Comparison of contrast enhanced MR-angiography-MRI and digital subtraction angiography in the evaluation of pancreas and/or kidney transplantation patients: initial experience.

To evaluate whether combined contrast enhanced MRA and MRI (ce-MRA-MRI) has the potential to replace intra-arterial DSA (i.a.DSA) in patients with impaired graft function or suspected of vascular complications after pancreas and/or kidney transplantation. 7 patients after combined pancreas-kidney and 22 patients after kidney transplantation underwent ce-MRA-MRI and i.a.DSA within a 3 days interval. Qualitative and quantitative comparison of the arterial and venous supply, the parenchyma and urinary collecting system was made. Both ce-MRA and i.a.DSA showed good results in the detection of arterial stenoses. However, ce-MRA falsely suggested stenoses if vascular clips were used; on the other hand, i.a.DSA was less informative if the graft arteries were very tortuous. Ce-MRA was superior in depicting the venous anatomy (p < 0.001) and the parenchymal enhancement of the pancreatic grafts. For the assessment of the contrast excretion, the pyelocalyceal system and the ureter of the renal graft ce-MRA-MRI was superior (p < 0.001), for small caliber arteries in the renal grafts i.a.DSA was of greater value (p < 0.001). The combination of ce-MRA and MRI is reliable for evaluating the vascular anatomy and has several advantages over i.a.DSA after pancreas and/or kidney transplantation. It can replace i.a.DSA in patients with impaired graft function or suspected of vascular complications after pancreas and/or kidney transplantation.

Addition of isradipine (Lomir) results in a better renal function after kidney transplantation: a double-blind, randomized, placebo-controlled, multi-center study.

BACKGROUND: After successful kidney transplantation patients may suffer from the adverse effects due to the use of calcineurin inhibitors. Calcium channel blockers are effective in the treatment of hypertension and may ameliorate cyclosporine- (CsA) induced impairment of renal function after kidney transplantation. Calcium channel blockers may also modulate the immune-system which may result in reduction of acute rejection episodes. PATIENTS AND METHODS: From June 1995 till 1997 the effect of isradipine (Lomir) on renal function, incidence and severity of delayed graft function (DGF), and acute rejection after kidney transplantation, was studied in 210 renal transplant recipients, who were randomized to receive isradipine (n=98) or placebo (n=112) after renal transplantation in a double-blind fashion. RESULTS: In the isradipine group renal function was significantly better at 3 and 12 months (P=0.002 and P=0.021) compared with the placebo group. DGF was present in both groups: isradipine: (28+6)/98 (35%); placebo: (35+9)/112 (40%), P=0.57. Severity of DGF was comparable in both groups (isradipine: 9.1+/-8.7 vs. placebo: 9.3+/-8.1 days). No statistical difference was found in incidence or severity of biopsy-proven acute rejection [isradipine: (42+6)/98 (49%) versus placebo: (46+9)/112 (49%), P=1.00]. Renal vein thrombosis was observed in eight patients. This proved to be associated with the route of administration of the study medication [6/45 (13%) on i.v. medication versus 2/165 (1%) on oral medication, P<0.001]. CONCLUSIONS: Addition of isradipine results in a better renal function after kidney transplantation, without effect on incidence or severity of DGF or acute rejection.

Experimental autologous substitute vascular graft for transplantation surgery.

Vascular complications in liver transplantation are a major cause of graft failure and mortality. The aim of the study was to create autologous vascular graft without risk of rejection. Posterior rectus fascia sheath lined with peritoneum was used for iliac artery replacement in seven mongrel dogs. The patency was followed by palpation and Doppler ultrasound. The grafts were removed after one month. Five grafts remained patent. The Doppler showed good, relatively increased flow (median flow rate: 383 cm/sec) after one month in all of the cases. Slight increase in diameter was present in all cases. By microscopy the five patent grafts showed viable morphology, fibroblasts, smooth muscle cells and thin fibrin layer in the wall. The grafts were lined partially with a neoendothelial monolayer and a thin fibrin layer. In conclusion, this graft presents an acceptable patency rate and low thrombogenicity, and could be useful in transplantation. Further investigations are needed to study the effect of immunosuppression and rejection on long-term morphology and patency of the grafts.

Nitric oxide production and nitric oxide synthase expression in acute human renal allograft rejection.

BACKGROUND: Nitric oxide (NO) is produced by nitric oxide synthases (NOS), which are either constitutively expressed in the kidney or inducible, in resident and infiltrating cells during inflammation and allograft rejection. NO is rapidly degraded to the stable end products nitrite and nitrate, which can be measured in serum and urine, and may serve as noninvasive markers of kidney allograft rejection. METHODS: Total nitrite and nitrate levels (NOx) were measured in serum and urine thrice weekly after an overnight fast in 18 consecutive patients following renal cadaveric transplantation. Inducible NOS (iNOS) and endothelial NOS (eNOS) expression was immunochemically determined in renal biopsy specimens with or without acute rejection (AR). RESULTS: Serum NOx levels increased days before AR and were significantly higher at the moment of AR (27+/-12.4 micromol/L) compared with recipients with an uncomplicated course (13+/-7.6 micromol/L), but not compared with recipients with cyclosporine (CsA) toxicity (20+/-13.0 micromol/L). Urinary NOx levels were significantly lower during AR (20+/-13.6 micromol/mmol creatinine) compared with an uncomplicated course (64+/-25.2 micromol/mmol creatinine) or CsA toxicity (53.8+/-28.3 micromol/mmol creatinine). Interstitial and glomerular iNOS expression was significantly increased in biopsy specimens showing AR. Unexpectedly, glomerular eNOS expression was significantly decreased in patients with AR. CONCLUSIONS: This study reports differences in NOx levels in serum and urine, which may help discriminate AR episodes from an uncomplicated course or CsA toxicity. As expected, renal iNOS expression is increased in acute allograft rejection. The decrease in glomerular eNOS expression suggests an intriguing link between acute and chronic rejection.

Cytomegalovirus pneumonitis after kidney transplantation is not caused by plugging of cytomegalic endothelial cells only.

In addition to life-threatening pneumonia, cytomegalovirus (CMV) may also cause subclinical pulmonary dysfunction after kidney transplantation. To investigate the role of plugging of cytomegalic endothelial cells in the pulmonary capillary bed, we prospectively determined specific carbon monoxide diffusion capacity (KCOc) and its components: the pulmonary diffusing membrane factor (Dm) and pulmonary capillary blood volume (Vcap) before and during CMV infection in 13 kidney transplant recipients and 13 controls. During CMV infection, mean KCOc decreased significantly by 28 % of the initial value (mean KCOc 79 vs 109; P < 0.005 ) due to a decrease in both Vcap and Dm. The KCOc in controls showed a significantly smaller decrease due to a slightly lower Vcap. We conclude that kidney transplant recipients with CMV infection have significant pulmonary diffusion disturbances due to a combination of lower Vcap and lower Dm. The most likely explanation for this phenomenon is a local inflammatory process due to CMV and not plugging of cytomegalic endothelial cells only.

Risk factors for long-term renal survival after renal transplantation: a role for angiotensin-converting enzyme (insertion/deletion) polymorphism?

Chronic progressive renal function loss is a main cause of long-term graft loss after initially successful renal transplantation. Transplanted kidneys share some risk factors for renal function loss, such as hypertension or proteinuria, with diseased native kidneys. Recently, it has been shown that renal function loss is influenced by the angiotensin-converting enzyme (ACE) (insertion/deletion [I/D]) genotype in renal disease in diseased native kidneys. This study examines whether donor or recipient ACE (I/D) genotype is a risk factor for graft loss after renal transplantation. To avoid bias by acute events, graft survival was studied, with patients dying with a functioning graft censored, starting at 12 mo after transplantation in a cohort of 367 patients transplanted between 1987 and 1994 with at least 2 yr of follow-up. Mean follow-up was 58 mo. ACE (I/D) genotype was determined by PCR on stored donor and recipient lymphocytes. Neither donor nor recipient ACE (I/D) genotype was associated with graft survival. However, Cox proportional hazards analysis identified recipient, but not donor, ACE (I/D) genotype D-allele to be independently associated with a shorter time to graft loss in subgroups of patients at high risk for graft loss defined by a creatinine clearance <50 ml/min (n = 108, P = 0.017) or proteinuria > or =0.5 g/24 h at 12 mo (n = 97, P = 0.0051) after transplantation. In conclusion, recipient ACE (I/D) genotype was associated with time to graft loss in a specific high-risk subgroup of the study population. This suggests that the effect of ACE (I/D) genotype on graft survival only becomes apparent when other risk factors are simultaneously present.

Primary renal graft thrombosis.

BACKGROUND: Renal allograft thrombosis is a serious complication of kidney transplantation that ultimately leads to graft loss. Its association with acute and hyperacute rejection is well documented; however, in a large proportion of patients the precise cause remains obscure. The exact incidence and the associated risk factors for those episodes of graft thrombosis lacking evidence of rejection have not yet been clearly established. METHODS: All reported episodes of graft thrombosis in 558 consecutive cadaveric kidney transplants performed in a single centre were examined to identify those without histopathological evidence of rejection, i.e. primary renal graft thrombosis. Univariate and multivariate types of analysis were applied to study the possibly related risk factors and any associated morbid event(s) of those episodes. Recipients without reported episodes of primary renal graft thrombosis (n = 493) represented the control group for the 34 identified cases. RESULTS: The calculated incidence of primary renal graft thrombosis was 6% (1.9% arterial, 3.4% venous and 0.7% both), comprising 45% of early (90 days) and 37% of 1-year graft losses in our centre. The multivariate analysis identified five independent risk factors for primary renal graft thrombosis: donor's right kidney P < 0.007, past history of venous thrombosis (renal or extrarenal) P = 0.000, and diabetic nephropathy P = 0.000 of the recipient, technical surgical problems P = 0.000, and recipient's haemodynamic status peri and early postoperatively P < 0.001. Primary renal graft thrombosis was related to the presentation with delayed graft function (DGF) P < 0.0005 and was significantly associated with extrarenal thromboembolic manifestations P < 0.0005. There was no association between primary renal graft thrombosis and recipient's age, sex, number of previous transplants, type of dialysis, pretransplant treatment with erythropoietin, antiplatelet agents, or oral anticoagulants, donor's age, sex, number or graft vessels, warm and cold ischaemia times, site of transplant (R/L iliac fossa) and type of immunosuppressive agent used for induction whether cyclosporin A (CsA) or OKT3. CONCLUSIONS: Primary renal graft thrombosis is an important cause of graft loss that may be accompanied by thrombosis of extrarenal sites and effective, safe prophylactic regimens are needed, especially for those at high risk.

Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.

PURPOSE: The purpose of this study was to investigate the effect of acitretin on the development of keratotic skin lesions, and on squamous cell carcinomas and basal cell carcinomas in a group of renal transplant recipients. PATIENTS AND METHODS: Forty-four renal transplant recipients with more than 10 keratotic skin lesions on the hands and forearms were enrolled onto a randomized, double-blind, placebo-controlled trial to test the possible skin cancer-preventing effect of a 6-month treatment with acitretin 30 mg/d. RESULTS: No deterioration in renal function occurred in any of the 38 assessable patients treated. During the 6-month treatment period, two of 19 patients (11%) in the acitretin group reported a total of two new squamous cell carcinomas, compared with nine of 19 patients (47%) in the placebo group who developed a total of 18 new carcinomas (chi 2 = 6.27, P = .01). The relative decrease in the number of keratotic skin lesions in the acitretin group was 13.4%, as compared with a relative increase in the placebo group of 28.2% (difference, 41.6%; 95% confidence interval, 11.5 to 71.7). Most patients treated with acitretin had mild mucocutaneous side effects, but these were easily manageable. Some patients experienced mild hair loss. With the exception of three patients, no increase in serum cholesterol or triglyceride above pretreatment levels was observed, and liver function remained unchanged in all patients. CONCLUSION: Acitretin 30 mg/d over 6 months had significantly more effect than placebo in the prevention of squamous cell carcinomas and reduced the occurrence of keratotic skin lesions in a group of renal transplant recipients with severe lesions. This effect was most pronounced in patients with a history of squamous cell carcinomas and basal cell carcinomas.

Pair-tested renal reserve filtration capacity in kidney recipients and their donors.

Subjects after kidney donation manifest an adaptive rise in GFR. In uninephrectomized rats, progressive glomerulosclerosis, which is induced by the compensatory glomerular hyperfiltration, develops. It has been assumed that testing the existence of renal reserve filtration capacity (RRFC) might be used to demonstrate such glomerular hyperfiltration in humans. In a paired way, the RRFC of 15 kidney recipients and their donors were investigated long term (4.9 +/- 0.8 (SE) yr) after surgery. Continuous infusions of (125I)iothalamate and (131I)hippuran were used to measure GFR and effective RPF (ERPF). RRFC was tested by the infusion of dopamine, amino acids, and a combined infusion of these agents. The GFR, ERPF, and RRFC of the recipients did not differ from that of their donors. RRFC had also been tested in 12 donors, before and short term (1.3 +/- 0.3 (SE) months) after the kidney donation. Thus, the RRFC of the kidney donors could be monitored longitudinally. GFR measured short term after kidney donation amounted to 62% (+/- 2.1% SE) of the value before donation and to 68% (+/- 1.7% SE; P < 0.005) of the value long term after donation. Short- and long-term ERPF both amounted to 68% of the value before donation. The RRFC tested with the amino acids of the donors before kidney donation did not differ from that either short-term or long term after donation. Likewise, the RRFC tested with the amino acids of the recipients was similar to that of the donors before kidney donation. In contrast, in kidney recipients and donors, both short and long term after donation, RRFC tested with dopamine was approximately halved compared with that of the donors before donation. It was concluded, first, that testing RRFC cannot be used to test the existence of maladaptive glomerular hyperfiltration in subjects with a single kidney: Second, GFR increases for years after kidney donation, probably because of the compensatory hypertrophy of the remaining kidney.

Effects of cyclosporin A withdrawal on renal function and renal stimulation in liver transplant patients treated with triple-drug immunosuppression for over 2 years.

The influence of CsA withdrawal on the glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) was prospectively studied in nine stable liver transplant recipients. Before CsA withdrawal (test 1), and 6 months thereafter (test 2) the renal function was determined by measuring GFR and the ERPF with 125I-iothalamate and 131I-hippuran respectively. The renal function was also stimulated with dopamine, with an amino-acid infusion and a combination of both. After CsA withdrawal the GFR increased, median from 74 ml min-1 to 90 ml min-1, (P < 0.04). The ERPF also increased, median from 310 ml min-1 to 380 ml min-1, (P < 0.03). In test 1 as well as in test 2 the renal function could be stimulated, especially with dopamine. GFR and ERPF improved, even after more than 2 years of CsA treatment. These results suggest that long-term CsA treatment impairs the renal function, though in these liver transplant patients CsA treatment did not prevent afferent and efferent arteriolar vasodilatation after renal stimulation. This reversible intrarenal vasoconstriction during CsA treatment may predict renal improvement after CsA withdrawal.

Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants.

BACKGROUND: Dietary fish oil exerts effects on renal hemodynamics and the immune response that may benefit renal-transplant recipients treated with cyclosporine. To evaluate this possibility, we studied the effect of fish oil on renal function, blood pressure, and the incidence of acute rejection episodes in cyclosporine-treated recipients of renal transplants. METHODS: In a randomized, double-blind trial, 33 recipients of first cadaveric kidney transplants who were treated with cyclosporine and prednisolone ingested 6 g of fish oil daily during the first postoperative year (the fish-oil group), whereas another 33 renal-graft recipients treated with cyclosporine and prednisolone ingested 6 g of coconut oil daily for three months after which time it was stopped (the control group). RESULTS: One year after transplantation, the fish-oil group had higher median values than the controls for glomerular filtration rate (53 vs. 40 ml per minute per 1.73 m2, P = 0.038) and effective renal plasma flow (214 vs. 178 ml per minute per 1.73 m2, P = 0.023) and lower mean arterial pressure (103 vs. 118 mm Hg, P = 0.0011). The cyclosporine doses in the two groups were similar. The cumulative number of rejection episodes was 20 in the controls, as compared with 8 in the fish-oil group (P = 0.029). One-year graft survival also tended to be better in the fish-oil group, (97 vs. 84 percent, P = 0.097). CONCLUSIONS: The daily administration of 6 g of fish oil during the first postoperative year has a beneficial effect on renal hemodynamics and blood pressure in renal-transplant recipients treated with cyclosporine. Although the fish-oil group had significantly fewer rejection episodes than the control group, graft survival at one year was not significantly better in the fish-oil group.

Prediction of recurrent cytomegalovirus disease after treatment with ganciclovir in solid-organ transplant recipients.

CMV disease often recurs after initially successful antiviral therapy. We retrospectively determined in a group of 36 organ transplant patients whether clinical, virological, or immunological parameters during or shortly after cessation of antiviral therapy can identify those at high risk of relapse. Eleven of 36 patients had recurrent CMV disease after ganciclovir therapy. Neither donor or recipient CMV serostatus, type of baseline immunosuppression, antirejection treatment, indication for antiviral treatment, nor presence of CMV in the blood during or after therapy (as detected by antigenemia, viremia, or a positive polymerase-chain-reaction signal) were helpful in identification of patients with subsequent relapse. However, quantitative monitoring of antigenemia fascilitated early diagnosis of relapse since 10 of 11 patients with > or = 10 antigen-positive cells per 50,000 PMNs relapsed (99.1%, 95% CI 58.7-99.8). IgM and IgG responses against CMV during primary infection were comparable in relapsing and nonrelapsing patients. During secondary infection relapse occurred only in the 4 patients with the lowest IgG responses. The number of activated CD8bright lymphocytes in the peripheral blood as determined by flow cytometry at the end of antiviral therapy was a strong risk factor for the subsequent clinical course: 6 of 7 patients (85.7%, 95% CI 42.1-99.6%) with < 100 x 10(3) HLADR+CD8bright cells/ml blood relapsed, while 8 of 8 (100%, 95% CI 63-100) with activated CD8bright cells above that level remained asymptomatic (P < .025). These data show that patients with a high risk of relapse of CMV disease can be identified at the end of antiviral therapy.