Warp Speed Drugs for Kidney diseases 2021

 In ASN Kidney News 2021, Feb issue, I created this figure that gives a sense of the amazing rapid development for kidney disease therapeutics. The figure appears in the Feb issue of kidney news. Created using biorender.com 

Topic Discussion: ACEI/ARB ( hold em or keep them going)

 The COVID19 pandemic has ignited an ongoing saga of holding ACEi/ARB when someone is hospitalized. Normally a consult note in nephrology would include holding of these agents before a cardiac cath, CABG, or major procedure ( with little data on doing it).

A recent study in JASN done using a novel methodology showed no real benefit in stopping these agents in late stage CKD patients in the Swedish Renal Registry for the last 10 years.  Advanced CKD ( GFR<30) on these agents were evaluated. A target trial emulsion technique was used on risk of stopping these agents for 6 months and their outcomes on 5 year mortality, and MACE and KRT. So while KRT risk increased, the MACE and mortality decreased. MACE was mainly driven by mortality. In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.

Meanwhile, in the COVID19 world,  REPLACE COVID published in Lancet was published. This trial began on March 31, 2020, within a few months of COVID-19 hitting North America and in the thick of the first wave. All COVID19 patients hospitalized , already on chronic ACEi or ARB  were randomized to either continue or stop their ACEi or ARB. In terms of the results, there was absolutely no difference in any of the outcomes, all cause death and length of stay. There was also no difference in the exploratory outcomes of ICU admission, ventilation, or hypotension requiring hemodynamics support. These findings are also bolstered by the similar findings from the BRACE CORONA trial published in JAMA in a slightly less sick cohort of 659 patients showing similar results. The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression.  The study found that in patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These two trial (RCTs done in pandemic)  findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with COVID19.  Check out this nice editorial on this in ASN kidney news 2021

There is an ongoing trial called STOP-ACEi. Do we really need that trial? Given we were able to do an RCT in a middle of a pandemic with sick patients with COVID19 and that showed no real difference in terms of outcomes of holding ACEi or ARBs, my guess is that STOP-ACEi will show the same. Unless there is hyperkalemia, or hypotension, no real strong indication to hold or stop these life saving cardiac medications.

Culture change will take time:  It is hard to convince nephrologists to start ACEi/ARB in late stage CKD, let alone convincing hospitalists or internists. It is hard to NOT to hold ACEi/ARB when creatinine is rising during an acute cardio-renal syndrome- convincing will take time. Hope these trials will help us continue these life saving agents in hospitalized patients( and ok to even stop them) but sometimes- nobody restarts them on discharge... 

Discussion via pics: Bile Cast Nephropathy

 

Image made via biorender.com
Images in that obtained from:

https://www.kidney-international.org/article/S0085-2538(15)55928-0/fulltext
https://rrtjournal.biomedcentral.com/articles/10.1186/s41100-020-00265-https://laboratoryinfo.com/types-of-crystals-in-urine/

Topic Discussion: Acute Peritoneal Dialysis during COVID-19

 As the NYC area had seen surge of cases in all health systems in March, April, May 2020, need for creative solutions to do dialysis was essential. NYU and Weill Cornell in NYC were two centers that really pioneered this method during the COVID-19 pandemic. 

This manuscript published in Kidney360 highlights 39 acute catheter placements and use of PD in the acute setting. Almost 40% even had recovery of AKI. 

Here is the Cornell data of 11 patients published in KI reports, 6 patients recovered.

Two concerns that most would have is:

1. Entering the rooms to do cycler and exchanges.
2. Can PD be done in prone ventilation as proning helped COVID19 patients recover?

See this picture from the NYU series

The figure shows placement of the cycler outside the ICU room and using longer connectors. Drain bags were used to obliviate use of drain line. The room was also HEFA filtered for airborne isolation.

Another series of patients in NYU was published in PD International on how they were able to do successful PD in vented patients with proning. Although the mortality was 100%, the venting was not effected and relative clearance was good. 

Perhaps, the silver lining of COVID19 related AKI-- return of Acute PD...

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.