Thursday, July 20, 2023

In the NEWs- New Myeloma Working Group Update-- Myeloma related renal disease management

 An important guideline/recommendation was published in Lancet thismonth. This is an evidence based summary by the International Myeloma Working Group on myeloma related kidney disease. A must read!

Here is a summary of the findings

1.      Diagnosis is important- the serum free light chain becomes the corner stone of diagnosis. An algorithm below summarizes the novel way of looking at it. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and FLCs measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed.

2.      How high is the involved FLC—can tell you if this is cast nephropathy vs looking for a glomerular process. In addition – the urine protein being selective vs non selective can aid in overflow proteinuria vs a true glomerular process.

3.      Kidney biopsy is NOT required but may be recommended if suspicious of cast nephropathy is high. Although recent studieshave shown that the IFTA and number of casts presents on renal bx can predictrenal outcomes.

4.      The IMWG criteria for renal response was recommended( change in eGFR)- see table below. This is used for many studies and validated.

5.      Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment( fluids, correction of hypercalcemia, avoiding NSAIDS)

6.      Mechanical approaches do not increase overall survival( plasma exchange- data is in the non bortezomib era, and HCO dialyzer- two RCTs showed no benefit).

7.      Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. The panel suggested to Start Daratumumab + Bortezomib + Dex early and then add IMiD starting cycle two once renal function has stabilized.

8.      Carfilzomib should not be first line in patients with CKD as risk of TMA( first time someone mentioning this)- glad the toxicities are being considered.. But then again- is the incidence of TMA from carfilzomib that high- I don’t think so.

9.      Dose adjustments are discussed for all anti Myeloma agents and their potential nephrotoxicities- mainly the TMA from carfilzomib. There are other renal toxicities of other agents as well not mentioned here.

10.    Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment

11.   Finally, with improved survival in myeloma, when should we consider kidney transplantation in pts. with ESKD? Should we use sustained MRD-negativity to select transplant candidates? What about the MGRS patients?—the consensus was 2 years of disease free state. But low level evidence.. I have seen sooner in most cases. Overall their outcomes are not great when compared to non myeloma ESKD. 

Friday, July 7, 2023

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. 

All Posts

Search This Blog