Graft Neutrophil Sequestration and Concomitant Tissue Plasminogen Activator Release During Reperfusion in Clinical Kidney Transplantation.

BACKGROUND: Inflammation, coagulation, and fibrinolysis are tightly linked together. Reperfusion after transient ischemia activates both neutrophils, coagulation, and fibrinolysis. Experimental data suggest that tissue plasminogen activator (tPA) regulates renal neutrophil influx in kidney ischemia and reperfusion injury. METHODS: In 30 patients undergoing kidney transplantation, we measured renal neutrophil sequestration and tPA release from blood samples drawn from the supplying artery and renal vein early after reperfusion. tPA antigen levels were measured using a commercial enzyme-linked immunosorbent assay kit. For each parameter, transrenal difference (Δ) was calculated by subtracting the value of the arterial sample (ingoing blood) from the value of the venous sample (outgoing blood). RESULTS: Positive transrenal gradients of tPA antigen occurred at 1 minute [Δ = 14 (3-46) ng/mL, P < .01] and 5 minutes [Δ = 5 (-3 to 27) ng/mL, P < .01] after reperfusion. At 5 minutes after reperfusion, a negative transrenal gradient of neutrophils was observed [Δ = -0.17 (-1.45 to 0.24) x 10E9 cells/L, P < .001]. At 1 minute after reperfusion, neutrophil sequestration into the kidney (ie, negative transrenal neutrophil count) correlated significantly with tPA release from the kidney (ie, positive transrenal tPA concentration), (R = -0.513 and P = .006). CONCLUSIONS: The findings suggest a proinflammatory role for tPA in ischemia and reperfusion injury in human kidney transplantation.

Matrix Metalloproteinase-9 and Graft Preservation Injury in Clinical Renal Transplantation.

BACKGROUND: Deleterious effects of matrix metalloproteinase-9 (MMP-9) have been established in experimental renal ischemia-reperfusion models but not in clinical renal transplantation thus far. METHODS: We studied MMP-9 and its physiological inhibitor tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in 45 consecutive patients of a larger trial in renal transplantation: perioperative anti-thymocyte globulin (group A, n = 15), perioperative basiliximab (group B, n = 16), and conventional triple therapy (group C, n = 14). In addition to systemic blood samples, local blood samples were obtained simultaneously at 1 and 5 minutes after reperfusion from iliac artery and graft vein for calculation of transrenal changes. Because anti-thymocyte globulin activates inflammation, group A was analyzed separately. Groups B and C were pooled (group BC). RESULTS: Anti-thymocyte globulin infusion caused a robust rise of MMP-9 in the systemic circulation in group A. No significant transrenal difference of MMP-9 or TIMP-1 occurred in either group during graft reperfusion. In group BC, strong transrenal release of MMP-9 at 1 minute after reperfusion correlated with cold ischemia time (R = 0.66, P = .0001) and was associated with delayed graft function (P = .052). CONCLUSIONS: Renal production of MMP-9 on graft reperfusion is associated with cold ischemia time and emergence of delayed graft function. MMP inhibition may offer a means to reduce reperfusion injury in renal transplantation.

Heme oxygenase 1 gene polymorphisms and outcome of renal transplantation.

Heme oxygenase isoenzyme HO-1 has been linked to several cytoprotective functions with a potentially beneficial role in transplantation. In the present study, the effect of genetic variation in HO-1 on renal allograft outcome was investigated. Six hundred and eighty patients subject to renal transplantation in a single transplant unit and their cadaveric kidney donors were included in this study. Four single-nucleotide polymorphisms and one microsatellite marker in the HO-1 gene region were analysed. Some statistically nominally significant associations were observed in preliminary analyses between polymorphisms studied and clinical outcomes, but after correction for multiple comparisons none remained significant. Our data suggest that the HO-1 gene polymorphisms studied have no significant role on outcome of kidney transplantation in the Finnish population.

Two decades of experience with cyclosporine in renal transplantation in Helsinki.

We present our experience on cyclosporine (CsA) triple immunosuppression in 2445 cadaveric kidney transplantations performed from 1984 to 2002 in Helsinki. Overall, delayed onset of graft function occurred in 30.2% and acute rejection in 25.6% of the transplantations. The 1-, 5-, and 10-year patient survival was 95.1%, 84.5%, and 69.1%; the graft survival rates were 90.0%, 74.9%, and 56.7%; and the death-censored graft survival, 93.3%, 83.5%, and 72.4%. During the study period, the 5-year patient survival improved from 70.8% to 90.6% and the graft survival from 58.2% to 88.0% with the graft half-life estimate of 1-year survivors improving from 7.6 to 21.8 years. Acute rejection episodes decreased from 33.0% to 19.9% and the calculated creatinine clearance at 1 year improved from 50.3 mL/min to 74.3 mL/min. Mean CsA dose diminished significantly, both at 3 weeks (from 8.2 mg/kg to 4.9 mg/kg) and at 1 year posttransplant (from 3.7 mg/kg to 2.8 mg/kg). In 16.7% of transplantations where azathioprine had to be discontinued early, significantly more rejections occurred (38.0% vs 23.2%) with inferior 1-year graft survival (80.2% vs 94.8%) compared to the transplantations continuing on triple therapy. Among 1-year survivors, the 6-month serum creatinine level was strongly associated with death-censored long-term graft survival. In this material, the CsA dosage at 1 year did not predict long-term graft survival.

Time course of serum prolactin and sex hormones following successful renal transplantation.

BACKGROUND: Chronic renal failure is commonly associated with disturbances in hypothalamic-pituitary-gonadal function. METHODS: The gonadotrophins, prolactin and estradiol or testosterone levels were measured immediately before renal transplantation, at discharge from the transplantation unit (19 +/- 8 days after Tx) and 6 months after transplantation in 21 patients, 7 females and 14 males, age range 21-60 years. RESULTS: The mean prolactin level was high during uremia and decreased rapidly after transplantation, from 441 to 167 mU/l in males and from 1,057 to 521 mU/l in females. Hypergonadotrophism was seen in most uremic patients, with the mean LH and FSH levels of 14.2 and 6.0 U/l in males and 14.7 and 4.0 U/l in females, respectively. A temporary change to hypogonadotrophic hypogonadism took place 2-3 weeks after transplantation and was followed by normalization of the hypothalamic-gonadal function. The levels of circulating sex steroids were suppressed when the patients were discharged from the transplantation unit but returned to the normal range at 6 months. CONCLUSIONS: We conclude that renal transplantation corrects the hyperprolactinemia induced by uremia and is followed by rapid onset of restoration of the hypothalamic-pituitary-gonadal axis.

Long-term results of 1047 cadaveric kidney transplantations with special emphasis on initial graft function and rejection.

We studied the effect of initial graft function and acute rejection on graft survival in 1047 cadaveric renal transplantations during 1991-1997 with a constant policy of donor selection, graft allocation, and immunosuppression. The overall 1- and 5-year patient survival rates were 96 % and 88 %, and the 1- and 5-year graft survival (GS) rates were 92 % and 78 %. Delayed graft function (DGF) occurred in 31 % and there were 1.2 % never-functioning grafts. One-year GS in transplantations with early graft function (EGF) was 95 % compared to 87 % in DGF (P < 0.001). Donor age and cause of death, type of graft perfusion and cold ischemia time, and type and length of dialysis treatment were significant factors in determining the onset of graft function. These factors did not have a significant direct effect on GS. Early ( < 100 days) acute rejection occurred in 25 %. In transplantations without rejection, the 1 and 5-year GS was 93.3 % and 80.8 %. In acute rejection responding to steroids, the GS was equal to that up to 3 years, but after that a significantly worse survival rate was observed (1- and 5-year GS: 93.6 % and 73.4 %). DGF was detrimental to GS both in transplantations without rejection and in all rejection types.

The clinical significance of conversion of complement-dependent cytotoxic T cell crossmatch test after renal transplantation.

The purpose of this study was to investigate the clinical relevance of conversion of post-transplant T cell crossmatch between kidney donor and recipient. This study comprises 892 cadaveric renal transplantations performed on 874 adult patients between August 1991 and December 1997. Recipient selection was based on a negative complement-dependent cytotoxic T cell crossmatch test with current (< or = 2 months old) serum. For this study, on day 0 and day 14 after transplantation, serum samples were collected for later crossmatching. On day 14 after transplantation, the crossmatch had converted to positive in 76 transplantations (8.5%). Acute rejection occurred in 50% of the converters and 22% of the non-converters (P < 0.005), and graft survival was significantly poorer (P < 0.025), being 85 vs 94% at 1 and 68 vs 83% at 5 years, respectively. In patients with delayed graft function, 1-year graft survival was 77% in the converters and 91% in the non-converters (P < 0.05). Conversion of T cell crossmatch, especially in connection with delayed graft function, identifies a subgroup of patients at high risk of severe rejection and poor graft survival.

Long-term graft outcome is not necessarily affected by delayed onset of graft function and early acute rejection.

BACKGROUND: Both acute rejection episodes and delayed graft function (DGF) have been shown to be associated with decreased 1-year renal allograft survival. In our center, the incidence and the intensity of acute rejection episodes have been reduced by cyclosporine-based triple-drug therapy. We have also shown that DGF alone is not a risk factor for long-term graft survival. METHODS: We have now investigated whether an acute rejection episode together with DGF significantly effects long-term graft outcome. This study involved 862 first cadaveric renal allografts and 182 regrafts. RESULTS: The incidence of DGF was 33% after first transplants and 44% after retransplants. The overall incidence of acute rejection episodes was 23% in first grafts and 28% in regrafts. After first grafts, there were no statistically significant differences in graft survival rates and half-lives between the early graft function (EGF) and DGF groups with or without acute rejection. In regrafts, graft survival was significantly higher in the EGF group without acute rejection than in the DGF group with acute rejection. However, if all other causes except chronic rejection were censored, the half-life in the EGF group without acute rejection was 17.3 years in first grafts, and in the DGF group with acute rejection, that number was 11.5 years in first grafts; for regrafts, the half-life was 12.3 years and 6.1 years, respectively. CONCLUSIONS: Acute rejection together with DGF could contribute to initial damage to the graft, and this might lead to later chronic allograft failure. In our study, this effect was evident only in the case of retransplants.

Sequential changes in vitamin D and calcium metabolism after successful renal transplantation.

A prospective study was made of sequential changes in the metabolism of vitamin D and calcium in 19 allograft recipient during the first year after successful renal transplantation. All but one of the patients received cyclosporine A combined with corticosteroids and azathioprine as immunosuppressive therapy. Shortly after transplantation most patients showed transient hypocalcemia and hypophosphatemia. At the time of transplantation 17 of 19 patients had an elevated plasma intact parathyroid hormone (PTH) level, and at the close of follow-up one in four patients. In six other patients intact PTH was within the reference range, but high in relation to simultaneously measured serum ionized calcium. According, one year after transplantation less than half of the patients showed complete resolution of hyperparathyroidism. The change towards normal in the metabolism of vitamin D began within the first post-transplantation week irrespective of the onset of diuresis. One to two weeks after transplantation 1,25(OH)2D3 and 24,25(OH)2D3 reached the lower limit of normal range. In these renal allograft recipients who received cyclosporine A the long-term values of serum 1,25(OH)2D3 did not differ from those of normal subjects.

Impaired renal function after pregnancy in renal transplant recipients.

Twenty-two renal transplant recipients had 29 posttransplant pregnancies and 39 male transplant recipients became fathers to 65 children between 1971 and 1991. Of the deliveries of the female patients, 62% took place between the third and sixth year after transplantation. Seven patients had 2 pregnancies. Mean follow-up time after the first posttransplant pregnancy was 7.5 years. The patients survived the pregnancy well, but the increase in serum creatinine concentration from the prepregnancy level, registered 3 months and 1 year after delivery, was higher than in matched control patients without pregnancy at corresponding times after transplantation (the increase in serum creatinine was 47.7 and 61.2 mumol/L in the pregnant patients versus -2.7 and 5.4 mumol/L in the control patients, P < 0.0001 and P < 0.02, respectively). All pregnant and control patients were alive at the end of follow-up, but the long-term graft survival of those with a pregnancy was significantly (P < 0.005) worse than in the control patients. Ten-year graft survival was 69% in the pregnant versus 100% in the control patients. Although 80% of the neonates born to a mother with a transplanted kidney were below the mean for gestational age, the weight and length at birth were within normal limits and no severe intrauterine growth retardation was documented.

Acute vascular rejection in renal transplantation--diagnosis and outcome.

Thirty episodes of histologically verified acute vascular rejection in kidney transplant recipients were studied. In 11 grafts the rejection was mainly vascular, whereas in 19 grafts a concomitant cellular rejection was seen. Histological features prognostic for bad outcome were glomerular necrosis and thrombi in the arteries and arterioles. Characteristic findings in transplant cytology, i.e., high number of monocytes and low number of lymphocytes and blast cells were noted prior to the onset of clinical signs of rejection, and this finding was also persisting throughout the rejection episode. The numbers of lymphocytes and blast cells were significantly lower in grafts with a pure vascular rejection than in grafts with a concomitant cellular rejection. Vascular rejection was reversible in 15 cases. As rescue therapy plasmapheresis and added immunosuppression were often successful.