David L. Nicol

Non-melanoma skin cancer risk in the Queensland renal transplant population

Summary Background Non‐melanoma skin cancer (NMSC) is an important complication of solid organ transplantation, especially in areas of high ultraviolet light exposure. Registry data may underestimate the scale of the problem.

NOVEL ASSOCIATION OF A DIVERSE RANGE OF GENES WITH RENAL CELL CARCINOMA AS IDENTIFIED BY DIFFERENTIAL DISPLAY

We have used differential‐display PCR ( DD‐PCR ) to compare renal‐cell carcinoma (RCC) and normal kidney gene expression with the aim of identifying genes specifically associated with RCC. Using a modified DD‐PCR approach, which was non‐radioactive, quicker and simpler than the conventional method, 24 cDNA samples were clearly up‐ or down‐regulated in RCC tissue from 4 patients. Fourteen of these showed high similarity to a number of known genes. Eight of these cDNA clones were chosen for further analysis. These were a regulator of G‐protein signalling (RGS‐5), Notch‐3, Na,K‐ATPase α subunit, HLA class II antigen, ETS‐like protein, transforming growth factor β–stimulated clone (TSC‐22), bladder cancer–related protein (BC10) and adipophilin. Semi‐quantitative RT‐PCR using specific primers to each of these genes confirmed differential expression in 67% to 83% of a further 12 RCC and normal kidney paired samples from 7 of the 8 cDNA clones. Northern analysis further confirmed the up‐regulation in expression of RGS‐5 and Notch‐3 in RCC. Further characterisation of these differentially expressed genes should lead to a better understanding of the changes that occur at the molecular level during RCC development and progression. Int. J. Cancer 88:726–732, 2000.

Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: A randomized controlled trial

Objective  To report the first systematic investigation of the cognitive effects of luteinizing hormone‐releasing hormone (LHRH) analogues in male patients, as LHRH analogues have been associated with memory impairments in women using these drugs for gynaecological conditions.

Vascular endothelial growth factor expression is increased in renal cell carcinoma

PURPOSE To compare the expression of VEGF in renal cell carcinoma (RCC) and normal kidney. MATERIALS AND METHODS RT-PCR and Western blot analysis were performed on tumour and normal adjacent kidney collected from 31 patients (29 RCC and 2 oncocytomas) as well as proliferating vascular endothelial cells (VEC) in culture. RESULTS Expression of 3 VEGF isoforms was detected in normal renal parenchyma and all ROC by RT-PCR, but was not apparent in proliferating VEC. In 27 RCC, Western blot analysis demonstrated 3-37 fold increases in VEGF expression when compared to normal parenchyma. Immunohistochemistry demonstrated VEGF staining of both tumour cells and adjacent vascular endothelium. Normal kidney showed no staining for VEGF. In the 2 remaining RCC and both oncocytomas VEGF was not increased. CONCLUSIONS VEGF expression is increased in RCC and may have a paracrine effect in these tumours in stimulating angiogenesis.

A COMPARISON OF THE EFFECTS OF DIALYSIS AND RENAL TRANSPLANTATION ON THE SURVIVAL OF OLDER UREMIC PATIENTS

BACKGROUND Patients over age 60 constitute half of all new patients accepted into the renal replacement therapy programs in Australia. However, the optimal treatment of their end-stage renal disease remains controversial. The aim of the present study was to compare survival for dialysis and renal transplantation in older patients who were rigorously screened and considered eligible for transplantation. METHODS The study cohort consisted of 174 consecutive patients over 60 who were accepted on to the Queensland cadaveric renal transplant waiting list between January 1, 1993 and December 31, 1997. Follow-up was terminated on October 1, 1998. Data were analyzed on an intention-to-transplant basis using a Cox regression model with time-varying explanatory variables. An alternative survival analysis was also performed, in which patients no longer considered suitable for transplantation were censored at the time of their removal from the waiting list. RESULTS There were 67 patients receiving a renal transplant, whereas the other 107 continued to undergo dialysis. These two groups were well matched at baseline with respect to age, gender, body mass index, renal disease etiology, comorbid illnesses, and dialysis duration and modality. The overall mortality rate was 0.096 per patient-year (0.131 for dialysis and 0.029 for transplant, P<0.001). Respective 1-, 3- and 5-year survivals were 92%, 62%, and 27% for the dialysis group and 98%, 95%, and 90% (P<0.01) for the transplant group. Patients in the transplant group had an adjusted hazard ratio 0.16 times that of the dialysis group (95% confidence interval 0.06-0.42). If patients were censored at the time of their withdrawal from the transplant waiting list, the adjusted hazard ratio was 0.24 (95% confidence interval 0.09-0.69). CONCLUSIONS Renal transplantation seems to confer a substantial survival advantage over dialysis in patients with end-stage renal failure who are rigorously screened and considered suitable for renal transplantation.

The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients

Mycophenolic acid kinetics have been reported to vary after renal transplantation, and mycophenolic acid area under the concentration–time curve (AUC) is the best predictor of suppression of graft rejection.

Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma.

The effect of captopril on tumour growth was examined in a xenograft model of human renal cell carcinoma (RCC). Inoculation of the human RCC cell line SN12K-1 (10(6) cells) under the left kidney capsule of severe combined immunodeficient (SCID) mice resulted in the growth of large tumours, with an increase in weight of the inoculated kidney of 3.69+/-1.63-fold (mean+/-s.d.) when compared with the contralateral normal kidney. In mice treated with captopril (19 mg kg(-1) day(-1) or 94 mg kg(-1) day(-1) administered in the drinking water), there was a significant dose-related reduction in tumour development; the tumour bearing kidneys weighed 1.9+/-0.42 and 1.55+/-0.42 times the normal kidneys, respectively (P< 0.05 compared with untreated animals). In vitro, captopril at clinically achievable doses (0.1-10 microM) had no significant effect on the incorporation of [3H]thymidine into SN12K-1 cells. Thus, this highly significant attenuation by captopril of in vivo tumour growth does not appear to be due to a direct effect on the proliferation of the tumour cells. Further studies are required to determine the mechanism of inhibition of tumour growth by captopril, in particular to evaluate the role of angiotensin II in this process.

OBESITY IS ASSOCIATED WITH WORSENING CARDIOVASCULAR RISK FACTOR PROFILES AND PROTEINURIA PROGRESSION IN RENAL TRANSPLANT RECIPIENTS

Obesity is associated with adverse cardiovascular (CV) parameters and may be involved in the pathogenesis of allograft dysfunction in renal transplant recipients (RTR). We sought the spectrum of body mass index (BMI) and the relationships between BMI, CV parameters and allograft function in prevalent RTR. Data were collected at baseline and 2 years on 90 RTR (mean age 51 years, 53% male, median transplant duration 7 years), categorized by BMI (normal, BMI ≤ 24.9 kg/m2; pre‐obese, BMI 25–29.9 kg/m2; obese, BMI ≥ 30 kg/m2). Proteinuria and glomerular filtration rate (eGFRMDRD) were determined.

Silibinin – A Promising New Treatment for Cancer

Silymarin and its major constituent, Silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. The aim of the present review is to examine the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinins anti-cancer actions reported to date in pre-clinical and clinical trials. The review will also discuss the results of current research efforts seeking to determine the extent to which the effectiveness of silibinin as an adjunct cancer treatment is influenced by such factors as histologic subtype, hormonal status, stromal interactions and drug metabolising gene polymorphisms. The results of these studies may help to more precisely target and dose silibinin therapy to optimise clinical outcomes for oncology patients.

Routine use of indwelling ureteral stents in renal transplantation.

An extravesical ureteral implantation with the routine use of an internal stent was performed in 358 transplants (351 cadaveric and 7 living related). The 1-year patient and graft survival was 93% and 87%, respectively, with a minimum followup of 2 years. Ureteral complications developed in 9 patients (2.6%), with 3 fistulas, 2 of which resolved spontaneously, and 6 stenoses following stent removal. Nephrostomy drainage and antegrade stenting were initially attempted in all cases of stenosis, and were successful in 4. Revision of the ureteral anastomosis was required in 1 case of fistula and 2 cases of stenosis (0.9%). Extrinsic compression resulted in ureteral obstruction in 3 cases (2 lymphoceles and 1 hematoma), which resolved following drainage. Stent related complications occurred in 8 patients (2.2%), including obstruction due to the stent in 2 cases, breakage during removal in 3 leaving fragments in the upper urinary tract, proximal migration of 2 stents that were retrieved via percutaneous nephrostomy and calculus formation on 1 stent in a patient with hyperparathyroidism, necessitating extracorporeal shock wave lithotripsy for stent removal. In the cases with ureteral or stent related complications 1-year patient and graft survival was 100%. These results suggest that ureteral stents used routinely in renal transplantation are associated with a low incidence of urinary leaks, early postoperative obstruction and subsequent surgery for urological complications. However, a small number of unique problems related to stent use or malfunction may occur. Minimally invasive strategies using percutaneous nephrostomy and antegrade stenting are effective in managing the majority of complications that occur following ureteral stenting in renal transplant recipients.