The role of androgen receptor gene in cyclosporine induced gingival overgrowth.

BACKGROUND AND OBJECTIVE: Gingival overgrowth is a prominent side effect of cyclosporine (CsA) therapy in renal transplant patients. Although the exact mechanism by which this drug induces gingival overgrowth is uncertain, marked variations in individual susceptibility to this drug suggest a genetic predisposition. Studies have shown that genetic variation (polymorphism) in the trinucleotide cytosine-adenine- guanine (CAG) sequence in exon 1 of the androgen receptor (AR) gene is related to altered activity of the AR as a transcription factor. However, the relationship between the length of the CAG repeat and gingival overgrowth has not yet been studied. The present study was carried out to determine whether there is an association between CsA-induced gingival overgrowth and the length of the CAG repeats in the AR gene. MATERIAL AND METHODS: Genomic DNA samples were prepared from the blood of 50 renal transplant patients with CsA-induced gingival overgrowth and from the blood of 100 renal transplant patients on CsA with no gingival overgrowth. RESULTS: The difference in allele distribution among the subjects with gingival overgrowth and control samples was statistically significant (p = 0.001). CONCLUSION: The findings suggest a link between CsA7induced gingival overgrowth and a smaller size of CAG repeat in the AR gene.

Factors affecting hemodialysis patients' satisfaction with their dialysis therapy.

Aim. To assess the degree of satisfaction among hemodialysis patients and the factors influencing this satisfaction. Methods. Patients were recruited from 3 Saudi dialysis centers. Demographic data was collected. Using 1 to 10 Likert scale, the patients were asked to rate the overall satisfaction with, and the overall impact of, their dialysis therapy on their lives and to rate the effect of the dialysis therapy on 15 qualities of life domains. Results. 322 patients were recruited (72.6% of the total eligible patients). The mean age was 51.7 years (±15.4); 58% have been on dialysis for >3 years. The mean Charlson Comorbidity Index was 3.2 (±2), and Kt/V was 1.3 (±0.44). The mean satisfaction score was (7.41 ± 2.75) and the mean score of the impact of the dialysis on the patients' lives was 5.32 ± 2.55. Male patients reported worse effect of dialysis on family life, social life, energy, and appetite. Longer period since the commencement of dialysis was associated with adverse effect on finances and energy. Lower level of education was associated with worse dialysis effect on stress, overall health, sexual life, hobbies, and exercise ability. Conclusion. The level of satisfaction is affected by gender, duration on dialysis, educational level, and standard of care given.

Extensive oral shedding of human herpesvirus 8 in a renal allograft recipient.

INTRODUCTION: Studies were conducted to investigate changes in the extent of human herpesvirus 8 (HHV-8) shedding and diversity of HHV-8 strains in the mouth of a renal allograft recipient who developed cutaneous post-transplantation Kaposi's sarcoma. METHODS: Matched oral and blood samples were obtained from a Saudi Arabian renal allograft recipient from 3 days before to 38 weeks after transplantation, and from his kidney donor. Polymerase chain reaction (PCR) protocols to amplify selected HHV-8 sub-genomic regions were applied to detect and quantify HHV-8 DNA. Sequence diversity was determined by cloning the PCR products and subjecting them to denaturing gradient gel electrophoresis and to nucleotide sequencing. RESULTS: Before transplantation, the recipient was seropositive for anti-HHV-8 immunoglobulin G, but the donor was seronegative; HHV-8 DNA could be detected in the recipient's blood, whole-mouth saliva (WMS) and buccal exfoliates, and the salivary viral load was estimated as 2.6 million genome-copies/ml. Post-transplantation, the recipient's salivary viral load initially increased to 4.1 million genome-copies/ml, and thereafter declined precipitously, coinciding with an increase in the dosage of valaciclovir given; HHV-8 DNA was detected most often in WMS compared with parotid saliva, and buccal and palatal exfoliates. Carriage of multiple HHV-8 strains was evident in blood and oral samples; whereas before transplantation strains belonging to genotypes A1 and A5 were observed, after transplantation genotype A5 strains became dominant and A2 strains emerged. CONCLUSION: Immunosuppression and antiviral prophylaxis may interact to influence the spectrum of oral HHV-8 strains and the extent of post-transplantation HHV-8 shedding into the mouth.

Alpha-interferon with ribavirin in the treatment of hemodialysis patients with hepatitis C.

INTRODUCTION: Hepatitis C Viral (HCV) infection is the leading cause of chronic liver disease in end-stage renal disease patients (ESRD). The impact of HCV on patient and graft survival posttransplantation is controversial. The most successful approach is to eliminate the virus while the patient is on dialysis prior to transplantation. The main aim of this pilot study was to assess the efficacy of combined alpha-interferon (alpha-IFN) and ribavirin treatment of HCV hemodialysis (HDx) patients, by comparing the sustained virological response to that obtained by local historical data on treatment with alpha-IFN alone. A secondary aim was to establish the optimal therapeutic dose of ribavirin in this regimen. METHODS: Twenty HCV-HDx patients who were histologically (liver biopsy) and virologically (HCV-PCR)-positive were selected randomly. They received combination therapy with 3 million units (MU) of alpha-IFN and 200 mg of ribavirin three times a week. Initially nine patients were treated for 24 weeks. Later, another 11 patients were randomly selected to give the combination for 48 weeks. RESULTS: Six of the nine patients who were treated for 24 weeks (66%) became HCV-PCR-negative by the end of the treatment period. They continued to have a sustain virologic response at 6 months after the cessation of therapy. Six of the 11 patients (55%) who were treated for 48 weeks became HCV-PCR-negative at the end, and at 6 months after cessation of treatment. Of the first six responders, 4 (66%) maintained a sustained virologic response at 1 year postcessation of therapy. Nine of the 11 patients had genotype 4 and 1. No side effects were reported for a ribavirin dose of 200 mg three times a week. CONCLUSION: This pilot study suggests that combination treatment for 24 weeks and 48 weeks with 3 MU alpha-IFN and 200 mg ribavirin three times a week, elicited a sustained virologic response in HDx patients with HCV infection better than IFN alone with minimal side effects. A prospective, double-blind, controlled study using pegylated INF plus ribavirin is currently underway.

Caring for hemodialysis patients in Saudi Arabia. Past, present and future.

There are currently 5706 patients receiving hemodialysis therapy in the Kingdom of Saudi Arabia - a 15 fold increase when compared to 1983. The annual increase in the number of patients on dialysis for 1999 is 696 (10 fold increase when compared to 1983). Besides the massive increase in the number of patients in the last 20 years, we have noticed a marked increase in the mean age of patients (51.3 years in 1999 as compared to 37.9 years in the early 80s). Diabetes mellitus which was an insignificant contributory etiology (4%) in the early 80s is now a major cause (16-25%). Similarly mortality has increased from 4% annually to 11-14% annually. This is largely due to increasing age and prevalence of diabetes mellitus. Within the expired cohort the mean age was 62.3 years compared to 51.3 years of the total dialysis population, and diabetes mellitus was present in 60.5% in those who expired. Moreover, ischemic heart disease was diagnosed in 50% before death. Tuberculosis and Hepatitis C virus incidences, however, have not improved over the years but the degree of rehabilitation has, largely due to better hemoglobin level and due to the technological advances in dialysis delivery. This article describes these changes, their causes and implications.

Hypercholesterolemia in renal transplantation.

OBJECTIVES: We conducted this study to evaluate the prevalence, and risk factors of hypercholesterolemia (HC) in renal transplant population. METHODS: We reviewed the records of the active renal transplant patients at two large transplant centers in Riyadh and Jeddah in Saudi Arabia transplanted between 1979 and November 1998. The patients were grouped according to the measurement of serum cholesterol level; group I (normal): below or equal 5.2 mmol/L, group II (mild HC): from 5.3-6.0 mmol/L, group III (moderate HC): from 6.1-8.0 mmol/L group IV (severe HC): above 8.0 mmol/L. RESULTS: There were 1096 patients' records included in the study. According to the level of measured serum cholesterol, there were 421 (38.4%) patients is group I, 256 (23.3%) patients in group II, 363 (33.1%) patients in group III and 57 (5.2%) patients group IV. We found no significant difference between the study groups in terms of gender (60% males, 40% females), mean duration of transplantation (66.9 months), between those transplanted before 1990 and those transplanted after 1990, donor type, prevalence of hypertension (85%), history of hypertension on dialysis, original kidney disease, frequency of rejections in the first year (28%), mean serum creatinine (220 mumol/L), cyclosporine mean dose (3.2 mg/kg/day) mean prednisone dose (0.15 mg/kg/day), number of patients on azathioprine (65%), the mean proteinuria (0.6 G/L) or number of antihypertensives. In comparison with the group with normal serum cholesterol level, the group with severe hypercholesterolemia had significantly higher mean age (40.6 versus 37.4 years), higher mean weight (72 versus 65.8 kg), rate of retransplantation (8.8% versus 3.1%), higher frequency of diabetics (35% versus 20%) and higher frequency of abnormal electrocardiogram (18.2% versus 5.2%). CONCLUSION: That hypercholesterolemia is a significant problem in the renal transplant population in Saudi Arabia. Risk factors for the development of hypercholesterolemia are mainly related to weight, age, diabetes and retransplantation.

Effect of lithium on cyclosporin induced nephrotoxicity in rats.

Psychoactive drugs provide essential intervention in the care of transplant recipients, yet little is known of their interaction with immunosuppressants such as cyclosporin (CSA). Lithium (Li) is an invaluable drug for the treatment of manic disorders in organ transplant patients. As both these drugs are known to produce renal toxicity, the concomitant use of CSA and Li may be potentially harmful. The present study was undertaken to investigate the effect of CSA and Li chloride individually and in combination on renal structure and function of rats. Male Sprague-Dawley rats were divided into the following eight groups of seven animals each: group I, control (vehicle only); group 2, Li (2 mEq/ kg i.p.) alone; group 3, CSA 12.5 mg/kg (subcutaneous); group 4, CSA 25 mg/kg; group 5, CSA 50 mg/kg; group 6, CSA 12.5 mg/kg + Li; group 7, CSA 25 mg/kg + Li; and group 8, CSA 50 mg/kg + Li. The drugs were given once a day for seven days; Li being administered 30 min before CSA. Twenty four hours after the last dose of drugs the animals were sacrificed and blood samples were analyzed for blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Li levels. The left kidney was analyzed for malondialdehyde (MDA) and conjugated dienes (CD) levels and right kidney was used for histopathological studies. Our results showed that Li alone did not produce any significant renal toxicity, whereas CSA dose dependently caused structural and functional changes in kidneys. However, significantly higher structural and functional impairment was observed in the animals treated with Li plus CSA as compared to CSA alone treated animals. Several fold increase in blood Li level was also noticed in the rats concomitantly treated with CSA and Li. A significant increase in MDA and CD in the rats treated with CSA plus Li suggests the role of oxidative stress in drug induced nephrotoxicity. These findings clearly demonstrate that even non toxic doses of Li may significantly exacerbate CSA induced nephrotoxicity in rats. The enhanced nephrotoxicity following concomitant use of these drugs may be attributed to significant increase in the bioavailability of Li and enhanced oxidative stress. Further clinical studies are warranted to investigate the interaction of these nephrotoxic drugs in human subjects.

Diabetes and renal transplantation: saudi experience.

We conducted this study to evaluate the prevalence and risk factors of diabetes mellitus (DM) in our renal transplant population. We retrospectively reviewed the records of the active renal transplant patients at two large transplant centers in Riyadh and Jeddah in Saudi Arabia, transplanted between 1979 and November 1998. The recipients were grouped according to the diagnosis of diabetes; group I: diabetes developed before transplantation (BTDM), group II: diabetes developed only after transplantation (ATDM) and group III: did not have diabetes (NDM). There were 1112 patients' records included in the study. The mean age was 38.2 years and the mean duration of transplantation was 66.9 months. There were 113(10.2%) patients in BTDM group, 134 (12.1%) patients in the ATDM group and 865 (77.8%) patients in the NDM group. There was no significant difference in the prevalence of hypertension among the study groups. In comparison to the other groups, the BTDM group had significantly more males (78.8%), more patients who were transplanted after 1990 (pre-cyclosporin era), more patients with grafts from living non-related donors (46%), higher incidence of acute rejection episodes (39%), higher mean serum creatinine and more patients treated with azathioprine (71%). The ATDM group had significantly higher mean age (46.4 years), higher mean duration of transplantation (91.5 months), higher rate of retransplantation (8.2%), higher mean serum cholesterol level (6.0mmol/L) and more frequently abnormal electrocardiogram (24.6%) than the other two groups. The ATDM group had comparable mean weight (70.2 kg) to the BTDM group but significantly higher than the NDM group (66.1kg). The NDM group had significantly higher mean dose of cyclosporine (3.3 mg/kg/day) and higher mean dose of prednisone (0.16 mg/kg/day) than the other groups. The only independent risk factor for developing DM after transplantation was advancing age. The currently used low-dose steroid therapy was not significantly associated with development of DM after renal transplantation. Nevertheless DM is an important co-morbid condition in the transplant population and is associated with increased risk for cardiovascular and cerebrovascular events.

A Prospective Study of Renal Biopsies Performed Over One-year at the Riyadh Armed Forces Hospital.

A prospective study of all native kidney biopsies performed over one year at the Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia was conducted. During this period, 52 kidney biopsies were performed of which, 49 had adequate tissue. All biopsies were processed for light microscopy, immunofluorescence and electron microscopy. The indications for biopsy included the nephrotic syndrome (n=28; 53.8%), asymptomatic proteinuria (n=12; 21.2%), acute nephritic presentation (n=7; 13.5%) and asymptomatic hematuria (n=7; 13.5%). Primary glomerulonephritis (GN), excluding IgA nephropathy (IgAN) was seen in 34 of the 49 patients (77.6%). Focal and segmental glomerulosclerosis and mesangial proliferative GN were the most common histological diagnoses (31% and 20.4% respectively). Surprisingly, we found a high prevalence of IgA nephropathy (IgAN) of 14.5% in comparison with other studies. The prevalence of mesangiocapillary glomerulonephritis (MCGN) was low (2%) and can only be explained as incidental. The study patients were followed-up for an average of 26.3 weeks. At the end of the observation period, 50% has unchanged course, 37.5% had improved their renal function and protein excretion, and 12.5% had deteriorated. The prognosis of different GN groups and renal survival rate cannot be assessed or calculated in this study because of the relatively short duration of follow-up. Our study further emphasizes the need for a national GN registry and long-term follow-up, in order to recognize the common patterns of GN, their natural histories, the appropriate line of management, and to try and arrest their progression to end-stage renal disease.

The diagnosis of segmental transplant renal artery stenosis by captopril renography.

The captopril renogram test has been shown to be a sensitive test for the diagnosis of renal artery stenosis in native and transplanted kidneys. Most reports have involved only stenosis of the main renal artery. Although segmental renal artery stenosis has been diagnosed successfully in native kidneys, it is not clear whether the captopril renogram test can diagnose segmental renal artery stenosis in a transplanted kidney. The authors report two cases of successful identification, by the captopril renogram test, of functionally significant stenosis in an intrarenal branch of a single transplant renal artery.

N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats.

BACKGROUND: Cyclosporin (CsA) has played an important role in the improvement of solid-organ transplant patients and graft survival. However, nephrotoxicity due to CsA remains an important clinical challenge. The renal toxicity of CsA is attributed to reduced renal blood flow which leads to hypoxia reoxygenation injury accompanied by excessive generation of oxygen-derived free radicals (ODFR). N-acetyl-L-cysteine (NAC) is a highly potent antioxidant that has been shown to reduce ODFR injury. In this study an attempt was made to assess the effect of NAC on CsA-induced lipid peroxidation and nephrotoxicity. METHODS: Adult Sprague-Dawley rats were treated orally with CsA (25 and 50 mg/kg) alone and in combination with different doses of NAC (10, 20 and 40 mg/kg) for a period of 3 weeks. Twenty-four hours after the last treatment, animals were sacrificed and blood was analysed for blood urea nitrogen (BUN) and serum creatinine (SCr), and kidney samples were analysed for lipid hydroperoxides, conjugated dienes and glutathione, and histopathological changes. RESULTS: Treatment of rats with CsA produced a significant increase in BUN and SCr level and histological abnormalities. CsA-induced impairment of renal toxicity was accompanied by significant increase in renal oxidative stress. NAC treatment significantly protected animals against CsA-induced structural and functional impairment of kidney. CONCLUSIONS: CsA-induced nephrotoxicity was significantly attenuated by NAC. This study clearly suggests the role of oxidative stress in the pathogenesis of CsA-induced nephrotoxicity. Concomitant use of antioxidants such as NAC to minimize CsA-induced nephrotoxicity in humans warrant further studies.

Aluminum exacerbates cyclosporin induced nephrotoxicity in rats.

Cyclosporin (CSA) has been universally used as an immunosuppressant for the management of allotransplantation and autoimmune diseases. However, nephrotoxicity of CSA limits its use to optimum level. Aluminum (Al) is an extensively distributed element in the environment and human exposure to this metal is unavoidable. Recent studies suggest that even a slight impairment of renal function may increase the Al body burden significantly, which may lead to neurotoxicity, nephrotoxicity, osteodystrophy or hypochromic anemia. In the present study, an attempt was made to study the effect of concomitant use of Al and CSA on structure and function of kidney in rats. This study was undertaken in two steps. In the first set of experiments, the effect of single dose of Al (1% Al2(SO4)3 18H2O) on the nephrotoxicity of multiple doses of CSA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) was studied, where as in the second set of experiments the effect of multiple doses of Al (0.25%, 0.5% and 1%) on single dose of CSA (50 mg/kg) was undertaken. Male Sprague-Dawley rats (weighing 230 +/- 20 g) were used in this study. CSA was given once a day by gavage for seven days, where as Al was given in drinking water for the same period. Twenty four hours after the last dose of CSA, animals were sacrificed and blood and kidney were collected for biochemical and histopathological studies. The bio-chemical parameters included blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Al levels. The kidney homogenates were assayed for malondialdehyde (MDA) and lipid hydroperoxides (LPH). Treatment of rats with CSA alone produced dose-dependent structural and functional changes in kidney. Although Al alone failed to produce any deleterious effect on renal function, it significantly increased the bioavailability and nephrotoxicity of CSA. Al also exacerbated CSA induced increase in oxidative stress (as evident by increased MDA and LPH). Thus, the exacerbation of CSA nephrotoxicity by Al may be attributed to increased bioavailability of CSA and excessive generation of free radicals following concomitant use of these drugs.

Hypertension in renal transplantation: saudi arabian experience.

To evaluate the prevalence, etiologic factors and therapy of hypertension in actively followed up transplant population in Saudi Arabia; we retrospectively reviewed the records of the active renal transplant patients at two large transplant centers in Riyadh and Jeddah in Saudi Arabia. These subjects were transplanted between January 1979 and November 1998. The patients were grouped according to the measurement of blood pressure; group 1 (considered normo-tensive): blood pressure below 140/90 mmHg, group2: blood pressure between 140-159/90-99, group 3: blood pressure 160-179/100-109 group 4: equal to or above 180/110. There were 1115 patients' records included in the study. The mean duration of transplantation was 66.9 +/- 50.1 months. According to the level of measured blood pressure, there were 641 (57.5%) patients in the normotensive group (group 1), 404 (36.3%) patients in the mildly hypertensive group (group 2) 64 (5.7%) patients in the moderately severe hypertension group (group 3) and only six (0.5%) patients in the severe hypertension group (group 4). The estimated prevalence of hypertension in this study was almost 85%. We found no significant difference in the prevalence of hypertension in terms of gender, year of transplantation, duration of transplantation, type of donor, number of previous transplants, diagnosis of renal artery stenosis, etiology of kidney disease, diagnosis of diabetes after transplantation, diagnosis of cerebrovascular accidents, or mean dose of prednisolone and cyclosporine. There was a statistically significant association between increased level of blood pressure and old age (above 50 years), original disease associated with hypertension, history of hypertension on dialysis, acute rejection (once or more), presence of protienuria (more than 0.3 mg/day), abnormality of ECG, or serum creatinine above 300 micromol/L. We conclude that hypertension is highly prevalent in the renal transplant population in Saudi Arabia. Risk factors for the development of hypertension or its complication should be more aggressively approached in order to protect the patients and their grafts alike.

Effect of Ramadan fasting on Moslem kidney transplant recipients.

This study was carried out to find out whether Ramadan fasting would affect the renal function in kidney transplant recipients with normal or impaired graft function. Twenty-three transplant recipients, 17 with a normal function and 6 with an impaired but stable function with plasma creatinine levels not exceeding 300 mmol/l, were included in this study. The mean posttransplant period was 2.0 (range 0.6-6.3) years. Urinary and serum biochemical parameters, ciclosporin A level, and hematocrit were checked weekly, during Ramadan as well as 1 week before and after. Statistical analysis showed no significant changes in all parameters before, during, and after Ramadan. In conclusion, our findings indicate that fasting during the month of Ramadan does not seem to be associated with any significant adverse effects in kidney transplant recipients with normal or impaired graft function and suggest that it is safe for those patients to fast during Ramadan after 1 year of renal transplantation.