In the NEWS: Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression

We know that Type 1 DM is a tough condition to have. Type 1 DM is an autoimmune condition where the immune system destroys the insulin-producing beta cells, resulting in a total lack of insulin, without which the body can’t regulate blood sugar. 

The “obvious solution”  would be to replace these lost cells, but transplantation introduces another problem: the immune system attacks any foreign cells, requiring toxic immunosuppression that comes with significant risks. We know this from our world in pancreas and kidney transplantation. 

In a brief report in NEJM, a group in Europe showed how edited cells that survived transplantation by becoming completely invisible to the immune system—a development that circumvents the immune rejection hurdle—and potentially removes the need for hostile immunosuppression. What the investigators did was to make the transplanted cells INVISIBLE to the immune system. They used CRISPR technology to remove HLA markers and then a viral technology to increase levels of CD47-- don't attack me signal. This made foreign cells look like your own.  What a clever idea.. The exact opposite of immunotherapy for cancer. 

They then went on to test this in a 42-year-old individual with Type 1 DM. And injected these edited cells into his forearm muscle with NO immunosuppression drugs and monitored him for 12 weeks. What happened?-- Edited cells SURVIVED and are not visible to the immune system, and started producing insulin within days. The patient responded to meals and was glucose responsive, and PET scans showed living functioning grafts. This is a fascinating move in science. They only used 7% of the possible dose, so the person still needed insulin. But this was a fascinating proof of concept we may be able to use in other autoimmune diseases, and introducing gene editing cells without the need for immunosuppression.

In the NEWS: Obesity Related CKD

Obesity-related Chronic Kidney Disease (Ob-CKD) encompasses a wide range of manifestations in persons with chronic kidney disease (CKD), from cases without known structural damage (hyperfiltration or albuminuria) to more advanced stages with obesity-related glomerulopathy (glomerular hypertrophy, podocytopathy, mesangial matrix expansion, focal and segmental glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and vascular lesions). Ob-CKD can also coexist with other kidney diseases, affect persons on dialysis, and in kidney transplant recipients.

In response to this complexity, Spanish Society of Nephrology (S.E.N.), Latin American Society of Nephrology and Hypertension (SLANH), and Spanish Society for the Study of Obesity (SEEDO) developed a consensus report proposing a classification system based on renal alterations and CKD stage (non-dialysis, dialysis, or transplant), aiming to standardize terminology and guide clinical management.  One of our principal aims is to diagnose individuals with obesity and CKD, classify, and subsequently individualize their treatment. What remains undiagnosed will remain untreated.

The effective treatment of Ob-CKD requires a multidisciplinary approach involving nutritional therapy, physical activity, pharmacological treatment, and bariatric surgery when indicated. The consensus also emphasizes the role of incretin-based therapies, which have been shown to promote weight loss and improve cardiorenal outcomes, including reductions in cardiovascular events and mortality in persons with Ob-CKD.

This was published in Kidney International 

See a sample below of cases related to Ob-CKD

Guest Post by

Dr. Maria J Soler

In the News: A new virus- Pegivirus induced CNS disease in organ transplants

A letter in NEJM describes a potential new neurological disease, pegivirus-associated encephalomyelitis (PAEM), linked to the common virus Pegivirus hominis (HPgV-1).  Four immunosuppressed patients presented with progressive optic neuropathy and myelopathy, including spastic paraparesis or tetraparesis and sensory disturbances. 

Two patients died within two years of symptom onset, while the others remained severely disabled.  MRI scans revealed a distinctive pattern of bilateral, symmetrical lesions in the anterior visual pathway and spinal cord's corticospinal tracts and posterior columns.  

HPgV-1 was detected in the patients' cerebrospinal fluid, serum, and brain tissue, but not in controls, suggesting a causative role.  Viral loads were highest in the optic nerve and spinal cord, and genomic sequencing revealed compartmentalization within the CNS, further supporting this link.  

The authors propose that PAEM, characterized by these specific clinical, radiological, and virological findings, may be underdiagnosed and that characteristic MRI findings should prompt HPgV-1 testing.

The appendix includes in-depth methods, results, discussion, and individual patient case reports.  It elaborates on the clinical presentation, MRI and CSF findings, HPgV-1 RNA detection and quantification, and full-genome sequencing analysis supporting viral compartmentalization within the CNS. Two of the 4 patients were renal transplant recipients. 

One of them was a  57-year-old kidney transplant recipient due to pANCA-associated vasculitis, presented with progressive hypoesthesia and weakness in his legs, followed by vision loss, nausea, vomiting, and cognitive difficulties. He was on CNI, MMF and steroids and had received cyclophosphamide in the past.  He developed bladder and bowel dysfunction and lost the ability to walk. MRI showed abnormalities in the optic nerves, chiasm, pyramids, and spinal cord. HPgV-1 RNA was detected in both serum and CSF.  Despite immunosuppression reduction and treatment with ribavirin, his condition didn't improve, and he died 17 months after symptom onset.  Autopsy revealed myelin loss, glial cell abnormalities, and T-cell and macrophage infiltration in affected brain regions. Viral loads were highest in the optic nerve and cervical spinal cord.

Another patient was a 62-year-old kidney transplant recipient due to polycystic kidney disease, experienced progressive paresthesia and leg weakness, leading to spastic tetraparesis.  She was on mTORi, Steroids and belatacept.  She later experienced vision loss. Spinal MRI revealed lesions in the cervical and upper thoracic spinal cord.  HPgV-1 RNA was detected in both serum and CSF.  Belatacept was discontinued, and she was maintained on methylprednisolone and later azathioprine.  Her condition was complicated by aspiration pneumonia, infections, and renal graft failure requiring ICU care.  While her neurological symptoms partially improved, allowing for ventilator weaning and improved arm strength, she remained paralyzed in her legs and required dialysis.  Follow-up revealed no HPgV-1 RNA in serum but persistent presence in CSF.

This new virus will require us to be more vigilant in the transplant world and perhaps even in the world of immunosuppression. 

In the NEWS: Intravitreal Anti VEGF agents and Kidney disease

 Check out this twitter feed I had done on the topic of Intravitreal Anti VEGF agents and the Kidney. 

In the News: Dense Deposit Disease and ApoE- the new connection

C3 glomerulopathy arises from irregularities in the alternative pathway of complement. It manifests as two types: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), identifiable by bright C3 staining in the glomeruli under immunofluorescence. EM distinguishes DDD by dense deposits along the glomerular basement membranes, contrasting with non-dense deposits in C3GN. A fascinating new study investigating 12 cases each of DDD, C3GN, and pretransplant kidney controls, laser microdissection (LCM) followed by mass spectrometry (MS) revealed a significant accumulation of complement proteins and regulatory factors in both C3GN and DDD compared to controls. Notably, DDD exhibited a much higher concentration of C5-9 and apolipoprotein E (ApoE) compared to C3GN. 

Image courtesy: pathologyoutlines.com 

ApoE staining aligned with dense deposit patterns in DDD but not in C3GN or controls, validated in 31 C3G cases. This is fascinating as perhaps ApoE staining may serve as a diagnostic tool for DDD, particularly when EM is unavailable, as it reflects the enriched presence of ApoE in dense deposits, distinguishing DDD from C3GN.

ApoE is a 34 kDa lipoprotein, that facilitates lipid transportation by binding to lipids. As we are aware, in various diseases like atherosclerosis, Alzheimer’s, and amyloidosis, ApoE plays pivotal roles in plaque formation and fibril assembly. Additionally, I learnt that it is also detected in fibrillary glomerulonephritis, immunotactoid glomerulonephritis, and monoclonal Ig deposition disease, potentially acting as a scaffolding protein. While its accumulation is significant in DDD, it's also found in other diseases but in lesser amounts. Staining for ApoE aids in diagnosing DDD alongside proliferative glomerulonephritis and bright C3 staining. Kidney accumulation of ApoE occurs predominantly in lipoprotein glomerulopathy and ApoE-related glomerulopathies. ApoE interacts with complement factors, inhibiting inflammation and regulating complement pathways. Moreover, it's a component of age-related macular degeneration but hasn't been previously identified in DDD dense deposits. This study suggests ApoE binds to heparan sulfate in the glomerular basement membrane, potentially acting as a chaperone for C5-9 proteins, contributing to dense deposit formation. Further investigation is warranted to confirm ApoE's interaction with C5-9 proteins and potential treatment strategies as a result. Kudos to the authors for making this connection. 

In the News: Is it prime for Xenotransplantation

A seminal paper in Lancet published in 2023 focuses on the immune response after pig-to-human kidney xenotransplantation. The study uses a comprehensive approach to characterize this response in detail. 

Two pig kidney xenografts transplanted into deceased human recipients were thoroughly analyzed using various methods including morphological evaluation, immunophenotyping, gene expression profiling, digital spatial profiling, and cell deconvolution. The findings indicate early signs of antibody-mediated rejection, with evidence of microvascular inflammation, immune deposits, endothelial cell activation, and positive xeno-reactive crossmatches. The inflammation primarily consists of innate immune cells like CD68+, CD15+, and NKp46+ cells. Gene expression analysis reveals increased activation of various immune-related pathways, such as monocyte and macrophage activation, natural killer cell response, endothelial activation, complement activation, and T-cell development. 

The injury associated with antibody-mediated rejection is concentrated in the glomeruli of the xenografts, with transcripts related to monocytes, macrophages, neutrophils, and natural killer cells being significantly enriched. This rejection pattern is distinct from control autografts and ischemia-reperfusion models. The study suggests that despite initial positive outcomes, antibody-mediated rejection might still be occurring in pig-to-human kidney xenografts. The findings highlight potential therapeutic targets to address the humoral aspect of rejection and improve the success of xenotransplantation.

Interestingly, in JAMA surgery, a case report is published at the same time. The paper presents a case involving a male individual in his 50s who was declared brain dead and had acute kidney injury on top of a history of chronic kidney disease (CKD) and hypertension. After all other organ donation options were exhausted, the individual received bilateral native nephrectomy and cessation of dialysis. Crossmatch-compatible xenotransplantation was performed using 10-gene-edited pig kidneys (UKidney). The pig kidneys were modified with 10 gene changes, including knockdowns, knockouts, and human transgene insertions. The recipient was treated with a complement inhibitor (anti-C5; eculizumab) prior to xenotransplantation, followed by standard induction therapy and maintenance immunosuppression. The pig kidneys were transplanted en bloc with their vasculature anastomosed to the recipient's arteries and veins, and the ureters connected to the recipient's bladder. The pig kidneys exhibited rapid function, producing significant amounts of urine within minutes of reperfusion, and urine concentration improved over time. Serum creatinine levels dropped significantly after xenotransplantation, and creatinine clearance improved as well.

Biopsies of the xenografts showed normal histology without evidence of thrombotic microangiopathy. The authors discuss that while this case series demonstrates the success of pig-to-human xenotransplantation in providing kidney function to a deceased individual with CKD, more research with living human recipients is needed to determine the long-term function of xenograft kidneys and their potential use as a solution for the organ shortage crisis. Although single case, it highlights the potential of xenotransplantation as a viable solution for addressing the shortage of organs, which results in preventable deaths annually.

In the News: Urine Na as a marker for diuresis success

A recent editorial in JAHA discusses the use of urinary sodium (UNa) as a biomarker for monitoring and guiding diuretic therapy in patients with acute heart failure (AHF). Activation of the renin-angiotensin system in heart failure leads to sodium retention, hyperaldosteronism, and increased sympathetic activity, contributing to fluid overload. The authors highlight that assessing diuretic response through traditional methods, such as weight loss and urine volume output, can be inaccurate and logistically challenging. Instead, they propose using UNa measurements from spot urine samples taken 2 hours after diuretic administration as a more dynamic and early indicator of diuretic response.

The European Society of Cardiology (ESC) guidelines recommend using spot UNa analysis to evaluate diuretic treatment response in AHF patients. A low UNa (<50-70 mEq/L) at 2 hours post-diuretic administration is associated with inadequate diuretic response and suggests the need for more intensive diuretic therapy. The paper discusses observational studies and expert opinions that support this approach. However, it also points out limitations, such as the influence of kidney function, concurrent conditions like chronic kidney disease (CKD) and cirrhosis, and the potential loss of UNa's predictive strength after the first day of treatment due to changes in sodium excretion patterns.

The authors present data from studies that endorse the feasibility and efficacy of UNa-guided diuretic therapy in AHF. They discuss the ENACT HF trial, which showed improved natriuresis, diuresis, and shorter hospitalization duration with UNa-guided diuretic treatment. Another ongoing study, PUSH-AHF, aims to provide more definitive results on natriuresis-guided therapy using a stepwise diuretic approach.

The authors acknowledge that UNa assessment alone may not fully capture diuretic response and recommend combining UNa measurements with other indicators of decongestion, such as urine output. They also emphasize the importance of accounting for different patient factors like fluid overload status, kidney function, and the type of diuretics used.

In conclusion, while UNa-guided diuretic therapy appears promising for AHF management.. interesting and simple to do.

Love this figure from the paper

In the NEWs- New Myeloma Working Group Update-- Myeloma related renal disease management

 An important guideline/recommendation was published in Lancet thismonth. This is an evidence based summary by the International Myeloma Working Group on myeloma related kidney disease. A must read!

Here is a summary of the findings

1.      Diagnosis is important- the serum free light chain becomes the corner stone of diagnosis. An algorithm below summarizes the novel way of looking at it. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and FLCs measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed.

2.      How high is the involved FLC—can tell you if this is cast nephropathy vs looking for a glomerular process. In addition – the urine protein being selective vs non selective can aid in overflow proteinuria vs a true glomerular process.

3.      Kidney biopsy is NOT required but may be recommended if suspicious of cast nephropathy is high. Although recent studieshave shown that the IFTA and number of casts presents on renal bx can predictrenal outcomes.

4.      The IMWG criteria for renal response was recommended( change in eGFR)- see table below. This is used for many studies and validated.

5.      Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment( fluids, correction of hypercalcemia, avoiding NSAIDS)

6.      Mechanical approaches do not increase overall survival( plasma exchange- data is in the non bortezomib era, and HCO dialyzer- two RCTs showed no benefit).

7.      Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. The panel suggested to Start Daratumumab + Bortezomib + Dex early and then add IMiD starting cycle two once renal function has stabilized.

8.      Carfilzomib should not be first line in patients with CKD as risk of TMA( first time someone mentioning this)- glad the toxicities are being considered.. But then again- is the incidence of TMA from carfilzomib that high- I don’t think so.

9.      Dose adjustments are discussed for all anti Myeloma agents and their potential nephrotoxicities- mainly the TMA from carfilzomib. There are other renal toxicities of other agents as well not mentioned here.

10.    Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment

11.   Finally, with improved survival in myeloma, when should we consider kidney transplantation in pts. with ESKD? Should we use sustained MRD-negativity to select transplant candidates? What about the MGRS patients?—the consensus was 2 years of disease free state. But low level evidence.. I have seen sooner in most cases. Overall their outcomes are not great when compared to non myeloma ESKD. 

In the NEWS: Biomarkers-- Hype or Hope for AIN

A new study in JCI sheds light into a potential biomarker for Acute Interstitial Nephritis. This entity has been the bane of Nephrologists' existence. Its a hard diagnosis to make and treatment is the usual- steroids. 

First came the urine eosinophils-- then they were found to be useless.  Apparently, despite several studies showing no clear benefit in diagnosing AIN, several folks love to order this useless test. 

A slew of biomarkers came and went but none were real superhits for AIN. TNF-alpha and IL-9 were two potential candidates over the last few years.  The authors of a recent study published in JCI performed urine proteomics to identify a potential candidate that maybe best and top contender for AIN- chemokine C-X-C motif ligand 9( CXCL9).  This was then externally validated and then confirmed in kidney tissue of AIN patients compared to control groups.  They also showed that urinary CXCL9 together with TNF-α and IL-9 is the optimal combination of biomarkers for AIN diagnosis.

Here is the visual abstract from the paper

What is this CXCL-9? Apparently, it is a monokine induced by IFN-γ, is a chemokine that binds to its receptor, CXCR-3, and promotes lymphocyte recruitment at sites of inflammation.

It has been shown to be associated with

acute cellular rejection( makes sense- similar to AIN)
predict future risk of rejection
AIN associated with immunotherapy ( inviting T cells and monokine)
Predicting any immune mediated events when using ICI therapy

Drawbacks-- may not tell you specifically what is the cause of the T cell invitation but can clearly tell you a clue. Urinary tests are usually challenging in oligo-anuric AIN. 

It seems that the combination of TNF-alpha, CXCL-9 and IL-9 may hold promise for AIN. 

Despite amazing advances in urinary markers in transplant rejection since last 15 years, we are not using it in clinical practice. 

Lets hope that it is the troponin for AIN else we are still doing renal bx to confirm these tough diagnosis. 

In the News: WhatsApp in Onconephrology

A recent study published looked at using a "mastermind" chat using WhatsApp for onconephrology discussion. This group was created using Whatsapp in 2019. Since then close to 100 members are part of an ongoing online discussion. This study evaluated the 2 years of chat content via a survey, keywords and a full qualitative thematic analysis.

1. The keywords showed the figure below- The bigger the font, the most commonly discussed topic. 

2. In terms of thematic analysis, the 3 common themes that emerged were: collaboration, case discussions and knowledge sharing.

3. In terms of the survey, the key figure is below.  It is interesting that after uptodate.com, the chat was used by many for knowledge discussion and topic question answering. This is fascinating and could be because many of the topic experts and uptodate.com chapter writers were on this chat. 

Use of mastermind chats like this should grow in medicine. This allows for small subspecialty fields to have like minded individuals e-meet and discuss tough clinical challenges, share important knowledge and eventually collaboration for research. A recent paper on CDK4/6 inhibitors causing ATN was a result of collaboration led by this chat. 

Check out this amazing tweetorial by Prakash G on this.

Our manuscript Utility of WhatsApp® for onconeph education is out @CKJsocial @kdjhaveri @Sebi_Lapman , authored by 2 phenomenal students Simoni Khashi and Nitya Wanchoo, Quality analysis done by Kayla Kinuf @HofstraU @HofstraKidney @UCKidney @uofcincy @UCincyMedicine Tweetorial pic.twitter.com/ll46aCv7x2

— Prakash Gudsoorkar MD, FASN, FNKF (@prakashneph) December 16, 2021

American Society of Onconephrology

We have come a long way in the last 13 years. The origins  of this field can be traced back to 2005 when the first book on this topic was released by Eric Cohen et al. The field of oncology has continued to rapidly evolve since then, and the advent of tyrosine kinase inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and immunotherapy has further necessitated the development of this new subspecialty. Onconephrology has since become its own rapidly-growing subspecialty. As many of you know my passion for this field has been evident on my blog for the last decade. With the help of the amazing founding members team, this organization was created this fall of 2021.

The website is at https://www.ason-online.org/ and twitter( @onconephsociety)

The mission is to promote research, clinical activities, and education related to onconephrology. 

More specifically, the primary objectives of this society shall be to further the investigation of onco-nephrology and reach a better understanding of the basic mechanisms involved as follows:

By informal group discussion of material that is of cross disciplinary interest as it pertains to care of patients with kidney disease and cancer.

By exchange of ideas pertaining to clinical experiences and experimental research

By consideration of problems encountered in onco-nephrology research. 

By the promotion of good fellowship and mutual trust among members of this organization.

By fostering education and identifying gaps in knowledge as it pertains to onconephrology.

Membership will be soon available. Let's welcome the beginning of the next phase of this field in nephrology.

​

In the NEWS: Immunotherapy and the Kidney( new data in 2021)- AKI and electrolytes

Immune checkpoint inhibitors (ICI) are a novel class of immunotherapy drugs that have vastly improved cancer care for patients. Data on AKI has been evolving. 

In a multicenter international study just published in JITC by Gupta et al involving 30 sites across 10 countries, researchers collected data on 429 patients with ICI-AKI and 429 control patients who did not develop ICI-AKI. Armed with the largest ICI-AKI database to date, the team of researchers was able to identify predictors, recovery potential and survival outcomes of those patients with ICI-AKI.

One of the most important findings from the two-year study reveals that among patients who take ICI again – even after an episode of ICI-AKI – only 16.5 percent developed recurrent ICI-AKI, which shows that most patients can still take these life-saving medications safely.

Additional findings show that in renal-recovery occurs in approximately two-thirds of patients with ICI-AKI. Early treatment with corticosteroid is associated with a higher likelihood of renal recovery. Lower baseline kidney function, proton pump inhibitor use and extrarenal immune-related adverse events are independent risk factors for developing ICI-AKI.

A related paper recently published in the journal Kidney International by Wanchoo et al looking at the scope of electrolyte disorders that are seen with ICI. Hyponatremia, hypokalemia and hypercalcemia were the most common findings. SIADH is the most common cause of hyponatremia and adrenal disorders led the way in the cause of hypercalcemia. 

Warp Speed Drugs for Kidney diseases 2021

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

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: 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.

In the News: AKI in COVID-19 patients, a study and a story ( pics and words)

(Our fearless fellows during COVID-19)

As we tackle the world of COVID-19, at Northwell, we faced a lot of AKI related to COVID-19.
We were able to gather this data and publish a large 13 hospital dataset from US looking at AKI related to COVID-19. The data was just released in Kidney International today. This study is dedicated to all the patients and families we helped treat and our fearless warriors in this fight- our faculty, fellows, nurses, and all nephrology division staff at the two main campuses of North Shore University Hospital and LIJ at Northwell. Without their hard work, this study wouldn't be possible. We wanted to share some of our data here ( as a summary) with some personal faculty/fellows pics from the last 2 months of hard work.

1. When NY became the epicenter of COVID-19, nephrologist across NY noticed an alarming number of patients who developed AKI, at rates higher than reported in China. Our study reports the AKI rate and describes the presentation and risk factors of AKI in this population. We reviewed health records of patients hospitalized with COVID-19 between March1- April 5th, 2020, and followed up through April 12th. The data was from 13 hospitals. Our final cohort had 5449 patients.

2. Out of 5449 patients, 1993 (37%) developed AKI (stage 1-47%, stage 2- 22% and stage 3- 31%).
Up to 14% of all AKI patients required renal replacement therapy. At the time of this writing, among patients with AKI, 694 died (35%), 519 (26%) were discharged and 780 (39%) were still hospitalized.

3. AKI occurred early in the course of hospitalization, with 37% either arriving with AKI or developing within 24 hours of admission.

4. AKI was primarily seen in Covid-19 patients with respiratory failure, with 89.7% of patients on mechanical ventilation developing AKI compared to 21.7% of non-ventilated patients.
276/285 (96.8%) of patients requiring RRT were on ventilators.

                                           (Our LIJ renal team with Dept of Medicine Chair)


5. We found that independent risk factors for AKI included older age, diabetes mellitus, cardiovascular disease, Black race, hypertension, vasopressor medications and need for ventilation. In our study, baseline ACE-inhib use and BMI were not risk factors for AKI.

6. Around 66% of the patients had a urine Na of <35, suggestive of a prerenal state. In urinalysis, 46% had +ve blood and 42% had +ve protein. Unfortunately, we do not have accurate data on urethral catheters and baseline proteinuria.

                                            ( Our North Shore Inpatient rounding teams)

7.Why was our AKI rate higher (37%) than the study reported (5%) by Cheng et al?
We cannot completely explain this difference, but their patients had lower rates of comorbidities and ventilation needs than our patients. Our rates seem consistent with reports from US hospitals that are going to be published soon. In a recent preprint from Mt Sinai in NY- AKI rate was also 40%. Another US study also published at the same time from New Orleans found a rate of 28%.

8. We found a close temporal relationship between AKI and timing of intubation. It is possible that these patients developed ATN during systemic collapse. Since the 66% of AKI patients had urine Na of <35, they could have prerenal AKI.

9. Although not a primary purpose of this study, among the 285 on dialysis, 55% died, 42% still in the hospital and 3% were discharged.

                                            (Our North Shore Inpatient rounding teams)

10. It is important to note that because of early censoring and incomplete hospital disposition data, we cannot make definitive inferences about outcomes. We will do an update on full outcomes in 30 days. This study to define the rate of AKI, timing and risk factors.

11 The goal of this study was a broad description of AKI in COVID-19 patients. We believe that it is very important this information becomes available rapidly for clinicians. A full assessment of all patients’ outcomes will require a longer period of time to allow for disease processes to fully play out.

                                               (Our chief and associate chief in action)

12 What limitations do we have? 1. The cause of AKI were not fully elucidated. 2. Since this is an observational study, we will not be able to make causal inferences between exposures and AKI. 3. CKD could not be assessed given EHR data mining.

13 What are the strengths of the study? This is the largest cohort to date of hospitalized patients with COVID-19 with a focus on AKI. Our identification of AKI is consistent with guidelines, well-validated and automatically calculated in real-time for almost 1 year.

Cause of AKI- likely ischemic ATN( but AKI can come in various variants as noted on my prior post but a recent NEJM article also highlights potential involvement of ACE2 and renal tropism in AKI seen with COVID-19. In addition, there is an excellent CPC this week in NEJM on AKI with COVID-19.

Check out the above updates and tweetorial by first author Jia Ng, MD

I want to share our new paper “Acute kidney injury in patients hospitalized with COVID-19”. @kidney_int @hofstrakidney @hofstramed @jam_hirsch @danielwross4 @purvasharma821 @hiteshhshah Richard Barnett @gracezra1 @sfishbane @kdjhaveri https://t.co/XzvPa1vKtk

[THREAD] pic.twitter.com/Rq24N6XrLR

— Jia Hwei Ng, MD, MSCE (@jiahweing) May 14, 2020

The real heroes of our renal fight against COVID-19- our dialysis nurses and technicians!