A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients.

BACKGROUND: Transplant recipients have an increased propensity to develop multiple actinic keratoses, which demonstrate an increased transformation rate into invasive squamous cell carcinoma. OBJECTIVE: To evaluate the efficacy and tolerability of topical photodynamic therapy with the new highly tumour-selective photosensitizer methyl aminolaevulinate vs. placebo in the treatment of actinic keratoses in transplant recipients. METHODS: Seventeen transplant recipients with a total number of 129 mild to moderate actinic keratoses were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Two lesional areas within a patient were randomized for two consecutive treatments of topical photodynamic therapy 1 week apart using either methyl aminolaevulinate or placebo cream. Sites were illuminated with 75 J cm(-2) of visible light delivered at 80 mW cm(-2) by a noncoherent light source. Complete resolution and reduction in the number or size of actinic keratoses within the lesional area relative to the initial findings were evaluated at weeks 4, 8 and 16 after treatment. RESULTS: The lesional areas treated with methyl aminolaevulinate were clinically cleared in 13 of 17 patients at 16 weeks. A partial response was recorded in a further three. No reduction in the size or number of actinic keratoses was observed in one area treated with methyl aminolaevulinate and in all placebo-treated areas. Adverse events, such as erythema, oedema and crust formation, were mild to moderate, and treatment was well tolerated by all patients. CONCLUSION: Photodynamic therapy using methyl aminolaevulinate is a safe and effective treatment for actinic keratoses in transplant recipients. It may also reduce the risk of transformation of actinic keratoses to invasive, potentially fatal, squamous cell carcinoma.

Differential use of cardiac troponin T versus I in hemodialysis patients.

BACKGROUND: Cardiac troponin T (cTnT) is frequently elevated in asymptomatic hemodialysis (HD) patients and predicts increased cardiovascular morbidity and mortality. Compared to cTnT, cardiac troponin I (cTnI) has a shorter half-life. How this influences its diagnostic reliability in chronic HD patients is only partially known. PATIENTS AND METHODS: First, in a cross-sectional study cardiac troponins were measured in 31 asymptomatic HD patients. A third-generation cTnT assay was used. The rate of false positive tests and the intraindividual variability were determined. Second, in a retrospective analysis over 12 months all acute events with clinical suspicion for acute coronary syndrome (ACS) were analysed in the same patients to determine the diagnostic power of cTnT by receiver-operating curve (ROC) plot. RESULTS: Cross-sectional study: 9 of 52 (17%) cTnT and 0/52 cTnI (0%) tests were positive in asymptomatic HD patients with a low intraindividual variability. Retrospective analysis: 16 acute clinical events with determination of cTnT were recorded, and in 4/16 an ACS was diagnosed. Using a cut-off level of 0.1 microg/l, the cTnT test reached a sensitivity of 100%, a specificity of 42%, a positive predicitive value of 36% and a negative predictive value of 100%, using a cut-off level of 0.2 microg/l the corresponding values were 75%, 58%, 38% and 88%. CONCLUSIONS: Cardiac TnT, but only rarely cTnI, is elevated in a significant number of asymptomatic HD patients. For diagnosis of ACS in HD patients, a combination of cTnT and cTnI may be used, since the former has higher sensitivity and the latter higher specificity. A higher threshold value for cTnT in HD patients could further increase its diagnostic accuracy.

Renal pathology and premortem clinical presentation of Caucasian patients with AIDS: an autopsy study from the era prior to antiretroviral therapy.

PRINCIPLES: Renal disease in patients with HIV infection is becoming increasingly frequent. A particular form of HIV-associated nephropathy (HIVAN) has been found in patients of predominantly African-American and Hispanic origin. However, only limited data are available on renal pathology and premortem clinical presentation of kidney disease in Caucasian patients with AIDS. METHODS: To determine the prevalence, clinical presentation and aetiology of renal disease in Caucasian patients with AIDS at the time of death we have performed a prospective autopsy study with 239 patients who died of AIDS between 1981 and 1989. None of these patients had received HIV-specific antiretroviral therapy. Autopsies and histological analyses were performed on the basis of a standardised protocol. Clinical and laboratory data were gathered according to a uniform questionnaire. RESULTS: 95% of patients were of Caucasian race. 75% of all patients had extended AIDS (stage IV). Clinical signs of nephropathy prior to death were found in 36% of patients, including proteinuria (18%), abnormal urinary sediment (19.5%), and renal insufficiency (11%). Histopathological lesions were present in 43% of the autopsies, with two or more distinct structural lesions in 12.5% of patients. Of the pathological findings 28% were glomerular or vascular, 33% were non-glomerular, and 29% were combined lesions. The remaining 10% were renal infiltrations of infectious agents or neoplastic tissue. The most common findings were ischaemic changes and vascular scars (18% of patients), as well as pyelo- and interstitial nephritides (12.2%). Importantly, FSGS was present in only 1.7% of patients, and only a single African patient had classical HIVAN. CONCLUSIONS: Renal involvement in HIV disease is very common at the time of death among patients of Caucasian origin. However, classical HIV-associated nephropathy is absent in this population. These findings suggest that kidney disease affects all races and supports the hypothesis that HIVAN is specifically related to non-Caucasian ethnicity. The results reflect renal disease unaffected by HIV-specific antiretroviral therapy.

Suppression of ICAM-1 expression in renal proximal tubular cells by 1,25-dihydroxyvitamin D3.

BACKGROUND: 1,25-Dihydroxyvitamin D(3) is mainly synthesized by renal proximal tubular cells. More recently, it has been shown to affect cell growth and TGF-beta(1) synthesis in glomerular and tubular renal cells in vitro, and to prevent glomerulosclerosis in vivo in subtotally nephrectomized rats. The mechanisms involved have not been fully identified. We asked whether 1,25-vitamin D(3) might interact with additional immunoregulatory functions of renal cells by studying its effects on the expression of the cellular adhesion molecules ICAM-1 (CD54) and VCAM-1 (CD106) in human proximal tubular cells in vitro (HK-2 cells). METHODS: Expression of adhesion molecules was assessed in HK-2 cells cultured under basal conditions and after stimulation with TNF-alpha plus IFN-gamma, by flow cytometry, gene transcription (RT-PCR) and measurement of soluble ICAM-1 in culture supernatant by ELISA. RESULTS: Unstimulated HK-2 cells did not express VCAM-1 and only little ICAM-1. 1,25-Vitamin D(3) had no effect on the expression of adhesion molecules in unstimulated cells. TNF/IFN stimulation resulted in a 4-fold increase in ICAM-1 and VCAM-1 expression. The TNF/IFN-induced increase in ICAM-1 expression was reduced by 1,25-vitamin D(3) dose dependently (10(-7) M vs. solvent: -30%; 10(-9) M: -18%; 10(-11) M: -17%). 25(OH)-vitamin D(3) had no effect. ICAM-1 mRNA concentration was increased in TNF/IFN-stimulated cells. 1,25-Vitamin D(3) treatment prevented the increase of ICAM-1 mRNA by 27% after 24-72 h incubation (p = 0.03). The TNF/IFN-induced increase in soluble ICAM in culture supernatants was unchanged by 1,25-vitamin D(3). VCAM-1 expression was unchanged by incubation with 1,25-vitamin D(3) under basal conditions and after TNF/IFN stimulation. CONCLUSION: 1,25-Vitamin D(3) inhibits cytokine-induced ICAM-1 but not VCAM-1 expression in renal proximal tubular cells in vitro. The present data support the hypothesis that 1,25-vitamin D(3) is not only synthesized by renal tubular cells, but may also affect immunoregulatory functions in these cells.

Skin cancers in organ transplant recipients: two cases of virus-induced neoplasms.

Immunosuppression profoundly influences the prevalence of skin disorders in transplant recipients. Skin tumors occur with high incidence and constitute a major part of transplantation-related morbidity and mortality. We report on 2 immunosuppressed patients presenting with rapidly growing epithelial and mesenchymal neoplasms after renal transplantation. The diagnostic approach, differential diagnosis and treatment options are discussed emphasizing the characteristics of cutaneous lesions in immunosuppressed transplant recipients.

[Current epidemiology and therapy of renal failure]. / Aktuelle Epidemiologie und Therapie des Nierenversagens.

The worldwide increase of chronic renal failure is a challenge for cost effective therapeutic modalities of high quality. It affords timely communication and cooperation between practitioners and specialists.

The 825C/T polymorphism of the G-protein subunit beta3 does not influence blood pressure and renal function in kidney transplant recipients.

BACKGROUND: Recently, a polymorphism at position 825 (C-->T) of the cDNA that encodes the beta3 subunit of heterotrimeric G proteins (Gbeta3) was found to be associated with essential hypertension. The T allele leads to the formation of a truncated splice variant (Gbeta3-s) with enhanced activity, promoting hypertension. We examined whether the T allele had an influence on blood pressure (BP) and early renal function after renal transplantation. METHODS: We determined the Gbeta3 genotype and T allele frequencies in renal transplant patients and examined associations with BP, BP medications, and renal function in the first year after transplantation. RESULTS: In renal transplant recipients (n=216) the frequency of the T allele was marginally increased (0.34 vs 0.29) compared with normal healthy blood donors (n=163). Age, sex and body mass index were similar in patients with the CC, CT and TT genotype. BP, number of BP medications, and serum creatinine levels were also similar for the three genotypes within the first year after transplantation. Significantly more patients with the TT genotype (48%) had glomerulonephritis as the underlying renal disease, compared with the CT (29%) and CC (27%) genotypes. CONCLUSIONS: The T allele of Gbeta3 does not have a negative impact on BP and early renal function in recipients of a renal allograft. The T allele might play a role in the pathogenesis of chronic glomerulonephritides.

Randomized trial of conversion from mycophenolate mofetil to azathioprine 6 months after renal allograft transplantation.

BACKGROUND: In the first year after renal allograft transplantation, triple therapy immunosuppression with cyclosporin (CsA), prednisone (P), and mycophenolate mofetil (MMF) is superior to a triple therapy treatment that includes azathioprine (AZA) instead of MMF. Whether long-term treatment with CsA-P-MMF is better than treatment with CsA-P-AZA is a matter of debate, as 3-year graft survival is similar in MMF- and AZA-treated patients. The purpose of the present study was to examine the short-term effect of changing MMF to AZA in low-risk renal allograft recipients 6 months after transplantation. METHOD: This was a randomized, open-label single-centre study, recruiting 48 low risk renal allograft recipients on CsA-P-MMF therapy 6 months after transplantation, comparing the outcome with continued MMF treatment (2 g b.i.d.) (group A, n=22) or switching MMF to AZA (1 mg/kg) treatment (group B, n=26). RESULTS: The outcome after a 6-months follow-up of patients in group A and group B was similar. Treatment failure rates (defined as clinically diagnosed acute rejection episodes) were 4.5% in group A and 3.8% in group B. There were no patient deaths and no graft failures during the 6-months observation period. Graft function was excellent and similar in both groups. CONCLUSION: Replacing MMF with AZA 6 months after transplantation in low-risk renal allograft recipients is safe and is not associated with altered graft function in the short term.

[Epidemiology of chronic hepatitis B and C among dialysis patients in Switzerland]. / Epidemiologie der chronischen Hepatitis B und C bei Dialysepatienten in der Schweiz.

BACKGROUND: Among patients with renal insufficiency undergoing chronic dialysis treatment, chronic hepatitis due to infection with viruses of the hepatitis B (HBV) or hepatitis C (HCV) type represents a serious medical problem. In contrast to other countries, detailed statistics on the prevalence of HBV and HCV infection are not available for dialysed patients in Switzerland. METHODS: The present study is based on a nationwide survey among the Swiss dialysis population which evaluated the prevalence of patients positive for either the HBs antigen (reflecting HBV infection) or anti-HCV antibodies (reflecting HCV infection) in 1999. From our survey we collected data on 1713 haemodialysis and 226 peritoneal dialysis patients, representing 92 and 65% of the respective dialysis populations in Switzerland. RESULTS: Of all patients (haemodialysis and peritoneal dialysis), 6.59% were HBV or HCV marker positive (HBV: 1.44%, HCV: 5.05%). In haemodialysis patients the prevalence was clearly higher for HBV (1.63%) and HCV (5.72%) compared to patients undergoing peritoneal dialysis (0.88 and 3.09% respectively). Laboratory parameters of hepatitis--as evidenced by an increase in liver transaminases--were present in 4% of the entire dialysis cohort, 0.6% having an increase in ALAT beyond 1.5 times the normal range. Patients undergoing treatment in haemodialysis units which do not implement additional precautions to prevent the spread of HCV among patients were more likely to be HCV marker positive with laboratory signs of hepatitis. A similar correlation was observed between HBV or HCV marker positivity and the number of patients treated per haemodialysis unit. Finally, the percentage of HBV/HCV marker positive patients on the Swiss kidney transplant list is comparable with that of HBV/HCV marker positive patients in the entire dialysis population.

[Extra-intestinal salmonella infections in kidney transplant patients]. / Extraintestinale Salmonellen-Infektionen bei nierentransplantierten Patienten.

Immunosuppression to prevent rejection of solid organ transplants is accompanied by an increased risk of infections. The most frequent diseases include cytomegalovirus as well as bacterial infections of the urinary tract and the lung. The rate of enteric salmonella infections is increased in transplant patients. We report on four cases of extraintestinal salmonellosis after kidney allotransplantation.

Metabolic aspects of phosphate replacement therapy for hypophosphatemia after renal transplantation: impact on muscular phosphate content, mineral metabolism, and acid/base homeostasis.

Hypophosphatemia caused by renal phosphate loss occurs frequently after kidney transplantation. In assumption of systemic phosphorus depletion, the presumed deficit commonly is replaced by oral phosphate supplements. However, such treatment is debatable, because intracellular phosphorus stores have not been assessed in this setting and may not be accurately reflected by serum phosphate concentrations. Moreover, disturbances in mineral metabolism from chronic renal failure, such as hypocalcemia and hyperparathyroidism, may be prolonged with oral phosphate supplements. Conversely, a neutral phosphate salt might improve renal acid excretion and systemic acid/base homeostasis for its properties as a urinary buffer and a poorly reabsorbable anion. Twenty-eight patients with mild early posttransplantation hypophosphatemia (0.3-0.75 mmol/L) were randomly assigned to receive either neutral sodium phosphate (Na(2)HPO(4)) or sodium chloride (NaCl) for 12 weeks and examined with regard to (1) correction of serum phosphate concentration and urinary phosphate handling; (2) muscular phosphate content; (3) serum calcium and parathyroid hormone (PTH); and, (4) renal acid handling and systemic acid/base homeostasis. Mean serum phosphate concentrations were similar and normal in both groups after 12 weeks of treatment; however, more patients in the NaCl group remained hypophosphatemic (93% versus 67%). Total muscular phosphorus content did not correlate with serum phosphate concentrations and was 25% below normophosphatemic controls but was completely restored after 12 weeks with and without phosphate supplementation. However, the percentage of the energy-rich phosphorus compound adenosine triphosphate (ATP) was significantly higher in the Na(2)HPO(4) group, as was the relative content of phosphodiesters. Also, compensated metabolic acidosis (hypobicarbonatemia with respiratory stimulation) was detected in most patients, which was significantly improved by neutral phosphate supplements through increased urinary titratable acidity. These benefits of added phosphate intake were not associated with any adverse effects on serum calcium and PTH concentrations. In conclusion, oral supplementation with a neutral phosphate salt effectively corrects posttransplantation hypophosphatemia, increases muscular ATP and phosphodiester content without affecting mineral metabolism, and improves renal acid excretion and systemic acid/base status.

1,25-dihydroxyvitamin D3 stimulates transforming growth factor-beta1 synthesis by mouse renal proximal tubular cells.

1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3] is a secosteroid hormone with effects on cell growth, differentiation and immunoregulatory functions in a number of tissues not primarily involved in mineral metabolism. We recently demonstrated growth-regulating effects of 1, 25-(OH)2 D3 on human mesangial cells and proximal tubular cells. To investigate whether 1,25-(OH)2 D3 might also affect the synthesis of cytokines and growth factors in proximal tubular cells, we assessed in the present study the expression and secretion of transforming growth factor-beta1 (TGF-beta1) in a mouse proximal tubular cell line (MCT) in vitro. TGF-beta1 synthesis was measured by a monospecific ELISA in culture supernatant. The secreted TGF-beta1 was proven to be biologically active by means of a bioassay system (CCL-64 mink lung epithelial cell proliferation assay). TGF-beta1 gene expression was assessed by RT-PCR. To analyze whether TGF-beta1 expression mediates the 1,25-(OH)2 D3-induced antiproliferative actions in MCT, proliferation studies in the absence or presence of a blocking monoclonal anti TGF-beta1-3 antibody were performed. 1, 25-(OH)2 D3 (10(-11) to 10(-7) M) specifically increased the TGF-beta1 protein secretion in MCT with a maximum at 10(-8) M. No detectable effect was found with 25 D3 at 10 times higher concentrations. A synthetic 20-epi analogue, MC 1288, increased TGF-beta1 secretion up to similar amounts at equimolar concentrations as the natural hormone 1,25-(OH)2 D3. Steady-state TGF-beta1 mRNA concentration in MCT was transiently increased by 1, 25-(OH)2 D3 between 12 and 24 h, returning to control values at 48 h. Blocking TGF-beta1 did not reduce or abrogate the antiproliferative effect of 1,25-(OH)2 D3. In conclusion, 1,25-(OH)2 D3 stimulates TGF-beta1 expression in renal proximal tubular cells, a growth factor with anti-inflammatory and profibrotic actions which plays an important role in the development and progression of nephrosclerosis.

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.

BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined.