Capsaicin-Loaded Chitosan Nanocapsules for wtCFTR-mRNA Delivery to a Cystic Fibrosis Cell Line.

Cystic fibrosis (CF), a lethal hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene coding for an epithelial chloride channel, is characterized by an imbalanced homeostasis of ion and water transports in secretory epithelia. As the disease is single-gene based, transcript therapy using therapeutic mRNA is a promising concept of treatment in order to correct many aspects of the fatal pathology on a cellular level. Hence, we developed chitosan nanocapsules surface-loaded with wtCFTR-mRNA to restore CFTR function. Furthermore, we loaded the nanocapsules with capsaicin, aiming to enhance the overall efficiency of transcript therapy by reducing sodium hyperabsorption by the epithelial sodium channel (ENaC). Dynamic light scattering with non-invasive back scattering (DLS-NIBS) revealed nanocapsules with an average hydrodynamic diameter of ~200 nm and a Zeta potential of ~+60 mV. The results of DLS-NIBS measurements were confirmed by asymmetric flow field-flow fractionation (AF4) with multidetection, while transmission electron microscopy (TEM) images confirmed the spherical morphology and size range. After stability measurements showed that the nanocapsules were highly stable in cell culture transfection medium, and cytotoxicity was ruled out, transfection experiments were performed with the CF cell line CFBE41o-. Finally, transepithelial measurements with a new state-of-the-art Ussing chamber confirmed successfully restored CFTR function in transfected cells. This study demonstrates that CS nanocapsules as a natural and non-toxic delivery system for mRNA to target cells could effectively replace risky vectors for gene delivery. The nanocapsules are not only suitable as a transcript therapy for treatment of CF, but open aspiring possibilities for safe gene delivery in general.

Chitosan Nanocomplexes for the Delivery of ENaC Antisense Oligonucleotides to Airway Epithelial Cells.

Nanoscale drug delivery systems exhibit a broad range of applications and promising treatment possibilities for various medical conditions. Nanomedicine is of great interest, particularly for rare diseases still lacking a curative treatment such as cystic fibrosis (CF). CF is defined by a lack of Cl- secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) and an increased Na+ absorption mediated by the epithelial sodium channel (ENaC). The imbalanced ion and water transport leads to pathological changes in many organs, particularly in the lung. We developed a non-viral delivery system based on the natural aminopolysaccharide chitosan (CS) for the transport of antisense oligonucleotides (ASO) against ENaC to specifically address Na+ hyperabsorption. CS-ASO electrostatic self-assembled nanocomplexes were formed at varying positive/negative (P/N) charge ratios and characterized for their physicochemical properties. Most promising nanocomplexes (P/N 90) displayed an average size of ~150 nm and a zeta potential of ~+30 mV. Successful uptake of the nanocomplexes by the human airway epithelial cell line NCI-H441 was confirmed by fluorescence microscopy. Functional Ussing chamber measurements of transfected NCI-H441 cells showed significantly decreased Na+ currents, indicating successful downregulation of ENaC. The results obtained confirm the promising characteristics of CS as a non-viral and non-toxic delivery system and demonstrate the encouraging possibility to target ENaC with ASOs to treat abnormal ion transport in CF.

Results of Transplantation of Kidneys Procured From Donors After Brain Death Aged 60 Years and Older.

OBJECTIVE: To analyze results of transplantation of kidneys procured from donors after brain death aged 60 years and older (hereafter denoted by "≥60") compared to kidneys procured from donors after brain death aged 40-59 years (hereafter denoted by "40-59") in medium-term follow-up period, and to assess factors that affect recipient and kidney graft survival. MATERIAL AND METHODS: 92 transplant recipients of kidneys procured from donors after brain death ≥60 were enrolled into the study. The control group were 363 recipients of kidneys procured from donors after brain death 40-59. RESULTS: Mean values of serum creatinine were higher in recipients of kidneys procured from donors after brain death ≥60 compared to control after 3 years: 168.2 ± 57.5 (n = 59) vs 147.9 ± 65.7 (n = 294), P < .05; and after 5 years: 196.2 ± 95.3 (n = 38) vs 157.3 ± 80.0 µmol/L (n = 211), P < .01. Restricted mean recipient survival time was 56.4 (95% confidence interval: 55.0-57.8) and 52.0 (48.0-56.1) months, P < .05; and kidney graft survival time was 51.6 (49.6-53.5) and 43.9 (39.0-48.9) months, P < .01 in recipients who received kidneys from donors after brain death 40-59 and from donors after brain death ≥60 respectively. In Cox regression, donor death due to cardiovascular disease proved to be the factor increasing risk of kidney graft loss (hazard ratio 1.553, P < .001). CONCLUSIONS: The survival and function of kidneys procured from donors after brain death ≥60 at medium-term follow-up remain worse compared to kidneys procured from donors after brain death 40-59, and the donor dependent risk factor of kidney graft loss is cardiovascular disease, which caused donor death.

Relationship Between Individual Components of the Extended-Criteria Donor Definition and the First Post-transplant Kidney Graft Resistance Index, Measured by Doppler Sonography.

BACKGROUND: Despite an increasing utilization of kidneys procured from expanded-criteria donors, little is known about the effects of particular expanded-criteria donors definition components, that is, hypertension, increased creatinine prior to procurement, and cerebrovascular cause of death on the kidney graft Doppler parameters measured shortly after transplantation, whose increased values are associated with unfavorable outcomes. Hence, we analyzed the relationship between expanded-criteria donors components and resistance index values measured within 2 to 3 days post-transplant. MATERIAL AND METHODS: The initial post-transplant resistance index value was measured in 676 consecutive successful first cadaveric kidney graft recipients without delayed graft function or early acute rejection episode. We analyzed resistance index values in 460 patients transplanted with organs from donors <50 years and in 216 recipients with organs from donors >50 years old. RESULTS: In general, expanded-criteria donors status did not influence the initial resistance index values in the whole study group. Unexpectedly, in older donor groups, both the occurrence of donor hypertension and cerebrovascular cause of death resulted in significantly lower resistance index values in kidney graft recipients (0.73 ± 0.10 vs 0.76 ± 0.11 in the non-hypertension group, P = .013 and 0.74 ± 0.11 vs 0.78 ± 0.10 in the non-cerebrovascular cause of death group, P = .015, respectively). In the Cox proportional regression model for graft survival, cerebrovascular cause of death was increasing the risk of graft loss by 55%, while recipient's age had the opposite effect, decreasing the risk of graft loss by 2% per year. CONCLUSIONS: Regardless of the limited influence of expanded-criteria donor status on first post-transplant resistance index value, the long-term observation shows moderate but significantly worse kidney graft survival, mostly as a result of the cerebrovascular cause of donor's death.

No Significant Influence of Reduced Initial Tacrolimus Dose on Risk of Underdosing and Early Graft Function in Older and Overweight Kidney Transplant Recipients.

BACKGROUND: Nowadays, a reduced initial daily dose of tacrolimus (Tac) (0.1-0.15 mg/kg) is recommended for the majority of kidney transplant recipients (KTRs). The aim of the study was to analyze the safety of such a regimen, including the risk of first inadequately low Tac blood level, acute rejection (AR) occurrence, or early graft dysfunction. METHODS: In 2011, we introduced a modified (0.1-0.15 mg/kg/d) initial Tac dosing regimen in older (>55 years) and/or overweight KTRs. To assure the safety of this protocol, we monitored the risk of inadequately low blood Tac level (<6 ng/mL) and incidence of AR or delayed graft function (DGF). The historical cohort with the higher Tac dosing regimen (0.2 mg/kg/d, n = 208) served as a control group. RESULTS: The mean Tac daily dose in 78 KTRs (group with reduced dosing) was 0.133 (95% confidence interval [CI], 0.130-0.136) mg/kg and was significantly lower than the standard, previously prescribed dose of 0.195 (95% CI, 0.194-0.197) mg/kg. Of note, induction therapy was employed twice more often in the reduced Tac dosing group. The dose reduction resulted in a slight, nonsignificant decrease in first Tac trough level. The percentages of patients with first Tac troughs <6 ng/mL (5.1% vs 4.8%), AR (6.4% vs 5.8%), and DGF (25.6% vs 31.2%) were similar in the reduced and standard dosing groups. CONCLUSION: The currently recommended reduction in Tac initial dosing does not increase the risk of inadequate immunosuppression and does not affect the early graft function. Regardless of Tac dose reduction, there is still a substantial risk of Tac overdosing in older or overweight KTRs.

Solid Organ Cancer and Melanoma in Kidney Transplant Recipients: TumorTx Base Preliminary Results.

BACKGROUND: Incidence of malignancy in transplant recipients is higher than in the general population. Malignancy is a major cause of mortality following solid organ transplantation and a major barrier to long-term survival for the kidney. The aim of this study was to estimate the incidence of solid organ malignancy (SOM) and melanoma in renal transplant recipients (RTR) transplanted at 2 representative transplant centers in Poland based on data from the Polish Tumor Registry. MATERIAL AND METHODS: We analyzed the medical data of 3069 patients who underwent kidney transplantation (KTx) between 1995 and 2015. RESULTS: In our study 112 SOM (3.6%) were diagnosed. The majority of patients were male (n = 71; 63.4%; P < .01). The mean age at KTx was 48.0 ± 13.1 years and the mean age at the time of cancer diagnosis was 55.9 ± 12.7 years. The average time of malignancy occurrence was 5.9 ± 5.0 years after KTx. SOM was the cause of death in 60 patients (53%). The most common were malignancies of gastrointestinal tract (25%), urinary tract tumors (23.2%), lung cancer (n = 18; 16%), and lymphoma (13.4%). We found an increase in the percentage of chronic glomerular nephropathy in the group of SOM (n = 56; 50%) compared with renal insufficiency of other etiologies. CONCLUSIONS: RTR in Poland are at a significant risk of malignancy development in a variety of organs, primarily urinary tract tumors and lymphoma. Cancers most frequently occurring in the general population such as lung and colorectal cancer are common in our RTR. On this basis an appropriate tumor screening schedule can be developed in individual countries.

Influence of Polypharmacy on the Quality of Life in Stable Kidney Transplant Recipients.

BACKGROUND: Kidney transplant recipients are frequently treated for other medical conditions and experience polypharmacy. The aim of our study was to evaluate quality of life in relation to medicines' burden in these patients. METHODS: We studied 136 unselected patients with mean post-transplant time of 7.2 ± 4.6 years. Quality of life was evaluated using a validated Polish version of the Kidney Disease Quality of Life-Short Form questionnaire. Data concerning the type (generic name) and number of currently prescribed medications were collected by interview survey. The participants were divided into 3 groups: group 1, patients with a maximum of 4 different medications (n = 37); group 2, patients with 4 to 9 medications (n = 76); and group 3, patients receiving at least 10 different medications (n = 23). RESULTS: The number of medicines taken regularly ranged from 2 to 16. Patients with ≥10 drugs had the highest body mass index and lowest estimated glomerular filtration rate. Patients treated with ≥10 drugs, compared to patients from the 2 other groups, had presented lower subscales results concerning the physical functioning (65.9 vs 84.5 in group 1 and 83.4 in group 2, P < .001 for both comparisons), pain (57.2 vs 82.7 and 76.5, respectively, P < .001 for both), social function (66.8 vs 82.1 and 80.4, respectively, P = .04 for both), and energy/fatigue (54.8 vs 67.7, P = .03 and 65.4, P < .05). Multivariate regression analysis revealed that the number of drugs independently influenced physical functioning, pain, and social function subscales. CONCLUSIONS: Polypharmacy is associated with lower quality of life in patients after successful kidney transplantation. The negative impact of polypharmacy is particularly seen regarding physical functioning and pain severity.

Successful Preemptive Kidney Transplantation With Rituximab Induction in a Patient With Focal Segmental Glomerulosclerosis and Massive Nephrotic Syndrome: A Case Report.

Primary focal segmental glomerulosclerosis (FSGS) recurs in 30% of patients receiving their first kidney transplant and often leads to graft loss. In the past, patients with FSGS and overt nephrotic syndrome rarely underwent transplantation. Rituximab (RTX), an anti-CD20-specific monoclonal antibody, was previously reported to be a valuable option in treating relapsing FSGS after kidney transplantation. We report here the first successful kidney transplantation in a young patient with primary FSGS and massive nephrotic syndrome treated with RTX induction. The patient was a 24-year-old woman who had developed nephrotic syndrome at the age of 4 years. FSGS was confirmed by results of a kidney biopsy, with subsequent treatment with cyclosporine and steroids, without remission. She was referred for a preemptive, deceased donor kidney transplant despite proteinuria levels reaching ∼10 g/d. She received induction therapy with 2 doses of RTX (375 mg/m2) at days 0 and 7, followed by tacrolimus 5 mg twice daily, mycophenolate mofetil 500 mg twice daily, and steroids after transplantation. Immediate kidney graft function was observed, with no proteinuria since day 13 posttransplant. The pretransplant soluble urokinase-type plasminogen activator receptor serum concentration was 4550 pg/mL; it decreased to 2191 pg/mL at day 13 and was 2073 pg/mL at 6 months' posttransplant. Thirty months after transplantation, the patient's serum creatinine level is 0.8 mg/dL, and no proteinuria has been observed. Successful kidney transplantation in a patient with pretransplant overt nephrotic syndrome secondary to FSGS, using rituximab as an induction therapy, is possible. Further recommendations for transplantation in such patients, however, should be based on results from larger clinical trials.

Effect of the Second Warm Ischemia Time and Its Components on Early and Long-term Kidney Graft Function.

BACKGROUND: During kidney transplantation, the total time of organ ischemia consists of first warm ischemia time (WIT1), cold ischemia time (CIT), and a second WIT (WIT2). Rising graft temperature during WIT2, which comprises the creation of vascular anastomoses, increases oxygen demand and tissue damage, especially in the kidney tubular cells. The aim of this study was to analyze the influence of WIT2 on early and long-term kidney graft function. METHODS: We performed a retrospective analysis of 554 consecutive adult recipients, who received their first kidney graft from a deceased donor between 2003 and 2013. RESULTS: Mean WIT2 was 25.2 min. Donors' sex, age, presence of hypertension, body mass index (BMI), and the cause of brain death showed no effect on WIT2. Weak positive correlations were found between the duration of WIT2 and both recipients' age (r = 0.11; P < .01) and BMI (r = 0.14; P < .01). Multivariate regression analysis confirmed the independent influence of age (ß = 0.107 [95% confidence interval, 0.017 to 0.197] per year; P = .02) but not BMI (P = .09). WIT2 influenced early graft function and was significantly longer in patients with primary graft nonfunction than in other recipients (35.3 vs 24.9 min; P < .01). According to receiver-operating characteristic curve analysis, a WIT2 value >26 min was predictive of primary graft nonfunction, with 64% specificity and 58% sensitivity. No correlations were found between WIT2 and estimated glomerular filtration rate in the long-term follow-up period. CONCLUSIONS: This study found that WIT2 may significantly influence the early graft function. We also found that the creation time of vascular anastomoses does not affect the long-term kidney graft excretory function.

Early and Long-Term Outcomes of Kidney Grafts Procured From Multiple-Organ Donors and Kidney-Only Donors.

BACKGROUND: The deceased-donor kidney pool consists of 2 different populations: multiple-organ donors (MOD) and kidney donors alone (KDA). In MOD, more complicated procedure and lowest priority for kidney procurement may affect graft survival. On the other hand, poor donor status and higher comorbidity are more frequent in KDA transplants. The aim of this study was to provide detailed characteristics of the 2 groups of kidney donors (KDA vs MOD) in our center and to analyze the potential influence of the donor type on the early and long-term kidney graft function and recipient outcome. METHODS: We performed a retrospective analysis of 729 first cadaveric kidney transplant recipients: 499 of them received the organ from MOD, 230 from KDA. RESULTS: The frequency of delayed graft function (DGF) was higher in KDA than in MOD transplants (38.7 vs 25.1%; P < .001). Multivariate logistic regression analysis revealed that donor age, KDA, and early acute rejection independently increased the risk of DGF occurrence, whereas recipient age and cold ischemia time increased the risk of primary graft nonfunction. Kidney excretory function was significantly worse in KDA up to 10 years after transplantation. There were no differences in kidney graft and patient survivals, frequency of proteinuria, acute rejection, and cytomegalovirus episodes, and post-transplantation diabetes. CONCLUSIONS: (1) The use of a kidney from KDA negatively affects early and late kidney graft function compared with MOD. (2) The long-term kidney graft and patient survivals are not affected by the type of organ procurement.

Donation and Transplantation of Kidneys Harvested From Deceased Donors Over the Age of 60 Years in the Upper Silesia Region.

BACKGROUND: Population aging and shortage of organs for transplantation result in increasing numbers of kidneys retrieved from elderly donors. The aim of this study was to analyze donation of kidneys from donors after brain death (DBD) over the age of 60 years (≥60), comorbidities that affect decisions on retrieval, and early results of kidney transplantation. METHODS: Ninety-six potential DBD ≥60 and 309 aged 40-59 years (40-59) reported in Upper Silesia, Poland, from 2004 to 2013 were enrolled in the study. RESULTS: DBD >60 presented a higher rate of coexisting hypertension (53% vs 34%), limb ischemia (10% vs 1%), and past stroke (6% vs 1%) compared with DBD 40-59 (P < .05), but no differences were observed in serum creatinine concentration (85 vs 84 µmol/L), coexisting coronary disease (14% vs 6%), or diabetes (10% vs 4%). The decision of withdrawal from retrieval was more frequent in DBD ≥60 (16% vs 7%; P < .05). Twelve months after kidney transplantation, serum creatinine concentration was higher in recipients of kidneys from DBD ≥60 compared with DBD 40-59 (169 vs 138 µmol/L; P < .001). The survivals of recipients (93% vs 95%) and kidney grafts (90% vs 93%) as well as rates of proteinuria >1.0 g/24 h (6% vs 2%) did not differ between the groups. CONCLUSIONS: A higher rate of comorbidities in potential kidney DBD ≥60 results in a lower retrieval rate in these donors. The function of kidneys harvested from DBD ≥60 12 months after transplantation is worse than those from DBD 40-59, but still acceptable.

Cardiovascular Risk Factors and Markers of Atherosclerosis in Stable Kidney Transplant Recipients.

BACKGROUND: There is limited evidence regarding the risk factors influencing vascular injury in kidney transplant recipients, except for accelerated vasculopathy and endothelial dysfunction in the pre-transplantation period of end-stage renal failure. Therefore, we performed a cross-sectional study to evaluate the role of traditional and novel or potential nontraditional risk factors in vascular and endothelial dysfunction in a cohort of stable kidney transplant recipients. METHODS: One hundred forty-two kidney transplant recipients at 8.4 ± 1.8 years after transplantation were enrolled into the study. Different markers of vascular injury, such as carotid intima-media thickness (IMT), pulse wave velocity (PWV), and peripheral arterial tonometry (PAT), were assessed. Inflammatory markers, oxidative stress and endothelial function surrogate markers, adhesion molecules, and parathormone and osteoprotegerin levels were measured. RESULTS: Among traditional risk factors, only age, pre-transplantation diabetes, left ventricular hypertrophy (LVH) and cardiovascular disease (CVD) were related to increased IMT and PWV, whereas PAT values were significantly decreased only in diabetics and patients with CVD and were similar in patients with and without LVH. In multivariate regression analysis, IMT was explained by age, previous CVD episodes, and higher high-sensitivity C-reactive protein levels, and PWV by age and pre-transplantation diabetes. The regression analysis failed to find any significant explanatory variables for PAT. CONCLUSIONS: 1. In stable kidney transplant recipients, age, pre-transplantation diabetes, previous cardiovascular episode, and systemic microinflammation were predictors of vascular injury. 2. PAT is poorly associated with traditional CV risk factors and does not correspond with levels of biochemical markers of endothelial dysfunction in those patients.

Past Cardiovascular Episodes Deteriorate Quality of Life of Patients With Type 1 Diabetes and End-stage Kidney Disease After Kidney or Simultaneous Pancreas and Kidney Transplantation.

BACKGROUND: The beneficial influence of kidney (KTx) or simultaneous pancreas and kidney transplantation (SPK) on quality of life (QOL) in patients with end-stage kidney disease caused by type 1 diabetes mellitus was confirmed in many studies. The aim of this study was to identify factors that influence QOL of patients in long-term follow-up after SPK or KTx. METHODS: Twenty-seven SPK and 26 KTx patients with good function of transplanted organs at least 1 year after transplantation were enrolled into the analysis. To estimate QOL of the recipients the Kidney Disease and Quality of Life Short Form was applied. RESULTS: Within the whole analyzed group, the necessity of exogenous insulin administration correlated (P < .05) with symptom/problem list (γ = -0.35), effects of kidney disease (-0.38), cognitive function (-0.47), sleep (-0.42), overall health (-0.47), physical functioning (-0.61), role-physical (-0.32), pain (-0.50), general health (-0.32), emotional well-being (-0.31), role-emotional (-0.36), social function (-0.33), energy/fatigue (-0.44), and the SF-12 physical composite (-0.44). History of cardiovascular episode correlated (P < .05) with symptom/problem list (γ = -0.59), effects of kidney disease (-0.46), burden of kidney disease (-0.56), sleep (-0.54), social support (-0.51), physical functioning (-0.55), role-physical (-0.70), pain (-0.60), general health (-0.57), emotional well-being (-0.45), role-emotional (-0.95), social function (-0.58), energy/fatigue (-0.59), SF-12 physical composite (-0.45), and SF-12 mental composite (-0.83). CONCLUSIONS: Exogenous insulin administration and history of cardiovascular episode are the most important factors influencing QOL in patients after SPK or KTx, particularly worsening its physical components.

Long-Term Outcomes of Kidney and Simultaneous Pancreas-Kidney Transplantation in Recipients With Type 1 Diabetes Mellitus: Silesian Experience.

BACKGROUND: Kidney transplantation (KTx) markedly reduces mortality in patients with end-stage kidney disease (ESKD) caused by type 1 diabetes mellitus (T1DM). The outstanding issue is whether transplantation should be limited only to KTx, with further insulinotherapy, or combined with pancreas transplantation in patients with ESKD/T1DM. The goal of this study was to compare the results of simultaneous pancreas-kidney transplantation (SPKTx) and deceased donor KTx and to identify factors affecting patient and kidney graft survival in patients with ESKD/T1DM. METHODS: Eighty-seven deceased donor KTx and 66 SPKTx operated on in the Silesia region of Poland between 1998 and 2013 were included in the retrospective analysis. RESULTS: During the mean 6.7 ± 3.6 years of follow-up, fewer cardiovascular episodes were observed in SPKTx recipients than in KTx recipients (1.5% vs 12.6%; P < .05). Five-year patient survival (80.7% in SPKTx vs 77.5% in KTx) and kidney graft survival (66.1% in SPKTx vs 70.4% in KTx) did not differ between study groups. There were no differences in patient survival (log-rank test, P = .99) or kidney graft survival (P = .99) based on Kaplan-Meier curves. Multivariable Cox proportional hazard analysis failed to identify factors explaining patient and kidney graft survival. Five-year pancreas graft survival was 58.9%. SPKTx recipients had significantly higher estimated glomerular filtration rates during the 7-year posttransplant period and less frequently developed proteinuria (6.1% vs 23%; P < .01). CONCLUSIONS: Pancreas transplantation reduced cardiovascular risk and prevented the development of proteinuria but did not improve patient and kidney graft survival in recipients with T1DM in the 7-year follow-up period.

No effect of pretransplantation bilateral nephrectomy on the resistive indices measured in the kidney allograft.

BACKGROUND: The cirrhotic kidney is the cause of sympathetic nervous system and the renin-angiotensin system activation leading to increased vascular resistance and arterial hypertension. The impact of unilateral or bilateral nephrectomy (UN or BN) performed before kidney transplantation on kidney graft intrarenal resistance has not been assessed yet. The aim of this study is to assess the intrarenal resistance parameters measured by Doppler ultrasound in the transplanted kidney in either nephrectomized or non-nephrectomized kidney transplant recipients. METHODS: Among 686 consecutive successful first cadaveric kidney graft recipients transplanted from 1998 to 2012, we identified 43 patients who underwent BN and 49 patients who underwent UN. Patients with acute rejection episodes within an early post-transplantation period were excluded. We have analyzed both pulsatility (PI) and resistance (RI) indices measured within the kidney graft before discharge from the hospital. RESULTS: The prevalence of hypertension in the follow-up period after transplantation was significantly lower in the BN group (65.1% versus 81.0% in other groups). Neither BN nor UN influenced the PI or RI values. The mean PI and RI values were 1.50 (1.38-1.61) and 0.75 (0.73-0.78) in BN, 1.48 (1.37-1.58) and 0.76 (0.73-0.79) in UN, and 1.47 (1.43-1.50) and 0.74 (0.73-0.75) in non-nephrectomized patients, respectively. The results of multivariate analysis confirmed the lack of influence of nephrectomy on kidney graft resistive indices. CONCLUSION: BN before transplantation resulted in lower frequency of hypertension, but it did not affect the intrarenal vascular resistance measured in the kidney graft.

Nutritional status and intrarenal resistive indices after kidney transplantation.

BACKGROUND: Obesity predicts vascular stiffness, which is prevalent among kidney transplant patients. However, the influence of obesity has not been established on parameters of renal vascular resistance variation. The aim of this study was to analyze the influence of nutritional status on intrarenal resistive parameters as measured in the early period after successful kidney transplantation by Doppler ultrasound. METHODS: Both pulsatility index (PI) and resistance index (RI) in the kidney graft were measured by Doppler sonography twice: at 2 to 4 days and before hospital discharge (mean 22 days; 95% confidence interval 21-23) after transplantation. Nutritional status was scored according to World Health Organization criteria. RESULTS: Among 513 patients, 29 were underweight; 280, normal; 166, overweight; and 38, obese. Both PI and RI values were significantly increased consistent with recipient nutritional status (analysis of variance: P < .001). Post hoc analysis showed significant differences in PI and RI measurements for obese versus underweight or normal weight groups. Multivariate analysis revealed an influence of body mass index on PI and RI measurements before hospital discharge to be independent of other variables, including recipient age, prior delayed graft function and cold ischemia time. CONCLUSIONS: Excessive nutritional status was associated with increased renal vascular resistance among kidney transplant patients. Nutritional status should be considered for the proper interpretation of intrarenal Doppler measurements.

Nephron underdosing as a risk factor for impaired early kidney graft function and increased graft loss during the long-term follow-up period.

BACKGROUND: It is generally accepted that kidneys procured from female donors may not perform optimally in male recipients, mostly due to their smaller size and nephron underdosing. Nowadays, conflicting results have been published regarding the detrimental effect of H-Y incompatibility on the long-term prognosis of male kidneys transplanted into female recipient. The aim of this study was an analysis of the impact of donor-recipient gender matching on early function and survival of grafts among a relatively homogenous cohort of kidney recipients. METHODS: We analyzed 477 consecutive first kidney transplants from deceased donors with longer than 3-month survival. Highly sensitized recipients and those with graft losses attributed to noncompliance were excluded from the study. Early kidney graft function was defined based on serum creatinine (Scr) concentrations at postoperative day 3 and the need for dialysis: immediate graft factors (IGF; Scr < 3mg/dL), slow graft function (Scr > 3mg/dL and no dialysis) or delayed graft function (DGF; dialysis in the first posttransplant week). RESULTS: The lowest 10.7% incidence of IGF was observed among male recipients of female kidneys (F-M). For female donor, the relative risk for IGF in female recipient was 3.13 (1.35-7.26) than in male recipient. The frequencies of DGF were similar. During the 5-year follow-up, 54 grafts were lost. The risk for loss was significantly higher in the F-M group: 19.6% vs 8.8% in the three other combined groups (odds ratio = 2.54; 95 confidence interval (1.41-4.59); P = .002). CONCLUSIONS: Transplantation of the female kidney to a male recipient impairs early kidney graft function increasing the risk of graft loss over a 5-year follow-up. This phenomenon seems to be related to nephron underdosing.

Acute kidney injury before organ procurement is associated with worse long-term kidney graft outcome.

BACKGROUND: As the disparity between the numbers of available organ donors and patients awaiting transplantation increases, different strategies have been proposed to extend the donor pool. Patients with acute kidney injury (AKI) developing during an intensive care unit (ICU) stay are often considered to be donors, but the long-term outcomes of such high-risk kidney transplantations is unknown. We analyzed the renal function and outcomes over 5 years of kidney grafts recovered from deceased donors diagnosed with AKI. MATERIALS AND METHODS: We collected data from 61 deceased kidney donors, identified in 1 ICU, and 120 kidney graft recipients who underwent transplantation between January 1999 and December 2006. Donors were stratified according to the RIFLE classification, based on their creatinine and urine output change from admission to the ICU and organ procurement. Recipient kidney graft function (eGFR) calculated according to the MDRD (Modification of Diet in Renal Disease) equation was estimated every 6 months. RESULTS: Among 61 donors, 10 (16.4%) developed AKI, including 7 classified as "risk", 2 as "injury," and 1 as "failure." The mean follow-up of kidney graft recipients was 49±18 months. The long-term risk for graft loss was significantly higher among the group of kidneys recovered from donors with AKI (27.8% vs 7.1%; P=.02; log-rank=0.07). Their excretory function was worse over the whole follow-up period. CONCLUSION: Patients with kidney grafts obtained from the donors with AKI showed a higher risk for graft loss and worse excretory function upon long-term follow-up.

Impact of early lymph node procurement to facilitate histocompatibility testing on long-term cadaveric kidney graft survival.

BACKGROUND: Prolonged cold ischemia time (CIT) is a clinically important causes of delayed graft function (DGF) after kidney transplantation. As DGF has been previously shown to have a deleterious influence on long-term graft survival, in the present study we analyzed the impact of early lymph node (LN) procurement on CIT, HLA mismatches, and long-term kidney graft outcome. MATERIALS AND METHODS: We evaluated 394 consecutive cadaveric procedures performed from 2001 to 2006, including 289 recipients, in whom LN were obtained before kidney procurement seeking to shorten the total time for HLA typing and crossmatch procedures. RESULTS: During 58±6 months, 24 patients died (918 [8.3%] in the early and 6 [5.7%] in late procurement group, P=ns) and 52 lost their kidney grafts (31 [10.7%] vs 21 [20%]; P=.025). Early procurement of LN performed in 73.4% of all kidney graft recipients shortened CIT by almost 7 hours (22.9 vs 16.1 hours; P<.001), with a nonsignificantly lower incidence of DGF (32.2% vs 41.0%; P=.13). However, a Cox proportional hazards regression model revealed that early procurement reduced the risk of death-censored kidney graft loss by roughly 40% (log-rank, P=.013). CONCLUSION: Early LN procurement in significantly shorten CIT and subsequently reduced the risk of long-term kidney graft loss.

Systemic vascular hemodynamics and transplanted kidney survival.

INTRODUCTION: High blood pressure and arterial stiffness contribute independently to cardiovascular mortality in uremic patients. High blood pressure is an established risk factor for chronic allograft nephropathy, recently named interstitial fibrosis/tubular atrophy (IF/TA). We sought to assess whether heart afterload determinants: arterial stiffness and vascular resistance or impedance accelerate kidney graft failure upon long-term observation. METHODS: Using a noninvasive method of blood pressure waveform analysis, (HDI/PulseWave/CR-2000), we studied 160 consecutive kidney transplant recipients, who were at least 3 months after transplantation, for systolic (SBP), diastolic, and mean blood pressure; pulse rate; systemic vascular resistance and impedance as well as large and small artery compliance. The associations of the hemodynamic parameters with relative increases in serum creatinine for every year of graft survival (ΔCreat) were assessed using multiple linear regression analysis. Relationships between systemic hemodynamics and kidney graft loss due to IF/TA were evaluated by Cox regression analysis, including serum creatinine, time after transplantation, delayed graft function, human leukocyte antigen mismatch, panel-reactive antibodies, cold ischemia time, donor age glomerular filtration rate as well as prescribed cardiovascular and immunosuppressive drugs. RESULTS: Over 6.6±0.4 years of follow-up, excluding four noncompliant patients, 11 patients died and 32 lost their kidney grafts, including 25 due to IF/TA. ΔCreat (10.3%±22.0%/y) was independently and positively associated with the initial SBP (ß=0.26; P=.001) and serum creatinine values (ß=0.16; P=.04). The risk of graft loss due to IF/TA was greater among patients with an increased serum creatinine (relative risk [RR]=59.5 per nlog-unit increase; P<.001) or higher SBP (RR=51.1 per nlog-unit increase; P=.04). Besides SBP, no other hemodynamic parameter was associated with graft failure. CONCLUSIONS: The rate of kidney graft function deterioration and risk of transplant loss due to IF/TA are not independently influenced by systemic arterial compliance, resistance, or impedance. SBP appears to be the key circulatory parameter independently affecting the progression of IF/TA, and should be a therapeutic target.