Therapeutic measures aimed at optimising organ function prior to transplantation—whether by conditioning the donor after determination of brain death or by improving organ preservation after kidney removal—have the potential to enhance outcomes after transplantation. The particular advantage is that, unlike any optimised immunosuppressive therapy, a favourable effect can be achieved without side effects for the organ recipient. In recent years, several such measures have been tested in controlled clinical trials on large patient cohorts following kidney transplantation. Hypothermic pulsatile machine perfusion, in particular, has become the focus of interest, but interventions in the donor prior to organ removal, such as the administration of low-dose dopamine until the start of cold perfusion as an example of conditioning antioxidant therapy and therapeutic donor hypothermia in the intensive care unit after brain death confirmation, have also significantly reduced the frequency of dialysis after transplantation with far less effort and cost. With regard to benefits for graft survival, the database for all procedures is less clear and controversial. The aim of this review article is to re-evaluate the available clinical evidence from large multicentre controlled trials, which have also significantly influenced later meta-analyses, and to assess the significance for use in routine clinical practice.

The quality of donor kidneys may be improved by taking therapeutic measures that begin before transplant. A recent large-scale prospective trial from the United States by Malinoski et al 1 Malinoski D. Saunders C. Swain S. et al. Hypothermia or machine perfusion in kidney donors. N Engl J Med. 2023; 388: 418-426 Crossref PubMed Scopus (6) Google Scholar reported that machine perfusion (MP) was superior to targeted donor hypothermia in reducing delayed graft function (DGF) after kidney transplant from a brain-dead donor (DBD). Delayed graft function was defined as need for dialysis during the first 7 days after transplant. However, the trial found no measurable effect on 1-year graft survival.

Renal biopsies are the gold standard for diagnosis, staging, and prognosis of underlying parenchymal kidney disease. This article provides an overview of the current indications and highlights ways to reduce bleeding complications in order to achieve optimal diagnostic yield with minimal risk to the patient. Novel indications have emerged from the increasing use of new molecularly targeted oncologic therapies in recent years, which often induce immune-mediated renal disease. On the other hand, the detection of specific antibodies against target antigens on podocytes in the sera of patients with new-onset nephrotic syndrome has now relativized the indication for biopsy in membranous nephropathy. The use of semi-automatic spring-loaded biopsy devices and real-time ultrasound considerably declined the complication rate and is the current standard. Percutaneous renal biopsies are overall a safe procedure if contraindications are considered. A coagulation disorder needs to be excluded beforehand, and an elevated blood pressure must be reduced to the normotensive range with medications. A laparoscopic approach or a radiology interventional procedure through the internal jugular vein may be considered for obtaining a kidney tissue sample if there is an urgent indication and a bleeding tendency cannot be adequately corrected. Major bleeding after a percutaneous renal biopsy can usually be managed with selective arterial embolization of the injured renal vessel. The use of a 16-gauge needle is the most reasonable compromise between diagnostic benefit and risk of complication. In the routine diagnostic, the biopsy specimen is examined with light microscopy, immunohistochemistry, and electron microscopy. Combination with modern molecular pathology techniques will contribute to more precise insights into the development and progression of kidney disease, which will likely refine future treatments in nephrology.

Background. Kidney transplant recipients are at increased risk of SARS-CoV-2 infection and a more severe course of COVID-19. Methods. We conducted a quantitative serologic testing of antibodies specific for the wild type of SARS-CoV-2 and the Omicron variant of concern before and after a third-dose vaccination, either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) in a cohort of 103 stable kidney transplant recipients (median [range] age, 58 [22–84] y, 57 men [55.3%]). Results. Third-dose vaccination increased the seroconversion rate from 57.3% to 71.8%. However, despite a marked rise of the antibody concentrations after the booster, 55.4% and 11.6% only formed neutralizing antibodies against the SARS-CoV-2 wild type and Omicron, respectively. Treatment with mycophenolic acid/mycophenolate mofetil (in strata of the dose quartiles), advanced age, and‚ above all‚ impaired renal function (eGFR <60 mL/min) adversely influenced the humoral immunity regarding seroconversion and inhibition of the wild type of SARS-CoV-2. Conclusions. Apart from immunosuppressive therapy, the humoral vaccination response is largely affected by nonmodifiable factors in kidney transplant recipients. With the currently leading and clinically easier Omicron variant, this puts into perspective the strategy to significantly enhance the protective efficacy of the available vaccines by reducing or temporarily stopping proliferation inhibitors, not least considering the inherent rejection risk with a possible deterioration of graft function.

Vaccine availability has contributed significantly to reducing the morbidity and mortality of the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients requiring long-term immunosuppressive therapy are exposed to an increased risk [1] as they are limited in developing an adequate vaccination response. A 66-year-old male with a history of pulmonary sarcoidosis presented with severe renal function impairment in October 2020. He had received steroids for longer than 1 year until 2017. Physical examination was normal. Laboratory results revealed a serum creatinine 2.59 mg/dL, urea 97 mg/dL, creatinine clearance 28 mL/min, serum calcium 3.08 mmol/L, intact parathyroid hormone 9.1 ng/L (normal 11.3–67.0), hydroxyvitamin D 45.1 ng/mL (30–100), soluble interleukin-2 receptor (sIL-2R) 1830 U/mL (158– 623), angiotensin-converting enzyme (ACE) 87.9 U/L (8.0–52.0), Creactive protein 6 mg/L and an inconspicuous sediment with a tubular proteinuria of 263 mg/g creatinine. On ultrasound, both kidneys were of normal size and shape. A recently performed computed tomography scan ruled out hilar adenopathy or recurrent interstitial lung disease. Based on the present findings and medical history, sarcoid interstitial nephritis was the most likely diagnosis. We decided not to do a renal biopsy because of an inherited coagulation disorder, and started with 0.5 mg/kg prednisolone. We intended to add azathioprine early because of known osteoporosis, to save steroids and because of severe kidney involvement with the risk of irreversible organ damage [2]. However, azathioprine needed to be stopped due to elevated liver enzymes. We initiated a second-line treatment with mycophenolate in January 2021. Before prescribing mycophenolate, our patient appeared somewhat under-immunosuppressed as indicated by a recurrent rise in sIL-2R. We temporarily increased prednisolone to 15 mg. He then achieved sustained stabilization of his kidney function with 5 mg prednisolone and 360 mg mycophenolic acid twice a day (Figure 1). He received two-dose BNT162b2 vaccination on 26 March and 7 May, but had no antibody response [EUROIMMUN antiSARS-CoV-2 ELISA assay negative for immunoglobulin G (IgG) and immunoglobulin A (IgA) on 2 July 2021]. Because of the increasing infection risk from the emerging SARS-CoV-2 delta variant, we paused mycophenolate on 9 July and administered another dose of BMT162b2 on 24 July. Subsequent antibody determination on 18 August targeting the specific SARS-CoV-2 spike protein S1 receptor binding domain with the aforementioned ELISA showed a pronounced immune response, with an IgG ratio of 9.01 and an IgA ratio of 5.18, respectively. Antibody levels are expressed as the ratio of the sample signal to a calibrator-assigned cut-off signal. Number and type of immunosuppressive drugs are major determinants of seroconversion failure after SARS-CoV-2 vaccination [3]. In a cohort study of 404 patients with rheumatic and musculoskeletal disease, most of the non-responders were

Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4–33.3] µmol/24 h versus 34.8 [IQR 25.6–46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06–1.45]; p = 0.007). During median follow-up for 5.3 [4.5–6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44–2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted.

Background. Postmortal organ donor rates remain low in Germany, whereas donor age has been increasing considerably in the last decades. As a consequence of low donation rates older and more marginal donor kidneys are accepted for transplantation. However, procured kidneys from very old a/o marginal donors may be considered as not suitable for transplantation as a single organ and subsequently be discarded. However, dual transplantation of both kidneys from such donors may provide an opportunity to nevertheless use these organs for renal transplantation, thereby providing the twofold nephron mass as a single kidney transplantation. Methods. We compared in this retrospective analysis the outcome of 10 recipients of a dual kidney transplantation (DKT) with 40 matched recipients of a single kidney transplantation (SKT). Recipients were matched for donor and recipient age (ie, a maximum age difference of +/- 10 years in a ratio of 1:4 for DKT vs SKT recipients). In addition, a second SKT control group of 10 SKT recipients being transplanted immediately before each DKT recipient with a kidney from a donor aged >= 65 years was used for comparison. All renal transplant recipients were observed for up to 3 years or until July 31, 2020. Results. Mean donor and recipient age was 77.2 +/- 4.6/75.1 +/- 6.6/82.1 +/- 7.9 and 66.4 +/- 5.8/66.1 +/- 6.0/64.8 +/- 8.4 for SKT group 1/SKT group 2/DKT, respectively. Procurement serum creatinine concentrations were significantly higher in the DKT group in comparison to the SKT control group 1 (P = .019) as was the rate of transplant artery atherosclerosis (P = .021). Furthermore, Kidney Donor Profile Index, and Kidney Donor Risk Index were significantly higher (P = .0138/P = .064, and P < .001/P = .038) in the DKT group than in SKT group 1 and 2. Rates of acute rejection and delayed graft function were not significantly different between groups, though biopsy-proven acute rejection was numerically higher in the SKT groups. Patient survival and overall and death-censored graft survival rates were also not significantly different between groups, although they tended to be higher after DKT. Conclusions. DKT provides an opportunity to successfully use postmortal kidneys even from donors aged >80 years and a Kidney Donor Profile Index >95% for renal transplantation. DKT may thereby increase the available pool of donors to better serve patients with end-stage renal disease on the waiting list.

Therapeutic hypothermia, hypothermic pulsatile machine perfusion (MP), and renal-dose dopamine administered to stable brain-dead donors have shown efficacy to reduce the dialysis requirement after kidney transplantation. In a head-to-head comparison of the three major randomized controlled trials in this field, we estimated the number-needed-to-treat for each method, evaluated costs and inquired into special features regarding long-term outcomes. The MP and hypothermia trials used any dialysis requirement during the first postoperative week, whereas the dopamine trial assessed >1 dialysis session as primary endpoint. Compared to controls, the respective rates declined by 5.7% with MP, 10.9% with hypothermia, and 10.7% with dopamine. Costs to prevent one endpoint in one recipient amount to approximately $17 000 with MP but are negligible with the donor interventions. MP resulted in a borderline significant difference of 4% in 3-year graft survival, but a point of interest is that the preservation method was switched in 25 donors (4.6%) for technical reasons. Graft survival was not improved with dopamine on intention-to-treat but suggested an exposure-response relationship with infusion time. MP was less efficacious and cost-effective to prevent posttransplant dialysis. Whether the benefit on early graft dysfunction achieved with any method will improve long-term graft survival remains to be established.

This study assessed if serum carnosinase (CNDP1) activity and concentration in patients with type 2 diabetes mellitus (T2D) with diabetic nephropathy (DN) differs from those without nephropathy. In a cross-sectional design 127 patients with T2D with DN ((CTG)5 homozygous patients n = 45) and 145 patients with T2D without nephropathy ((CTG)5 homozygous patients n = 47) were recruited. Univariate and multivariate regression analyses were performed to predict factors relevant for serum CNDP1 concentration. CNDP1 (CTG)5 homozygous patients with T2D with DN had significantly lower CNDP1 concentrations (30.4 ± 18.3 vs 51.2 ± 17.6 µg/ml, p < 0.05) and activity (1.25 ± 0.5 vs 2.53 ± 1.1 µmol/ml/h, p < 0.05) than those without nephropathy. This applied for patients with DN on the whole, irrespective of (CTG)5 homozygosity. In the multivariate regression analyses, lower serum CNDP1 concentrations correlated with impaired renal function and to a lesser extend with the CNDP1 genotype (95% CI of regression coefficients: eGFR: 0.10–1.94 (p = 0.001); genotype: − 0.05 to 5.79 (p = 0.055)). Our study demonstrates that serum CNDP1 concentrations associate with CNDP1 genotype and renal function in patients with T2D. Our data warrant further studies using large cohorts to confirm these findings and to delineate the correlation between low serum CNDP1 concentrations and renal function deterioration in patients with T2D.

A previous donor intervention trial found that therapeutic hypothermia reduced delayed graft function (DGF) after kidney transplantation. This retrospective cohort study nested in the randomized dopamine trial (ClinicalTrials.gov identifier: NCT000115115) investigates the effects of spontaneous donor hypothermia (core body temperature <36°C) on initial kidney graft function, and evaluates 5-year graft survival. Hypothermia assessed by a singular measurement in the intensive care unit 4-20 hours before procurement was associated with less DGF after kidney transplantation (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.34-0.91). The benefit was greater when need for more than a single posttransplant dialysis session was analyzed (OR 0.48, 95%CI 0.28-0.82). Donor dopamine ameliorated dialysis requirement independently from hypothermia in a temporal relationship with exposure (OR 0.93, 95%CI 0.87-0.98, per hour). A lower core body temperature in the donor was associated with lower serum creatinine levels before procurement, which may reflect lower systemic inflammation and attenuated renal injury from brain death. Despite a considerable effect on DGF, our study failed to demonstrate a graft survival advantage (hazard ratio [HR] 0.83, 95%CI 0.54-1.27), whereas dopamine treatment was associated with improved long-term outcome (HR 0.95, 95%CI 0.91-0.99 per hour).

Background A previous donor intervention trial found that induction of mild therapeutic hypothermia in the brain-dead donor reduced the dialysis requirement after kidney transplantation. Consequences on the performance of cardiac allografts after transplantation were not explored to date. Methods Cohort study investigating 3-year heart allograft survival according to spontaneous core body temperature (CBT) assessed on the day of organ procurement. The study is nested in the database of the randomized trial of donor pretreatment with low-dose dopamine (ClinicalTrials.gov identifier: NCT000115115). Results Ninety-nine heart transplant recipients who had received a cardiac allograft from a multiorgan donor enrolled in the dopamine trial were grouped by tertiles of the donor's CBT assessed by a mere temperature reading 4 to 20 hours before procurement (lowest, 32.0-36.2°C; middle, 36.3-36.8°C; highest, 36.9-38.8°C). Baseline characteristics considering demographics of donors and recipients, concomitant donor treatments, donor hemodynamic, and respiratory parameters as well as underlying cardiac diseases in recipients, pretransplant hemodynamic assessments, including pretransplant inotropic/mechanical support, urgency, and waiting time were similar. A lower CBT was associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile; P = 0.02, and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93°C; P = 0.02) when CBT was included as continuous explanatory variable in the Cox regression analysis. Conclusions A lower CBT in the brain-dead donor before procurement may associate with an unfavorable clinical course after heart transplantation. More research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended.

e appreciate the comments and thoughts Mensink organs and that the most important issue was the macroscopic Wet al have regarding our recently published Extended Pancreas Donor Program study on the extension of donor age for pancreas transplantation. We would like to respond to and clarify a few points. Mensink et al suggested that very strict selection criteria were used in our study for the extended criteria organs, accounting for the low number of 61 standard organs and 18 extended donor criteria (EDC) organs after about 3 years. However, these low numbers are not a result of any special or strict selection criteria. The standard group was completed in March 2013 after reaching the planned number of patients; thereafter, only inclusion of patients that received an EDC (donor age, 50-60 years or body mass index [BMI], 30-34 kg/m) organ was allowed. Unfortunately, Germany suffered from a marked decline in donor numbers from >1200 donors per year before 2012 to <900 in the following years. With this drastic reduction of donor and transplantation numbers, inclusion rate was substantially decreased mainly due to lack of organ supply. In our correspondence with the different transplant centers, we received feedback that surgeons used the same risk evaluation parameters as for regular

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 μg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Renal‐dose dopamine has fallen out of favor in the intensive care unit ( ICU ) during past years due to its ineffectiveness to prevent impending or to ameliorate overt renal failure in the critically ill. By contrast, growing evidence indicates that low‐dose dopamine administered to the stable organ donor after brain death confirmation improves the clinical course of transplanted organs after kidney and heart transplantation. Ensuring a thorough monitoring for potential circulatory side effects, employment of dopamine at a dose of 4 μg/kg/min is safe in the deceased donor. Among recipients, the advantageous effect is easy to achieve, inexpensive, and devoid of adverse side effects. The mode of action relies on dopamine’s propensity to mitigate injury in various cell systems from isolated transplantable organs under cold storage conditions. The present review article summarizes the clinical evidence of dopamine donor pretreatment in solid organ transplantation and focuses on the underlying molecular mechanisms of cellular protection. Introducing the routine use of low‐dose dopamine for the management of the brain‐dead donor in the ICU before procurement provides an evidence‐based strategy to improve graft outcome after kidney transplantation without conferring harm to non‐renal grafts, namely to livers and hearts, in cases of multi‐organ donation.