Anti-SARS-CoV-2 Revaccination Success in Kidney Transplant Recipients With No Initial Humoral Response Is Linked to Primary Vaccine Type.

Background: While anti-SARS-CoV-2 vaccination success in kidney transplant recipients (KTR) after two doses and 1273-mRNA was associated with higher seroconversion rates compared to BNT162b2-mRNA in our "DIA-Vacc Study" (NCT04799808), it remains unclear whether this may also be the case in non-responding KTR after a third vaccination dose. Materials and Methods: Non-responding KTR (after two mRNA vaccinations) were investigated 4.5-6 months after study enrollment at first vaccination. One hundred sixty-six of 193 received a third vaccination between 3.5 and 5 months after the initial study enrollment and were always investigated 4 weeks later, exploring humoral immune response (ELISA) and specific cellular responses (interferon-γ release assay). Sixty-seven of 193 measurements in KTR were done immediately before the third vaccination or in KTR without further vaccination at 4.5-6 months. Results: Of 193 KTR with no initial immune response 4 weeks after the second vaccination, 106/87 were immunized twice with 1273-mRNA/BNT162b2-mRNA, respectively. Additional mRNA booster vaccination led to positive seroconversion rates of 30-50%, while 16% of the initial non-responders demonstrated a delayed seroconversion without any booster vaccination. Using logistic regression analysis, a positive IgG response after the third vaccination was 23% more likely if the primary vaccine type was 1273-mRNA compared to BNT162b2-mRNA (OR = 4.420, 95% CI [1.208-16.173], p = 0.025). Primary vaccine type, a weak anti-SpikeS1 IgG response 4 weeks after second vaccination (3.2-35.2 BAU/ml, p < 0.001) and a lack of MMF/MPA as part of the immunosuppressive treatment (trend, p = 0.06) but no other variables studied correlated with seroconversion success. Conclusion: This observational study adds important evidence toward using 1273-mRNA as the primary mRNA vaccine type for immunosuppressed KTR.

Risk of strong antibody decline in dialysis and transplant patients after SARS-CoV-2mRNA vaccination: Six months data from the observational Dia-Vacc study.

Background: Vulnerable dialysis and kidney transplant patients show impaired seroconversion rates compared to medical personnel eight weeks after SARS-CoV-2mRNA vaccination. Methods: We evaluated six months follow up data in our observational Dia-Vacc study exploring specific cellular (interferon-γ release assay) or/and humoral immune responses after 2x SARS-CoV-2mRNA vaccination in 1205 participants including medical personnel (125 MP), dialysis patients (970 DP) and kidney transplant recipients (110 KTR) with seroconversion (de novo IgA or IgG antibody positivity by ELISA) after eight weeks. Findings: Six months after vaccination, seroconversion remained positive in 98% of MP, but 91%/87% of DP/KTR (p = 0·005), respectively. Receptor binding domain-IgG (RBD-IgG) antibodies were positive in 98% of MP, but only 68%/57% of DP/KTR (p < 0·001), respectively. Compared to MP, DP and KTR were at risk for a strong IgG or RBD-IgG decline (p < 0·001). Within the DP but not KTR group male gender, peritoneal dialysis, short time on dialysis, BNT162b2mRNA vaccine, immunosuppressive drug use and diabetes mellitus were independent risk factors for a strong decline of IgG or RBD antibodies. The percentage of cellular immunity decline was similar in all groups. Interpretation: Both vulnerable DP and KTR groups are at risk for a strong decline for IgG and RBD antibodies. In KTR, antibody titres peak at a markedly lower level and accelerated antibody decline is mixed with a delayed/increasing IgG, RBD-IgG, or cellular immune response in a 16% fraction of patients. In both populations, immune monitoring should be used for early timing of additional booster vaccinations. Funding: This study was funded by the Else Kröner Fresenius Stiftung, Bad Homburg v. d. H., grant number Fördervertrag EKFS 2021_EKSE.27.

10-Year Evaluation of Adherence and Satisfaction with Information about Tolvaptan in ADPKD: A Single-Center Pilot Study.

PURPOSE: Tolvaptan is the only approved drug for the treatment of autosomal dominant polycystic kidney disease (ADPKD) and causes significant polyuria with secondary polydipsia. Up to now, there is no study that examines tolvaptan adherence and satisfaction with information received about tolvaptan in ADPKD patients 10 years after starting tolvaptan therapy. PATIENTS AND METHODS: This pilot study includes 12 ADPKD patients that were formerly enrolled in the tolvaptan registration trials and have continued to use tolvaptan thereafter. Data were collected once via questionnaires on patients' self-reported adherence (MARS-D: Medication Adherence Report Scale - German version) and satisfaction with the information received about tolvaptan (SIMS-D: Satisfaction with Information about Medicines Scale - German version) at the time of the present study. In addition, serum creatinine levels and clinical data were evaluated. RESULTS: The MARS-D demonstrated strong adherence to tolvaptan (range of possible score: 5-25; median: 23.5; range of individual results: 5). The SIMS-D showed a high level of satisfaction with the information received about the action and usage of tolvaptan (SIMS-D AU subscale; range of possible score: 0-9; median: 9, range of individual results: 1), but also revealed dissatisfaction regarding the information received about potential problems of tolvaptan in 42% of the participants (SIMS-D PP subscale; range of possible score: 0-8; median: 8, range of individual results: 6). During treatment with tolvaptan, the eGFR decreased from 78.8 ± 15.9 mL/min/1.73 m2 to 48.3 ± 19.4 mL/min/1.73 m2 (P < 0.0001). CONCLUSION: Although patients reported strong adherence to tolvaptan, there was still dissatisfaction with the information received about potential problems with tolvaptan. Therefore, our data suggest conduction of at least one patient survey on adherence and satisfaction with the information received about tolvaptan during any tolvaptan treatment to improve patient education regarding the use of tolvaptan in slowing down of ADPKD.

Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine.

BACKGROUND: Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality. METHODS: We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273. RESULTS: SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients. CONCLUSION: Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

Comparative study of microvascular function: Forearm blood flow versus dynamic retinal vessel analysis.

OBJECTIVE: Recently, dynamic retinal vessel analysis (DVA) has gained interest for investigation of microvascular function but comparative measurements with standard methods like the forearm blood flow technique (FBF) are uncommon till now. METHODS: We recruited 23 high-risk cardiovascular patients (Risk) and 17 healthy persons (Ctrl). During the FBF experiment, postocclusive reactive hyperaemia (RH) as well as endothelium-dependent and independent vasodilation was measured by infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) into the brachial artery. The dynamic vessel analyzer was applied for measurement of the retinal arterial and venous response to flickering light during DVA and for determination of the central retinal arterial (CRAE) and venous equivalent (CRVE). RESULTS: Forearm blood flow technique was significantly attenuated in the patient group during postocclusive RH (p < .005). The increase of FBF in response to SNP did not differ significantly between the two groups (p = .09). In contrast, the FBF response to ACh was significantly blunted in the patient group (p < .05), indicating endothelial dysfunction. DVA did not detect any difference of retinal arterial (p = .68) or retinal venous (p = .93) vasodilation between both groups. The CRAE (p = .55) and CRVE (p = .83) did not differ significantly in either group. CONCLUSIONS: Forearm blood flow and DVA cannot be regarded as equivalent methods for testing of microvascular function. Possible explanations include differences in the vascular beds and vessel diameters examined as well as differences in the trigger mechanisms applied. Further studies are needed to define the role of DVA in this context.

Con: Tolvaptan for autosomal dominant polycystic kidney disease-do we know all the answers?

According to recent literature, tolvaptan ameliorates the natural decline of renal function in autosomal dominant polycystic kidney disease. Tolvaptan is an orally available vasopressin V2 receptor antagonist. We describe herein the remaining questions and problems: it is unclear from the published work what influence tolvaptan has on total kidney volume. The consequences of hepatotoxicity for the subsequent dosing of tolvaptan have not been reported. A vasopressin V2 antagonist will cause polyuria and polydipsia and tolvaptan may influence quality of life (QOL), however, there are no QOL data. The cost-effectiveness of tolvaptan is borderline. It is unknown at which stage of renal failure tolvaptan therapy may have to be stopped. There are no established criteria to determine the ineffectiveness of tolvaptan. It is presently undecided whether a steady high water intake is able to imitate the renal effects of tolvaptan. Finally, the cause of worsening glomerular filtration rate after the start of tolvaptan is unknown.

A new apparatus for standardized rat kidney biopsy.

Survival biopsies are frequently applied in rat kidney disease models, but several drawbacks such as surgical kidney trauma, bleeding risk and variable loss of kidney tissue are still unsolved. Therefore, we developed an easy-to-use core biopsy instrument and evaluated whether two consecutive kidney biopsies within the same kidney can be carried out in a standardized manner. On day 0, 18 Lewis rats underwent a right nephrectomy and 9 of these rats a subsequent first biopsy of the left kidney (Bx group). 9 control rats had a sham biopsy of the left kidney (Ctrl group). On day 7, a second kidney biopsy/sham biopsy was performed. On day 42, all animals were sacrificed and their kidneys were removed for histology. Biopsy cylinders contained 57±28 glomeruli per transversal section, representing an adequate sample size. PAS staining showed that the biopsy depth was limited to the renal cortex whereas surgical tissue damage was limited to the area immediately adjacent to the taken biopsy cylinder. On day 42, the reduction of functional renal mass after two biopsies was only 5.2% and no differences of body weight, blood pressure, proteinuria, serum creatinine, glomerulosclerosis, interstitial fibrosis or number of ED-1 positive macrophages were found between both groups. In summary, our apparatus offers a safe method to perform repetitive kidney biopsies with minimal trauma and sufficient sample size and quality even in experimental disease models restricted to one single kidney.

Injured kidney endothelium is only marginally repopulated by cells of extrarenal origin.

The role of bone marrow marrow-derived cells after kidney endothelial injury is controversial. In this study, we investigated if and to what extent extrarenal cells incorporate into kidney endothelium after acute as well as during chronic endothelial injury. Fischer F-344wt (wild type) rat kidney grafts were transplanted into R26-hPAP (human placental alkaline phosphatase) transgenic Fischer F-344 recipient rats to allow identification of extrarenal cells by specific antibody staining. A severe model of renal thrombotic microangiopathy was induced via graft perfusion with antiglomerular endothelial cell (GEN) antibody and resulted in eradication of 85% of the glomerular and 69% of the peritubular endothelium (GEN group). At week 4 after injury, renal endothelial healing as well as recovery of the kidney function was seen. Endothelial chimerism was evaluated by double staining for hPAP and endothelial markers RECA-1 or JG-12. Just 0.25% of the glomerular and 0.1% of the peritubular endothelium was recipient derived. In a second experiment, chronic endothelial injury was induced by combination of kidney transplantation with 5/6 nephrectomy (5/6 Nx group). After 14 wk, only 0.86% of the peritubular and 0.05% of the glomerular endothelium was of recipient origin. In summary, despite demonstration of extensive damage and loss as well as excellent regeneration, just a minority of extrarenal cells were incorporated into kidney endothelium in rat models of acute and chronic renal endothelial cell injury. Our results highlight that kidney endothelial regeneration after specific and severe injury is almost exclusively of renal origin.

Influence of peritoneal dialysis solution on measurements of fluid status by bioimpedance spectroscopy.

PURPOSE AND METHODS: The accurate estimation of volume status is a central problem in dialysis patients. Recently, a bioimpedance spectroscopy (BIS) device (BCM Body Composition Monitor FMC, Germany) has attained growing interest in this regard. By processing the raw data for extracellular water (ECW) and intracellular water (ICW) by means of a validated body composition model, this device allows a quantification of the individual fluid overload (FO) compared to a representative healthy population. In this study, we addressed the issue whether the presence of peritoneal dialysate has an impact on measurements of FO by BIS in PD patients. RESULTS: Forty-two BIS measurements using the BCM device were performed both in the absence (D-) and presence (D+) of peritoneal dialysate in 17 stable PD patients. Data for ECW, ICW and FO (D+; D-) were analyzed by paired t test and linear regression. Mean FO was 0.99 ± 1.17 L in D- and 0.94 ± 1.27 in D+ (p = n.s. paired t test). Linear regression demonstrated an excellent degree of conformity between FO (D-) and FO (D+) (r (2) = 0.93). CONCLUSION: The presence of peritoneal fluid in PD patients has a negligible influence on measurements of FO by BIS. The BIS measurements can be therefore conveniently and reliably done without emptying the peritoneal cavity; this may facilitate the use of BIS in this particular group of patients.

Should we prescribe blood pressure lowering drugs to every patient with advanced chronic kidney disease? A comment on two recent meta-analyses.

Antihypertensive treatment is an essential, life-prolonging measure in primary hypertension. It prevents apoplexy, myocardial infarction, and hypertensive kidney failure. Chronic kidney failure is associated with hypertension and an accelerated form of arteriosclerosis. Demise from cardiovascular affliction is a leading cause of death in renal patients (chronic renal failure stages II-IV, renal failure requiring dialysis, renal transplantation). What, then, is the role of antihypertensive treatment in such patients, and, specifically, what is achieved by renin-angiotensin-aldosterone (RAA) system modifying agents? Two meta-analyses have recently investigated these issues. An article in The Lancet evaluated eight studies on dialysis patients (n = 1679). It concluded that antihypertensives are beneficial in reducing cardiovascular morbidity and mortality. However, we criticize these conclusions and show that the data are not convincingly in favor of antihypertensive treatment. A meta-analysis in the American Heart Journal assessed the role of antihypertensive agents and RAA system modifying drugs in 45,758 patients (from 25 studies), who were in stages I-III of renal failure, i.e., not (yet) requiring dialysis. The authors claim that angiotensin- -converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) significantly reduced cardiovascular outcomes. However, our analysis of the data is not consistent with their conclusions. It showed that the results were quite mixed, that the authors may have overemphasized the positive results, and that considering all the results, it should be concluded that antihypertensive treatments, including those with ACEI/ARB, may not be superior to placebo (sic!) in renal patients. Rather than doing meta-analyses, larger primary studies are needed to reveal the real role of antihypertensive treatments in renal patients.

Altered phenotype of natural killer cell subsets after haploidentical stem cell transplantation.

OBJECTIVE: Haplotype-mismatched CD34(+) selected allogeneic stem cell transplantation (HASCT) has been described as a therapeutic option for patients with acute myeloid leukemia. The success of this regimen is based mainly on natural killer (NK) cell-mediated antileukemia effects. MATERIALS AND METHODS: We prospectively investigated NK-cell (CD56(+)/CD3(-)) reconstitution, including expression of antileukemia effector molecules in patients undergoing HASCT. RESULTS: Although absolute NK-cell numbers rapidly increased, their phenotype notably differed compared to healthy controls. In fact, the "effector" CD56(dim) subset was significantly reduced, as was the NKG2D expression on "regulatory" CD56(bright) cells. Perforin was completely absent on NK cells in one-third of patients. The expression of Fas-ligand (Fas-L) on NK cells as well as soluble Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plasma levels were also significantly lower after HASCT. In contrast, expression of TRAIL on CD56(dim) cells and interleukin-15 plasma levels were upregulated. Because the death rate due to relapse or infectious complications was high in the initial phase of the trial, subsequent patients received an adoptive infusion of donor NK cells followed by interleukin-2 in vivo in order to augment NK-cell function. This led to a distinct upregulation of perforin and Fas-L on the CD56(dim) subset accompanied by increased NK-cell cytotoxicity in vitro. CONCLUSION: The phenotype of reconstituting NK cells after HASCT is significantly altered. Whether the clinical outcomes of patients undergoing this regimen can be improved by a cytokine-based modulation of NK-cell activity needs to be determined.

The graft content of donor T cells expressing gamma delta TCR+ and CD4+foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors.

PURPOSE: Recently, high numbers of regulatory T cells within the stem cell graft were described to be associated with less graft-versus-host disease (GVHD) after related peripheral blood stem cell transplantation (PBSCT). Studies in mice also suggest a distinct role of gamma delta TCR(+) T cells in mediating GVHD. Therefore, the aim of this study was to define the yet-unknown role of regulatory and gamma delta TCR(+) T cells in human PBSCT from unrelated donors. EXPERIMENTAL DESIGN: The frequency of both T-cell subsets within the graft was analyzed in 63 patients receiving unrelated allogeneic PBSCT. The respective amounts were quantified by flow cytometry and PCR and further correlated with clinical outcome. RESULTS: The grafts contained a median of 11.2 x 10(6)/kg CD4(+)foxp3(+) and 9.8 x 10(6)/kg gamma delta TCR(+) T cells, respectively. Patients receiving more CD4(+)foxp3(+) cells had a lower cumulative incidence of acute GVHD II-IV (44% versus 65%, P=0.03). Interestingly, in patients who received higher concentrations of donor gamma delta TCR(+) T cells, acute GVHD II-IV was more frequent (66% versus 40%, P=0.02). In multivariate analysis, only the graft concentration of gamma delta TCR(+) T cells (P=0.002) and a positive cytomegalovirus status of the recipient (P = 0.03) were significantly associated with the occurrence of acute GVHD II-IV. CONCLUSION: Graft composition of T-cell subsets seems to affect the outcome of patients receiving allogeneic PBSCT from unrelated donors. Therefore, selective manipulation or add-back of particular subsets might be a promising strategy to reduce the incidence of GVHD.