18 May 2022 Episode 262: Actual state of the epidemic; COVID and kidney dysfunction

Wed, 05/18/2022 - 10:32

Dear colleagues,

As you will see: we are not yet done with omicron !

In the second paragraph, I will discuss some reviews on the effect of COVID on kidney function and also critically review some case reports on (temporary) kidney dysfunction after vaccination.

See

Please note that I will be absent for a while and I’ll be back early June.

Par 1 Actual state of the pandemic

Ep 262-1: Very interesting global analysis by  Katelyn Jetelina: we are heading to a new peak, but for those who are vaccinated, there is a very small chance of landing in the hospital.  However,  severe disease isn’t the only outcome, vulnerable people around you may not be protected by their vaccine, and more cases means more variants.

  • South-Africa is in its 5th wave, with rising hospitalizations but low number of deaths

 

 

 

  • Australia and New Zealand are entering the winter, with, per million, higher numbers of infections and of COVID deaths than US

 

 

  • China sticks to zero COVID, but vaccination of elderly is only 30 % (see also Ep 262-2)

 

  • Extensive data on US (see text)

 

  • According to UK report: self-reported long COVID is close to 10 % even in triple vaccinated subjects with omicron infection.

 

Ep 262-2: Jun Cai Nat Med May 2022 Modeling consequences of omicron in China

  • The level of immunity induced by the March 2022 vaccination campaign =  insufficient to prevent an Omicron wave that would result in exceeding critical care capacity with a projected intensive care unit peak demand of 15.6-times the existing capacity and causing approximately 1.55 million deaths.
  • Protecting vulnerable individuals by ensuring accessibility to vaccines and antiviral therapies, and maintaining non-pharmaceutical interventions could be sufficient to prevent overwhelming the healthcare system.

 

 

  • Subunit vaccines refer to using a third dose of subunit (S protein or RBD) vaccines as booster after two doses of inactivated vaccines as priming.
  • Vaccinating elderly refers to vaccinating approximately 52 million people ≥60 years have not been vaccinated yet as of March 18, 2022.
  • 50% uptake and 80% efficacy corresponds to a scenario where 50% of symptomatic cases receive an antiviral therapy with an efficacy of 80% in preventing hospitalization and death.
  • 100% uptake and 89% efficacy corresponds to a scenario where all symptomatic cases  receive an antiviral therapy with an efficacy of 89% in preventing hospitalization and death (corresponds to efficacy pf Paxlovid).
  • School closure corresponds to a scenario where, on the top of baseline strategy, all schools remain closed for the duration of the epidemic.
  • School and workplace closure corresponds to a scenario, where on the top of baseline strategy, all schools and workplaces remain closed for the duration of epidemic
  • Rt: 3.0, 2.5, and 2.0 correspond to scenarios assuming different levels of non-pharmaceutical interventions (NPIs) leading to reduced values of the reproduction number.
  • Note that no strict NPI is implemented in the baseline scenario.

 

Clearly, according to this model, vaccinating elderly and rolling out effective antivirals seems essential!

 

Ep 262-3: ECDC report of 13 May is warning for the BA.4/5 wave in Europe, which has begun in Portugal.   Therefore a second booster (4th dose) is indicated in people of > 80 yrs old.

It may also become indicated for individuals > 60 yrs and other vulnerable subjects, if it turns out that the (potentially further evolved?) variant is pathogenic (increases hospitalizations) in fully vaccinated + boosted individuals.

 

 

 

Ep 262-4: Heid Ledford in Nature Briefing 15 May 2022 on prolonged shedding of SARS-CoV-2 “ghosts” in feces with possible relation to  long COVID:

 

Ep 262-4 A: Natarajan in Med June 2022 followed 113 individuals with mild-moderate COVID over 7 months:

Fecal SARS-CoV-2 RNA is detected:

  • Week 1  in 50 %.
  • Month 4: 12.7 %
  • Month 7: 3.8 %

GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding.

 

 

 

 

Ep 262-4 B:  Zollner Gastroenterology Apr 2022: Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases (IBD) patients.

 

In this study, viral RNA was found for 7 months in gut epithelium and, remarkably, CD8 T cells in 24/46 IBD patients, BUT NOT in feces and the virus could not be cultivated.

 

Post-acute sequelae of COVID-19 were reported from the majority of patients with viral antigen persistence, but not from patients without viral antigen persistence.

 

Ep 262-4 C: Chertow Res Square: SARS-CoV-2 RNA was detected in all 44 cases and across 79 of 85 anatomical locations and body fluids sampled !!

Autopsies in a diverse population who died from or with COVID up to 230 days after symptoms onset

 

With a few exceptions, the overall burden of SARS-CoV-2 RNA decreased by a log or more across tissue categories among mid cases, and further decreased among late cases.

However, several mid and late cases had high levels (5 N gene copies/ng RNA input) detected among multiple tissues.

Further, persistence of low-level SARS-CoV-2 RNA (0.0004 to <0.5 N gene copies/ng RNA input) was frequently detected across multiple tissue categories among all late cases, despite being undetectable in plasma

 

We detected sgRNA (subgenomic RNA is a sign of replication) in at least one tissue in over half of  cases (14/27) beyond D14, suggesting that prolonged viral replication may occur in extrapulmonary tissues as late as D99.

 

Patients are aligned from shortest to longest duration of illness (DOI) prior to death, listed at the bottom of the figure, and grouped into early (≤14 days), mid (15-30 days), and late (≥31 days) DOI

 

Ep 262-4 D: Denise Goh finds replicating SARS-CoV-2 in two patients with long COVID in the appendix resp breast tissue.

 

CONCLUSIONS:

 

  1. Omicron BA.4/5 is conquering the South (e.g. South-Africa, Australia), but is also approaching to the North (e.g. Portugal and China). We are not yet done with omicron. Vaccination (inckuding 4th vaccine in vulnerable people) should limit the impact.
  2. Renewed interest in SARS-CoV-2 lingering in the GI tractus as potential cause of long COVID.  However, persistence of some antigenic material in the right place i.e. the follicular dendritic cells of the germinal centers in the B cell zones of lymphoid organs is certainly not a bad thing, as it will stimulate B cells to mature and diversify

 

 

 

 

 

Par 2 Kidney dysfunction and failure associated with COVID and with vaccination

 

2.1. Association with COVID

 

Ep 262-5: Texeira Int J Mol Sciences Feb 2022

 

Epidemio

 

Acute kidney injury (AKI) and particularly AKI requiring renal replacement therapy (RRT) are clearly more frequent in COVID-hospitalized patients: figures 20-50 %

 

AKI-RRT in COVID-19 consistently associated with an increased risk of death and carrying a short-term mortality rate of 50% across diverse cohorts

 

Baseline kidney disease has been consistently found to be an independent risk factor.

 

Long COVID may significantly affect the kidneys

 

Clinical and histopathological featurs

 

               https://my.clevelandclinic.org/health/diseases/16426-acute-tubular-necrosis

 

  •  Proteinuria and hematuria relatively prominent

 

  • AKI in COVID-19 appears to be closely tied to the progression of respiratory failure, but it is also an independent predictor of poor outcome

 

Pathogenesis

 

  • Various indirect contributors:
    • Ischemia, hypotension, sepsis, nephrotoxic medication
    • cytokine storm, dysregulation of the angiotensin II pathway and complement system, endothelial dysfunction, abnormal platelet activation, hypercoagulation, microangiopathy

 

  • Direct effect of SARS-CoV-2?
    • Virus has been shown by some, but not others
    • Vir-uria very limited

 

Potential therapeutic targets:

  • Inhibition of lysosomal acidification?
  • Modulation of renin-angiotensin-aldosterone system ?
  • Inhibition of complement?

Little clinical evidence of success until now.

 

 

Proposed overview

 

 

 

 

Binding of SARS-CoV-2 with the ACE2 receptor and entry into kidney proximal tubule cells. Proposed schematic diagram depicting the binding of SARS-CoV-2 spike protein to the apical membrane of the kidney proximal tubule cells, followed by the internalization of the virus through endocytosis and its entry into lysosomes.

The crucial transporters responsible for lysosomal acidification are shown. The role of carbonic anhydrase inhibitors, such as acetazolamide, in impairing lysosomal acidification via interference with the activity of acid-importing H+-ATPase and NHE-6 is highlighted.

The proximal-tubule-specific plasma membrane transporters are shown.

 

PT: proximal tubule; DCT: distal convoluted tubule; CCD: cortical colleting duct; IMCD:

inner medullary collecting duct. NHE = sodium-hydrogen anti-porter ; SGLT-2 = sodium-glucose co-transporter; CLC = chloride-hydrogen channel; NBC-e1 = electrogenic sodium-bicarbonate cotransporter.

 

 

Ep 262-6:  Sidar Copur J Nephrology March 2022 is largely consistent with the previous paper and provides a nice schedule of acute and post-acute kidney injury.

 

 

 

Ep 262-7: Mahalingasivam in Nature Reviews Nephrology is more critical about the claims on very high impact of COVID on kidney function and calls for better controlled studies.  These are the key points:

 

  • Patients who are receiving in- centre dialysis have a higher risk of exposure to SARS- CoV-2 than members of the general population, owing to their limited ability to isolate.
  • Studies have found a dose–response of increasing risk of mortality from COVID-19 with decreasing kidney function, with particularly high mortality seen in people with kidney failure and those on kidney replacement therapy.
  • Evidence of how infection risk can be mitigated in patients with chronic kidney disease is often of poor quality due to the many challenges of conducting epidemiological research in fragmented health- care settings.
  • Observational studies of associations between risk factors, such as chronic kidney disease or transplantation, and outcomes, such as COVID-19-related mortality, can be distorted as a result of collider bias, and thus care must be taken in study design and evaluation.
  • Recognizing the challenges that affect epidemiological studies in pandemic settings together with information on local health contexts enables rigorous assessment of study quality; adequate reporting of aspects relevant to local care availability enables readers to identify studies that contribute robust findings to the literature.
  • To confront the challenges wrought by future pandemics, a sustainable and integrated global infrastructure is needed to identify evidence- based approaches to minimize infection transmission and adverse outcomes.

 

2.2. Kidney dysfunction post vaccination

 

Ep 262-8: Lim in Vaccines presents 5 cases of post-vaccination new-onset kidney disease in Korea.

 

(1) IgA nephropathy presenting with painless gross hematuria after Moderna vaccine

(2) Minimal change disease presenting with nephrotic syndrome after Janssen vaccine

(3) Thrombotic microangiopathy after Astra-Zeneca

(4) Two cases of acute tubulointerstitial nephritis presenting with acute kidney injury, one after Moderna and the other after Pfizer

 

As the authors state themselves: Since this is not a controlled study, the specific pathophysiologic link and causality between the kidney diseases and COVID-19 vaccination are difficult to confirm.

 

Ep 262-9: Leclercq in AJKD also describes a case of minimal changes disease with acute tubular injury, nephrotic syndrome and hypertension 2 weeks after Astra-Zeneca. In the discussion 5 other case reports on nephrotic syndrome and acute kidney injury after Pfizer vaccine are referred to.

 

MCD has also been previously described following vaccination against other pathogens, including  influenza, tetanus-diphtheria-poliomyelitis, and hepatitis B virus.

 

Ep 262-10: Schaubshlager in Clin Nephrol describes 6 patients who developed glomerular or acute tubulointerstitial disease shortly after receiving COVID-19 vaccinations (3 Moderna, 2 Pfizer-BioNTech) mRNA and 1 received Ad 26 Janssen vaccine.  Also these authors admit: It is difficult to ascertain any causal relationship between COVID-19 vaccination and onset/recurrence of kidney diseases.  

 

Ep 262-11: Liew finally describes a case of acute interstitial nephritis after Astra-Zeneca.

 

Most of these cases responded to temporary steroids and kidney replacement therapy.

 

 

CONCLUSIONS

 

  1. Pre-existing kidney disease and acute kidney injury during COVID provide a bad prognosis and may also have long-term effects.
  2. COVID can negatively influence kidney function indirectly (hypotension, thrombosis, cytokine storm…), but to what extent SARS-CoV-2 directly infects and dysregulates the kidney remains unclear.
  3. There are case reports of kidney dysfunction after all major vaccines used in the West, but the causal relationship is unclear.  

     

See you in 2 weeks

 

Best wishes,

 

Guido