Optimized donor management and organ preservation before kidney transplantation.

Kidney transplantation is a major medical improvement for patients with end-stage renal disease, but organ shortage limits its widespread use. As a consequence, the proportion of grafts procured from extended criteria donors (ECD) has increased considerably, but this comes along with increased rates of delayed graft function (DGF) and a higher incidence of immune-mediated rejection that limits organ and patient survival. Furthermore, most grafts are derived from brain dead organ donors, but the unphysiological state of brain death is associated with significant metabolic, hemodynamic, and pro-inflammatory changes, which further compromise patient and graft survival. Thus, donor interventions to preserve graft quality are fundamental to improve long-term transplantation outcome, but interventions must not harm other potentially transplantable grafts. Several donor pretreatment strategies have provided encouraging results in animal models, but evidence from human studies is sparse, as most clinical evidence is derived from single-center or nonrandomized trials. Furthermore, ethical matters have to be considered especially concerning consent from donors, donor families, and transplant recipients to research in the field of donor treatment. This review provides an overview of clinically proven and promising preclinical strategies of donor treatment to optimize long-term results after kidney transplantation.

High prevalence of retinal endothelial dysfunction in obesity WHO class III.

BACKGROUND: The extent of retinal endothelial dysfunction (ED) in patients with obesity is unknown. We evaluated markers of endothelial dysfunction to assess cardiovascular risk in patients with obesity WHO III° and their interrelation with classical cardiovascular risk factors. METHODS: 120 patients (mean age 42.7±10.6 years, 87 women) were prospectively evaluated for metabolic and cardiovascular risk using anthropometry, cardiovascular risk factors, lipid and glucose profiles. Intima media thickness (IMT) as marker of subclinical atherosclerosis, ED of retinal vessels, and the arteriole-to-venule ratio (AVR) of retinal vessels were assessed. RESULTS: The mean BMI in our cohort was 48.7 kg/m(2). We diagnosed an overall prevalence of impaired glucose metabolism of 69.2%. 71.6% and 65.2% presented with arterial hypertension or dyslipidemia, respectively. Prevalences of retinal ED, pathologically reduced AVR, and enlarged IMT were 62.7%, 56.6% and 30%, respectively. Markers of endothelial function demonstrated correlation of neck to height ratio with dilatation of arteries (r=-0.333, p=0.01) and HDL cholesterol with dilatation of veins (r=-0.393, p=0.002). AVR was significantly related to neck circumference (r=-0.269, p=0.004). CONCLUSION: Retinal ED, AVR, and IMT as direct noninvasive surrogate measures of cardiovascular risk showed a high prevalence in patients with obesity WHO III°. We found no association of classical parameters for metabolic or cardiovascular risk with markers of endothelial dysfunction. Therefore, we have to hypothesize that other factors also play a pivotal role in the development of vascular pathology in patients with obesity.

Patient and Graft Survival After Dual Kidney Transplantation With Marginal Donors in Comparison to Matched Control Groups.

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.

Effects of a clinical pathway on quality of care in kidney transplantation: a non-randomized clinical trial.

PURPOSE: Standardization of care is essential for improving outcome of kidney transplantation (KT). Clinical pathways (CPs) are known to standardize and improve perioperative care for a number of interventions. In transplantation medicine, however, pertinent evidence is very limited. This study evaluates effects of a CP on quality of care in KT. MATERIALS AND METHODS: Consecutive patients (n=32) undergoing KT between July 2006 and August 2007 who were treated with a CP were compared to patients (n=44) treated without CP between January 2005 and June 2006. Several quality indicators regarding process and outcome were compared between groups. RESULTS: Quality of care was significantly higher in the CP group for the following indicators: timely removal of central venous catheters, wound drains, and Foley catheters and control of cyclosporine levels, respiratory exercising, and pain control. Median stay decreased non-significantly from 21.4 to 18.3 days. There was significantly less delayed graft function in the CP group. All other outcome indicators showed no significant differences. CONCLUSIONS: Implementation of a CP for KT improves the quality of perioperative treatment by standardizing care. Regarding effects on outcome, no clear conclusion can be drawn. We recommend that large randomized studies are conducted to evaluate the latter issue.

Non-phenacetin analgesics and analgesic nephropathy: clinical assessment of high users from a case-control study.

BACKGROUND: A recent large-scale case-control study on analgesic nephropathy (SAN) [1] found no increased risk of end-stage renal disease (ESRD) in users of combined or single formulations of phenacetin-free analgesics. In a subgroup of 22 high users, however, a dose-dependent increased risk was found, which raised the question if these patients presented or not with analgesic nephropathy (AN). METHODS: The individual questionnaires of this subgroup of high users were reviewed, and the total lifetime intake of different types of analgesics was calculated. For evidence of AN, the following data were considered: (1) the amount and type of analgesics consumed, (2) the cause of ESRD, as diagnosed by the nephrologist in charge of the patient and (3) renal imaging and other relevant laboratory data. RESULTS: This group of ESRD patients consumed on average 7.8 kg of antipyretic analgesics (range 30.8-2.7 kg) over an average of 21.5 years (range 35-6 years). Single analgesics were exclusively used by 12 patients (54.5%) and combined analgesics by 5 patients (22.7%), while 5 patients used both. None of the patients was diagnosed as having AN, and a review of the questionnaires did not disclose evidence suggestive of AN. The possibility that, irrespective of AN, the analgesic (ab)use contributed to the progression of existing renal diseases cannot be answered in the absence of well-defined criteria. The data supporting the existence of such an analgesic-associated nephropathy (AAN) are, however, not consistent and most likely due to confounding by indication. CONCLUSION: In a group of ESRD patients with high use of non-phenacetin analgesics, no evidence of AN was found. There is no evidence that (ab)use of analgesics or NSAIDs other than phenacetin leads to a pathologically or clinically defined renal disease that could be named AN or AAN.

Pneumocystis jiroveci pneumonia in a patient with Wegener's granulomatosis treated efficiently with caspofungin.

A patient with Wegener's granulomatosis was on steroids (20 mg prednisolone per day) when he fell ill with an atypical pneumonia caused by Pneumocystis, which was diagnosed by detection of antigen in repeated bronchial lavage specimens. Because other treatment options were contraindicated, he received intravenous caspofungin starting with a loading dose of 70 mg and a maintenance dose of 50 mg daily over 3 weeks thereafter. The patient's complaints subsequently resolved within days after initiation of treatment. Tolerability of the drug was excellent. No relapse occurred during the ongoing 4 years, although immunosuppressive therapy continued.

Evaluation of hepatocyte growth factor as a sensitive marker for early detection of acute renal allograft rejection.

BACKGROUND: It has been shown that hepatocyte growth factor (HGF), besides its well-established hepatotrophic effect in liver regeneration, is involved in the regeneration of the kidney after injury. In the present study we investigated whether HGF can serve as a marker for detection of acute rejection in the early posttransplantation period. METHODS: HGF levels were determined in pre- and posttransplant sera (up to day 21) of 26 recipients with biopsy-proven acute rejection, 30 recipients with acute tubular necrosis (ATN), and 32 recipients without posttransplant complications. RESULTS: Although no association was found between pretransplant HGF and death-censored functional graft survival, receiver operating characteristic (ROC) curves demonstrated that HGF measured during the entire posttransplant study period, and especially on days 3 to 5, was a good marker for differentiating recipients who subsequently developed acute rejection from recipients with an uncomplicated course (P<0.0001, specificity 87%, sensitivity 84%). HGF measured from day 3 until day 21 posttransplantation, and especially on days 7 to 9, was also a sensitive marker for differentiating recipients with ATN from recipients with an uncomplicated course (P<0.0001). If considered in combination with sCD30, the diagnostic value of HGF was further improved. While 73% of samples from patients with impending rejection were positive for both HGF and sCD30, 94% of samples from nonrejecting patients were double-negative and none of the samples from this group fell into the double-positive category (P<0.0001). CONCLUSIONS: Our data suggest that HGF measured during the early posttransplant period might be a useful parameter for early detection of acute renal allograft rejection.

Multislice CT-angiography in percutaneous postinterventional hematuria and kidney bleeding: Influence of diagnostic outcome on therapeutic patient management. Preliminary results.

BACKGROUND: The aims of this study were to assess the value of multislice CT-angiography (MS-CT-A) in percutaneous postinterventional kidney bleeding and to determine the influence of diagnostic outcome on therapeutic patient management. A recommendation for the interdisciplinary patient work-up for the emergency room was offered. METHODS: Between April 2003 and January 2006, 12 patients with hematuria and clinically suspected renal bleeding underwent MS-CT-A for emergency diagnostic assessment. The spectrum of kidney injuries on CT was analyzed according to an organ-scaling scheme. The efficacy of MS-CT-A with regard to confirmation of active arterial bleeding was evaluated as well as the therapeutic consequences for patient management. RESULTS: In seven patients (59%) staged grade V renal injury, active renal arterial bleeding was detected on CT-A. Patients immediately underwent therapeutic angiography with confirmation of arterial bleeding and successful embolization. Four patients (33%) were staged grade I renal injury with subcapsular kidney hematoma but no active hemorrhage. Therefore, these patients were not exposed to further therapeutic intervention. One patient (8%) was diagnosed grade II renal injury with superficial cortical renal parenchyma tear and no active bleeding on CT-A. CONCLUSIONS: MS-CT-A is a valuable, fast and objective emergency tool for assessment of postinterventional renal hemorrhage. Detection of contrast material extravasation to affirm ongoing arterial bleeding and to localize bleeding site at the level of segmental or interlobar renal artery is a predictor for the need for further treatment and justifies therapeutic radiological or surgical management.

Acetylcysteine for prevention of contrast nephropathy: meta-analysis.

BACKGROUND: Contrast nephropathy is associated with increased in-hospital morbidity and mortality and leads to extension of hospital stay in patients with chronic renal insufficiency. Acetylcysteine seems to be a safe and inexpensive way to reduce contrast nephropathy. We aimed to assess the efficacy of acetylcysteine to prevent contrast nephropathy after administration of radiocontrast media in patients with chronic renal insufficiency. METHODS: We did a meta-analysis of randomised controlled trials comparing acetylcysteine and hydration with hydration alone for preventing contrast nephropathy in patients with chronic renal insufficiency. The trials were identified through a combined search of the BIOSIS+/RRM, MEDLINE, Web of Science, Current Contents Medizin, and The Cochrane Library Databases. We used incidence of contrast nephropathy 48 h after administration of radiocontrast media as an outcome measure. FINDINGS: Seven trials including 805 patients were eligible according to our inclusion criteria and were analysed. Overall incidence of contrast nephropathy varied between 8% and 28%. Since significant heterogeneity was indicated by the Q statistics (p=0.016) we used a random-effects model to combine the data. Compared with periprocedural hydration alone, administration of acetylcysteine and hydration significantly reduced the relative risk of contrast nephropathy by 56% (0.435 [95% CI 0.215-0.879], p=0.02) in patients with chronic renal insufficiency. Meta-regression revealed no significant relation between the relative risk of contrast nephropathy and the volume of radiocontrast media administered or the degree of chronic renal insufficiency before the procedure. INTERPRETATION: Compared with periprocedural hydration alone, acetylcysteine with hydration significantly reduces the risk of contrast nephropathy in patients with chronic renal insufficiency. The relative risk of contrast nephropathy was not related to the amount of radiocontrast media given or to the degree of chronic renal insufficiency before the procedure.

Soluble CD30 as a predictor of kidney graft outcome.

BACKGROUND: In the present study, we investigated whether the soluble form of CD30 (sCD30), a marker for T helper 2-type cytokine-producing T cells, is increased in sera of potential kidney graft recipients. We also investigated whether the pretransplantation serum sCD30 content is related to kidney graft survival. METHODS: Pretransplantation sera of 844 cadaver kidney recipients from three transplant centers in Germany were tested for serum sCD30 content using a commercially available ELISA kit. RESULTS: Kidney graft recipients showed a significantly higher serum sCD30 content than healthy controls (P<0.0001). High sCD30 serum content was associated with graft rejection. The 2-year graft survival rate in recipients with a high pretransplantation serum sCD30 was 68+/-6%, significantly lower than the 86+/-1% rate in recipients with a low sCD30 (P<0.0001). Importantly, high sCD30 was indicative of an increased risk of graft loss even in recipients without lymphocytotoxic alloantibodies. CONCLUSION: These data show that an elevated pretransplantation serum sCD30 reflects an immune state that is detrimental for kidney graft survival.

Compression stockings limit the incidence of postoperative lymphocele in kidney transplantation.

BACKGROUND: Lymphoceles account for considerable morbidity rates after kidney transplantation. As yet, there is no therapeutic strategy to prevent the formation of lymphoceles. The lower limb provides a large reservoir for lymphatic tissue. Prophylactic compression therapy limits tissue volume and edema formation and may therefore reduce postoperative lymph flow. PATIENTS AND METHODS AND RESULTS: In a non-randomized prospective study using a historical control group prior to 2006 as comparison from our center (2004-2008: total n=126), we found that lymphoceles are significantly diminished on the ipsilateral lower limb of the operative side when patients wear class II compression stockings (n=69) for four weeks after transplantation compared to patients achieving standard antithrombotic therapy by compression class I stockings (n=57) for thrombosis prophylaxis until full mobilization (33% versus 15%, p-value<0.05). Furthermore, a significantly lower percentage of patients needed surgical treatment of the lymphoceles for obstructive complications after class II compression (4% versus 18%, p-value<0.01). These findings were independent of the recipients' demographics, the duration of the surgical procedure, and the operating surgeon. CONCLUSION: Further studies are needed to demonstrate the usefulness of compressing stockings for the reduction of lymphoceles after kidney transplantation. This approach would not only reduce post-transplantation morbidity, but also provide an easy and cost-effective treatment without side-effects.

Improved arteriole-to-venule ratio of retinal vessels resulting from bariatric surgery.

Obesity causes increased morbidity and mortality from metabolic and cardiovascular disease (CVD). We investigated the effect of bariatric surgery on endothelial dysfunction (ED) in retinal vessels as a marker of metabolic and cardiovascular risk in patients with obesity WHO III.Thirty consecutive patients (19/11, w/m) were evaluated by anthropometry, lipid profile, and oral glucose tolerance test before and after bariatric surgery (Mannheim Obesity Study (MOS); NCT 00770276). Risk stratification was performed by the presence of metabolic syndrome (MetS) according to ATP-III (adult treatment panel-III). Subclinical atherosclerosis was assessed by measurement of intima-media thickness (IMT). Flicker light response of retinal vessels was used as measures of ED. We measured their arteriole-to-venule ratio (AVR) for evaluation of vascular pathology. After a median of 9 months following bariatric surgery, mean weight loss was 39.4 kg (37.3%). Remission of impaired glucose metabolism was achieved in 53.3% of affected patients. Dyslipidemia improved significantly (triglycerides -61.3 mg/dl, P < 0.0001, total cholesterol -28.2 mg/dl, P = 0.002, and low-density lipoprotein cholesterol were reduced -24.5 mg/dl, P = 0.008). This resulted in a significant reduction of patients classified for MetS (27 vs. 9, P < 0.0001). Adiponectin increased by 2.08 µg/l (P = 0.032) and high sensitivity C-reactive protein (hs-CRP) and soluble intercellular cell adhesion molecule (sICAM) decreased (-7.3 mg/l, P < 0.0001 and -146.4 ng/ml, P = 0.0006). AVR improved significantly (+0.04, P < 0.0001), but neither Flicker light response nor IMT changed significantly. Retinal AVR is ameliorated after bariatric intervention. As an increased AVR results from either or both widening retinal arteriolar caliber and narrowing retinal venular caliber, an improvement in small vessel profile is evident 9 months after bariatric surgery.

The interleukin-6 promoter (-597/-572/-174)genotype does not affect interleukin-6 production in hemodialysis patients.

Kidney transplant recipients with the interleukin-6 (IL-6) GGG/GGG promoter (-597/-572/-174)genotype were shown to have a better long-term outcome. Further, the same (-597/-572/-174)genotype was found to be associated with less IL-6 production in healthy control subjects. To verify this observation in potential kidney transplant recipients, IL-6 production was analyzed in 85/142 hemodialysis patients. We could not confirm an impaired IL-6 secretion in carriers of the GGG/GGG (-597/-572/-174)genotype and propose a significantly lower IL-6 production in hemodialysis patients versus healthy control subjects to explain this. However, we suggest subsequent studies of IL-6 production in kidney allograft recipients to further elucidate the pathophysiological relevance of IL-6 for transplant outcome.

Treatment of proteinuria with low-molecular-weight heparin after renal transplantation.

The development of nephrotic-range proteinuria after renal transplantation is an unfavourable prognostic factor for graft survival. In contrast to that in other nephropathies, the role of renin-angiotensin blockade in kidney transplantation is less well defined, and its anti-proteinuric effect is markedly reduced in the presence of segmental glomerulosclerosis. Here, we describe two patients who developed severe proteinuria after renal transplantation, despite effective blood pressure control with an ACE inhibitor. Histological changes were consistent with IgA-nephropathy and focal segmental glomerulosclerosis. Both patients were treated with low-molecular-weight heparin in addition to pre-existing ACE inhibition. This regimen led to a significant and long-lasting reduction of proteinuria. Our data suggest that low-molecular-weight heparin possesses strong renoprotective properties, thus confirming previous data from experimental nephropathies. This approach might represent a promising new strategy for treatment of proteinuria after kidney transplantation.

SCG/Kinjoh mice: a model of ANCA-associated crescentic glomerulonephritis with immune deposits.

BACKGROUND: Spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice spontaneously develop crescentic glomerulonephritis (CGN), systemic vasculitis, and perinuclear ANCA (pANCA), and have been suggested as an animal model for human antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AASV). Since no systematic serologic, immunohistologic, or structural evaluation had been performed thus far, we reinvestigated the development of ANCA and CGN in these mice. METHODS: SCG/Kj mice were subjected to serologic and urinary analysis, as well as histologic evaluation of the kidneys by standard light, immunofluorescence, and electron microscopy at regular intervals during the course of the disease. RESULTS: Perinuclear ANCA developed as early as the 6th week of life, increasing both in frequency and titer in up to 100% of animals at week 20. Crescent formation began at week 10 and peaked at week 16, maximally affecting 57% of glomeruli. Crescent formation was initiated by "activated" podocytes that formed cell bridges between tuft and Bowman's capsule. The typical picture of a diffuse immune complex nephritis was found in all animals as early as 8 weeks. Fluorescence intensity increased with age and became strongly positive for immunoglobulin (Ig)A, IgM, IgG, and C3 in the mesangium and along the peripheral capillary loops. CONCLUSION: Although ANCAs were found in the majority of animals, the massive presence of glomerular immune deposits differed from the pauci-immune pattern found in human AASV, making this model not completely representative for human ANCA-associated CGN. However, the spontaneous and concomitant development of pANCA, small vessel vasculitis, and CGN raises the opportunity to analyze pathogenetic links between these disease manifestations in vivo.