Topic Discussion: Primary aldosteronism: You can’t find it if you don’t look for it

Here is a guest post straight from the author of a recent study in Annals of Internal Medicine. 

Visual abstract from Annals of IM website.

As a group of clinical hypertension specialists and researchers, my co-authors and I performed this study out of concern of under-recognition of primary aldosteronism as a common cause of secondary hypertension. Treatment-resistant hypertension occurs in about 20% of adults with hypertension and primary aldosteronism is a common cause of treatment-resistant hypertension. Identification and appropriate management of primary aldosteronism can reduce the risk of development and progression of heart disease and chronic kidney disease. Although guidelines recommend testing for primary aldosteronism in all patients with treatment-resistant hypertension, prior evidence in small, local health systems suggested extremely low rates of screening with plasma renin and aldosterone levels.

In a nationally representative cohort of over 250,000 Veterans with treatment resistant hypertension we found that rates of guideline-based testing for primary aldosteronism from 2000 to 2017 occurred in less than 2% of patients in whom it’s recommended. We identified several patient-, provider-, and center-level factors associated with better screening practices (such as being seen by an endocrinologist or nephrologist, or being cared for at a non-rural medical center). We were surprised to observe that patient adherence, which was identified by medication fills from the pharmacy, was not associated with screening practices. We found that patients who were screened were 4-times more likely to be managed with evidence-based antihypertensive therapy with mineralocorticoid antagonists (regardless of the screening results) compared with patients who were not screened. We also found that patients who were screened had much better blood pressure control over time, also regardless of the results of the screening.

Overall, we observed widespread and concerning missed opportunities for primary aldosteronism screening and for appropriate treatment of patients with treatment-resistant hypertension. The fact that screening practices are strongly associated with evidence-based treatment of apparent treatment-resistant hypertension and blood pressure control over time suggests that good provider behaviors beget other good behaviors, that there are major gaps in provider knowledge of the importance of screening these patients, and that there are likely barriers to implementing appropriate management for these patients. 

These findings suggest a need to improve education of providers and to leverage innovative tools to increase screening and appropriate management of patients with treatment resistant hypertension.

Tweetorial: https://twitter.com/jordy_bc/status/1343678945393315840?s=20

 

Post by:  Jordana Cohen, MD, MSCE

Assistant Professor of Medicine and Epidemiology

Perelman School of Medicine, University of Pennsylvania

In the News: Immune checkpoint inhibitors in the renal transplant patient

 

Use of immunotherapy in the renal transplant patient is challenging. Initial case reports had shown over and over acute rejections. In 2017, we had tried a novel way to prevent rejection in a single case report published in NEJM( using mini steroid pulse and mTOR over CNI use). Since then, we have used this approach successfully in several patients to allow for good tumor response and prevent rejection. But one case, two cases, three cases cannot tell the whole story.  More data is needed. A recent meta-analysis done on use of immunotherapy and transplant patients showed of 44 patients,  18 were reported to have acute rejection. Median time from immune checkpoint inhibitors to acute rejection diagnosis was 24 (interquartile range, 10–60) days. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Fifteen (83%) had allograft failure and 8 (44%) died. Three patients had a partial remission (17%), 1 patient achieved cancer response (6%), and 5 patients had stable disease (28%).

Other studies similar to this have showed similar rejection rates of 40%. No studies have tested the clinical efficacy of the use of these agents in renal transplant patients.

In a recent study published in Kidney International, we collected 69 cases from 23 institutions from US, Canada and Europe. This is the largest study to look at both transplant outcomes and efficacy of these agents in renal transplants patients.

Acute rejection rate 42% (29 out of 69), median ICI to rejection=24 days. Rejection is severe: cellular rejection and mixed cellular and antibody-mediated rejection are both common. Once rejection happened, 65% lost allograft.

What are the risk factors of rejection? Being on 3-agents immunosuppression and mTOR inhibitor use were associated with LOWER risk of rejection. This is an interesting finding. This is to tell us the obvious- the less the immunosuppression- the risk for rejection increases but the mTOR finding is interesting( caution- still low Ns). Take a look at this paper as well.
We looked at rejection rate and cancer objective response rate in skin squamous cell carcinoma (cSCC) and melanoma, two most common cancer types in our cohort. In cSCC, rejection rate 37.5%, ORR 36.4% and ICI may be associated with longer overall survival. In melanoma: rejection rate 54.5% (# of immunosuppression agent-dependent), ORR 40%. OS did not differ but limited by small # of patients and short follow-up.

An important figure that is hidden in the supplemental content is below: This tell us the majority of the changes done by centers when immunotherapy was initiated, see the % who increased steroids, converted CNI to mTOR inhibitors, dc CNI , dc MMF. etc.  Interesting changes which were made are not at all standardized. 

Although our study is to our knowledge the largest multicenter cohort of patients with advanced solid malignancies with kidney transplant who received ICI to date, there are several limitations Firstly it is retrospective and small-sample nature of our cohort limited our ability to adjust for a number of confounders in multivariable analysis for the risk of graft rejection. Also less than half of acute rejection were biopsy proven, which limits the accuracy of the diagnosis of rejection. The comparison of outcomes using these historical cohorts suffers from the lack of power due to the small number of cases, but provides a pragmatic approach to address the risk of rejection and objective response rate. Lastly, immunosuppression modification was the providers’ choice at each institution and not standardized.

So what now? This tells us that immunotherapy is a feasible option for kidney transplant pts but with very high risk of rejection.

mTOR inhibitor plus steroid mini-pulse may be effective in preventing rejection?
Or should we continue the immunosuppressive meds “as is” or at least 2 of them and then give the immunotherapy as efficacy was amazing in cSCC and prevent the rejection as well.
What this study also told us is that- stopping the immunosuppression when planning to give immunotherapy doesn’t really help in cancer outcomes or renal transplant outcomes? So should we be even stopping them??

A collaborative effort led by Naoka Murakami from around the world. 

Concept Map: Kidney involvement in chronic myelomonocytic leukemia and myeloproliferative neoplasms

 

This concept map is based on an article in KI reports in 2020.

Topic Discussion: Remdesivir in CKD and ESRD patients- what is the data thus far

Acute kidney injury (AKI) occurs at a rate of 30-40% in hospitalized patients with COVID-19.
Chronic kidney disease (CKD) and ESKD are also common comorbidities in patients who develop severe COVID-19. Data on use of these agents in CKD and ESRD is limited. 

The active metabolite of remdesivir is eliminated by the kidneys and can accumulate in patients with reduced estimated glomerular filtration rate (eGFR); moreover, the sulfobutylether-β-cyclodextrin (SBECD)carrier is known to accumulate in these patients. 

The largest clinical trials evaluating the use of this agent in COVID-19 excluded patients with stage 4 CKD or those requiring dialysis.

A multicenter study from Northwell health, BWH, MGH and U of Miami( of 18 patients) and a large study from India (46 patients) recently looked at use of remdesivir in CKD, AKI and ESKD patients. All patients studied had eGFR<30cc/min. 

In the USA study, treatment was well-tolerated, with few other AEs attributed to remdesivir. Five patients discontinued remdesivir early, only 2 of them due to AEs attributed to remdesivir (burning at IV site during the final dose and worsening kidney function); the remainder stopped due to improved clinical status (N=2) or patient preference (N=1). Overall 28-day mortality was 44% (8/18). Among patients requiring intensive care at the time of remdesivir initiation, 8 of 11 died. All 7 patients who were not requiring intensive care at baseline survived to 28 days.

In the India study, most patients tolerated the infusion well. Liver function remained stable in 28 (60.9%) cases. No patient had a severe rise in AST/ALT >5 times the upper limit of normal, therefore therapy was not required to be discontinued for this reason in any of the patients. No kidney function abnormalities attributable to drug were observed. Fourteen (30.4%) patients died, 24 (52.2%) patients were discharged from the hospital after recovery.

 

Publication	USA( Estiverne et al)	India ( Thakare et al)
Total # of AKI on dialysis	3	19
Total # of AKI non on dialysis	5	11( 5 transplant patients)
Total # of CKD patients	8	15
Total # of ESKD patients	2	16
LFT abnormalities attributed to agent	3	3
Remdesivir induced AKI	1	0
Got 5 days course	16	46
Got 10 days course	2	0

Concept Map: Pre eclampsia (PEC)

 

Here is a figure based concept map of pre-eclampsia using biorender.com 

Vaccines and the Renal patient- COVID19

As vaccines are arriving at a rapid rate (historic) for SARs-COv2, most of the United States is still dealing with a larger more deadlier wave of infections. Hospitals at most of the US are again at a standstill with what we had seen in March, April in NY. 

mRNA vaccine.. we are not used to that technology in the medical world. While reading more on this topic, I found this simplified version by Dr Daniel Goldstein, CT surgeon at Montefiore and a well known voice of COVID care on Linkedin. I have made some changes and additions to his thoughts. 

mRNA Vaccines: A primer
The process, simplified:

1. Use DNA, enzymes to create the mRNA sequence that codes for part of SARSCoV2 spike protein
2. Attach 5’cap, poly-A tail and UTRs for stability and better translation
3. Purify and get rid of reagents, enzymes other additives
4. Encapsulate in lipid nanoparticle (phospholipids, PEG, cholesterol) to protect and facilitate delivery into cells.
5. Store in cold (or extremely cold) until use
6. Inject intramuscularly (2 shots, 3-4 wks apart)
7. Encapsulated mRNA taken up by muscles cells.
8. mRNA released into cytoplasm where protein building machinery (ribosomes) will bind to it sequentially and produce many spike proteins. Average 20 sec - couple of mins to make one protein
9. mRNA has half-life about 10 hrs. Sufficient to make lots of protein. Eventually broken down by RNAses.
10. Protein is bound to cell surface where it is recognized as foreign by immune system
11. Ab production, and Ag specific memory B cells and T follicular helper cells are produced
12. More robust response of the above with 2nd injection as body has been “primed”

Advantages of mRNA vaccine:
1. Non-infectious
2. Doesn’t insert into DNA (nucleus).
3. Half life, immunogenicity and delivery can be regulated
4. Quick to make

Disadvantages to me: Seem none, except it's a new technology. 

Well we are in a pandemic with a new deadly virus- I would roll those shirts and get the vaccine. What is the data on our renal patients.- Essentially none. 

ESKD patients:

To my knowledge, ESKD patients were not in the large vaccine trials but these are vulnerable populations. The UK released a statement of the patients who are most vulnerable in nephrology. 

Renal Transplant patients:

Although initial clinical trials of COVID-19 vaccines did not include immunosuppressed patients, we would expect the vaccines to offer protection against COVID-19 infection in these extremely vulnerable patients. An effective COVID-19 vaccine should reduce staff and patient infection resulting in lower rates of serious illness and death. What is interesting as few studies done during the pandemic showed that the renal transplant patients do have a good immune response to the virus( not a lowered one).  Studies from Germany and the US showed decent antibody converting. This suggests that vaccines would work in the organ transplant patients and provide amazing protection.

CKD and patients with autoimmune glomerular diseases: No data exists but vaccines would be helpful here as well.

Nephrology community awaits the arrival of the vaccines...