In the NEWS: Biomarkers-- Hype or Hope for AIN

A new study in JCI sheds light into a potential biomarker for Acute Interstitial Nephritis. This entity has been the bane of Nephrologists' existence. Its a hard diagnosis to make and treatment is the usual- steroids. 

First came the urine eosinophils-- then they were found to be useless.  Apparently, despite several studies showing no clear benefit in diagnosing AIN, several folks love to order this useless test. 

A slew of biomarkers came and went but none were real superhits for AIN. TNF-alpha and IL-9 were two potential candidates over the last few years.  The authors of a recent study published in JCI performed urine proteomics to identify a potential candidate that maybe best and top contender for AIN- chemokine C-X-C motif ligand 9( CXCL9).  This was then externally validated and then confirmed in kidney tissue of AIN patients compared to control groups.  They also showed that urinary CXCL9 together with TNF-α and IL-9 is the optimal combination of biomarkers for AIN diagnosis.

Here is the visual abstract from the paper

What is this CXCL-9? Apparently, it is a monokine induced by IFN-γ, is a chemokine that binds to its receptor, CXCR-3, and promotes lymphocyte recruitment at sites of inflammation.

It has been shown to be associated with

acute cellular rejection( makes sense- similar to AIN)
predict future risk of rejection
AIN associated with immunotherapy ( inviting T cells and monokine)
Predicting any immune mediated events when using ICI therapy

Drawbacks-- may not tell you specifically what is the cause of the T cell invitation but can clearly tell you a clue. Urinary tests are usually challenging in oligo-anuric AIN. 

It seems that the combination of TNF-alpha, CXCL-9 and IL-9 may hold promise for AIN. 

Despite amazing advances in urinary markers in transplant rejection since last 15 years, we are not using it in clinical practice. 

Lets hope that it is the troponin for AIN else we are still doing renal bx to confirm these tough diagnosis. 

Topic Discussion: Renal injury biomarkers

Finding a troponin for renal injury has been the quest for the last 10 years for many researchers in Nephrology. A recent article in AJKD nicely summarizes this quest in a core curriculum review. The lead author is from the renal fellow network.

Some key points:
1. Most biomarkers that have been discovered in the recent years have been mainly looking at proximal tubular injury and glomerular permeability.
2.While creatinine and albuminuria are always considered conventional, it was interesting to see that they included cystatin C as a conventional marker as oppose to novel. Clinically, doubt the use of this marker has blossomed yet.
3. Most common settings most of the newer markers have been checked are: post cardiac surgery, intensive care unit settings and contrast nephropathy
4. The best part of the paper is the discussion of urinary versus serum biomarkers and how in certain cases urinary markers could be most helpful but there could be contamination. Serum biomarkers are excellent to have during anuric settings but are they specific for kidney injury?
5. There are many tables that are good to review to go over most of the new markers that have been evolving in the last 5 years.

IN THE NEWS: FSP-1

 Urinary FSP1 as a possible acute glomerulonephritis biomarker.  Apparently when you have renal injury, it leads to accumulation of fibroblast specific protein 1 (FSP-1) in the kidney and this could serve as a biomarker. A paper in JASN showed that this urinary FSP-1 was elevated significantly more in crescentic GN and later even became undetectable after treatment.  The authors suggest that it could be screening test for active GN.  Interestingly, the same group had found this elevation in diabetic nephropathy as well,  Take a look at the original paper in JASN.  Is it really? or is it a marker of podocyte damage. Take a look at similar paper now using FSGS showing that it might reflect detachment of foot processes. The same authors have shown that this entity is EMT in tubular interstitial fibrosis.  And HIVAN as well.  Is FSP1 measurement as measuring podocyturia? Or are we truly getting to a potential urinary marker?

TOPIC DISCUSSION: BIOMARKERS

A recent article in AJKD June 2011 issue reviews the up and coming bio markers to replace creatinine in renal injury.
Lets summarize what they have to say:
1. In the differential diagnosis of AKI, currently we use FeNa to help distinguish renal vs pre renal and if  need be urinalysis and biopsy.  Proposal is to eventually use: IL-18, Kim -1, NgAL, NAG

2. In early detection of renal injury, currently we use crt and GFR, would would help is cystatin C and perhaps GST, IL18, KIM-1, NGAL, NAG and L-FABP.

3. In prognosis, we currently use AKIN and RIFLE criteria based on crt.  What might help is cystatin C and above ones as well.

So far, I continue to use only and only one marker, Creatinine- the best marker to date for renal disease; and perhaps proteinuria for progression of kidney disease.  I have ordered cystatin C sometimes, but never really helped me clinically.  So hoping some of these markers or PANEL of markers might be more helpful than what we currently use in renal disease.

Ref:
http://www.ncbi.nlm.nih.gov/pubmed/21411200