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.

Differentiation between irreversible and reversible rejection in renal transplant patients by monitoring of phytohemagglutinin-induced cytotoxicity.

Phytohemagglutinin (PHA)-induced cytotoxicity against adherent HeLa cells, a reproducible test for primary T cell cytotoxicity, was used in the followup of 34 renal transplant recipients and related to the outcome. During the 1st week, two uncomplicated cases showed a decrease in cytotoxicity of more than 20% and it remained low. One patient with a cytomegalovirus (CMV) infection showed a marked increase in cytotoxicity (37%) and it remained high. In 31 patients with a rejection episode, a change of -20 to +20% was observed. During the 2nd week, all 10 patients who developed an irreversible rejection showed an increase of more than 20% (mean, 29 +/- 8%), in contrast to only 2 of 21 patients with a reversible rejection (mean, -1 +/- 15%, P less than 0.001). There were no differences between these two groups in lymphocyte and T lymphocyte counts, or in prednisone or azathioprine dose or blood urea nitrogen levels. These results indicate that regular assessment of PHA-induced cytotoxicity may be useful in the followup of renal transplant patients.

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.

The effects of dietary supplementation with fish oil on renal function and the course of early postoperative rejection episodes in cyclosporine-treated renal transplant recipients.

In a randomized prospective coconut oil (daily 6g[63% C8:0 and 36% C10:0] [EPA-] [n = 48])-controlled trial, we investigated the effect of a one-month dietary supplementation with daily 6 g fish oil (30% C20:5 omega-3 and 20% C22:6 omega-3 as their methyl esthers [EPA+] [n = 40]) on the incidence and course of early postoperative rejection in 88 first cadaveric, cyclosporine-treated renal transplant recipients. At one month there were no differences in renal function and incidence of rejection episodes. When analyzed separately for rejection (re+) or nonrejection (re-), the rejecting and fish oil-treated patients showed a significant better recovery of renal function after a histologically confirmed rejection episode, creatinine clearance being 43 ml/min/1.73m2 in the EPA+re+group versus 27 ml/min/1.73 m2 in the EPA-re+group (P less than 0.05), and serum creatinine being 183 and 283 mumol/l (P less than 0.05), respectively. The prerejection renal function and the decline of renal function during the rejection episode did not differ significantly between the EPA+re+ and the EPA-re+ groups. The nonrejecting fish oil-treated patients showed no better renal function than the nonrejecting coconut oil-treated patients. However, cyclosporine trough levels were significantly higher in the fish oil-treated group (EPA+re- 251 versus EPA-re- 200 ng/ml [P less than 0.05]). From these results we conclude that dietary supplements with fish oil favorably influence renal function in the recovery phase following a rejection episode in cyclosporine-treated renal transplant recipients. We further conclude that one month after grafting there is no difference in the incidence of rejection episodes between the fish- and coconut oil-treated patients. The same holds true for renal function in the absence of rejection, and for the decline in renal function during a rejection episode.

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.

Complement activation associated with active cytomegalovirus infection in renal transplant patients, and its absence in transplant rejection episodes.

In 20 patients with a cadaveric renal allograft, serial measurements were made of the serum complement factors C3, C4, factor B (FB), and C3d, the stable conversion product of C3. Measurements were started immediately before transplantation and continued thereafter once a week to investigate whether these assays help to differentiate between acute allograft rejection (R) and an active cytomegalovirus (CMV) infection. Fifteen patients had one or more R episodes, and 9 patients suffered from an active CMV infection. Six patients had an R episode and subsequently a CMV infection 13-64 days after R. No significant changes were found in the levels of C3, C4, and FB during R or CMV infection. C3d levels remained unchanged or decreased slightly during R. However, there was a 43-500% increase in the C3d level during CMV infection. This difference in the behavior of levels of C3d during R and CMV infection is significant (P less than 0.01), and suggests that serial measurements of C3d may be useful in differentiating CMV infection from R after renal transplantation.

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.

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.

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.

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.

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.

Unexpected severe reversible cyclosporine A-induced nephrotoxicity in a patient with systemic lupus erythematosus and tubulointerstitial renal disease.

We describe a patient with systemic lupus erythematosus and impaired renal function probably mainly due to tubulointerstitial disease. After a six-week course of low-dose cyclosporine A, she developed a severe but reversible loss of glomerular filtration rate and effective renal plasma flow despite of low cyclosporine A plasma levels. Based upon the observed fall of the filtration fraction, the rise in the relative clearance of 99Tc-dimercaptosuccinic acid and the increase in proteinuria, we suggest that in this case the tubules and/or interstitium are the main targets for cyclosporine A nephrotoxicity. Neither our patient's clinical symptoms nor her serologic parameters improved possibly because of the low dosage and/or short duration of cyclosporine A treatment. We conclude that one should be cautious when treating patients with systemic lupus erythematosus and pre-existing renal disease with cyclosporine A especially when tubulointerstitial abnormalities are present and/or other nephrotoxic drugs are used.

The effect of low-dose dopamine on renal function in uninephrectomized patients: special emphasis on kidney donors before and after nephrectomy.

In rats, uninephrectomy and subtotal renal ablation result in the development of hypertension and proteinuria, and, in a progressively downhill course of renal function, to end-stage renal disease. These events are attributed to glomerular hyperfiltration of remnant glomeruli. In man, however, long-term effects of unilateral nephrectomy appear to be less disastrous. The infusion of a low dose of dopamine (1.5-2.0 micrograms/kg/min) can be used to test the presence of a reserve filtration capacity i.e., the absence or existence of glomerular hyperfiltration. In order to investigate whether in man glomerular hyperfiltration occurs after unilateral nephrectomy, the effects of low-dose dopamine on glomerular filtration rate (clearance of 125I-iothalamate) and effective renal plasma flow (clearance of 131I-hippurate) of 18 uninephrectomized patients were investigated and compared with the effects of low-dose dopamine on those parameters of 32 healthy volunteers. Special interest was given to a subgroup of 10 kidney donors who were investigated before and after nephrectomy. Median values for the percentage of a dopamine-induced rise in the glomerular filtration rate were 4.5% in the uninephrectomized subjects and 10.0% in the control subjects (p less than 0.01). Median dopamine-induced increase in effective renal plasma flow as 22.5% and 35.0%, respectively (p less than 0.01). In the kidney donors the median percentage of a dopamine-induced change in the glomerular filtration rate was 12.4% before and 5.9% after nephrectomy (p less than 0.05%). It is concluded firstly, that renal reserve filtration capacity is decreased after unilateral nephrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversible stenosis of the renal artery in cadaver kidney grafts: a report of three cases.

Regression of segmental renal artery stenosis was observed in three recipients of cadaver kidney allografts. At the time the stenoses were diagnosed the patients were severely hypertensive, had decreased renal function and elevated plasma renin activities. They were treated with antihypertensives and two of them with dipyridamole. Within a year, antihypertensive treatment could be discontinued in two patients, while the stenoses decreased considerably in all three patients. There was concomitant improvement in renal function and plasma renin activity. The role of dipyridamole remains uncertain.

Pneumatosis intestinalis related to cytomegalo-virus infection--a new etiology?

Five patients who developed pneumatosis intestinalis in the course of a cytomegalo virus (CMV) infection after cadaveric kidney transplantation are described. Based on the fact that CMV is known to cause intestinal ulcers, we postulate a causal relationship between CMV and pneumatosis intestinalis.

Phytohemagglutin-induced lymphocyte cytotoxicity in hemodialysis patients with hepatitis B virus infection.

Phytohemagglutinin (PHA)-induced or primary cytotoxicity in vitro which is mediated by T lymphocytes, was studied during hepatitis B virus (HBV) infection in 45 hemodialysis patients, and related to liver cell damage and recovery. HBsAg positive patients with raised transaminases had increased primary cytotoxicity similar to nine otherwise healthy subjects with acute hepatitis B. HBsAg positive patients with normal transaminases showed decreased primary cytotoxicity and recovered patients showed normal values. Increased primary cytotoxicity could not be attributed to an increase in T lymphocytes, as all groups of hemodialysis patients had decreased lymphocyte and T-lymphocyte counts without significant differences between them. In the follow-up study none of the 13 HBsAg positive patients with normal transaminases recovered. However, five of the 18 patients with raised transaminases did recover from hepatitis B, accompanied by a decrease in cytotoxicity. These results show that an increased PHA-induced lymphocyte cytotoxicity corresponds with the occurrence of liver cell damage and subsequent recovery in hemodialysis patients with HBV infection. This suggests that cytotoxic T lymphocytes are involved in liver cell damage and recovery in HBV infection.

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.

[An adenovirus epidemic in patients with kidney transplantation]. / Een adenovirusepidemie onder niertransplantatiepatiënten.

During weekly routine virological screening of kidney transplant patients 12 out of 15 patients within a period of four months were found to be infected with adenovirus. All isolates were of the same serotype, type AdII + 35/HII. However, DNA restriction enzyme analyses showed the presence of two different DNA variants which were associated with three different epidemiological episodes. The epidemic probably started with reactivation of latent virus in a limited number of patients, after which it spread nosocomially. None of the patients showed signs or symptoms clearly attributable to adenoviruses, although adenovirus could not be excluded as a cofactor in the fatal outcome of hepatitis in one of the patients. Adenovirus apparently can easily spread nosocomially. Since literature data suggest that adenovirus infections of transplant patients may result in serious complications, adenovirus should not be neglected in virological screening protocols for kidney transplant patients.

[The use of juvenile kidneys for transplantation in adults]. / Het gebruik van kindernieren voor transplantatie bij volwassenen.

In view of the shortage of cadaveric donors a retrospective study has been performed to determine the results of transplantation of paediatric cadaver donor kidneys into adult recipients. Graft- and patient survival and renal function in the 31 cases, analysed in this study, showed no adverse effect of the use of pediatric donor kidneys. No vascular complications were encountered. In only one case ureteric leakage occurred and was treated successfully. It is concluded that paediatric age is no criterion for donor exclusion and that paediatric donors are to be regarded as a valuable source of cadaveric kidneys for transplantation. Also the possibility to perform nephrectomies in anencephalic newborn infants is to be considered.