COVID19 continues in 2022- a disruptive NY perspective

 As we wish everyone Happy New Year in 2022, the year has not really started off happy for many in the NY area( or most of the United States and the world).  Omicron variant is flourishing over mankind. 

In March 2020, I had witnessed one of the most horrific moments of my career and life as we all saw death and sobering misery in NYC. But at the same time, human kind and all health care had a mission and calling to somehow combat this virus.

2 years later now Jan 2022, we are back in a similar situation. I was on service in early Dec 2021 and life was "covid" normal with mostly non covid admissions and a good mix of interesting nephrology consult cases. Conferences were hybrid and we were doing relatively ok.

Fast forward 3 weeks, and life has changed again. More COVID19 patients in the hospital, some sick, some not. More PPE again.. cafeterias restricting folks on eating, visiting not allowed, people scared again to talk to each other. This time around, there is less fear but more fatigue. This time around, there is sickness but not fear of death. There is more disruption. Disruption everywhere...

This wave is different. I call it the wave of disruption. More nurses, PA, NP, physicians are out and coverage and planning for coverage is challenging. Luckily most have mild symptoms and are returning to work. This wave is causing more cancellations due to disruptions and not due to fear. This wave is causing more delay in health care due to personnel out due to mild covid symptoms or a positive PCR than sickness. 

This wave is different as there are more incidental PCR positive findings in both inpatient and outpatient world and we are testing so frequently. The patient who comes in for a fall and femur fracture by chance is found to have PCR + in the ER.  This wave is not the SOB, DOE coming in with oxygen requirements for acute COVID. Don't get me wrong, there are some who are coming in with that as well.

This wave is different, it's the wave of " We know COVID treatment better". We know steroids and remdesivir work and avoid intubation if not necessary and we are doing it.. We are doing an amazing job discharging patients and keeping death rates low.. This wave is more disruptive and harm will happen due to shortened and shrinking staff in health care.

This wave is different as there is minimal to no AKI. There is less lung involvement and hence less AKI ( perhaps). Early treatment maybe making a difference. Most of this wave is going to be outpatient phone calls from dialysis units, transplant patients turning positive and what do we do... Most of the phone calls I am receiving are from patients turning positive either because they tested for a trip or have mild symptoms. This will overwhelm the outpatient practices.  Virtual visits are back to decrease the disruption again.. This wave will cause dialysis patient placement issues. Cohorts and special units may be possible in 2020 and 2021 but this wave, omicron is everywhere-- perhaps cohort the non COVID ones maybe a better option.

Phone calls from patients, friends, co-workers and family members are constantly telling me- I am positive.  Omicron seems inescapable. This variant is everywhere.. NY is again an epicenter for this wave and leading the front in the US( not a proud moment). And this is despite our vaccination rates. 

While, this Jan 2022 seems gloom and doom, we have achieved so much in the last 2 years.
Vaccination in record time for almost all age groups, preventing severe cases and death; RCTs showing how some medications and therapies work well such as steroids and perhaps in some cases remdesivir.  We have learnt Acute PD again, we have learnt to juggle immunosuppression for GNs and transplant patients. We have learnt to transplant in a pandemic. We have learnt to multi task and do hospitalist work again. Despite the anger and distress in the world, we have learnt to become more human again and help each other more.

While I am not a trained immunologist, I am hoping that Omicron stays mild and takes over Delta and Delta won't have any human hosts left and this would be a silver lining and perhaps an end to the pandemic. With so many people infected ( despite vaccination), endemic status maybe in sight..

Let's hope that 2022 is the year of mankind and not the virus!

COVID19 vaccine induced glomerular diseases?- a literature update May 2021

The vaccine for COVID19 has been a lifesaver for many around the world. As expected, as you upregulate your immune system- you are going to get some flare ups of your immune system. Thus far, what are we noticing Minimal change disease, MN and IgA nephropathy. 

Several published cases of podocytopathies- mainly minimal change disease- either de-novo or relapse have been reported ( 4 cases thus far)

https://www.kidney-international.org/article/S0085-2538(21)00493-2/fulltext (Pfizer-BioNTech )

https://www.sciencedirect.com/science/article/pii/S0272638621005096 (Pfizer-BioNTech) 

https://www.ajkd.org/article/S0272-6386(21)00602-8/fulltext ( Pfizer-BioNTech )

https://www.kidney-international.org/article/S0085-2538(21)00478-6/fulltext (Pfizer-BioNTech)

IgA nephropathy flaring up has been reported ( 3 cases thus far)

https://www.kidney-international.org/article/S0085-2538(21)00465-8/fulltext ( Moderna)

https://www.kidney-international.org/article/S0085-2538(21)00286-6/fulltext (Moderna)

Relapse of Membranous Nephropathy  ( one case)

https://www.kidney-international.org/article/S0085-2538(21)00494-4/fulltext (Sinovac’s COVID-19 vaccine.)

Acute transplant rejection has been reported

https://www.kidney-international.org/article/S0085-2538(21)00466-X/fulltext ( Pfizer-BioNTech)

While we cannot be totally sure if this is vaccine related- timing maybe a factor. I am sure there will be many more to be added to this list.

Despite this, the vaccine saves lives! Remember severe COVID19 disease led to significant AKI and ATN and even several cases of glomerular diseases. Such vaccine associated immune responses should not deter one from getting vaccinated. Overall, even the flu vaccine and other vaccines have been associated with several glomerular diseases such as MCD and membranous nephropathy.  Given mass vaccinations happening around the world, there will be cases of vaccine induced GNs( but still very very rare)

Topic Discussion: Electrolytes Disorders with COVID19

AKI has been reported with COVID19 ,electrolyte disorders have been less well described. A recent paper in CKJ describe the full spectrum of electrolyte disorders seen with COVID19.

The most common presentation was hyponatremia and hypochloremia together (second vertical bar) in 1289 (12.4%), followed by hyponatremia alone (third vertical bar) in 1150 (11.1%).

What about patients with eGFR<60 but >15? 30.3% had hyponatremia, 11.1% had hyperkalemia, and 19.7% had hypochloremia. Hypocalcemia was seen in 19.2% of patients. Hyperphosphatemia (13.9%) and hypermagnesemia (12.2%) were seen in fewer patients.

What about ESKD patients?

In these patients the most common disorders were hypochloremia (62%), hyponatremia (40.9%), and hyperkalemia (23.4%). Hyperphosphatemia was seen in 45.7% of patients but we had some missing phosphorus data.

What about kidney transplant recipients? The most commonly seen were hyponatremia (42.4%), hyperkalemia (16.7%), and hypochloremia (19%).

Limitations: Purely descriptive.

But highlights for the first time and the largest to date on the various electrolyte disorders in hospitalized COVID-19 patients. Further studies are needed to look at mortality outcomes related specifically to each electrolyte disorder.

Prevalence of Hyponatremia related to COVID19 has been described in the NY region. Looking at the spectrum of both hyponatremia and hypernatremia and it's relation to patient outcomes has not been well studied.

To take this further, Na disorders were evaluated in detail with outcome of mortality. This is published in NDT. Among 9946 patients included in the study ,4808 (48.3%) had normonatremia, 3532 (35.5%) had mild hyponatremia, 904 (9.1%) had moderate/severe hyponatremia, 319 (3.2%) had mild hypernatremia, and 383 (3.8%) had moderate/severe hypernatremia. When examined by decile of age, dysnatremia occurred in 46-54% of patients in each group, with hyponatremia the predominant disorder across all age groups. The proportion of patients who experienced in-hospital death was highest for those with moderate/severe hypernatremia (232/383 [60.6%]), followed by mild hypernatremia (163/319 [51.1%]), moderate/severe hyponatremia (261/904 [28.9%]), mild hyponatremia (818/3532 [23.2%]) and normonatremia (1089/4808 [22.6%]), a trend seen across all age groups. 

U-shaped pattern was seen in the relationship between admission serum sodium level and the odds of in-hospital death, with hyponatremia and hypernatremia both significantly associated with mortality, even after full adjustment for demographics, comorbid conditions and illness severity. Compared to hyponatremia, hypernatremia carried a strong association with in-hospital death, in both mild and moderate/severe categories, and across all ages, a relationship that persisted even following correction for serum glucose. While hypernatremia has  been shown to be  a strong predictor of mortality in prior studies, this finding is novel for COVID-19. 

Both hyponatremia and hypernatremia were also associated with a prolonged hospital length of stay. The magnitude of the odds ratio was substantial, especially for moderate/severe hypo- and hypernatremia, and was not substantively changed after multivariable adjustment. This suggests that at least a portion of the prolonged hospitalization may be directly related to electrolyte disorder management. 

This is the largest study to describe prevalence and outcomes of both hyponatremia and hypernatremia in a diverse population of almost 10,000 patients hospitalized with COVID-19. Other similar studies just published in the endocrine literature as well.

IN the News: Pediatric AKI related with COVID19 and MISC- tale of two NY centers

 

A recent study published in Kidney International looked at a single health system 4 hospital admissions of AKI with COVID19 and MISC in children in NY. It was during the first wave in 2020.  

Over 150 patients met inclusion criteria; 97 (63.8%) with acute-COVID-19 and 55 (36.2%) with MIS-C, AKI occurred in 11.8% of the cohort; 8 with acute-COVID-19 and 10 with MIS-C.  All but one patient with AKI were admitted to a pediatric intensive care unit (PICU). There was no significant difference in age, or ethnicity in those with and without AKI. Those who identified as black had 2.86 times higher odds of AKI (p=0.042; 95%CI 1.04-7.93). 

Majority of AKI occurred early in the course of hospitalization, 72% (N=13) within 24 hours of admission. MIS-C patients with AKI had greater rates of systolic dysfunction, compared to those without AKI (80% vs 49%, p= 0.038).  AKI, in unadjusted models, was associated with a lower serum albumin level (OR 0.17)and higher white blood cell counts (OR 1.11). In addition, patients with AKI had 8.4 day greater length of stay. Major Limitations: 1. Small sample size precluded adjustment for confounders 2. As this was an observational study, we are unable to determine causal associations. 3. Single health system/region of the country
Strengths of this study: One of the largest, detailed cohorts of pediatric patients at the epicenter of the COVID-19 outbreak and represents a diverse racial, ethnic and socioeconomic population.

Similar to reports in other PICU patients, pediatric COVID-19-related AKI was associated with longer lengths of stay published in Kidney360 also from NY area. In that study, 57 children who met inclusion criteria, 46% (26/57) were found to have AKI.  All patients had resolution of AKI at discharge, with 61% achieving recovery by day 2. One patient required dialysis. When compared to those without renal injury, the AKI cohort was older (p < 0.001) and with higher median peak values of CRP (p <0.001), IL-6 (p <0.05), ferritin (p < 0.001), and procalcitonin (p <0.05). More patients with AKI had left ventricular systolic dysfunction (p < 0.001) and lymphopenia (p <0.01), when compared to those without AKI. No differences in Body Mass Index or sex were found. 

These findings may reflect the inflammatory cascade’s complex role in development and perpetuation of COVID-19 related AKI. In addition, decreased intravascular volume and distributive/cardiogenic shock may have contributed to AKI in the MIS-C cohort. 

Check out the tweetorial by Abby Baselely 

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... 

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: 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

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 

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).

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.  

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.

Topic Discussion: COVID and Kidneys- the biopsy experience

As we expand our understanding of COVID-19 related AKI, in the last few weeks, more studies are emerging on what might be the main kidney biopsy findings with COVID related AKI.
We have now established the incidence being around 30-40% in the US.

What is exactly going on in the kidney? Is the virus attacking the kidney or is the renal disease a consequence of "being sick" and or  "inflammatory state".

This figure from an article in JASN summarizes the potential way the SARS-Cov2 might be effecting the kidney



Two recent biopsy series from Columbia and Northwell Nephrology showed the variety of pathology reported in COVID-19



In addition, an autopsy series (specific) to the kidneys showed ATN only.  Finally, in KI, a series of anti GBM were reported in UK related to COVID-19

All recent papers added interesting few things to the ongoing literature.

1. ATN is by far the most common presentation for AKI( if not pre renal)- even in transplanted kidney. Pigment nephropathy from myoglobin or hemoglobin is rare. Vitamin C overdose induced oxalate nephropathy is rare.
2. Podocytopathies( MCD and cGN) are the most common glomerular findings
3. Other glomerular diseases are a varied amount( TMA, ANCA, Membranous GN, anti GBM)
4. The virus was not found in the kidney with immunohistochemistry in all 3 studies.

Does the kidney get infected?- time will tell.. data is mixed