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...

2020: What a year for Nephrology

As we enter the end of 2020( finally), we are starting to see some hope for the vaccines as a lifeline as we enter the rising COVID-19 surge.  For nephrology, 2020 has been a positive and negative year. 

Let's start with the negatives:
1. Covid19 led to development of more AKI than we had imagined and several of those patients dying as a result. Very few survived the RRT-related AKI
2. Our dialysis patients had a tough battle leading to an increased mortality
3. Many transplant centers were on hold and several on the wait list had a high mortality and so did some of our transplant patients.
4. All conferences and meetings were virtual( taking away the networking opportunity for many)
5. All fellowship interviews went virtual( hard to assess candidates candidly)
6. Research ( non covid19) came to a halt and or was interrupted 

But there is a silver lining to the COVID19 pandemic for nephrology:

1. Increased data and outcomes research on AKI as a result of the pandemic
2. Rise of HOME dialysis ( which was dormant for years) came more to the forefront( including acute PD)
3. Rise of the Nephrologists as front line COVID19 warriors leading to perhaps more applications this year
4. SGLT2i studies infiltrating NEJM multiple times making a mark on diabetic and non diabetic kidney disease
5. Novel therapeutics in autoimmune renal diseases are on a rise
6. Virtual conferences allowed for more quicker and swifter transfer of knowledge ( and more attendance)
7. Collaboration on research rose super fast with trials such as STOP-COVID
8. Gender and Ethnic diversity was evident in Kidney week this year and kept it's strength in 2020
9. More incentives and compensations increases for nephrologists will reign in 2021
10. Increase interest in subspecialization in Nephrology 

Nephrology Workforce ( entire ACKD issue)

An entire issue devoted to Workforce in Nephrology just published in ACKD. Matt Sparks and Samira Faroukh really takes us via an amazing ride of articles. Here is a list of the topics and articles and a collection of visual abstracts. I really admire this issue and salute the editors on doing this task. As we are at the crossroads of nephrology renaissance- this issue is very timely. Hope we can inspire more residents and students to enter the ever growing nephrology workforce. 

Reenvisioning the Adult Nephrology Workforce: The Future of Kidney Care in the United States

Current State of the Workforce in Nephrology

Current Paradigms and Emerging Opportunities in Nephrology Training

International Medical Graduates in Nephrology: A Guide for Trainees and Programs

Current State and Future of Research in Nephrology

The Nephrology Clinician Educator: Pathway and Future

Opportunities for Subspecialization in Nephrology

Critical Care Nephrology Workforce

Transplant Nephrology Workforce

Interventional Nephrology Workforce

Palliative Care/Geriatrics Nephrology Workforce

Private Practice Nephrology Workforce

Let's STOP-COVID

In March 2020, as deaths from COVID-19 surged across the world, we orchestrated the largest nationwide study of critically ill patients with COVID-19 assembled to date in the United States. This grassroots, unfunded project was made possible with the help of over 400 collaborators across the US, including research coordinators, medical students, residents, fellows, and attendings across a variety of specialties. Together, we gathered detailed, patient-level data from over 5,000 patients with COVID-19 admitted to ICUs at 68 sites. This was the start of STOP-COVID (Study of the Treatment and Outcomes in Critically Ill Patients With COVID-19).

All data were painstakingly extracted by manual chart review and entered into a centralized online database. Here is a snapshot of a few of our recent studies.

 *In the first manuscript, we examined risk factors for 28-day mortality among 2215 critically ill patients. We found that 784 (35.4%) patients died within 28 days, with wide interhospital variation in both treatments (e.g., proning) and outcomes (e.g., death). Factors associated with death included older age, male sex, morbid obesity, coronary artery disease, cancer, acute organ dysfunction, and, notably, admission to a hospital with fewer ICU beds. Admission to a hospital with <50 versus ≥100 ICU beds associated with a >3-fold increased risk of death in multivariable analyses. Results are published in JAMA Internal Medicine

 

*We utilized a ‘target trial emulation’ approach to test whether early use of tocilizumab decreases mortality in critically ill patients with COVID-19. Of 3924 patients included in our analysis, 433 (11%) were treated with tocilizumab in the first 2 days of ICU admission, and these patients had a 30% lower risk of death compared with those not treated with tocilizumab. The beneficial effect of tocilizumab on survival was consistent across categories of age, sex, and illness severity. Notably, we found that patients with a more rapid disease trajectory, defined as three days or fewer from symptom onset to ICU admission, appeared to benefit from tocilizumab to a greater extent than patients with a slower disease trajectory(60% lower risk of death). Results are published in JAMA Internal Medicine with an accompanying editorial.

 

*We studied risk factors for acute kidney injury treated with renal replacement therapy (AKI-RRT) in 3099 patients. We identified several patient-level risk factors for AKI-RRT, including chronic kidney disease, male sex, non-White race, and higher D-dimer. Among patients who survived to hospital discharge, one in three remained RRT-dependent at discharge, and one in six remained RRT dependent 60 days after ICU admission. Results are published in JASN 

*We investigated the incidence, risk factors, and outcomes associated with in-hospital cardiac arrest and CPR in 5019 patients. We found that 14% of patients had in-hospital cardiac arrest, of whom 57% received CPR. Patients who had in-hospital cardiac arrest were older, had more comorbidities, and were more likely to be admitted to a hospital with a smaller number of ICU beds compared with those who did not have in-hospital cardiac arrest. Cardiac arrest was associated with poor survival, with only 12% surviving to hospital discharge, and even fewer (only 7%) surviving to hospital discharge with no more than mildly impaired neurologic function. Results are published in BMJ 

*We examined the clinical course of critically ill patients with COVID-19 with and without pre-existing kidney disease. Dialysis patients had a shorter time from symptom onset to ICU admission compared with other groups, and were more likely to present with altered mental status on admission. Half the patients with CKD died within 28 days of ICU admission versus 35% of patients without CKD, with dialysis patients having the highest risk of death. Results are published in AJKD.

 

*In a propensity score matched analysis, we examined the association between solid organ transplant (SOT) status with death and other clinical outcomes. Receipt of mechanical ventilation, development of acute respiratory distress syndrome, and receipt of vasopressors were similar between SOT recipients and non-recipients, as was the risk of 28-day mortality. Results are published in AJT.

Data collected by the STOP-COVID collaborators has provided valuable insight into the risk factors, outcomes, and treatment strategies for critically ill patients with COVID-19. This is just the beginning… more to come as we analyze more data.

Shruti Gupta, MD, MPH
David E Leaf, MD, MMsc

---------------------------------------------------------

( Full list of collaborators obtained from JAMA Internal Medicine website) 

The Study of the Treatment and Outcomes in Critically Ill Patients With COVID-19 (STOP-COVID) investigators include the following: Carl P. Walther (site principal investigator [PI]) and Samaya J. Anumudu (Baylor College of Medicine); Justin Arunthamakun (site PI), Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, and Thuy-Duyen Nguyen, (Baylor University Medical Center); Shahzad Shaefi (site PI), Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, and Juan D. Valencia (Beth Israel Deaconess Medical Center); Sushrut S. Waikar (site PI) and Zoe A. Kibbelaar (Boston Medical Center); Ambarish M. Athavale (site PI), Peter Hart, Shristi Upadhyay, and Ishaan Vohra (Cook County Health); Adam Green (site PI), Jean-Sebastien Rachoin, Christa A. Schorr, and Lisa Shea (Cooper University Health Care); Daniel L. Edmonston (site PI) and Christopher L. Mosher (Duke University Medical Center); Alexandre M. Shehata (site PI), Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Mehta, and Aquino Williams (Hackensack Meridian Health Mountainside Medical Center); Samantha K. Brenner (site PI), Patricia Walters, Ronaldo C. Go, and Keith M. Rose (Hackensack Meridian Health Hackensack University Medical Center); Miguel A. Hernán (Harvard T.H. Chan School of Public Health); Rebecca Lisk, Amy M. Zhou, and Ethan C. Kim (Harvard University); Lili Chan (site PI), Kusum S. Mathews (site PI), Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily A. Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Pattharawin Pattharanitima, and Emily J. Gallagher (Icahn School of Medicine at Mount Sinai); Allon N. Friedman (site PI), John Guirguis, Rajat Kapoor, Christopher Meshberger, and Katherine J. Kelly (Indiana University School of Medicine/Indiana University Health); Chirag R. Parikh (site PI), Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, and Samir C. Gautam (Johns Hopkins Hospital); Mary C. Mallappallil (site PI), Jie Ouyang, Sabu John, Ernie Yap, Yohannes Melaku, Ibrahim Mohamed, Siddhartha Bajracharya, Isha Puri, Mariah Thaxton, Jyotsna Bhattacharya, John Wagner, and Leon Boudourakis (Kings County Hospital Center); H. Bryant Nguyen (site PI) and Afshin Ahoubim (Loma Linda University); Kianoush Kashani (site PI) and Shahrzad Tehranian (Mayo Clinic, Rochester); Leslie F. Thomas (site PI) and Dheeraj Reddy Sirganagari (Mayo Clinic, Arizona); Pramod K. Guru (site PI) (Mayo Clinic, Florida); Yan Zhou (site PI), Paul A. Bergl, Jesus Rodriguez, Jatan A. Shah, and Mrigank S. Gupta (Medical College of Wisconsin); Princy N. Kumar (site PI), Deepa G. Lazarous, and Seble G. Kassaye (MedStar Georgetown University Hospital); Michal L. Melamed (site PI), Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Neelja Kumar, Michael Chang, and Jyotsana Thakkar (Montefiore Medical Center/Albert Einstein College of Medicine); Ritesh Raichoudhury (site PI), Akshay Athreya, and Mohamed Farag (New York-Presbyterian Queens Hospital); Edward J. Schenck (site PI), Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, and William Whalen (New York-Presbyterian/Weill Cornell Medical Center); David M. Charytan (site PI), Ashley Macina, Sobaata Chaudhry, Benjamin Wu, and Frank Modersitzki (New York University Langone Hospital); Anand Srivastava (site PI), Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, and Alexander J. Hodakowski (Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine); Juan Carlos Q. Velez (site PI), Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, and Muner M. B. Mohamed (Ochsner Medical Center); Rupali S. Avasare (site PI) and David Zonies (site PI) (Oregon Health and Science University Hospital); David E. Leaf (site PI), Shruti Gupta (site PI), Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, and Ariel L. Mueller (Partners Healthcare, Brigham and Women’s Hospital, Brigham and Women’s Faulkner Hospital, Massachusetts General Hospital, and Newton Wellesley Hospital); Roberta E. Redfern (site PI), Nicholas S. Cairl, Gabriel Naimy, Abeer Abu-Saif, Danyell Hall, and Laura Bickley (ProMedica Health System); Chris Rowan (site PI) and Farah Madhani-Lovely (site PI) (Renown Health); Vasil Peev (site PI), Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, and Joy-Marie Hermes (Rush University Medical Center); Anne K. Sutherland (site PI), Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Peter Cangialosi, and Mark Liotta (Rutgers/New Jersey Medical School); Jared Radbel (site PI), Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, and Jayanth S. Vatson (Rutgers/Robert Wood Johnson Medical School); Shuchi Anand (site PI), Joseph E. Levitt, and Pablo Garcia (Stanford Healthcare, Stanford University School of Medicine); Suzanne M. Boyle (site PI), Rui Song, and Ali Arif (Temple University Hospital); Jingjing Zhang (site PI), Sang Hoon Woo, Xiaoying Deng, Goni Katz-Greenberg, and Katharine Senter (Thomas Jefferson Health); Moh’d A. Sharshir (site PI) and Vadym V. Rusnak (Tulane Medical Center); Muhammad Imran Ali, Terri Peters, and Kathy Hughes (United Health Services Hospitals); Anip Bansal (site PI), Amber S. Podoll, Michel Chonchol, Sunita Sharma, and Ellen L. Burnham (University of Colorado Anschutz Medical Campus); Arash Rashidi (site PI) and Rana Hejal (University Hospitals Cleveland Medical Center); Eric Judd (site PI), Laura Latta, and Ashita Tolwani (University of Alabama-Birmingham Hospital); Timothy E. Albertson (site PI) and Jason Y. Adams (University of California, Davis, Medical Center); Steven Y. Chang (site PI) and Rebecca M. Beutler (Ronald Reagan-UCLA [University of California, Los Angeles] Medical Center); Carl E. Schulze (Santa Monica-UCLA Medical Center); Etienne Macedo (site PI) and Harin Rhee (University of California, San Diego, Medical Center); Kathleen D. Liu (site PI) and Vasantha K. Jotwani (University of California, San Francisco, Medical Center); Jay L. Koyner (site PI) (University of Chicago Medical Center); Chintan V. Shah (site PI) (University of Florida Health–Gainesville); Vishal Jaikaransingh (site PI) (University of Florida Health–Jacksonville); Stephanie M. Toth-Manikowski (site PI), Min J. Joo (site PI), and James P. Lash (University of Illinois Hospital and Health Sciences System); Javier A. Neyra (site PI) and Nourhan Chaaban (University of Kentucky Medical Center); Rajany Dy (site PI), Alfredo Iardino, Elizabeth H. Au, and Jill H. Sharma (University Medical Center of Southern Nevada); Marie Anne Sosa (site PI), Sabrina Taldone, Gabriel Contreras, David De La Zerda, Alessia Fornoni, and Hayley B. Gershengorn (University of Miami Health System); Salim S. Hayek (site PI), Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’Hayer, Chelsea Meloche, Rafey Feroze, Kishan J. Padalia, Abbas Bitar, Jeff Leya, John P. Donnelly, and Andrew J. Admon (University of Michigan); Jennifer E. Flythe (site PI), Matthew J. Tugman, and Emily H. Chang (University of North Carolina School of Medicine); Brent R. Brown (site PI) (University of Oklahoma Health Sciences Center); Amanda K. Leonberg-Yoo (site PI), Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, and Charles R. Vasquez (University of Pennsylvania Health System); Amar D. Bansal (site PI), Natalie C. Ernecoff, Sanjana Kapoor, Siddharth Verma, and Huiwen Chen (University of Pittsburgh Medical Center); Csaba P. Kovesdy (site PI), Miklos Z. Molnar (site PI), and Ambreen Azhar (University of Tennessee Health Science Center and Memphis Veterans Affairs Medical Center/Methodist University Hospital); S. Susan Hedayati (site PI), Mridula V. Nadamuni, Shani Shastri, and Duwayne L. Willett (The University of Texas Southwestern Medical Center and Parkland Health and Hospital System); Samuel A. P. Short (University of Vermont Larner College of Medicine); Amanda D. Renaghan (site PI) and Kyle B. Enfield (University of Virginia Health System); Pavan K. Bhatraju (site PI) and A. Bilal Malik (University of Washington Medical Center); Matthew W. Semler (Vanderbilt University Medical Center); Anitha Vijayan (site PI), Christina Mariyam Joy, Tingting Li, Seth Goldberg, and Patricia F. Kao (Washington University in St. Louis/Barnes Jewish Hospital); Greg L. Schumaker (site PI) (Wellforce Health System, Lowell General Hospital); Nitender Goyal (site PI), Anthony J. Faugno, Greg L. Schumaker, Caroline M. Hsu, Asma Tariq, Leah Meyer, Ravi K. Kshirsagar, Aju Jose, and Daniel E. Weiner (Wellforce Health System, Tufts Medical Center); Marta Christov (site PI), Jennifer Griffiths, Sanjeev Gupta, and Aromma Kapoor (Westchester Medical Center); and Perry Wilson (site PI), Tanima Arora, and Ugochukwu Ugwuowo (Yale School of Medicine).

Concept Map: Glomerular Diseases with Immunotherapy

 A recent systematic review discussed GNs cases seen with immune checkpoint inhibitors. This concept map( part of the paper) is displayed here.

https://www.kireports.org/article/S2468-0249(20)31640-5/fulltext

The above review was done before the listed two articles were published 

5 additional cases of renal vasculitis( pre dominantly ANCA negative)
Another case of membranous nephropathy(this time PLA2R positive)

Even after addition of the above cases, vasculitis would still be the most common and podocytopathies following that. C3 GN would be the third most common. 

Detective Nephron: Next Venture

 

Check out the next venture of Detective Nephron in the Oct 2020 issue of Kidney News. 

https://www.kidneynews.org/kidney-news/fellows-corner/detective-nephron/detective-nephron-october-november-2020

Topic Discussion: Outcomes of AKI in COVID-19

 As COVID19 surged the NY area, March-May 2020 is when the AKI surge happened at most northeast hospitals. Initial reports from us and others showed that the incidence of AKI was high- close to 40%. 

At that time, almost 39% of patients were still admitted. Now there are 99% discharged allowing for complete outcome analysis. Here is our data on the outcomes of AKI in AJKD when all have been discharged. 

The aim of this study was to investigate in-hospital death and kidney outcomes among hospitalized patients with COVID-19 and AKI.  We reviewed health records of 9657 patients hospitalized with #COVID-19 between March1- April 27^th, 2020, and followed up to the day of discharge/death. The data was from 13 hospitals. To investigate the impact of AKI on in-hospital death, we performed cox regression using AKI as a time-varying exposure and in-hospital death as the outcome.

In the cohort 40% of patients developed AKI (incidence rate of 38.3 per 1000 patient-days). Those who developed AKI had higher proportion with DM, heart disease, chronic kidney disease and had a more severe illness. The death rate was much higher in the AKI requiring dialysis( 6.4 times more) compared to AKI not requiring dialysis (3.4 times more) compared to no AKI. 

What matters to us is what happens to patients who survived? - how many had CKD, how many were sent on dialysis?  The big finding-- Among patients with AKI non-dialysis requiring who had survived, 74% had kidney recovery at the time of discharge. For patients with AKI-on dialysis and survived, 67% had kidney recovery at discharge. For the remainder who did not have kidney recovery, 91.7% remained on dialysis at the time of discharge.  Among those with AKI-on dialysis who survived, the presence of chronic kidney disease was the only independent risk factor associated with need for dialysis at discharge. 60 and 90 day outcomes are lacking and will be eventually useful. 

Regardless of need for dialysis or kidney recovery at discharge, hospitalized COVID-19 patients who experienced any form of AKI should be followed closely post-discharge to assess ongoing kidney function.  Our 13 hospital sites were all in metropolitan NY during the early part of the pandemic; is the major limitation.  

So in patients hospitalized with #COVID-19, those with AKI was associated with higher risk of death, particularly among those who needed dialysis. Most surviving patients with AKI had kidney recovery upon discharge.

Another recent study from a NY metro area showed similar findings in JASN.  Of 3993 hospitalized patients with COVID-19, AKI occurred in 1835 (46%) patients; 347 (19%) of the patients with AKI required dialysis. Of survivors with AKI who were discharged, 35% had not recovered to baseline kidney function by the time of discharge. An additional 36% patients who had not recovered kidney function at discharge did so on posthospital follow-up.

Finally, a research letter in CJASN showed some outcomes data from yet another NY center. Patients with AKI had higher mortality than patients without AKI (40% versus 8%).  Among the patients with AKI, 48% recovered to their baseline kidney function. Among the 52% who did not recover to their baseline kidney function, 43 received dialysis, among which 34 were dialysis dependent and 26 died (60%), and 111 did not receive dialysis, among which 80 (72%) died.  

Consult Rounds: Hyponatremia from Anti depressants

 As nephrologists we often get called on SIADH from medications. Anti depressants a class of agents that we do consider to cause hyponatremia. Which ones are more likely vs others has always been interesting to know? A study from Denmark has a detailed look into this matter. 

The odds of developing hyponatremia in one large study was the highest in clomipramine, followed by nortriptyline, citalopram, paroxetine, duloxetine, venlafaxine, sertraline and amitriptyline. It had the least odds of association with mirtazapine, mianserin and escitalopram. The development was highest in the first 2 weeks of starting treatment( with the highest incidence of hyponatremia in the first 2 weeks in citalopram and lowest in mianserin. 

So, SSRI had the most association, SNRIs had slightly lower and non adrenergic specific serotogenic antidepressants had the least association. 

Topic Discussion: Gut Microbiota and UTIs

 

A Gut Microbiota – Urinary Tract Infection Connection

It is presumed that gut bacteria are the source for urinary tract infection, but is there any proof? If so, could changing the gut microbiota impact urinary tract infection?

Lee et al. evaluated this premise in a cohort of 168 kidney transplant recipients and profiled the gut microbiota serially using 16S rRNA deep sequencing. They reported that having higher gut abundance of E. coli was a risk factor for development of E. coli. They further performed strain analysis on matched fecal-urine specimens and found that the E. coli in the urine most closely resemble the E. coli in the gut from the same patients, supporting a gut origin of UTIs .

A follow up analysis identified that the gut abundances of two commensal bacteria, Faecalibacterium and Romboutsia, are associated with a decreased risk for UTIs. 

The data suggest the possibility that manipulation of the gut microbiota could alter the balance of commensal bacteria and pathogenic bacteria and could decrease the risk of UTIs, especially in patients with recurrent UTIs. Indeed, there is some recent evidence in case reports. In a case series by Tariq et al., patients with recurrent UTIs and recurrent C. difficile infections underwent fecal microbial transplantation for recurrent C. difficile infections and had a significant decrease in the number of UTIs after fecal microbial transplantation.

Whether gut microbial-based therapies can break the cycle of recurrent UTIs is still not known. Nevertheless, these therapies could be a novel approach to treating this common problem.

Image credit: http://www.sci-news.com/biology/gut-microbiota-manipulate-our-minds-05956.html

Concept Map: Various antigens in Membranous Nephropathy

 

This is a simple concept map of various novel antigens discovered in the last 10 years for membranous nephropathy. The links below are references for the above data.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581930/

https://www.kidney-international.org/article/S0085-2538(18)30825-1/pdf

https://www.kidney-international.org/article/S0085-2538(20)30956-X/fulltext

https://pubmed.ncbi.nlm.nih.gov/32534052/

https://pubmed.ncbi.nlm.nih.gov/31901340/

https://www.nejm.org/doi/full/10.1056/NEJMoa0810457

Topic Discussion: ESRD patients and COVID-19

While we saw several rising cases of AKI associated with COVID-19, the ESKD population was also vulnerable to this virus. With COVID-19, we didn't know if we would see worsening effects on ESRD or beneficial ( given a not so robust immune system in ESRD).  But the proximity and being in a closed dialysis unit did put most of them at risk. 

Studies from China and Europe on ESKD patients with COVID-19 were limited to small numbers and single centers. One of the first studies from US from CUMC was limited by less then 100 patients as well. It did show poor outcomes of 59 patients where 31% had died.

A Study from UK did discuss the concerns for an urban dialysis center ( on risk of hospitalizations). Of 1530 patients (median age 66 years; 58.2% men) receiving dialysis, 300 (19.6%) developed COVID-19 infection, creating a large demand for isolated outpatient dialysis and inpatient beds. An analysis that included 1219 patients attending satellite dialysis clinics found that older age was a risk factor for infection. COVID-19 infection was substantially more likely to occur among patients on in-center dialysis compared with those dialyzing at home. 

A study from the Bronx in NY also showed poor outcomes for hospitalized ESKD patients. Elevated inflammatory markers were associated with in hospital death.

Another UK study also found a high prevalence of seropositivity in the outpatient dialysis units. 

Alberici et al.describe their clinical experience with MHD patients cared for at 4 outpatient dialysis facilities that are part of the Brescia Renal COVID Task Force. In a period of 1 month, viral positivity was detected in 94 of their 643 ESRD HD patients (15%). Important findings in the study were the mild form of symptomatology at presentation, the high rate of overall mortality (29%), and emergence of usual risk factors for mortality and acute respiratory distress syndrome in SARS-CoV-2–positive HD patients. In addition, although certain patients were deemed more stable and were managed in the outpatient facility, 3 of those subsequently died, and a substantial portion had significant worsening of their symptoms.

Goicoechea et al. describe the clinical course and outcomes of 36 patients from 2 dialysis facilities caring for 282 patients that were admitted to a tertiary hospital in Madrid based on positive reverse transcription polymerase chain reaction for SARS-CoV-2. They report a mortality rate of 30.5%, and 33% of their patients required mechanical ventilation. 

At our health system of over 23 hospitals in NY, we decided to compare the outcomes of ESKD patients to non ESKD patients. The data was from 13 hospitals and our final cohort had 419 (4%) with ESKD and 10,063 (96%) without ESKD.This is the largest study to date.

What did we find:( similar tweetorial by first author Jia Ng)

I want to share our new paper “Outcomes of patients with ESKD hospitalized with COVID-19”. @kidney_int @hofstrakidney @hofstramed @jam_hirsch @rimdamyeloma @mala_sachdeva @sfishbane @kdjhaveri Susana Hong

https://t.co/B2jd3RO4lt
[THREAD] pic.twitter.com/4S03hTRHAo

— Jia Hwei Ng, MD, MSCE (@jiahweing) August 16, 2020

1. Patients with ESKD were older, had a greater percentage self-identified as Black, and more comorbid conditions.

2. Patients with ESKD had a higher rate of in-hospital death than those without (31.7% vs 25.4%), odds ratio 1.38, 95% confidence interval 1.12 - 1.70). This increase rate remained after adjusting for demographic and comorbid conditions (adjusted odds ratio 1.37, 1.09 - 1.73).

3. Patients with ESKD had similar rates of mechanical ventilation as those without ESKD (89 [21.2%] vs 2076 [20.6%]). There was no difference in the odds of mechanical ventilation between the groups.

4. The odds of length of stay of seven or more days was higher in the group with compared to the group without ESKD in both the crude (1.62, 95%CI 1.27 - 2.06) and in the adjusted analysis (1.57, 95% 1.22 - 2.02)

5. We conducted stratified analyses to investigate the risk factors of death in the subgroups of ESKD and the non-ESKD separately, with the hypothesis that the risk factors of death and the magnitude of risk factors would differ between the two groups.

6. For patients without ESKD, the independent risk factors for in-hospital death increased age, male sex, cardiovascular disease, cancer, requiring ventilation, requiring vasoactive meds, high blood urea nitrogen, low albumin, high CRP and high ferritin.

7. The diagnosis of hypertension and use of an ACE inhibitor or ARB were associated with a lower risk of in-hospital death in the non-ESKD group.

8. Among patients with ESKD, independent risk factors for in-hospital death were increased age, requiring ventilation and lymphopenia, elevated BUN and high serum ferritin. Black race was associated with a significantly lower risk of death among patients with ESKD.

9. The protective effect of HTN in the non-EKSD group, and the protective effect of Black race in the ESKD group defy easy explanation. Perhaps APOL1 has some protective cardiac effect?

10. This is a large cohort of hospitalized patients with #COVID-19 comparing ESKD and non-ESKD in a diverse patient population. We had prespecified operational definitions for exposures, covariates and outcomes, as well as rigorous adjudication by two independent reviewers for ESKD exposure.

11. What limitations do we have?--Despite the larger size of this study compared to other reports, the ESKD sample may still have been relatively underpowered to find other statistically significant risk factors in mortality. Also there was inability to adjust for remdesivir and dexamethasone. As the evidence of these 2 drugs came after the surge of #COVID-19 cases in our health system, only a small proportion of patients received these drugs.

12. We had 11 PD patients in our admitted cohort. This was also published in a special report as well. Of 419 hospitalized patients with ESKD, 11 were on chronic PD therapy (2.6%). Among those 11, 3 patients required mechanical ventilation, 2 of whom died. Of the entire cohort, 9 of the 11 patients (82%) were discharged alive. While fever was a common presentation, more than half of our patients also presented with diarrhea. Interestingly, 3 patients were diagnosed with culture-negative peritonitis during their hospitalization. Seven patients reported positive SARS-CoV-2 exposure from a member of their household.

In conclusion, among patients hospitalized with COVID-19, those with ESKD had a higher rate of in-hospital death compared to those without ESKD. 

Two recent studies also show the outpatient HD infection and admission rates. A study published in AJKD from Canada showed from universal screening, 4.6% were infected. 

Another French study in KI showed a low incidence of infection of 3.3% in a large >40,000 dialysis patients. Older age, low albumin, and cardiac disease were risk factors for mortality. 

Taken together, the results suggest both a need for further research and the continued need for careful infection control procedures in the ESKD population at risk for #COVID-19.