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Sune Moeller Skov-Jeppesen,1,2 Nicky Anúel Petersen,1 Knud Bonnet Yderstraede,2,3 Boye L Jensen,4 Claus Bistrup,2,5 Lars Lund1,2 1Department of Urology, Odense University Hospital, Odense, Denmark; 2Clinical Institute, University of Southern Denmark, Odense, Denmark; 3Department of Endocrinology, Odense University Hospital, Odense, Denmark; 4Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; 5Department of Nephrology, Odense University Hospital, Odense, DenmarkCorrespondence: Sune Moeller Skov-Jeppesen, Department of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense, 5000, Denmark, Tel +45 51210911, Fax +45 65411726, Email sun_mjep@hotmail.comBackground: Low-intensity extracorporeal shockwave therapy (LI-ESWT) has been suggested as a treatment for vascular diseases such as ischemic heart disease, diabetic foot ulcers, and erectile dysfunction. Primarily, LI-ESWT is known for its ability to stimulate angiogenesis and activation of stem cells in target tissues. Application of LI-ESWT in chronic progressive renal diseases is a novel area. The aim of the present review was to summarize available data on the effects of LI-ESWT used in the setting of renal diseases.Methods: We systematically searched PubMed, Medline, and Embase databases for relevant studies. Our review included the results from preclinical animal experiments and clinical research.Results: Eleven animal studies and one clinical study were included in the review. In the animal studies, LI-ESWT was used for the treatment of hypertensive nephropathy (n=1), diabetic nephropathy (n=1), or various types of ischemic renal injury (ie, artery occlusion, reperfusion injury) (n=9). The clinical study was conducted in a single-arm cohort as a Phase 1 study with patients having diabetic nephropathy. In animal studies, the application of LI-ESWT was associated with several effects: LI-ESWT led to increased VEGF and endothelial cell proliferation and improved vascularity and perfusion of the kidney tissue. LI-ESWT reduced renal inflammation and fibrosis. LI-ESWT caused only mild side effects in the clinical study, and, similarly, there were no signs of kidney injury after LI-ESWT in the animal studies.Conclusion: LI-ESWT, as a non-invasive treatment, reduces the pathological manifestations (inflammation, capillary rarefaction, fibrosis, decreased perfusion) associated with certain types of renal disease. The efficacy of renal LI-ESWT needs to be confirmed in randomized clinical trials.Keywords: review, kidney disease, extracorporeal shockwave therapy, ESWT

Sune Moeller Skov-Jeppesen,1– 3 Knud Bonnet Yderstraede,3,4 Boye L Jensen,5 Claus Bistrup,3,6 Milad Hanna,7 Lars Lund1,3 1Department of Urology, Odense University Hospital, Odense, Denmark; 2OPEN, Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark; 3Clinical Institute, University of Southern Denmark, Odense, Denmark; 4Department of Endocrinology, Odense University Hospital, Odense, Denmark; 5Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; 6Department of Nephrology, Odense University Hospital, Odense, Denmark; 7Department of Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UKCorrespondence: Sune Moeller Skov-JeppesenDepartment of Urology, Odense University Hospital, Sdr. Boulevard 29, Odense C, 5000, DenmarkTel +45 51210911Fax +45 65411726Email sun_mjep@hotmail.comPurpose: Treatment with low-intensity shockwave therapy (LI-ESWT) is associated with angiogenesis and is suggested as a treatment for different types of vascular diseases. It was hypothesized that LI-ESWT improves the renal filtration barrier and halts the progression of GFR decline in diabetic kidney disease (DKD) potentially through VEGF and NO formation. We present the first data on LI-ESWT in human DKD.Methods: The study was designed as an interventional, prospective, one-arm, Phase 1 study. We investigated change in GFR and albuminuria in 28 patients with DKD treated with six sessions of LI-ESWT over three weeks. The patients were followed for six months. Urine excretion of kidney injury markers, vascular endothelial growth factor (VEGF) and nitric oxide metabolites (NOx) was studied after LI-ESWT.Results: There were no significant changes in GFR and albuminuria up to six months after LI-ESWT compared to baseline. Urine VEGF was transiently reduced one month after LI-ESWT, but there were no other significant changes in urine VEGF or NOx after LI-ESWT. Secondary analysis showed that NOx increased after LI-ESWT in patients who had low levels of NOx at baseline. Kidney injury marker trefoil factor 3 (TFF3) increased acutely after the first session of LI-ESWT indicating transient endothelial repair. Other markers of kidney injury were stable in relation to LI-ESWT.Conclusion: LI-ESWT treatment did not significantly improve kidney function and albumin excretion. It is concluded that LI-ESWT is not harmful. A randomized blinded study should be performed to clarify whether adjunctive treatment with LI-ESWT is superior to standard treatment of DKD.Keywords: albuminuria, clinical trial, diabetic kidney disease, glomerular filtration rate, ESWT, extracorporeal shockwave therapy

Abstract Background Neutrophil gelatinase associated lipocalin (NGAL) is a biomarker of kidney injury. We examined plasma levels of NGAL in a cohort of 57 kidney allograft recipients (Tx group, 39 ± 13 years), a uraemic group of 40 patients remaining on the waiting list (47 ± 11 years) and a control group of 14 healthy subjects matched for age, sex and body mass index (BMI). The kidney graft recipients were studied at baseline before transplantation and 3 and 12 months after transplantation and the uraemic group at baseline and after 12 months. Methods NGAL was measured using a validated in-house Time-Resolved Immuno-flourometric assay (TRIFMA). Repeated measurements differed by < 10% and mean values were used for statistical analyses. Spearman rank order correlation analysis and the Kruskal-Wallis non-parametric test were used to evaluate the association of NGAL concentrations with clinical parameters. Results Plasma NGAL levels before transplantation in the Tx and uraemic groups were significantly higher than in the healthy controls (1,251 μg/L, 1,478 μg/L vs. 163 μg/L, p < 0.0001). In the Tx group NGAL concentrations were associated with serum creatinine (R = 0.51, p < 0.0001), duration of end-stage renal failure (R = 0.41, p = 0.002) and leukocyte count (R = 0.29, p < 0.026). At 3 and 12 months plasma NGAL concentrations declined to 223 μg/L and 243 μg/L, respectively and were associated with homocysteine (R = 0.39, p = 0.0051 and R = 0.47, p = 0.0007). Conclusions Plasma NGAL is a novel marker of kidney function, which correlates to duration of end-stage renal failure (ESRD) and serum creatinine in uraemic patients awaiting kidney transplantation. Plasma NGAL is associated with homocysteine in transplanted patients. The prognostic value of these findings requires further studies.

Abstract: Background: The outcome of pediatric kidney transplantation depends on several factors, among these are the complications, which occur in relation to the surgical procedure. In this study, we present our experience with pediatric kidney transplantation in a steroid-free immunosuppression regimen, from a surgical point of view. Methods: Patient charts of pediatric kidney transplantations in the period 1998–2011 were reviewed. Surgical complications, acute rejection, and patient and graft survivals were recorded. Results: Sixty-one renal transplantations were performed in 58 patients. Thirty patients (49.1%) experienced a surgical complication, of which 11 (18%) required an explorative laparotomy. Overall the five-year Kaplan-Meier patient survival rate was 96.2% and the graft survival rate was 88.6%. Nine patients (14.7%) had an acute rejection episode within the first year after transplantation. No correlation was observed between surgical complications and acute rejection episodes or graft loss. Conclusions: This study indicated a high incidence of surgical complications among pediatric kidney transplantations when using a steroid-free immunosuppression regimen. Despite this, we observed high overall patient and graft survival, supporting the trend toward steroids avoidance in pediatric kidney transplantation. [Copyright &y& Elsevier]

Significance Statement: Proteinuria predicts accelerated decline in kidney function in CKD. The pathologic mechanisms are not well known, but aberrantly filtered proteins with enzymatic activity might be involved. The urokinase-type plasminogen activator (uPA)-plasminogen cascade activates complement and generates C3a and C5a in vitro / ex vivo in urine from healthy persons when exogenous, inactive, plasminogen, and complement factors are added. Amiloride inhibits uPA and attenuates complement activation in vitro and in vivo . In conditional podocin knockout (KO) mice with severe proteinuria, blocking of uPA with monoclonal antibodies significantly reduces the urine excretion of C3a and C5a and lowers tissue NLRP3-inflammasome protein without major changes in early fibrosis markers. This mechanism provides a link to proinflammatory signaling in proteinuria with possible long-term consequences for kidney function., Background: Persistent proteinuria is associated with tubular interstitial inflammation and predicts progressive kidney injury. In proteinuria, plasminogen is aberrantly filtered and activated by urokinase-type plasminogen activator (uPA), which promotes kidney fibrosis. We hypothesized that plasmin activates filtered complement factors C3 and C5 directly in tubular fluid, generating anaphylatoxins, and that this is attenuated by amiloride, an off-target uPA inhibitor., Methods: Purified C3, C5, plasminogen, urokinase, and urine from healthy humans were used for in vitro / ex vivo studies. Complement activation was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and ELISA. Urine and plasma from patients with diabetic nephropathy treated with high-dose amiloride and from mice with proteinuria (podocin knockout [KO]) treated with amiloride or inhibitory anti-uPA antibodies were analyzed., Results: The combination of uPA and plasminogen generated anaphylatoxins C3a and C5a from intact C3 and C5 and was inhibited by amiloride. Addition of exogenous plasminogen was sufficient for urine from healthy humans to activate complement. Conditional podocin KO in mice led to severe proteinuria and C3a and C5a urine excretion, which was attenuated reversibly by amiloride treatment for 4 days and reduced by >50% by inhibitory anti-uPA antibodies without altering proteinuria. NOD-, LRR- and pyrin domain-containing protein 3-inflammasome protein was reduced with no concomitant effect on fibrosis. In patients with diabetic nephropathy, amiloride reduced urinary excretion of C3dg and sC5b-9 significantly., Conclusions: In conditions with proteinuria, uPA-plasmin generates anaphylatoxins in tubular fluid and promotes downstream complement activation sensitive to amiloride. This mechanism links proteinuria to intratubular proinflammatory signaling. In perspective, amiloride could exert reno-protective effects beyond natriuresis and BP reduction., Clinical Trial Registry Name and Registration Number: Increased Activity of a Renal Salt Transporter (ENaC) in Diabetic Kidney Disease, NCT01918488 and Increased Activity of ENaC in Proteinuric Kidney Transplant Recipients, NCT03036748 ., (Copyright © 2024 by the American Society of Nephrology.)

Background: The aim of this study was to provide an overview of age, sex and primary renal disease (PRD) distribution among first kidney transplant recipients across Europe., Method: The European Renal Association (ERA) Registry database was used to obtain data on patients aged 20 years or older receiving their first kidney transplant between 2010 and 2019 from 12 European countries. The numbers and percentages of recipients in each age, sex and PRD group were calculated by country, donor type and year., Results: In total, 99 543 adults received a first kidney transplant. Overall, 23% of the recipients were 65 years or older, 36% were female, and 21% had glomerulonephritis and 15% diabetes mellitus as PRD. Compared with deceased donor kidney transplant recipients, living donor kidney transplant recipients were less often 65 years or older (13% versus 26%), more often had glomerulonephritis (25% versus 20%) and less often diabetes mellitus (8% versus 17%) as PRD. We found large international differences, which were most prominent for age and PRD and less prominent for sex. Over time, the largest change in recipient characteristics was observed for the percentage of recipients aged 65 years or older, increasing from 18% in 2010 to 28% in 2019 for all countries combined with a similar trend in most countries., Conclusion: We observed large differences for age and PRD distribution between recipients of living and deceased donor kidneys and between European countries. Over time, the percentage of older first kidney transplant recipients increased., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: The association between gestational diabetes mellitus (GDM) and incident kidney disease, the mediating effects of diabetes and hypertension, and the impact of severity of metabolic dysfunction during pregnancy on the risk of incident kidney disease were investigated in this study., Research Design and Methods: This Danish, nationwide, register-based cohort study included all women giving birth between 1997 and 2018. Outcomes included chronic kidney disease (CKD) and acute kidney disease, based on diagnosis codes. Cox regression analyses explored the association between GDM and kidney disease. A proxy for severity of metabolic dysfunction during pregnancy was based on GDM diagnosis and insulin treatment during GDM in pregnancy and was included in the models as an interaction term. The mediating effects of subsequent diabetes and hypertension prior to kidney disease were quantified using mediation analyses., Results: Data from 697,622 women were used. Median follow-up was 11.9 years. GDM was associated with higher risk of CKD (adjusted hazard ratio [aHR] 1.92; 95% CI 1.67-2.21), whereas acute kidney disease was unrelated to GDM. The proportions of indirect effects of diabetes and hypertension on the association between GDM and CKD were 75.7% (95% CI 61.8-89.6) and 30.3% (95% CI 25.2-35.4), respectively, as assessed by mediation analyses. The CKD risk was significantly increased in women with insulin-treated GDM and no subsequent diabetes compared with women without GDM (aHR 2.35; 95% CI 1.39-3.97)., Conclusions: The risk of CKD was significantly elevated after GDM irrespective of subsequent development of diabetes and hypertension. Furthermore, women with severe metabolic dysfunction during pregnancy had the highest CKD risk., (© 2024 by the American Diabetes Association.)

Background: In solid organ transplant (SOT) recipients, the humoral response following COVID-19 vaccination is reduced, as a result of their immunosuppressed treatment. In this study, we investigated antibody concentrations after booster vaccinations until the fifth dose, the latter by monovalent or bivalent BA1 or BA4/5 vaccines. In addition, we evaluated the efficacy of vaccination by recording breakthrough infections, hospitalizations, and deaths., Method: This prospective cohort study included 438 SOT recipients (>18 years) vaccinated with mRNA vaccines against COVID-19 from January 2021 until March 2023. Blood samples were drawn before and after each vaccination and tested for SARS-CoV-2 spike RBD IgG antibodies with the lowest and highest cut-off at 7.1 and 5,680 BAU/mL, respectively. Vaccine information, breakthrough infections, and hospitalizations were collected from the medical records., Results: Most participants received BNT162b2 and 61.4% received five vaccine doses. The response proportion in SOT recipients increased from 86.7% after the fourth dose to 93.0% following the fifth dose. Antibody concentration decreased with 142.7 BAU/mL between the third and fourth dose (median 132 days, Quartile 1: 123, Quartile 3: 148) and 234.3 BAU/mL between the fourth and fifth (median 250 days, Quartile 1: 241, Quartile 3: 262) dose among those without breakthrough infection (p=0.34). When comparing the Omicron BA.1 or Omicron BA.4/BA.5 adapted vaccines, no significant differences in antibody concentration were found, but 20.0% of SOT recipients receiving a monovalent fifth vaccine dose had a breakthrough infection compared to 4.0% and 7.9% among those who received BA.1 and BA.4/BA.5 adapted vaccines, respectively (p=0.04). Since January 2021, 240 (54.8%) participants had a breakthrough infection, and 22 were hospitalized, but no deaths were observed., Conclusions: The fifth COVID-19 vaccine dose raised antibody response to 93.0% of the study population. Additional booster doses, as well as bivalent vaccines, led to higher levels of antibody concentration in SOT recipients. We found a lower incidence of breakthrough infections among SOT recipients after receiving a bivalent vaccine as a fifth dose compared to those receiving a monovalent dose. Antibody concentrations did not wane when the time between doses was prolonged from four to eight months., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Christophorou, Nilsson, Petersen, Lindvig, Davidsen, Abazi, Poulsen, Pedersen, Justesen, Johansen, Bistrup, Madsen and Johansen.)

Background: Kidney transplant recipients receive maintenance immunosuppressive therapy to avoid allograft rejection resulting in increased risk of infections and infection-related morbidity and mortality. Approximately 98% of adults are infected with varicella zoster virus, which upon reactivation causes herpes zoster. The incidence of herpes zoster is higher in kidney transplant recipients than in immunocompetent individuals, and kidney transplant recipients are at increased risk of severe herpes zoster-associated disease. Vaccination with adjuvanted recombinant glycoprotein E subunit herpes zoster vaccine (RZV) prevents herpes zoster in older adults with excellent efficacy (90%), and vaccination of kidney transplant candidates is recommended in Danish and international guidelines. However, the robustness and duration of immune responses after RZV vaccination, as well as the optimal timing of vaccination in relation to transplantation remain unanswered questions. Thus, the aim of this study is to characterize the immune response to RZV vaccination in kidney transplant candidates and recipients at different timepoints before and after transplantation., Methods: The Herpes Virus Infections in Kidney Transplant Patients (HINT) study is a prospective observational cohort study. The study will include kidney transplant candidates on the waiting list for transplantation (n = 375) and kidney transplant recipients transplanted since January 1, 2019 (n = 500) from all Danish kidney transplant centers who are offered a RZV vaccine as routine care. Participants are followed with repeated blood sampling until 12 months after inclusion. In the case of transplantation or herpes zoster disease, additional blood samples will be collected until 12 months after transplantation. The immune response will be characterized by immunophenotyping and functional characterization of varicella zoster virus-specific T cells, by detection of anti-glycoprotein E antibodies, and by measuring cytokine profiles., Discussion: The study will provide new knowledge on the immune response to RZV vaccination in kidney transplant candidates and recipients and the robustness and duration of the response, potentially enhancing preventive strategies against herpes zoster in a population at increased risk., Trial Registration: ClinicalTrials.gov (NCT05604911)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Kidney transplant candidates may be incompatible with their intended living donors because of the presence of antibodies against HLA and/or ABO. To increase the possibility of finding an acceptable kidney donor for these patients, the Scandiatransplant Exchange Program (STEP) program within Scandiatransplant was launched in 2019., Methods: This is a retrospective review of our experiences from the first 4 y of the STEP program, including details about the match runs, performed transplantations, and recipient outcomes within the program., Results: During 2019-2022, 11 match runs and 4 reruns were performed. In total, 114 pairs and 6 anonymous donors participated in these match runs. Fifty-one pairs (45%) participated in 1 match run, 31 pairs (27%) participated in 2 match runs, and 32 pairs (29%) participated in ≥3 match runs. Seventy-two individuals (63%) participated because of HLA incompatibility, 19 (17%) because of ABO incompatibility, and 7 (6%) because of both HLA and ABO incompatibility.Forty percent of the patients enrolled in the program underwent transplantation. In total, 49 transplantations have so far been performed within the program, and 46 (94%) of the recipients had a functioning kidney graft at follow-up in February 2023., Conclusions: The STEP program offers sensitized patients an enlarged pool of living donors and a chance of a compatible international living donor, resulting in an increased number of total transplantations. Currently, STEP is one of the largest transnational kidney exchange programs and has improved the situation for patients waiting for kidney transplantation in Scandiatransplant., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Albuminuria in kidney transplant recipients (KTRs) is associated with hypertension and aberrant glomerular filtration of serine proteases that may proteolytically activate the epithelial Na + channel (ENaC). The present nonrandomized, pharmacodynamic intervention study aimed to investigate if inhibition of ENaC increases Na + excretion and reduces extracellular volume in KTRs dependent on the presence of albuminuria. KTRs with and without albuminuria (albumin-to-creatinine ratio > 300 mg/g, n = 7, and <30 mg/g, n = 7, respectively) were included and ingested a diet with fixed Na + content (150 mmol/day) for 5 days. On the last day, amiloride at 10 mg was administered twice. Body weight, 24-h urine electrolyte excretion, body water content, and ambulatory blood pressure as well as plasma renin, angiotensin II, and aldosterone concentrations were determined before and after amiloride. Amiloride led to a significant decrease in body weight, increase in 24-h urinary Na + excretion, and decrease in 24-h urinary K + excretion in both groups. Urine output increased in the nonalbuminuric group only. There was no change in plasma renin, aldosterone, and angiotensin II concentrations after amiloride, whereas a significant decrease in nocturnal systolic blood pressure and increase in 24-h urine aldosterone excretion was observed in albuminuric KTRs only. There was a significant correlation between 24-h urinary albumin excretion and amiloride-induced 24-h urinary Na + excretion. In conclusion, ENaC activity contributes to Na + and water retention in KTRs with and without albuminuria. ENaC is a relevant pharmacological target in KTRs; however, larger and long-term studies are needed to evaluate whether the magnitude of this effect depends on the presence of albuminuria. NEW & NOTEWORTHY Amiloride has a significant natriuretic effect in kidney transplant recipients (KTRs) that relates to urinary albumin excretion. The epithelial Na + channel may be a relevant direct pharmacological target to counter Na + retention and hypertension in KTRs. Epithelial Na + channel blockers should be further investigated as a mean to mitigate Na + and water retention and to potentially obtain optimal blood pressure control in KTRs.

Introduction: Contrast-enhanced CT (CECT) is widely used for diagnostic purposes. The use of contrast medium carries a risk for postcontrast acute kidney injury (PC-AKI), especially in patients with AKI or chronic kidney disease (CKD). Current guidelines recommend prophylactic intravenous hydration to prevent PC-AKI in high-risk patients. Oral hydration is non-inferior to intravenous hydration in patients with moderate CKD, but it has not been evaluated in high-risk patients., Methods and Analysis: The ENRICH trial will enrol 254 patients with estimated glomerular filtration rate ≤30 mL/min/1.73 m 2 undergoing intravenous CECT, who are block randomised (2-4-2) with stratification for CKD stage, diabetes status, and indication for referral to prophylactic treatment with oral or intravenous hydration. PC-AKI is defined as an absolute increase in SCr of >0.3 mg/dL or >1.5 from baseline at 2-5 days. Renal function will also be evaluated <90 days, <7 days and 1-3 days before intravenous CECT, and 25-40 days after intravenous CECT. Secondary outcomes include dialysis, renal adverse events, hospitalisation due to hydration-related or contrast-related sequelae, and all-cause mortality ≤30 days postcontrast. Pre- and postcontrast plasma and urinary biomarkers will be evaluated for diagnostic and prognostic accuracy of the primary and secondary outcomes., Ethics and Dissemination: Oral hydration is patient-friendly and less costly compared with intravenous hydration. If oral hydration is non-inferior to intravenous hydration in high-risk patients, it could be implemented as new hydration strategy, which will facilitate the clinical diagnosing of elective patients with severe CKD without unnecessary resource utilisation. The protocol is approved by the Regional Scientific Ethical Committee for Southern Denmark (S-20210126), and the Data Protection Agency (21/66779). The study is conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported in international peer-reviewed journals., Trial Registration Number: NCT05283512., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Since the first kidney transplant was conducted in Denmark in 1964, almost 10,000 transplants have been performed. Graft survival has improved over the past two decades despite the increase in age and comorbidities in both donors and recipients, but organ shortage remains a challenge. The focus of this review is to describe the challenges in kidney transplant and highlight the progress achieved in solving these challenges.

Objective: Pregnant women with type-1 diabetes have an increased risk of preeclampsia with kidney injury and cardiovascular complications. Urine excretion of plasmin and soluble membrane attack complex (sC5b-9) is elevated in severe preeclampsia. We hypothesized a coupling between these events and that active plasmin promotes intratubular complement activation and membrane deposition., Methods: Stored urine and plasma samples from pregnant women with type-1 diabetes (n = 88) collected at gestational weeks 12, 20, 28, 32, 36 and 38 were used. In the cohort, 14 women developed preeclampsia and were compared with 16 nonpreeclampsia controls., Results: Urine C3dg and sC5b-9-associated C9 neoantigen/creatinine ratios increased and were significantly higher in women who developed preeclampsia. Plasma concentrations did not change with gestation. Urine plasmin(ogen) correlated to urine C3dg (r = 0.51, P < 0.001) and C9 neoantigen (r = 0.68, P < 0.001); urine albumin correlated to C3dg (r = 0.44, P < 0.001) and C9 (r = 0.59, P < 0.001). Membrane-associated C3dg and C9 neoantigen was detected in urinary extracellular vesicles from patients but not controls at 36 weeks. Receiver operating characteristic curves showed that C3dg and C9 neoantigen were inferior to albumin as predictive biomarkers for preeclampsia., Conclusion: In preeclampsia, urinary excretion of activated complement relates significantly to albuminuria and to plasmin(ogen) but not to activation in plasma. Intratubular complement activation in preeclampsia is a postfiltration event tightly related to proteinuria/plasminogenuria and a possible mechanistic link to cellular damage and kidney injury., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Solid organ transplant (SOT) recipients have shown suboptimal antibody response following COVID-19 vaccination. Several risk factors for the diminished response have been identified including immunosuppression and older age, but the influence of different comorbidities is not fully elucidated., Method: This case-control study consisted of 420 Danish adult SOT recipients and 840 sex- and age-matched controls, all vaccinated with a third homologous dose of either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. The primary outcome was differences in humoral immune response. The secondary outcome was breakthrough infections. Additionally, we looked for factors that could predict possible differences between the two groups., Results: Response rate increased from 186/382 (49%) to 275/358 (77%) in SOT recipients and remained on 781/790 (99%) to 601/609 (99%) in controls following a third vaccine dose. SOT recipients had significantly lower median antibody concentrations after third dose compared to controls (332.6 BAU/ml vs 46,470.0 BAU/ml, p <0.001). Lowest median antibody concentrations were seen in SOT recipients with liver disease (10.3 BAU/ml, IQR 7.1-319) and diabetes (275.3 BAU/ml, IQR 7.3-957.4). Breakthrough infections occurred similarly frequent, 150 (40%) among cases and 301 (39%) among controls (p = 0.80)., Conclusion: A third COVID-19 vaccine dose resulted in a significant increase in humoral immunogenicity in SOT recipients and maintained high response rate in controls. Furthermore, SOT recipients were less likely to produce antibodies with overall lower antibody concentrations and humoral immunity was highly influenced by the presence of liver disease and diabetes. The prevalence of breakthrough infections was similar in the two groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Balsby, Nilsson, Petersen, Lindvig, Davidsen, Abazi, Poulsen, Holden, Justesen, Bistrup and Johansen.)

X-linked hypophosphatemic rickets (XLH) and m.3243A&gt;G mitochondrial disease share several clinical findings, including short stature, hearing impairment (HI), nephropathy, and hypertension. Here, we report on a case with the rare coincidence of these two genetic conditions. In early childhood, the patient presented with hypophosphatemia and bone deformities and was clinically diagnosed with XLH. This was genetically verified in adulthood with the identification of a de novo pathogenic deletion in phosphate-regulating endopeptidase homolog X-linked (PHEX). In addition, the patient developed HI and hypertension and when his mother was diagnosed with m.3243A&gt;G, subsequent genetic testing confirmed the patient to carry the same variant. Over the next two decades, the patient developed progressive renal impairment however without nephrocalcinosis known to associate with XLH which could indicate an m.3243A&gt;G-related kidney disease. Parallel with the progression of renal impairment, the patient developed hyperphosphatemia and secondary hyperparathyroidism. In conclusion, this case represents a complex clinical phenotype with the reversal of hypo- to hyperphosphatemia in XLH potentially mediated by the development of an m.3243A&gt;G-associated nephropathy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Following nephrectomy, the remaining kidney tissue adapts by an increase in glomerular filtration rate (GFR). In rats, hyperfiltration can be transferred by plasma. We examined whether natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) increase in plasma proportionally with kidney mass reduction and, if so, whether the increase relates to an increase in GFR., Methods: Patients (n = 54) undergoing partial or total unilateral nephrectomy at two Danish centres were followed for 1 year in an observational study. Glomerular filtration rate was measured before, and 3 and 12 months after surgery. Natriuretic propeptides (proANP and proBNP) and aldosterone were measured in plasma before and at 24 h, 5 days, 21 days, 3 months and 12 months. Cyclic guanosine monophosphate (cGMP) was determined in urine., Results: There was no baseline difference in GFR between total and partial nephrectomy (90.1 mL/min/1.73 m2 ± 14.6 versus 82.9 ± 18; P = 0.16). Single-kidney GFR increased after 3 and 12 months (12.0 and 11.9 mL/min/1.73 m2, +23.3%). There was no change in measured GFR 3 and 12 months after partial nephrectomy. ProANP and proBNP increased 3-fold 24 h after surgery and returned to baseline after 5 days. The magnitude of acute proANP and proBNP increases did not relate to kidney mass removed. ProANP, not proBNP, increased 12 months after nephrectomy. Plasma aldosterone and urine cGMP did not change. Urine albumin/creatinine ratio increased transiently after partial nephrectomy. Blood pressure was similar between the groups., Conclusion: ANP and BNP increase acutely in plasma with no relation to degree of kidney tissue ablation. After 1 year, only unilateral nephrectomy patients displayed increased plasma ANP, which could support adaptation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Aim: Cyclooxygenase-2 (COX-2) activity protects against oxidative stress and apoptosis early in experimental kidney injury. The present study was designed to test the hypothesis that COX-2 activity attenuates fibrosis and preserves microvasculature in injured kidney. The murine unilateral ureteral-obstruction (UUO) model of kidney fibrosis was employed and compared with human nephrectomy tissue with and without chronic hydronephrosis., Methods: Fibrosis and angiogenic markers were quantified in kidney tissue from wild-type and COX-2 -/- mice subjected to UUO for 7 days and in human kidney tissue. COX-enzymes, prostaglandin (PG) synthases, PG receptors, PGE 2 , and thromboxane were determined in human tissue., Results: COX-2 immunosignal was observed in interstitial fibroblasts at baseline and after UUO. Fibronectin, collagen I, III, alpha-smooth muscle actin, and fibroblast specific protein-1 mRNAs increased significantly more after UUO in COX-2 -/- vs wild-type mice. In vitro, fibroblasts from COX-2 -/- kidneys showed higher matrix synthesis. Compared to control, human hydronephrotic kidneys showed (i) fibrosis, (ii) no significant changes in COX-2, COX-1, PGE 2 -, and prostacyclin synthases, and prostacyclin and thromboxane receptor mRNAs, (iii) increased mRNA and protein of PGE 2 -EP 2 receptor level but unchanged PGE 2 tissue concentration, and (iv) two- to threefold increased thromboxane synthase mRNA and protein levels, and increased thromboxane B 2 tissue concentration in cortex and outer medulla., Conclusion: COX-2 protects in the early phase against obstruction-induced fibrosis and maintains angiogenic factors. Increased PGE 2 -EP 2 receptor in obstructed human and murine kidneys could contribute to protection., (© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients and candidates. The long-term durability of the antibody (AB) response is unknown. The same applies to a dose-dependent immune response., Methods: We studied the durability of the vaccine response after 18 months in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs). Both groups received either a normal dose (ND) or a double dose (DD) of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine. The average pneumococcal AB geometric mean concentration (GMC) was evaluated. A level ≥ 1 mg/L was considered protective against invasive pneumococcal disease (IPD)., Results: Sixty WLPs and 70 KTRs were included. The proportion of participants protected declined from 52% to 33% in WLPs and from 29% to 16% in KTRs, with the previously significant dose-effect in WLPs no longer present (40% DD vs. 27% ND; p = 0.273). Average pneumococcal AB GMCs remained significantly above baseline levels (all groups p ≤ 0.001). Drug-induced immunosuppression diminished the vaccine dose-effect., Conclusions: At follow-up, the pneumococcal prime-boost vaccination still provided significantly elevated average pneumococcal AB GMCs in both populations. Though the proportion of participants protected against IPD in WLP-DD and WLP-ND were statistically comparable, a DD may still be recommended for WLPs (EudraCT: 2016-004123-23).

Background: Pneumococcal prime-boost vaccination is recommended for solid organ transplant recipients, but is not thoroughly tested in this population. Furthermore, a pneumococcal vaccine dose effect has never been investigated, though observed in healthy adults. To assess whether a double dose of 13-valent pneumococcal conjugate vaccine (PCV13) and of 23-valent pneumococcal polysaccharide vaccine (PPV23) increases the immunogenicity of prime-boost vaccination in kidney transplant recipients (KTRs) and patients on the kidney transplant waiting list (WLPs), a phase 3, randomized, non-blinded trial was conducted., Methods: KTRs and WLPs were in parallel groups assigned either normal or double dosage of both vaccines 12 weeks apart. A 'protective response' was an average geometric mean concentration ≥ 1 mg/L based on 12 vaccine shared serotype-specific IgG antibodies. Furthermore, number of antibodies with ≥ 2-fold rises and individual serotype-specific antibody concentrations were evaluated. Follow-up was 48 weeks., Results: Seventy-four KTRs and 65 WLPs were enrolled. In WLPs, double dosage resulted in a significantly higher proportion of participants with a 'protective response' (66.7%), 5 weeks after PPV23, compared to normal dosage (35.5%), p = 0.015. KTRs exhibited no dose effect. After PPV23, all four groups had increased their number of serotypes with ≥ 2-fold rises (p ≤ 0.05 for both WLPs groups; p ≤ 0.01 for both KTRs groups). Vaccines were safe, well tolerated and still immunogenic at week 48., Conclusions: Data suggests that double dosage of pneumococcal vaccines used according to the prime-boost strategy might be recommendable for WLPs. Furthermore, our data supports PPV23́s additive effect to PCV13 in KTRs and WLPs. (EudraCT: 2016-004123-23)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: We studied factors related to humoral response in solid organ transplant (SOT) recipients following a three-dose regimen of an mRNA-based SARS-CoV-2 vaccine., Method: This was a prospective study of SOT recipients who received a third homologous dose of the BNT162b2 (Pfizer-BioNTech) vaccine. The anti-spike S1 IgG response was measured using the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) with a cut-off of 7.1 BAU/mL. Multiple logistic regression was used to determine the factors associated with humoral response., Results: In total, 395 SOT recipients were included. Anti-spike IgG was detected in 195/395 (49.4%) patients after the second dose and 261/335 (77.9%) patients after the third dose. The overall mean increase in antibody concentration after the third dose was 831.0 BAU/mL (95% confidence interval (CI) 687.4-974.5) and 159 (47.5%) participants had at least a 10-fold increase in antibody concentration after the third dose. The increase in antibody concentration was significantly higher among patients with detectable antibodies after the second dose than those without. Cumulative time from transplantation and liver recipients was positively associated with an antibody response, whereas older age, administration of prednisolone, and proliferation inhibitors were associated with diminished antibody response., Conclusion: Although the third dose of the BNT162b2 vaccine improved humoral responses among SOT non-responders following the second dose, the overall response remained low, and 22.1% did not develop any response. Patients at risk of a diminished vaccine response require repeated booster doses and alternative treatment approaches.

Kidney transplantation is associated with increased risk of cardiovascular morbidity. Interleukin (IL)-17A mediates kidney injury. Aldosterone promotes T helper 17 lymphocyte differentiation and IL-17A production through the mineralocorticoid receptor. In this exploratory, post hoc substudy, it was hypothesized that a 1-yr intervention with the mineralocorticoid receptor antagonist spironolactone lowers IL-17A and related cytokines and reduces epithelial injury in kidney transplant recipients. Plasma and urine samples were obtained from kidney transplant recipients from a double-blind randomized clinical trial testing spironolactone ( n = 39) versus placebo ( n = 41). Plasma concentrations of cytokines interferon-γ, IL-17A, tumor necrosis factor-α, IL-6, IL-1β, and IL-10 were determined before and after 1-yr treatment. Urine calbindin-to-creatinine, clusterin-to-creatinine, kidney injury molecule-1-to-creatinine, osteoactivin-to-creatinine, trefoil factor 3 (TFF3)-to-creatinine, and VEGF-to-creatinine ratios were analyzed. Blood pressure and plasma aldosterone concentration at inclusion did not relate to plasma cytokines and injury markers expect for urine TFF3-to-creatinine ratios that correlated positively to blood pressure. None of the cytokines changed in plasma after spironolactone intervention. Plasma IL-17A increased in the placebo-treated group. Spironolactone induced an increase in plasma K + (0.4 ± 0.4 mmol/L). This increase did not correlate with plasma IL-17A or urine calbindin and TFF3 changes. Ongoing treatment at inclusion with angiotensin-converting enzyme inhibitor and/or ANG II receptor blockers was not associated with changed levels of IL-17A and injury markers and had no effect on the response to spironolactone. Urinary calbindin and TFF3 decreased in the spironolactone-treated group with no difference in between-group analyses. In conclusion, irrespective of ongoing ANG II inhibition, spironolactone has no effect on plasma IL-17A and related cytokines or urinary injury markers in kidney transplant recipients. NEW & NOTEWORTHY The mineralocorticoid receptor antagonist spironolactone had no direct anti-inflammatory effects on prohypertensive interleukin-17A or distal nephron epithelial injury markers in kidney transplant recipients.