Kidney Transplant Patient Immunological Hyporesponsiveness to SARS-CoV-2 Vaccination

Background: Multiple studies have shown an association between immune status and SARS CoV-2 disease severity, however data on specific immunosuppressive medications is not fully described. Immunocompromised individuals are at increased risk of mortality and morbidity therefore, vaccination against COVID-19 is essential. Research also suggests that elevated IgG levels post-vaccination correlate with host viral neutralization. We present data indicating that induction and maintenance immunosuppression therapy affects responsiveness to SARS CoV-2 vaccination among kidney transplant recipients. Method(s): 48 kidney transplant patients at our institution were retrospectively analyzed after receiving two doses of the SARS CoV-2 mRNA type vaccine between January and March 2021. Kidney transplantation occurred between 1983 and 2020. SARS-CoV-2 spike antigen-specific IgG levels were measured after 30-days to evaluate immunological responsiveness to the vaccine. Result(s): 35% of study subjects showed detectable peak COVID IgG serum levels 30 days after the second vaccine dose while 65% showed no response. Of the nonresponders, (62%) were predominantly heavily immunocompromised;on either high dose Mycophenolate (at least 720 mg twice daily) in addition to standard Calcineurin inhibitor/Sirolimus +\- Prednisone), or had received high dose Thymoglobulin (6 mg/kg or more) within a year of vaccination. This contrasts to published reports of over 95% immunological responsiveness or viral neutralization after the second vaccination dose among immunocompetent patients. Conclusion(s): Induction therapy with Anti-Thymocyte globulin and maintenance immunosuppression with Mycophenolate serve as the cornerstone of transplantation management. However, their utilization impacts B cell proliferation which is hypothesized to reduce antibody production and the effectiveness of the SARS-CoV-2 vaccine in transplant patients. This finding supports the need for a third or possibly fourth booster dose to achieve a sustained and effective response in combination with ongoing immunological surveillance post-vaccination among transplant patients.

IgA Nephropathy as a Potential Complication of SARS-CoV-2 Vaccination

Introduction: Vaccination against COVID-19 is essential, however an immunological flare is a potential rare complication resulting in glomerulonephritis with IgA deposits in the mesangium. We present a case of a patient who developed IgA nephropathy postvaccination. Case Description: 48-year-old woman with a past medical history of Leukocytoclastic vasculitis and hypertension presented to the Emergency Department with fatigue, nausea, epigastric pain, foamy urine and a diffuse erythematous purpuric rash within days of receiving the SARS CoV-2 vaccination. Her creatinine was 1.92 mg/dL and urinalysis showed 3+blood and 30 mg/dL of protein. COVID-19 testing was negative. Protein/ creatinine ratio was 2.1 g/g and urine microscopy showed dysmorphic red blood cells. Serologies for HIV, Hepatitis B and C were negative. Further testing revealed negative ANA, normal ASO titer, absent cryoglobulins, rheumatoid factor < 20, C3 158 (nl) and C4 35 (nl). However, IgA level was elevated at 462 mg/dL (reference 70-312 mg/dL). Patient was started on prednisone at a dose of 1mg/kg with a presumptive diagnosis of IgA vasculitis/ HSP. Subsequent skin biopsy was consistent with leukocytoclastic vasculitis while kidney biopsy showed glomerular deposition of IgA and endocapillary hypercellularity. At one month follow-up with nephrology, prednisone taper was started because of good clinical response and partial remission with UPCR reduction to 1 g/g. Prednisone was gradually tapered over the next 2 months. At her 3 month follow-up she was found to be in complete remission with a UPCR 0.2 g/g and her creatinine was 0.83 mg/dL Discussion: We present a case of IgA nephropathy post-SARS CoV-2 mRNA vaccination. It has been speculated that the mRNA lipid nanoparticle-encapsulated platform contained within the mRNA vaccine produces such a robust CD4 and CD8 T-cell response that pro-inflammatory cytokines activate this immune complex associated glomerular disease. In conclusion, SARS CoV-2 vaccination may potentially trigger IgA nephropathy in predisposed patients. Steroid therapy may be efficacious in managing this rare complication.

Impact of Immunosuppressive Medications on SARS-CoV-2 Vaccination Response in Kidney Transplant Patients

Purpose: The COVID-19 pandemic portends significant morbidity and mortality in immunocompromised individuals. Vaccination against COVID-19 among immunocompromised population is an essential step to minimize deadly complications. Numerous studies have shown an association between immune status, disease severity, and suboptimal responsiveness to vaccination. Additionally, data suggests that elevated IgG levels correlated with host viral neutralization. We herein present data indicating that induction and maintenance immunosuppression therapy affects responsiveness to vaccination among kidney transplant recipients. Method(s): The study data was retrospectively analyzed for 48 kidney transplant patients who received mRNA type COVID-19 vaccine at our institution. Majority of patients received vaccination between January and March 2021;two doses in total. The 30 days post-vaccination SARS-CoV-2 spike antigen-specific IgG levels were measured to assess immunological response to vaccine. Result(s): The included patients underwent kidney transplantation between 1983 and 2020. Among these patients, 35% showed detectable peak COVID IgG serum levels 30 days after the 2nd vaccine dose. A total of 31 patients (65%) did not show any response;majority of these non-responders (62%) were heavily immunocompromised, either on high dose Mycophenolate (at least 720 mg twice daily) in addition to standard Calcineurin inhibitor/Sirolimus+/-Prednisone), or had received high dose Thymoglobulin (6 mg/kg or more) within a year of vaccination. Among immunocompetent patients, over 95% immunological responsiveness or viral neutralization after the second vaccination dose has been reported. Conclusion(s): Anti-thymocyte globulin as induction immunosuppression and antimetabolites like Mycophenolate as maintenance immunosuppression serve as the cornerstone of transplantation management. However, their utilization impacts B cell proliferation, thereby reducing antibody production and the effectiveness of the SARS-CoV-2 vaccine in transplant patients. The ability of these immunosuppressive medications to suppress responsiveness to the SARS CoV-2 vaccine supports the need for 1) regular immunological surveillance post-vaccination among transplant patients, and 2) the need for a third or possibly fourth booster dose to achieve a sustained and effective response.

Transplant Graft TMA Injury Post COVID-19 Vaccination

Purpose: Vaccination against SARS-CoV-2 is essential. Complicating this effort are reports of a suboptimal response to the SARS-CoV-2 spike protein in patients on immunosuppressive medications and possible thrombotic microangiopathy (TMA) in renal transplant patients who receive the mRNA type vaccines. Method(s): 48 year old male with end stage renal disease who received a living unrelated transplant in 2015. Pre-operative creatinine was 10.42 mg/dL and decreased to 2.48 mg/dL within a week. Patient received Basiliximab induction and maintained on tacrolimus and mycophenolate (MMF). One month post-transplant patient was diagnosed with TMA. Tacrolimus was stopped and patient was switched to Sirolimus and continued on MMF. Patient was followed closely by transplant nephrology for the next 5 years with a baseline creatinine of 1.9 mg/dL, protein to creatinine ratio below 0.5 mg/mg and well controlled diabetes. No DSA Class I or II detected on regular testing. Patient was compliant with all prescribed medications. On January 25 2021 patient received Pfizer Vaccine. Second Pfizer vaccine administered on February 18 2021. A week later creatinine was noted to be 3.44 mg/dL. Repeat creatinine of 4.27 mg/dL. Biopsy revealed diffuse lymphocytic interstitial inflammation, peritubular capillaritis, and C4D negative. Findings consistent with chronic TMA. DSA testing revealed Class II DSA:DQ2 (SI-5933), Allosure 1.2 %. BK < 500 and CMV undetected. Patient received therapeutic plasma exchange, IV Ig infusion and steroids while on MMF and sirolimus. His creatinine decreased to 2.9 mg/dL on discharge. Over the next 6 months graft function deteriorated. He is now CKD stage 5 and under evaluation for a second transplant. Result(s): There are case reports of COVID-19 vaccine administration and transplant graft dysfunction. A possible mechanism involves the mRNA lipid nanoparticleencapsulated platform producing such a robust CD4 and CD8 T-cell response that pro-inflammatory cytokines are activated or that immune complex associated glomerular disease occurs resulting in the development of TMA in susceptible patients. Conclusion(s): A possible link between SARS CoV-2 vaccination and kidney transplant TMA warrants the implementation of close surveillance of vaccinated transplant patients, particularly susceptible individuals. More research is needed to determine if this link exists.

Pericardial Effusion: A Potential Late Complication of COVID-19 Infection

Purpose: COVID-19 infection involves entry of SARS-CoV-2 virus into cells via interaction between its spike protein and angiotensin converting enzyme resulting in an NF-kappabeta mediated inflammatory response. A cytokine storm may cause organ dysfunction. Cardiac manifestations without pulmonary symptoms is uncommon but has been described in the literature during an acute infection. We report a rare case of a potential late cardiac complication months after an acute COVID-19 infection. Method(s): A 62-year-old male with hypertension and end stage renal disease on hemodialysis three times a week presented with fever, arthralgia and myalgia. He denied chest pain or respiratory symptoms. Patient tested positive for COVID-19 and received conservative management only. Over the next nine months he reported persistent fatigue and new onset of shortness of breath. He continued to be very compliant with dialysis. On presentation to the hospital, all laboratory investigations, including BUN (27mg/dL) were within normal limits. Chest X- ray revealed cardiomegaly. Echocardiogram showed a large circumferential pericardial effusion without tamponade. Pericardiocentesis was accomplished with removal of 1700 ml of bloody fluid. Cell count, LDH, protein and glucose was normal. Fungal, aerobic, and anaerobic cultures of the pericardial fluid was negative. No malignant cells were detected. Patient had gradual resolution of his symptoms. Serial echocardiograms at 1, 3 and 5 months revealed a persistent small pericardial effusion. Result(s): Cardiac manifestations of SARS-CoV-2 includes myocarditis, pericarditis and pericardial effusions. In case reports, the presence of the cardiac inflammatory state occurred simultaneously with an acute COVID-19 infection. In our case the COVID-19 infection occurred over nine months earlier yet remains a plausible explanation for his hemorrhagic pericardial effusion due to the absence of other identified causes. Further, COVID-19 molecular PCR testing of pericardial testing remains low yield due to its specific development for nasopharyngeal swab sampling. Conclusion(s): Cardiac manifestations of SARS-CoV-2 infection typically occur at the time of diagnosis. A late cardiac complication of COVID-19 may include pericardial inflammation with effusion. Further data and testing needs to be developed to confirm the diagnosis and guide therapy.

Transplant Graft TMA Injury Post COVID-19 Vaccination

Vaccination against SARS-CoV-2 is essential. Complicating this effort are reports of a suboptimal response to the SARS-CoV-2 spike protein in patients on immunosuppressive medications and possible thrombotic microangiopathy (TMA) in renal transplant patients. 48-year-old male who received a living unrelated transplant in 2015. Pre-operative creatinine was 10.42 mg/dL and decreased to 2.48 mg/dL within a week. Patient received Basiliximab induction and maintained on tacrolimus and mycophenolate (MMF). One month post-transplant patient was diagnosed with TMA. Tacrolimus was stopped and patient was switched to Sirolimus and continued on MMF. Patient was followed closely by transplant nephrology for the next 5 years with a baseline creatinine of 1.9 mg/dL, protein to creatinine ratio below 0.5 mg/mg and well controlled diabetes. No DSA Class I or II detected on regular testing. Patient was compliant with all prescribed medications. On January 25 2021 patient received Pfizer Vaccine. Second Pfizer vaccine administered on February 18 2021. A week later creatinine was noted to be 3.44 mg/dL. Repeat creatinine of 4.27 mg/dL. Biopsy revealed diffuse lymphocytic interstitial inflammation, peritubular capillaritis, and C4D negative. Findings consistent with chronic TMA. DSA testing revealed Class II DSA:DQ2 (SI- 5933), Allosure 1.2 %. BK < 500 and CMV undetected. Patient received therapeutic plasma exchange, IV Ig infusion and steroids while on MMF and sirolimus. His creatinine decreased to 2.9 mg/dL on discharge. Over the next 6 months graft function deteriorated. He is now CKD stage 5 and under evaluation for a second transplant. There are case reports of COVID-19 vaccine administration and transplant graft dysfunction. A possible mechanism involves the mRNA lipid nanoparticle-encapsulated platform producing such a robust CD4 and CD8 T-cell response that pro-inflammatory cytokines are activated or that immune complex associated glomerular disease occurs resulting in the development of TMA in susceptible patients. A possible link between SARS CoV-2 vaccination and kidney transplant TMA warrants the implementation of close surveillance of vaccinated transplant patients, particularly susceptible individuals. More research is needed to determine if this link exists.

Pericardial Effusion: A Potential Late Complication of COVID-19 Infection

COVID-19 infection involves entry of SARS-CoV-2 virus into cells via interaction between its spike protein and angiotensin converting enzyme resulting in an NF-kB mediated inflammatory response. Cardiac manifestations without pulmonary symptoms is uncommon but has been described in the literature during an acute infection. We report a rare case of a potential late cardiac complication months after an acute COVID-19 infection. 62-year-old male with hypertension and end stage renal disease on hemodialysis three times a week. Patient presented with fever, arthralgia and myalgia. He denied chest pain or respiratory symptoms. Patient tested positive for COVID-19 and received only treatment of symptoms. Over the next nine months he reported persistent fatigue and new onset of shortness of breath. He continued dialysis without interruption. His symptoms progressed resulting in hospital admission. All laboratory investigations, including BUN (27mg/dL), were within normal limits. Chest Xray revealed cardiomegaly. Echocardiogram showed a large pericardial effusion without tamponade. Pericardiocentesis was accomplished with removal of 1700 ml of bloody fluid. Cell count, LDH, protein and glucose was normal. Fungal, viral, aerobic and anaerobic cultures of the pericardial fluid was negative. No malignant cells detected. Serial echocardiograms at 1, 3 and 5 months revealed a persistent small pericardial effusion. Cardiac manifestations of SARS-CoV-2 includes myocarditis, pericarditis and pericardial effusions. In case reports, the presence of the cardiac inflammatory state occurred simultaneously with an acute COVID-19 infection. In our case the COVID-19 infection occurred over nine months earlier yet remains a plausible explanation for his hemorrhagic pericardial effusion due to the absence of other identified causes. Further, COVID-19 molecular PCR testing of pericardial testing remains low yield due to its specific development for nasopharyngeal swab sampling. Cardiac manifestations of SARS-CoV-2 infection typically occur at the time of diagnosis. A late cardiac complication of COVID-19 may include pericardial inflammation with effusion. Further data and testing needs to be developed to confirm the diagnosis and guide therapy.