Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is an important cause of renal artery stenosis, particularly in young females. Polymorphisms of the renin-angiotensin (RA) system have been implicated in the pathogenesis of hypertension and atherosclerotic vascular disease, and may play a role in the development of FMD. Examination of polymorphisms by PCR for angiotensin-converting enzyme (ACE) I/D, angiotensin II type 1 receptor (AT(1)R) A1166C and angiotensinogen (AGT) M235T and T174M was undertaken in 43 patients with typical multifocal renal arterial FMD (MF-FMD) and in 89 controls. The age of NIF-FMD patients at the time of diagnosis of hypertension did not differ (38.6 + 11.1 years vs 35.5 +/- 10.3 years, P = 0.12) from controls and the proportion (95% vs 86%, P = 0.14) of females was similar. Allele frequencies did not differ significantly between groups, except that MF-FMD patients had a significantly higher frequency of the ACE I allele than control subjects (0.62 vs 0.47, P = 0.026). Since the ACE I allele is associated with lower circulating ACE levels and possibly lower tissue levels of angiotensin II (Ang II), and since Ang II modulates vascular smooth muscle cell growth and synthetic activity, the I allele might predispose to defective remodelling of the arterial media, and thus to the development of MF-FMD. This contrasts with atherosclerotic renal artery stenosis, coronary stent restenosis and carotid intimal thickening, which are diseases affecting the arterial intima, and which are associated with increased frequency of the D allele.

Epstein-Barr virus encephalitis in a renal allograft recipient diagnosed by polymerase chain reaction on cerebrospinal fluid and successfully treated with ganciclovir

Epstein–Barr virus (EBV) encephalitis has been reported rarely in the context of solid-organ and bone-marrow transplantation [1]. We report a case of a renal transplant recipient who developed EBV encephalitis following OKT3 therapy for acute allograft rejection. The diagnosis was expedited by the detection of EBV DNA in the cerebrospinal fluid (CSF) by nested polymerase chain reaction (PCR). Moreover, clinical recovery and clearance of CSF EBV DNA appeared to follow the institution of parenteral ganciclovir treatment.

Analytical validation for a series of marker compounds used to assess renal drug elimination processes

Renal drug elimination is determined by glomerular filtration, tubular secretion, and tubular reabsorption. Changes in the integrity of these processes influence renal drug clearance, and these changes may not be detected by conventional measures of renal function such as creatinine clearance. The aim of the current study was to examine the analytic issues needed to develop a cocktail of marker drugs (fluconazole, rac-pindolol, para-aminohippuric acid, sinistrin) to measure simultaneously the mechanisms contributing to renal clearance. High-performance liquid chromatographic methods of analysis for fluconazole, pindolol, para-aminohippuric acid, and creatinine and an enzymatic assay for sinistrin were developed or modified and then validated to allow determination of each of the compounds in both plasma and urine in the presence of all other marker drugs. A pilot clinical study in one volunteer was conducted to ensure that the assays were suitable for quantitating all the marker drugs to the sensitivity and specificity needed to allow accurate determination of individual renal clearances. The performance of all assays (plasma and urine) complied with published validation criteria. All standard curves displayed linearity over the concentration ranges required, with coefficients of correlation greater than 0.99. The precision of the interday and intraday variabilities of quality controls for each marker in plasma and urine were all less than 11.9% for each marker. Recoveries of markers (and internal standards) in plasma and urine were all at least 90%. All markers investigated were shown to be stable when plasma or urine was frozen and thawed. For all the assays developed, there were no interferences from other markers or endogenous substances. In a pilot clinical study, concentrations of all markers could be accurately and reproducibly determined for a sufficient duration of time after administration to calculate accurate renal clearance for each marker. This article presents details of the analytic techniques developed for measuring concentrations of marker drugs for different renal elimination processes administered as a single dose to define the processes contributing to renal drug elimination.

Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation

Background. A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. Methods. A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. Results. Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs nonrejecters (P = 0.04). The average median concentration (+/- SD) in the biopsy-proven rejecter group was 5.09 +/-1.16 ng/ml, compared to 9.20 +/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57 +/-1.47 ng/rnl, compared with 9.20 +/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. Conclusion. A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol

Aims Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect charges in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers. to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. Methods Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (Mean +/- s.d.) was calculated as the ratio of the amount excreted in urine and thearea-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. Results The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/-3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). Conclusions This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes call be used to simultaneously investigate pathways of renal drug elimination.

Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-beta, interleukin-10, and tumor necrosis factor alpha (TNF-alpha) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P =.001), immune-mediated liver disease (P =.018), normal pre-OLT creatinine clearance (P =.037), and fewer HLA class 1 mismatches (P =.038) were independently associated with rejection, Renal impairment occurred in 80% of patients and was moderate or severe in 39%, Clinical variables independently associated with renal impairment were female sex (P =.001), pre-OLT renal dysfunction (P =.0001), and a diagnosis of viral hepatitis (P =.0008), There was a significant difference in the frequency of TNF-alpha -308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-alpha -308 polymorphism and graft rejection approached significance (P =.06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT, Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions.

Familial adult renal neoplasia

Our understanding of the molecular mechanisms underlying the tumorigenesis of renal cell carcinoma (RCC) has partially come from studies of RCC related familial cancer syndromes such as von Hippel-Lindau (VHL) disease and hereditary papillary RCC (HPRC). These studies have led to the identification of RCC related genes, which, besides allowing accurate diagnosis of these diseases, have been found mutated or abnormally expressed in the sporadic counterparts of these familial renal tumours. To date, a number of renal tumour related syndromes have been described. We review recent advances in this field and discuss a genetic approach to managing familial cases of renal tumours occasionally encountered by cancer geneticists and urologists.

The therapeutic potential of dopamine modulators on the cardiovascular and renal systems

In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Gludopa is selective for the kidney thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.

Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.