for 2010

https://www.pediatric-nephrology.com/index.php?option=com_lyftenbloggie&view=entry&year=2010&month=12&day=30&id=371:pgrxiv&Itemid=27

Chronic renal allograft dysfunction

This month's Kidney International has a special extra edition on Chronic renal allograft dysfunction.
This supplement has >10 articles that highlights latest development in transplantation on pathogenetic mechanisms of T and B cells in Chronic rejection, IF/TA and then few chapters on fibrosis and genomic studies.
Risk factors, infections and immune monitoring are also discussed.

Few of them are linked below:
http://www.ncbi.nlm.nih.gov/pubmed
http://www.ncbi.nlm.nih.gov/pubmed/21116312
http://www.ncbi.nlm.nih.gov/pubmed/21116316

TOPIC DISCUSSION: Hypokalemic Nephropathy

Yes... Hypokalemia that is chronic can lead to decrease in GFR and nephropathy. How so?
Also known as kaliopenic nephropathy
1. Hypokalemia can lead to a renal concentrating defect leading to polyuria and polydipsia- DI
2. Chronic tubular damage can occur as a result and lead to proximal tubular damage as well
3. Tubular interstitial disease develops
4. Proteinuria can be seen
5. Renal cysts can be noted
6. There is also impairment of  renal angiogenesis, evidenced by progressive capillary loss, reduced endothelial cell proliferation, and loss of VEGF expression in one study.
7. Histologically:- tubular atrophy, interstitial infiltration of macrophages, and fibrosis
Ref:
http://www.ncbi.nlm.nih.gov/pubmed/18178802
http://www.ncbi.nlm.nih.gov/pubmed/17928827
http://www.ncbi.nlm.nih.gov/pubmed/20828906

KRND Needs YOU!

KRND Needs YOU!

CMV in solid Organ transplantation!

CMV infections are fairly common in solid organ transplantations.  A nice review in Nature Review Nephrology this month highlights prophylaxis treatment, active treatment and serology testing. What I found very useful wa a table on dosage recommendations for ganciclovir and valganciclovir in varied renal function states. 

A nice section on anti viral resistance also reveals some important data on use of foscarnet and when there is UL97 mutations.  These strains usually have ganciclovir resistance.  The UL54 strain mutation can have resistance to even foscarnet and cidofivir.  The advent of commercially available genotyping allows for rapid results of UL97 or 54 and allow for personalized treatment of CMV viremia or disease.  

Resistant CMV guidelines

1. Increase dose of ganciclovir 

2. Change to foscarnet with or without continued ganciclovir

3. Change to Cidofovir only if pol mutations are not present otherwise it cross reacts with ganciclovir resistance.

4. leflunomide has been tried in few cases.

5. CMV immunoglobulin (IVIG) as a last resort and if there is organ damage happening.

Check it out

http://www.ncbi.nlm.nih.gov/pubmed/20978468

CLINICAL CASE 30, ANSWERS AND SUMMARY

Tenofovir can cause proximal tubular damage? Recent data show it to damage what part of the cell?

Nucleas 2%

Mitochondria 71%

MRP-2 Channel 17%

NK ATPase pump 7%

The HIV drug Tenofovir, as we all know , can be nephrotoxic. Proximal tubular damage is what we usually see with full blown Fanconi syndrome as well in some cases.  What the organic anion drug do in the proximal tubule cell?  It is delivered to the basolateral membrane of the proximal tubule cell and its transported into the cell by the organic anion transporter OAT-1.  Once it enters the cell, the drug is secreted into the urinary space via MRP-2 and MRP-4 ( multidrug resistance protein transporters).  The damage we see with this drug is via direct mitochondrial DNA depletion and damage done by the drug within the cell.  Disturbances in the secretory pathway ( increased OAT-1 or decreased MRP efflux) can lead to increased drug levels in the cell and ultimate mitochondrial damage.  MRP-2 is a good answer but mitochondria is the best answer as the damage really is via mitrocondria that leads to the final proximal cell tubulopathy. 

This has been shown in EM findings or ultrastructual findings that show eisonophilic intracytoplasmic inclusions within the proximal tubular epithelial cells, that are the giant mitochondria seen usually.  The mitochondria have abnormal cristae and hence don't function.  

This ultimately leads to strange shaped and large shaped mitochondria that are non functional and tenofovir induced toxicity. 

A nice reference from KI is listed below:

http://www.ncbi.nlm.nih.gov/pubmed/20811330

In the NEWS: Angiopoietin like 4 , a glycoprotein that might change the face of glomerular disease.

A recent study published in Nature Medicine reveals some very interesting findings. The researchers in Alabama showed that glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of minimal change disease and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Mice with no Angptl4 had no proteinuria.  
This is exciting in many ways: This might suggest that this specific protein might be the type of nephrotic syndrome that responds to steroids, so if you have elevations of this protein in your urine or blood you have a certain nephrotic syndrome that will respond to steroids and decrease proteinuria. Lets see what this pans out in human studies.  Great work by the scientists at Alabama on this breakthrough discovery. Check out the link below.

http://www.ncbi.nlm.nih.gov/pubmed/21151138