The rising global incidence of acute and chronic kidney diseases has increased the demand for renal replacement therapy. This issue, compounded with the limited availability of viable kidneys for transplantation, has propelled the search for alternative strategies to address the growing health and economic burdens associated with these conditions. In the search for such alternatives, significant efforts have been devised to augment the current and primarily supportive management of renal injury with novel regenerative strategies. For example, gene- and cell-based approaches that utilize recombinant peptides/proteins, gene, cell, organoid, and RNAi technologies have shown promising outcomes primarily in experimental models. Supporting research has also been conducted to improve our understanding of the critical aspects that facilitate the development of efficient gene- and cell-based techniques that the complex structure of the kidney has traditionally limited. This manuscript is intended to communicate efforts that have driven the development of such therapies by identifying the vectors and delivery routes needed to drive exogenous transgene incorporation that may support the treatment of acute and chronic kidney diseases.

https://www.frontiersin.org/articles/10.3389/fmed.2023.1143028/pdf

Still finding ways to augment the existing management of acute and chronic kidney diseases with targeted gene and cell therapies: Opportunities and hurdles

Worldwide, vaccination against severe acute respiratory syndrome coronavirus 2 has reduced the case fatality rate of coronavirus disease 2019 (COVID-19) in patients with kidney disease,1 but vaccination hesitancy remains a problem for various reasons. In patients with glomerular disease, there is the concern that vaccination may trigger a relapse of disease activity and a further decline in residual kidney function. In the absence of reliable data, advising patients on the individual risks and benefits has been challenging. Up until January 2022, numerous case reports and series reported 40 relapses of glomerulonephritis, kidney vasculitis, or podocytopathies in a temporal association with a coronavirus vaccine.2 Minimal change disease (MCD) relapsed preferentially after the first vaccine dose, whereas other entities relapsed after the second or third dose.2 However, in data on the background incidence of glomerular disease in nonvaccinated controls of the same population, the role of the vaccine as a trigger of a relapse has remained questionable. In this issue of JASN, Canney et al. report data from a British Columbia Canadian clinical and pathology registry, which followed a large sample of 1105 patients with glomerulonephritis, kidney vasculitis, and podocytopathies from December 14, 2020, to September 21, 2021. The study aimed to investigate whether the rollout of COVID-19 vaccines affect the relapse risk of these disease entities. Most patients received a mRNA vaccine (67% BNT162b2, 30% mRNA-1273), with the remainder (3%) receiving ChAdOx1. During this period, they defined a disease relapse as an increase of serum creatinine and proteinuria. A total of 134 (12.1%) patients experienced a relapse during the 281 days of follow-up. Among these, 24 relapses were considered as vaccine-associated relapses, defined as relapses occurring within a period of 30 days after vaccine administration. Overall, the authors found no increase of disease relapse after the first dose of COVID-19 vaccine administration (hazard ratio=0.65; 95% confidence interval, 0.32 to 1.32) but a two-fold increase after subsequent doses (hazard ratio=2.16; 95% confidence interval, 1.03 to 4.51). The risk of a disease flare during 210 days of follow-up in the absence of COVID-19 vaccine exposure ranged from 6% in membranous nephropathy (MN) to 19% in lupus nephritis (LN). The absolute risk after administration of a second or third vaccine dose of developing a disease relapse varied from 1%–2% in ANCA-associated vasculitis, MCD, MN, and FSGS to 3%–5% in IgA nephropathy and LN.3 Further sensitivity analysis extending the time period to 45 days after vaccination (see Figure 1) and restriction analysis to patients who received at least one vaccine (92% of the cohort) or two vaccines (89%) confirmed the association of glomerular disease relapse with administration of a second or third vaccine dose.3Figure 1.: A total of 1105 patients with established glomerulonephritis were followed in the registry. Most patients received two doses of COVID-19 vaccines. Relapses occurred in 134 patients during a follow-up period of 281 days, of whom 24 had a relapse within 30 days of vaccine administration. There is an increased risk after administration of the second or third dose of COVID-19 vaccine administration, and a minimal increased absolute risk for all entities studied. The histopathology picture was kindly provided by Dr. Victoria Bardsley (Department of Pathology, Addenbrooke’s Hospital, Cambridge, United Kingdom) and shows active necrosis in a patient with established ANCA-GN undergoing kidney biopsy 24 days after her fourth vaccine dose. IgAN, IgA nephropathy.There are several limitations of the work presented by Canney et al.3 The registry did not capture hematuria, which may be dispensable in podocytopathies but would add to specificity for a relapse of glomerulonephritis and kidney vasculitis. A survey in Japan identified 27 cases presenting with gross hematuria after COVID-19 vaccination.4 Among the 27 patients, only four underwent a kidney biopsy, and only one relapse was associated with an increase in serum creatinine.4 Gross hematuria usually occurs within the first days after vaccination, and usually resolves without specific therapy.5 These findings could imply that Canney et al. might have missed some relapses of glomerulonephritis, which anyway may have consequences for future kidney function decline. In the report by Canney et al., none of the 24 patients with a recurrence of glomerular disease after COVID-19 vaccination required a kidney biopsy, and only four (17%) of the patients had a change in immunosuppression, defined by a changing pattern in prescription.3 This again argues that most of the disease relapses were mild in nature, although their long-term effect on kidney function decline would warrant further follow-up. Notably, only three patients received a third vaccine dose because administration of booster doses was uncommon during the study period, whereas many countries are now offering fifth and sixth doses to immunocompromised patients. Subanalysis investigating differences between approved mRNA vaccines (BNT162b2 versus mRNA-1273) would provide important information because mRNA-1273 elicits a better humoral vaccine response,6 without increasing the rate of side effects7 and thus presumably also the risk of disease flare-ups. The work by Canney et al.3 highlights that disease relapses after mRNA COVID-19 vaccines are infrequent and that most of these disease relapses are self-limiting without a need to perform a repeat kidney biopsy or modification of immunosuppression. This is important information when discussing the pros and cons of vaccination with our patients, and it increases confidence in stating that mRNA vaccines are safe to use in most patients. COVID-19 vaccines are effective, even in immunosuppressed individuals. Analysis of the VISION network reported a vaccine effectiveness against hospitalization in the pre-Omicron era of 77% versus 90%.8 Reduced vaccine responses are reported in patients with ongoing “high-dose” immunosuppression, namely higher doses of steroids, alkylating agents, rituximab, mycophenolate mofetil, or calcineurin inhibitors,2 and in the absence of a humoral response or a low antibody response to prior COVID-19 vaccines, further booster doses, ideally with the adapted bivalent mRNA vaccines, should be offered. There is a clear benefit to vaccination in individuals with glomerular diseases because these patients often have worsening of kidney function,9 higher frequencies of severe forms of COVID-19,2 and reduced viral clearance,10 leading to prolonged days of hospitalization. However, there is limited information about the use of a third and fourth vaccine doses, which are now regularly recommended to patients with glomerular disorders. Repetitive stimulation of the immune system may further increase the frequency of disease relapses, and the cumulative risk upon several vaccine doses may reach a higher degree of clinical significance. Even with this study, we remain with this uncertainty—whether patients with a disease relapse after a COVID-19 vaccine will develop further relapses when subsequent doses are administered. The latter scenario seems likely, and prevaccine administration of low-dose immunosuppression (i.e., steroids) might be considered in such cases. Potential differences in relapse risk between mRNA and viral-vectored vaccines remain to be clarified. Disclosures H.-J. Anders reports consultancy fees and lecture fees from AstraZeneca, Bayer, Boehringer-Ingelheim, GSK, Janssen, Kezar, Novartis, Otsuka, Previpharma, Sanofi, and Vifor; research funding from Boehringer-Ingelheim; honoraria from Lilly and Otsuka; and an advisory or leadership role for JASN and Nephrology Dialysis Transplantation. A. Kronbichler reports consultancy for Catalyst Biosciences, Delta4, Otsuka, UriSalt, Vifor, and Walden Biosciences; research funding for Otsuka and Vifor; honoraria from Otsuka and Vifor; and an advisory or leadership role for the Catalyst Biosciences (advisory board), European Renal Association (scientific advisory board), Immunonephrology Working Group Young Nephrologists’ Platform, Otsuka (advisory board), and Vifor Pharma (advisory board); and honoraria from Delta4, Otsuka, and Vifor. Funding H.-J. Anders is funded by the Deutsche Forschungsgemeinschaft (AN372/30-1). 

mRNA COVID-19 Vaccines and Their Risk to Induce a Relapse of Glomerular Diseases

Background: Considering the indeterminate effects following the administration of three doses of the SARS-CoV-2 vaccine to patients under dialysis, the present study aimed to evaluate the immunogenicity rates of patients who received the three-dose vaccine. Methods: MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Controlled Trials were searched to select the relevant literature to perform the present review. We included randomized controlled trials, non-randomized trials, prospective, observational cohort, and case-control studies to assess the humoral and cellular immune responses following the administration of the three-dose SARS-CoV-2 vaccine to patients receiving dialysis. Results: Overall, 38 studies are included in the meta-analysis presented in this paper. For patients on dialysis, the overall humoral antibody response rate is 97% following three doses of mRNA or viral vector vaccines and 100% following four doses of the SARS-CoV-2 vaccine. A subgroup analysis shows that the antibody response rate is 96% for patients on hemodialysis (HD) and 100% for those receiving peritoneal dialysis (PD). The antibody response rate in the different immunogen-vaccinated groups tends to be higher than that in the same immunogen-vaccinated group (99% vs. 96%). For those who exhibit no response following two doses of the vaccine, the third and fourth doses can elevate the antibody response rate to 81%, and that number for low responders increases to 96%. However, the pooled results obtained from the relatively few trials conducted indicate that the positive T-cell response rate only increases to 59% following three doses of the vaccine. The antibody response rate is not different between dialysis and non-dialysis groups (relative risk = 0.95, 95% CI 0.90–1.02) following three doses of the vaccine. The relative risks for a SARS-CoV-2 breakthrough infection, all-cause mortality, and hospital admissions are 0.59 (95% CI 0.30–1.04), 0.63 (95% CI 0.35–1.12), and 0.53 (95% CI 0.37–0.74), respectively, when comparing three doses with two doses of the vaccine administered to the dialysis population. Conclusions: The third or fourth dose of the SARS-CoV-2 vaccine significantly increases the immunogenicity rates in dialysis patients, and this beneficial effect does not vary with the type of vaccine (the same or different immunogen vaccination), dialysis modality (HD or PD), or previous low response following the administration two doses of the vaccine. We believe that healthcare workers should encourage patients receiving dialysis to receive a third or fourth vaccine dose to strengthen their immunity against SARS-CoV-2.

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Immunogenicity Rates after SARS-CoV-2 Three-Dose Vaccination in Patients under Dialysis: A Systematic Review and Meta-Analysis

mRNA COVID-19 Vaccines and Their Risk to Induce a Relapse of Glomerular Diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081878

Structural and physiological changes of the kidney with age and its impact on chronic conditions and COVID-19

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected patients with kidney disease, causing significant challenges in disease management, kidney research and trainee education. For patients, increased infection risk and disease severity, often complicated by acute kidney injury, have contributed to high mortality. Clinicians were faced with high clinical demands, resource shortages and novel ethical dilemmas in providing patient care. In this review, we address the impact of COVID-19 on the entire spectrum of kidney care, including acute kidney injury, chronic kidney disease, dialysis and transplantation, trainee education, disparities in health care, changes in health care policies, moral distress and the patient perspective. Based on current evidence, we provide a framework for the management and support of patients with kidney disease, infection mitigation strategies, resource allocation and support systems for the nephrology workforce. In this Review, the authors summarize the challenges associated with the care of patients with kidney disease during the COVID-19 pandemic. They describe the major challenges and missed opportunities, global inequalities in health care, and offer a framework for future pandemic preparedness. 

/pdf/impact-of-the-covid-19-pandemic-on-the-kidney-community-3ofri2u7.pdf

Nicholas Carlson

Papers

Impact of the COVID-19 pandemic on the kidney community: lessons learned and future directions