Adam Tegzess

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.

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.

Cytomegalovirus antigenemia as a useful marker of symptomatic cytomegalovirus-infection after renal-transplantation - a report of 130 consecutive patients

In earlier work we demonstrated that CMV immediate early antigens can be detected in peripheral blood leukocytes of patients with active CMV infection. We now report a comparison of the antigenemia assay and an anti-CMV ELISA in a prospective longitudinal study of 130 renal transplant recipients who were monitored for active CMV infection during the first 3 months after transplantation. Active CMV infection developed in 56 patients. The antigenemia assay had a sensitivity of 89% and a specificity of 93% in the diagnosis of active CMV infection; for the ELISA these figures were 95 and 100%, respectively. In 22 of the 56 patients a CMV syndrome occurred. Antigenemia was demonstrated in all 22 patients while an antibody response occurred in 21 of them. The antigenemia assay became positive 8 +/- 7 days before the onset of symptoms while the antibody response was observed 4 +/- 9 days after the onset of symptoms. The pattern of antigenemia was helpful for monitoring the course of the infection. The maximum level of antigenemia was significantly higher and its duration significantly longer in symptomatic than asymptomatic infection. We conclude that CMV antigenemia is a sensitive, specific, and early marker of CMV infection. The antigenemia assay is of great value in monitoring patients with a high risk of CMV infection.

THE EFFECTS OF DIETARY SUPPLEMENTATION WITH FISH OIL ON RENAL-FUNCTION IN CYCLOSPORINE-TREATED RENAL-TRANSPLANT RECIPIENTS

The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega-3 (EPA) and 20% C22:6 omega-3 for three months on renal function variables was investigated in a placebo-controlled (6 g corn oil, 50% C18:2 omega-6) prospective, randomized, double-blind study in stable cyclosporine-treated renal transplant recipients, at least nine months after grafting. Ten patients ingested placebo capsules and eleven patients fish oil. When measuring glomerular filtration rate and effective renal plasma flow (ERPF) before (baseline [BL]) and after 3 months of oil ingestion nothing changed in the placebo-treated group: GFR-BL = 64.5 GFR-3 months = 60 ml/min/1.73m2 (NS; median, Wilcoxon test) ERPF BL = 229.5 and ERPF-3 months = 242.5 ml/min/1.73m2 (NS). In the fish oil-treated group GFR rose by 20.3% from GFR-BL = 56 to GFR-3 months = 68 ml/min/1.73m2 and ERPF by 16.4% from ERPF-BL 218 to ERPF-3 months = 245 ml/min/1.73m2, (P less than 0.01). In the placebo-treated group mean arterial pressure and calculated total renal vascular resistance (TRVR) did not change: MAP-BL = 106 mmHg and MAP-3 months = 109 mmHg, TRVR being 20856 dyne.sec/cm5 and 19862 dyne/sec/cm5, respectively (NS). In the fish oil-treated group MAP and TRVR fell by 8.6% and 21.1%, respectively: MAP-BL = 106 mmHg and MAP-3 months = 98 mmHg (P less than 0.01), TRVR-BL = 21952 dyne/sec/cm5 and TRVR-3 months = 17087 dyne/sec/cm5 (P less than 0.01). According to these results fish oil supplementation has considerable effects on renal function and blood pressure in stable CsA-treated renal transplant recipients.

HUMAN-IMMUNODEFICIENCY-VIRUS TRANSMISSION BY ORGAN DONATION - OUTCOME IN CORNEA AND KIDNEY RECIPIENTS

The human immunodeficiency virus (HIV) is reportedly transmitted by sexual contact, sharing of infected needles among intravenous drug abusers, blood and blood products, artificial insemination, and kidney transplantation. This study reports on cornea and kidney recipients of two HIV-infected donors. HIV was transmitted to two kidney recipients who developed symptoms of acute HIV infection (i.e., fever, leukopenia, mild thrombopenia, splenomegaly) starting 12 days after transplantation. These signs of acute infection ended with seroconversion of HIV antibodies on approximately the 56th day after transplantation. The three cornea recipients showed no signs of acute infection and no HIV antibodies were detected up to three years after transplantation. The nontransmission observed in our cases, however, may not be representative of cornea transplantations in general. HIV is neurotropic in the later stages of the disease, and transmission of other neurotropic viruses like rabies and Creutzfeldt-Jakob disease by cornea transplantation has been reported. All tissue and organ donors should be tested for anti-HIV prior to donation.

Expression of Inducible and Endothelial Nitric Oxide Synthases, Formation of Peroxynitrite and Reactive Oxygen Species in Human Chronic Renal Transplant Failure

Nitric oxide (NO·) is produced by NO synthases (NOS) and can interact with reactive oxygen species (ROS) to form peroxynitrite, which induces protein damage by formation of nitrotyrosine. NO· has a promotional effect on acute rejection. To investigate the role of NO· during chronic renal transplant failure (CRTF), we studied the expression of eNOS and iNOS in conjunction with H2O2 production and the formation of nitrotyrosines.

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.

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.

PNEUMATOSIS INTESTINALIS IN PATIENTS AFTER CADAVERIC KIDNEY-TRANSPLANTATION - POSSIBLE RELATIONSHIP WITH AN ACTIVE CYTOMEGALOVIRUS-INFECTION

Four patients are described with pneumatosis intestinalis following cadaveric kidney transplantation, all with severe cytomegalovirus (CMV) infection. Two patients had a primary infection and 2 patients had a reactivation of CMV. One patient died because of disseminated CMV infection. Multiple inclusion bodies were found at postmortem examination in lungs and liver, and at the site of the ulcers in the gastrointestinal tract. Two patients had, concomitantly, an active, nonobstructive duodenal ulcer. In a control population of 17 patients who suffered from a duodenal ulcer post-transplant without any evidence of CMV-infection, we could not demonstrate pneumatosis intestinalis. We suggest a possible causal relationship between pneumatosis intestinalis and active CMV infection. The mechanisms that could be responsible for this relationship are discussed.

Renal hemodynamics after lung transplantation : A prospective study

Renal function impairment is common after solid organ transplantation, due to the nephrotoxicity of cyclosporine. Moreover, in patients with severe respiratory failure, renal function is often impaired. This renal function impairment may predispose patients to further renal function impairment after lung transplantation. Therefore, renal hemodynamics were measured in 44 patients before lung transplantation and 1, 6, 12, 18, 24, and 30 months after transplantation. After transplantation, a decline in renal function occurred, with a progressive fall in glomerular filtration rate (GFR) of 33 +/- 4% at 12 months and 42 +/- 9% at 30 months. Effective renal blood flow fell by 22 +/- 5% at 12 months and remained stable thereafter. Changes in effective renal plasma flow (ERPF) were less pronounced than those of effective renal blood flow, due to a fall in hematocrit after transplantation. Blood pressure and renal vascular resistance increased significantly, consistent with the effects of cyclosporine. Prior to transplantation, renal function impairment with intense renal vasoconstriction had been found in a subset of the patients. Remarkably, the decrease in renal function after transplantation was less pronounced in patients with renal function impairment prior to transplantation, as indicated by significant negative correlations between pretransplantation GFR and the percentage change in GFR after transplantation, and pretransplantation ERPF and the percentage change in ERPF after transplantation. This suggests that the net course of renal hemodynamics after lung transplantation is the result of the opposed effects of cyclosporine nephrotoxicity and the favorable effects of the normalization of respiratory status. In conclusion, after lung transplantation a decline in renal function occurs that is less pronounced in patients with renal function impairment and intense renal vasoconstriction prior to transplantation. Such a renal function impairment, therefore, should not be considered a contraindication to lung transplantation.