Donor organ intervention before kidney transplantation: Head-to-head comparison of therapeutic hypothermia, machine perfusion, and donor dopamine pretreatment. What is the evidence?

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.

Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy.

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.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

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.

Dopamine in transplantation: Written off or comeback with novel indication?

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.

Dopamine and lipophilic derivates protect cardiomyocytes against cold preservation injury.

Donor heart allografts are extremely susceptible to prolonged static cold storage. Because donor treatment with low-dose dopamine improves clinical outcome after heart transplantation, we tested the hypothesis that dopamine and its lipophilic derivate, N-octanoyl dopamine (NOD), protect cardiomyocytes from cold storage injury. Neonatal rat cardiomyocytes were treated with dopamine or NOD or left untreated and subsequently subjected to static cold storage (8-12 hours). Dopamine- and NOD-treated cardiomyocytes displayed a better viability compared with untreated cells after hypothermia. In untreated cardiomyocytes, cell damage was reflected by lactate dehydrogenase (LDH) release and a decrease in intracellular ATP. NOD was approximately 20-fold more potent than dopamine. Similarly to cardiomyocytes in vitro, rat hearts perfused with NOD before explantation showed significantly lower LDH release after static cold storage. ATP regeneration and spontaneous contractions after cold storage and rewarming only occurred in treated cardiomyocytes. Hypothermia severely attenuated isoprenaline-induced cAMP formation in control but not in dopamine- or NOD-treated cells. Esterified derivates of NOD with redox potential and lipophilic side chains reduced cell damage during cold storage similarly to NOD. In contrast to dopamine, neither NOD nor its derivates induced a significant ß-adrenoceptor-mediated elevation of cellular cAMP levels. The ß1-adrenoceptor antagonist atenolol and D1/D2 receptor antagonist fluphenazine had no impact on the protective effect of NOD or dopamine. We conclude that dopamine as well as NOD treatment mitigates cold preservation injury to cardiomyocytes. The beneficial effects are independent of ß-adrenoceptor or dopaminergic receptor stimulation but correlate with redox potential and lipophilic properties.

Vagal stimulation in brain dead donor rats decreases chronic allograft nephropathy in recipients.

BACKGROUND: Although it has been shown that a vagus nerve stimulation of brain dead (BD) donors leads to an improvement of renal function in recipients in an acute allograft rejection model, its influence on chronic allograft nephropathy is still unknown. In the present study, we assessed the influence of donor vagus nerve stimulation on survival, renal function and histology in a chronic allograft model. METHODS: Brain death was induced in Fisher rats, and electro-stimulation of the vagus nerve was applied in one group (BD + vagus) during the whole course of BD (6 h). Unstimulated BD Fisher donor rats served as controls. Allogeneic Lewis rats were used as recipients and no immunosuppressive medication was administered. Blood and urine samples were collected every second week. Banff classification was assessed from harvested allografts. RESULTS: Vagal stimulation of BD donors resulted in an improved survival of recipients. Long-term renal function was significantly better in these recipients as reflected by improved creatinine clearance. Banff classification revealed significantly reduced vasculopathy and less tubulopathy in the BD + vagus group. CONCLUSIONS: In conclusion, our data demonstrate a long-lasting beneficial effect of vagus nerve stimulation in BD donors on the renal transplantation outcome. Hence, activation of the cholinergic anti-inflammatory pathway in BD donors may represent a novel therapeutic modality to reduce chronic allograft nephropathy without any side effects for the recipient.

Donor Conditioning and Organ Pre-Treatment Prior to Kidney Transplantation: Reappraisal of the Available Clinical Evidence.

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.

Renal Biopsy for Diagnosis in Kidney Disease: Indication, Technique, and Safety.

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.

SARS-CoV-2 Vaccination in Kidney Transplant Recipients-Stratified Analysis of the Humoral Immune Response.

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.

UW is superior compared with HTK after prolonged preservation of renal grafts.

BACKGROUND: In recent clinical studies, the efficacy of histidine-tryptophan-ketoglutarate (HTK) in kidney transplantation was questioned. This study compares the efficacy of University of Wisconsin (UW) and HTK solutions on transplantation outcome. MATERIALS AND METHODS: Rat kidneys were preserved for different periods of cold ischemia (CIT). Heat capacity of the solutions, temperature of the grafts, renal function (RF), and histology were assessed before and after transplantation, respectively. RESULTS: After prolonged CIT, recipient survival was superior in the UW - (100%) compared with the HTK group (10%). In the latter, severe tubular necrosis, DNA damage, and renal inflammation were observed, reflected by an increased KIM-1, IL6, and P-selectin expression. CIT correlated negatively with RF in both groups. RF recovered significantly faster in the UW group. LDH-release and ATP depletion after cold storage of tubular cells were lower in UW than in HTK. Heat capacity was significantly higher for UW than for HTK. Accordingly, renal temperature was lower. CONCLUSIONS: Prolonged preservation in UW solution results in a better renal function and less tissue damage compared with HTK, possibly due to improved cooling and better cell viability of the graft. The use of HTK for renal allografts should therefore be reconsidered, particularly when CIT is expected to be long.

Effects of N-acetylcysteine on renal hemodynamics in contrast media-induced nephropathy.

BACKGROUND: N-acetylcysteine (NAC) has been proposed to prevent radiocontrast nephropathy in high-risk patients. METHODS: The effect of single-dose and prolonged administration of NAC before application of either the ionic, high-osmolar radiocontrast agent diatrizoate sodium (DTZ) or the nonionic, low-osmolar radiocontrast agent iohexol (IOH) in a rat model combining uninephrectomy, salt depletion, and administration of indomethacin was explored. Arterial blood pressure and total, cortical, and medullary blood flow were continuously recorded in anesthetized Sprague-Dawley rats. RESULTS: NAC had no effect on renal hemodynamics in control rats. Both DTZ and IOH induced biphasic changes in renal blood flow and cortical renal blood flux and persistently reduced medullary blood flux. Neither single-dose nor prolonged administration of NAC prevented the hemodynamic changes following administration of DTZ or IOH, respectively. Acute prophylactic administration of NAC prevented increased urinary ET excretion after injection of IOH and, to a smaller degree, of DTZ. Both an ionic, high-osmolar (DTZ) and a nonionic, low-osmolar (IOH) radiocontrast agent induce marked changes in renal hemodynamics in salt-depleted rats treated with indomethacin. CONCLUSIONS: Renal perfusion is not affected by NAC application in a model of experimental contrast nephropathy in rats. Other effects of NAC might thus account for the presumed renoprotective properties.

Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study.

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.

CORMs protect endothelial cells during cold preservation, resulting in inhibition of intimal hyperplasia after aorta transplantation in rats.

Allograft vasculopathy is the leading cause for chronic transplant loss. We investigated if the addition of carbon monoxide releasing molecules (CORMs) to the preservation solution would protect the endothelium from cold preservation injury in an aortic transplantation model. In particular, we tested if CORM preserve vascular functioning and limit neo-intima formation following cold preservation (Cp). Abdominal aortas from Lewis or Fisher rats were subjected to Cp in University of Wisconsin (UW) solution to which 50 µm of CORM-3 was added or not. Hereafter, whole mount staining, acetylcholine mediated vasorelaxation (AMV) and aortic transplantation was performed. In vitro CORM-3 protected human umbilical vein endothelial cells from Cp injury and prevented denudation and intercellular gap formation in aortic grafts. Cp resulted in loss of AMV of aorta segments. By contrast, AMV was preserved after the addition of CORM-3 during Cp. Two months after transplantation Cp of aorta grafts resulted in an increased adventitial remodelling and neo-intima formation. This was significantly blunted by CORM-3 in syngeneic recipients. Our study demonstrates that addition of CORM-3 to UW solution prevents endothelial damage, thereby maintaining vascular function directly after cold preservation. Hence, our findings might offer a novel strategy to prevent vascular damage during CP.

Effects of donor pretreatment with dopamine on graft function after kidney transplantation: a randomized controlled trial.

CONTEXT: Kidney graft function after transplantation can be improved through pharmacological donor pretreatment to limit organ injury from cold preservation. OBJECTIVE: To determine whether pretreatment of brain-dead donors with low-dose dopamine improves early graft function in human renal transplant recipients. DESIGN, SETTING, AND PATIENTS: Randomized, open-label, multicenter, parallel-group trial of 264 deceased heart-beating donors and 487 subsequent renal transplants performed at 60 European centers between March 2004 and August 2007 (final follow-up, December 31, 2008). Eligible donors were stable under low-dose norepinephrine with a normal serum creatinine concentration on admission. INTERVENTIONS: Donors were randomized to receive low-dose dopamine (4 mug/kg/min). MAIN OUTCOME MEASURES: Dialysis requirement during first week after transplantation. RESULTS: Dopamine was infused for a median of 344 minutes (IQR, 215 minutes). Dialysis was significantly reduced in recipients of a dopamine-treated graft. Fewer recipients in the treatment group needed multiple dialyses (56/227; 24.7%; 95% CI, 19.0%-30.3%; vs 92/260; 35.4%; 95% CI, 29.5%-41.2%; P = .01). The need for multiple dialyses posttransplant was associated with allograft failure after 3 years (HR, 3.61; 95% CI, 2.39-5.45; P < .001), whereas a single dialysis was not (HR, 0.67; 95% CI, 0.21-2.18; P = .51). Besides donor dopamine (OR, 0.54; 95% CI, 0.35-0.83; P = .005), cold ischemic time (OR, 1.07; 95% CI, 1.02-1.11 per hour; P = .001), donor age (OR, 1.03; 95% CI, 1.01-1.05 per year; P < .001), and recipient body weight (OR, 1.02; 95% CI, 1.01-1.04 per kg; P = .009) were independent explanatory variables in a multiple logistic regression model. Dopamine resulted in significant but clinically meaningless increases in the donor's systolic blood pressure (3.8 mm Hg; 95% CI, 0.7-6.9 mm Hg; P = .02) and urine production before surgical recovery of the kidneys (29 mL; 95% CI, 7-51 mL; P = .009) but had no influence on outcome. CONCLUSION: Donor pretreatment with low-dose dopamine reduces the need for dialysis after kidney transplantation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00115115.

ANCA-associated vasculitis following influenza vaccination: causal association or mere coincidence?

Whether autoimmune or rheumatic disease may be precipitated after vaccination is controversially discussed among experts. Here we describe 4 cases of new onset or relapsing antineutrophil cytoplasmic antibodies associated vasculitis occurring in timely association with influenza vaccination. In the literature different subtypes of vasculitis have been repeatedly reported after influenza vaccination. Several trials in patients with preexisting auto-immune disease failed to indicate an increased risk for disease recurrence after influenza vaccination but these investigations might be underpowered to detect this very rare but relevant side effect. Although our report does not prove a causal association between vaccination and vasculitis, it seems possible that in rare cases vaccination might induce vasculitic disease.

Hypothermic injury: the mitochondrial calcium, ATP and ROS love-hate triangle out of balance.

BACKGROUND/AIMS: Catecholamines prevent hypothermic cell death which accounts for severe tissue damage and impaired allograft function after prolonged organ preservation. Here, we identified cellular processes which govern hypothermia-mediated cell death in endothelial cells and how they are influenced by dopamine. METHODS: Lactate dehydrogenase assay, intracellular ATP, reactive oxygen species and reduced thio-group measurement, intracellular calcium measurement and mitochondrial calcium staining were performed in the study. RESULTS: Intracellular ATP was almost completely depleted within 12 hrs of hypothermic preservation in untreated human umbilical vein endothelial cells (HUVEC), while dopamine pre-treatment significantly delayed ATP depletion. 4 hrs after hypothermia a redox imbalance was observed in untreated cells, which increased with the duration of hypothermia. The redox imbalance was primarily caused by depletion of SH reduction equivalents and was significantly inhibited by dopamine. In addition, hypothermia-induced Ca(2+) influx and mitochondrial Ca(2+) accumulation were both prevented by dopamine. The protective effect of dopamine was abrogated by ionomycin and sodium azide and partly by oligomycin and CCCP. CONCLUSIONS: Our data demonstrated that loss of intracellular ATP, generation of a redox imbalance and accumulation of intracellular Ca(2+) underlie cold preservation injury. Dopamine improves the redox balance, prevents intracellular Ca(2+) accumulation and delays ATP depletion.