Topic Discussion: Anti-PD-1 Therapy and the Kidney

Anti PD-1 Inhibitors and the Kidney

This includes two proteins called programmed death-1 (PD-1), which is expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), which is expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical "shield" protecting tumor cells from being destroyed by the immune system. Another protein involved in the pathway and also expressed by cells in the immune system, programmed death ligand -2 (PD-L2).

Anti-PD-1 agents are humanized monoclonal antibodies that bind the PD-1 receptor, which are present on tumor infiltrating lymphocytes and Tregs. They prevent the engagement of PD-1 to its ligand on the tumor cells (PD-L1 and PD-L2) thereby asserting its antitumor activity.

Nivolumab

Nivolumab is the first anti-PD-1 antibody tested initially in melanoma.  In December 2014, the U.S. Food and Drug Administration (FDA) granted an accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma. Since then, there have been use of this agent’s approval in lymphoma and renal cell cancer as well.  There also has been some interest of this agent to be used in myeloma.

In one trial, there was an increased incidence of elevated creatinine in the nivolumab-treated group as compared to the chemotherapy-treated group (13% vs. 9%).  Steroids help resolve the renal dysfunction in 50% of the cases. It is presumed to be AIN from an immune mediated process. The FDA label has guidelines to start steroids as the creatinine rises rapidly.  A pubmed search revealed no published cases of AIN or acute renal failure in the peer reviewed literature.

Pembrolizumab

Pembrolizumab (MK-3475) is another monoclonal antibody (MAb) therapy designed to directly block the interaction between PD-1 and its ligands, without antibody dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). This drug also has been used in melanoma and other hematological malignancies since 2014. 

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4.

The time to onset of autoimmune nephritis was 11.6 months after the first dose of pembrolizumab(5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy.

Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.

Mae et al. from Yale presented a poster in ASN Kidney Week 2015 that highlighted 2 cases of biopsy proven AIN from this agent (Abstract: [TH-PO1051).

It’s not just the kidney- apparently this immune mediated reaction that is initiated might be leading to hepatitis, uveitis, pancreatitis, myocarditis and other concerns. 

Literature search thus far has not revealed any published cases of AIN from this agent. Given this immune mediated reaction- the kidney can be a potential target. I won’t be surprised if both vasculitis and allergic nephritis can be noted on kidney biopsies with these agents. 

Washington Univ You Tube based Nephropathology CPC series : Case 1

The Nephrology 2016 Match: Where do we go from here and a call for help!!!

The 2016 match for nephrology was just released. This is the first year following the ALL-in policy for the nephrology match. Clearly, this is a great way to benefit the candidate and the candidate get’s to see all programs and ranks based on their choice. 

ASN just released the key points that the match data revealed.

You can find the PDF of the information on this link. 

1.     There was a increase in programs (18%) and positions certified in the match.  Well this is because it was an ALL IN process so most programs participated. No big deal.

2.     The number of matched fellows increased—great! That is good news but this doesn’t imply increased interests.

3.     The number of applicants rose 11%- Perhaps reflection that we had ALL –in process and last few years-we never saw those candidates data. Since both the numerator and the denominator increased- we are counting candidates that we hadn't accounted for years ago. Not really an improvement!!

4.     Slight uptick in USA grads applying and major down trend in IMGs applying- big loss as they were the main stay for nephrology workforce last few years.

5.     Unfilled positions rose to a new high 58%-- biggest bummer of this process

Good news:

More US grads. More overall applicants( skeptic on that one as data is now due to ALL-in)

Bad news:

Still many more unmatched spots and programs. There are programs in the country unmatched 100%.

Do we have solutions?

While increasing interest in med school and residency is important and critical- clearly it is NOT working at a national level.  At the end of the day, re-imbursement of nephrologists calls the shots. We need to really push hard on the government level for more reimbursement for renal physicians.  A shortage will happen eventually, there will be a major medical need crisis and then hopefully there will be an uptrend in the salaries of nephrologists—even that is a dream in never never land.

What are programs going to do? Many programs fear- "they might be next."  Downsizing fellowship spots is an option and perhaps hiring physician assistants to help out with day to day duties.  Researchers will be asked to more clinical time, clinical educators will have to more clinical time and teach less--- all trickling down to less innovation and research in nephrology and less time with trainees.

Applicants to research positions are down-trending. This means that pure clinical fellowships that are big university centers( 2 year)- will fill.  The ones that won’t will be large research positions and or small community programs( perhaps).  Perhaps programs need to cater towards what the applicants want out of a renal fellowship-- times have changed( Nephrology was not what it was 20 years ago).

Time will change this. As any ups and downs in an economy- there will be eventually a shortage of nephrologists as this trend continues and eventually, there will be an upswing.

Clearly, I am being schizophrenic in this post but I am happy and sad with these results.

Clearly, the national strategy we have might not be working.  We need to all put our heads together( both academic and private nephrologists) to really come up with OUT of box ideas to change this trend.  

It’s a call for HELP and we need it soon!

Quizlet: Parasitic Infections and the Kidney

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC88933/pdf/cm000055.pdf

B cell malignancies and the Kidney

B cell malignancies and the Kidney from kdj200

Topic Discussion: What causes glomerulomegaly?

What causes glomerulomegaly?

Congenital cyanotic heart disease
Cor pulmonale
Obesity and Sleep apnea
Sickle cell disease
Polycythemia vera
Alcoholism
Hepatic steatosis
Cystic fibrosis

What is the most common physiological abnormality in all of the above

Hypoxemia! Perhaps a combination of metabolic demands of some of these illnesses, hypertrophy of the erythropoietin producing cells, passive congestion causes in the systemic circulation and increased viscosity all might be leading to glomerular damage and proteinuria as a result.

What does glomerulomegaly mean on pathology?

There is going to be focal and diffuse hypercellularity, segmental or global sclerosis, mesangial thickening
Vessels:- capillary congestion, hyalinization of afferent and efferent arterioles
Tubular atrophy
Interstitial Fibrosis

Reference: http://www.ncbi.nlm.nih.gov/pubmed/9402101

IN the NEWS: ESRD re-admissions: where do we stand and what can we do?

ESRD re-admissions are a major concern. A recent KI paper discusses what the nephrology literature has found regarding this very important issue. Unfortunately, no studies have tested interventions in how to avoid re-admissions for our dialysis patients.  The authors propose certain areas for research.

An interesting concept that is discussed in table 3 of the paper is the potential places where the factors might be of the risk and how we can target our research in those 5 areas.

1.       The patient related risk factors ( socio-demographics, social support .etc)

2.       Index hospitalization( the first hospitalization and how to void re-admissions related to that admission, med reconciliation, structured communication from inpatient to outpatient units)

3.       Nephrologist ( timing of first visit post discharge, extra weekly visit for the hospitalized patient, effect of targeted structured eval only addressing certain key variables such as dry weight, access, medications changes)

4.       Dialysis unit- coordination with inpatient dialysis unit and ER of the hospital

5.       Payment structure- effect of resource redistribution in different payer models

Check out the paper here.