Arterial stiffness and functional properties in chronic kidney disease patients on different dialysis modalities: an exploratory study.

BACKGROUND: Abnormalities of vascular function and accumulation of oxidative stress have been associated with chronic kidney disease (CKD). Dialysis modalities, peritoneal dialysis (PD) and haemodialysis (HD) may differentially impact on vascular function and oxidative stress. METHODS: Patients undergoing living donor transplantation were studied for vascular stiffness using pulse wave velocity measurements, and inferior epigastric arteries were harvested to examine in vitro stiffness and functional properties and evidence of oxidative stress. Forty-one patients were studied representing PD (n = 12), HD (n = 14) and non-dialysed recipients (n = 15). RESULTS: We demonstrated differences in stiffness from in vivo and in vitro measurements such that non-dialysis < HD < PD groups. The stiffness measurements did not correlate with duration of CKD nor dialysis duration, but did so with phosphate levels (r = 0.356, P = 0.02). From the in vitro isometric force experiments, HD arteries demonstrated decreased contractility and endothelium-dependent relaxation compared with PD and non-dialysis vessels. Level of oxidative stress (as indicated by the 8-isoprostane level) was 30% higher in HD arteries than in PD arteries. Protein expression of inducible nitric oxide synthase, NADPH subunits and xanthine oxidase was upregulated in HD arteries, while superoxide dismutase was downregulated. The compromised vascular function in HD arteries was improved by pharmacological means that eliminated oxidative stress. CONCLUSIONS: We report associations between vasomotor function and oxidative stress in the vasculature of patients receiving different dialysis therapies. Oxidative stress, which may be differentially augmented during PD and HD, may play an important role in the vascular dysfunction in dialysis populations.

Differential microvasculature dysfunction in living kidney donor transplant recipients: nondialyzed versus dialyzed chronic kidney disease patients.

We hypothesized that there was differential vasomotor dysfunction in the microcirculation between nondialyzed and dialyzed chronic kidney disease (CKD) patients. During live donor kidney transplantation procedures, skin arterioles (SkA; internal diameter = 120 +/- 5 microm) from donors (n = 27) and recipients (nondialysis = 15; dialysis = 20) were dissected from the abdominal wall at the incision site. In vivo aortic pulse wave velocity (PWV) was also measured. In the in vitro isometric force measurement, nondialyzed SkA exhibited comparable contraction to donor SkA, whereas dialyzed SkA had 60 and 40-50% increase in contraction in response to depolarization and agonist (that is, phenylephrine, serotonin and endothelin-1) stimulation, respectively. The acetylcholine-induced relaxation in the nondialyzed SkA was decreased by 50% compared with dialyzed SkA. However, pre-incubation with superoxide dismutase greatly enhanced the relaxation response in the nondialyzed, but not in the dialyzed SkA and donor SkA. Pre-incubation with N(G)-nitro-L-arginine methyl ester (L-NAME) elevated the resting tension and left-shifted the concentration response curve of phenylephrine-stimulated contraction in the donor-SkA. L-NAME only increased the resting tension in the nondialyzed vessel. In vitro stiffness positively correlated with PWV (R(2) = 0.302, p = 0.001), and dialyzed SkA was 60% stiffer than nondialyzed and donor SkA. The acetylcholine relaxation was negatively correlated with PWV in donors and recipients (R(2) = 0.282, p = 0.01). In conclusion, we have uniquely demonstrated differential microvasculature dysfunction between nondialyzed and dialyzed CKD patients.

Upregulation of matrix metalloproteinase-2 in the arterial vasculature contributes to stiffening and vasomotor dysfunction in patients with chronic kidney disease.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in chronic kidney disease patients on maintenance dialysis. Given the importance of matrix metalloproteinase-2 (MMP-2) in matrix integrity, vascular cell function, and structural stability, we hypothesized that MMP-2 was elevated in the macrovasculature in dialyzed chronic kidney disease patients compared with chronic kidney disease patients not on dialysis and kidney donors. METHODS AND RESULTS: Arteries from live kidney donors (A(donor); n=30) and recipients (nondialysis [A(nondialyzed)], n=17; dialysis [A(dialyzed)], n=23 [peritoneal dialysis, n=10; hemodialysis, n=13]) were harvested during the transplantation procedure. Compared with A(donor), MMP-2 upregulation was evident in both recipient groups. Protein expression of latent plus active MMP-2 in A(dialyzed) was 2-fold that in A(nondialyzed). MMP-2 activity increased with length of dialysis (r=0.573, P=0.004). In A(dialyzed), medial elastic fiber fragmentation was pronounced, and the ratio of external elastic lamina to media was negatively correlated with MMP-2 activity (r=-0.638, P=0.001). A(dialyzed) was 25% stiffer than A(nondialyzed); this increased stiffness correlated with MMP-2 activity (r=0.728, P<0.0001) and the severity of medial calcium deposition (r=0.748, P=0.001). The contractile function and endothelium-dependent relaxation were reduced by 35% to 55% in A(dialyzed) and were negatively associated with MMP-2 activity (r=-0.608, P=0.002; r=-0.520, P=0.019, respectively). Preincubation with MMP-2 inhibitor significantly improved contractility and relaxation in A(dialyzed). CONCLUSIONS: We describe a strong correlation between MMP-2 activation and elastic fiber disorganization, stiffness, calcification, and vasomotor dysfunction in the arterial vasculature in dialyzed chronic kidney disease patients. These findings may contribute to an improved understanding of mechanisms important in vascular health in chronic kidney disease patients.

Matrix metalloproteinase-2 and -9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease.

AIMS: Chronic kidney disease (CKD) and diabetes are the prominent risk factors of cardiovascular disease (CVD). Matrix metalloproteinase (MMP)-2 and -9 regulate vascular structure by degrading elastic fibre and inhibit angiogenesis by generating angiostatin. We hypothesized that MMP-2 and -9 were up-regulated in the arterial vasculature from CKD patients with diabetes, compared with those without diabetes. METHODS AND RESULTS: During living donor transplantation procedures, arteries from donors (n = 8) and recipients (non-diabetic, n = 8; diabetic, n = 8; matched in age, gender, and dialysis treatments) were harvested. Diabetic arteries had increased MMP-2 and -9 activities by 42 and 116% compared with non-diabetic ones. Diabetic arteries were the stiffest, and the stiffness measurement was highly correlated with the summation of MMP-2 + MMP-9 activities (r = 0.738, P = 0.0002). Pulse wave velocity measurements correlated with MMP activity (r = 0.683, P = 0.005). Elastic fibre degradation and calcification were worst in diabetic vessels. The phosphate level, which was 25% higher in diabetic patients, correlated with MMP activity (r = 0.513, P = 0.04) and in vitro stiffness (r = 0.545, P = 0.03), respectively. Angiostatin expression was doubled, whereas vascular endothelial growth factor was 50% reduced in diabetic compared with non-diabetic vessels. Microvascular density in diabetic vessels was 48% of that in non-diabetic ones, and it was strongly associated with MMP activity (r = -0.792, P < 0.0001) and vasorelaxation (r = 0.685, P = 0.0009). CONCLUSION: Using a matched case-control design, we report up-regulation of MMP-2 and -9 in diabetic CKD arteries and correlate those with stiffening, impaired angiogenesis, and endothelial dysfunction. These findings may help to explain the high susceptibility of CVD in diabetic and non-diabetic CKD patients.

Economic and ethical impact of extrarenal findings on potential living kidney donor assessment with computed tomography angiography.

To determine the prevalence and spectrum of extrarenal findings in a screening population of potential living kidney donors undergoing renal Computed tomography angiography (CTA) and evaluate their impact on subsequent patient management and imaging costs. Two radiologists retrospectively reviewed 175 consecutive renal CTA's performed for assessment of potential living kidney donors. Extrarenal radiological findings were recorded and classified according to high, medium, or low importance based on clinical relevance and the need for further investigations and/or treatment. The cost of additional imaging examinations was calculated using 2002 Canadian (British Columbia) reimbursements. There were 73 extrarenal findings in 71/175 (40.6%) of the potential kidney donors in the study population. Findings were categorized as of high clinical importance in 18 (10.3%) cases, including lung lesions, bowel tumors, and liver tumors and as medium importance in 31 (17.7%). Twenty-two (12.6%) individuals had findings categorized as low importance, probably of no clinical significance and requiring no follow-up. Further potential evaluation of the 49 patients (28%) with highly and moderately significant extrarenal findings may require an additional $6137 (mean $35.1 per each case of all the screened patients). Transplantation of a kidney from a living donor is an excellent alternative to cadaveric allografts. Potential living kidney donors are a highly selected population of healthy individuals, screened for significant past or current medical conditions before undergoing CTA. Despite this screening, potentially significant extrarenal findings (classified as high or medium importance) were revealed in 28% of patients. These patients may require further investigations and/or treatment. The referring physician and patient should be aware of such potentially high probability, which may require further nontransplant related evaluation and treatment. This has medical, legal, economic, and ethical implications.

Attitudes and predictive factors for live kidney donation in British Columbia. A comparison of recipients and wait-list patients.

INTRODUCTION: Live donor kidney transplantation (LDKT) is both medically and economically superior to cadaver kidney transplantation in the treatment of patients with chronic renal failure. Unfortunately, fewer than 50% of patients on the transplant waiting list have a relative or friend who contacts the transplant program about possible donation. We hypothesized that both the potential recipient and potential donor have identifiable and modifiable characteristics that contribute to the likelihood of a live donor transplant. MATERIALS AND METHODS: Specifically-designed and validated questionnaires addressing personal characteristics, knowledge and beliefs about LDKT were mailed to patients who had previously received a LDKT (N = 163) and patients on the cadaver transplant waiting list (N = 251). Response rates were 81% and 67% respectively. RESULTS: There were significant differences between groups in age, ethnicity, marital status, hours worked per week, annual income, and time on the waiting list. Significant differences were found between groups in both knowledge and beliefs about live donor kidney transplantation. All wait-list patients could identify at least one family member (mean = 7 potential donors per wait-list patient) who might serve as a live kidney donor but less than 13% of these potential donors have actually undergone an evaluation. CONCLUSIONS: In British Columbia, an enormous pool of potential live kidney donors exists for patients who are currently waiting for a cadaver kidney transplant. Educational strategies designed for wait-list patients may correct knowledge deficits and alter unfavorable beliefs about LDKT which, in turn, may increase their willingness to seek and accept an offer of live kidney donation.

Attitudes and predictive factors for live kidney donation: a comparison of live kidney donors versus nondonors.

BACKGROUND: Live donor kidney transplantation (LDKT), although far from risk free, is a reasonably safe procedure for medically suitable donors. We hypothesized that both potential recipients and donors have identifiable and modifiable factors that contribute to the likelihood of LDKT. The objectives of this study were to describe and quantify these factors using anonymous, confidential questionnaires. METHODS: Specifically designed questionnaires addressing personal characteristics, knowledge, and beliefs about LDKT were mailed to 127 previous donors and 387 relatives of patients newly listed on the cadaver transplant wait-list. Ninety-eight (77%) and 243 (63%) responses were returned by donors and nondonors, respectively. RESULTS: There were significant differences between groups in gender, ethnicity, hours worked per week, and annual income. Significant differences were seen in both knowledge and beliefs about LDKT. Most donors indicated they made their decisions without lengthy deliberation or research about kidney donation. Only 20% of nondonors feel they are well informed about LDKT. CONCLUSION: It is likely possible to improve knowledge about LDKT among friends and relations of patients with renal failure, but it is not certain that this will lead to increased donation because most donors don't appear to deliberate or research organ donation before making a commitment to donate. Strategies to educate potential donors should initially focus on the recipient.

A prospective comparison of simultaneous and sequential live-donor renal transplantation.

BACKGROUND: Traditionally, we have performed live- donor renal transplantations sequentially with a cold ischemic time (preservation time) of approximately 3 hr. By performing live-donor renal transplantations simultaneously, cold ischemic times can be reduced to 30 min or less. The purpose of this prospective study was to compare clinical outcomes and biologic markers of kidney function between live-donor renal transplantations performed either simultaneously or sequentially. METHODS: Nine consecutive live-donor renal transplantations were performed in a simultaneous manner by two transplant surgeons. For comparison, 18 consecutive live-donor transplantations were performed sequentially by a single surgeon. Donor and recipient demographic factors, before transplantation, were compared. Posttransplantation comparisons included daily serum creatinine measurements for 5 days, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) for 72 hr postoperatively, nuclear glomerular filtration rate (GFR) at 18 hr postoperatively, creatinine clearance at 96 hr postoperatively, and creatinine clearance at 3 and 6 months posttransplantation. RESULTS: There were no differences in donor and recipient demographic factors preoperatively between the two groups. With simultaneous and sequential recipients, only the cold ischemic times were significantly different (simultaneous: mean=23.6 min; sequential: mean=191.7 min; P<0.01). After transplantation, no differences were detected in the daily fall of serum creatinine, nuclear GFR at 18 hr, or creatinine clearance at 96 hr, 3 months, or 6 months. In both groups, urinary NAG excretion reached a peak at 1 hr postoperatively and then slowly returned to baseline by 72 hr. There was no difference in the amount of NAG excretion between the two groups. CONCLUSIONS: Our study found that there is no difference in tubular injury or postoperative GFR in live-donor kidney transplantations performed simultaneously or sequentially. Our findings indicate that a modest prolongation of the cold ischemic time has no detectable influence on posttransplantation renal function for live-donor transplantations.