Andrew Bofinger

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 (AT1R) 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 MF-FMD patients at the time of diagnosis of hypertension did not differ (38.6u2009+u200911.1 years vs 35.5u2009±u200910.3 years, Pu2009=u20090.12) from controls and the proportion (95% vs 86%, Pu2009=u20090.14) 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, Pu2009=u20090.026). 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.

Increased severity of multifocal renal arterial fibromuscular dysplasia in smokers

Renal arterial fibromuscular dysplasia (FMD) is a significant cause of renovascular hypertension, especially in younger females. Tobacco constituents have been shown to stimulate proliferation and synthetic activity of cultured human vascular smooth muscle cells. We examined the relationship between smoking and severity of FMD in a group of 50 subjects with the multifocal form of renal arterial FMD. A detailed smoking history was obtained by interview, clinical data at diagnosis of FMD were obtained from medical records, and angiograms were reviewed. Clinical and angiographic features were compared between smokers and non-smokers. Twenty-four subjects were smokers. At the time of diagnosis of FMD, smokers were of younger mean age than non-smokers (38.7 years vs 48.9 years, P < 0.01), had a shorter median history of hypertension (1.5 years vs 8.5 years, P < 0.05), and had a higher prevalence of unilateral renal atrophy (67% vs 27%, P < 0.01). the distribution of age at diagnosis of fmd was unimodal in non-smokers and bimodal, with a discrete group of younger subjects, in smokers. we conclude that cigarette smoking is associated with an earlier onset and increased severity of disease in a susceptible subgroup of patients predisposed to multifocal renal arterial fmd.

Mycobacterium fortuitum endocarditis in a patient with chronic renal failure on hemodialysis

Summary A case of infective endocarditis due to M. fortuitum in a 54 yr old female with chronic renal failure on hemodialysis is presented. Clinical, microbiological and autopsy findings are discussed.

Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a significant cause of renal artery stenosis, especially in young females. A rare association between FMD and α1-antitrypsin (α1-AT) deficiency has been reported. We compared the α1-AT phenotype distribution in 83 patients with renal arterial FMD with those published for Australian populations. α1-AT phenotyping was performed by isoelectric focusing between pH 4.2 and pH 4.9 on polyacrylamide gels with PiM1M2, PiFM (non-deficiency alleles), PiMS and PiMZ (deficiency alleles) markers. Following phenotyping, α1-AT genotyping was performed in 10 patients to confirm the presence of S and/or Z alleles. The phenotype distribution and allele frequencies were similar to those reported for normal subjects from two Australian populations (72 (86.7%) PiMM phenotype, one (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) PiMZ and one (1.2%) PiSZ), suggesting that α1-AT deficiency is not a common aetiological factor in renal arterial FMD. However, despite FMD being three times less common in males than females, and carotid artery dissection being a rare occurrence, a male with PiMS deficiency phenotype presented with internal carotid artery dissection and had bilateral renal artery FMD. Further, a patient with PiSZ deficiency phenotype was one of two sisters with FMD and was more severely affected than her PiMM normal phenotype sibling. These two patients from the present series together with nine culled from the literature with α1-AT deficiency phenotype and FMD suggest that the chance combination of α1-AT deficiency and FMD may predispose to severe manifestations of FMD.

Efficacy and side-effect profile of sevelamer hydrochloride used in combination with conventional phosphate binders

Background:u2003 Poor phosphate control is common among patients with end‐stage renal disease. Sevelamer hydrochloride has been demonstrated to be a safe and effective phosphate binder when used as a monotherapy. However, cost limits its usefulness in many countries. Data assessing its effectiveness and safety in combination with conventional phosphate binders are lacking.

Low‐density lipoprotein subfraction profiles in dialysis patients

Summary: Uraemic dyslipidaemia is a major risk factor for cardiovascular disease in end‐stage renal failure patients. In patients without renal failure, high levels and qualitative abnormalities of low‐density lipoprotein (LDL) are known to be atherogenic. Recently, LDL subfraction analysis has associated premature coronary artery disease with a high prevalence of small, dense LDL particles characterizing the LDL subclass phenotype B. We therefore examined the lipid profiles, LDL subfraction distribution and phenotypes in our population of haemodialysis (HD; n= 30) and peritoneal dialysis patients (PD; n= 17), and compared them to 40 asymptomatic, non‐uraemic volunteers. Dialysis patients had significantly higher triglyceride and VLDL cholesterol concentrations and lower HDL cholesterol and smaller LDL peak particle diameters. PD patients had significantly higher total cholesterol, glycated haemoglobin and fasting blood glucose levels with smaller LDL peak particle diameters (24.4 [0.1] vs 24.8 [0.1 nm] than HD. Both groups showed significant negative correlations between plasma triglyceride and LDL peak particle diameter, and positive correlations between HDL cholesterol and LDL peak particle diameter. All the PD patients expressed the B phenotype (LDL peak diameter ± 25.5 nm) compared to 73% of HD patients. This study demonstrates that HD and especially PD patients have atherogenic lipid profiles which are associated with a predominance of small dense LDL particles and the highly atherogenic LDL subclass phenotype B.

Hereditary fibrinogen A alpha-chain amyloidosis

Sir, Hereditary fibrinogen A alpha-chain amyloidosis is an infrequently described clinical entity with a characteristic disease phenotype. We describe the first case from Australia. Accurate diagnosis of this disease may avoid unnecessary, potentially hazardous treatment and allow consideration of appropriate directed therapies. A 62-year-old male was seen following a diagnosis of nephrotic syndrome in August 2004. He presented with marked peripheral and sacral oedema, hypertension and proteinuria. He was diagnosed with polymyalgia rheumatica 2 months previously, when he had presented with myalgias, joint stiffness and elevated systemic inflammatory markers. At this time, he was treated with prednisolone 50 mg daily. His symptoms and elevated inflammatory markers resolved, however, his symptoms recurred intermittently with reduction in his prednisolone dose. There was no family or personal history of renal disease or proteinuria, however, he had mild untreated hypertension noted previously. He had never smoked tobacco and did not drink alcohol. His only medication was prednisolone. Examination revealed hypertension with blood pressure of 170/90 mm Hg, no cardiac murmurs and marked peripheral and sacral oedema. There was no hepatosplenomegaly, macroglossia or peripheral neuropathy. Full general physical examination was otherwise unremarkable. Initial investigations revealed proteinuria of 5.22 g per 24 hours. Urine microscopy showed occasional cellular casts and urine leukocyte count of 10610/L. The serum creatinine was 100 mmol/L, albumin 32 g/L and cholesterol 8.9 mmol/L. He had a mild neutrophilia 10610/L with normal haemoglobin and platelet count. Alkaline phosphatase and coagulation screen was normal. A renal ultrasound showed abnormally echogenic kidneys of normal size. Autoantibody screen, hepatitis B, C, and human immunodeficiency virus serology were negative. He was treated with frusemide titrated to 80 mg twice daily, candesartan 16 mg daily, atorvastatin 10 mg daily and his prednisolone was gradually reduced to 5 mg daily. Renal biopsy revealed large glomerular deposits of amorphous eosinophilic material with no interstitial deposits seen. A Congo red stain for amyloid was positive and exhibited apple-green birefringence under polarised light (Fig. 1, 2). Congo red stains following potassium permanganate pre-treatment remained positive. Immunofluorescence showed strong reactivity for lambda light chain and weak reactivity for IgA and IgG in the amyloid depositis. Stains for IgM and kappa light chain were negative. The amyloid A immunoperoxidase stain (AA) demonstrated weak and patchy reactivity compared with the strong diffuse staining of the positive control and was considered to be equivocal. Electron microscopy confirmed the presence of randomly arranged amyloid fibrils measuring 10 nm in diameter in mesangial areas. Subsequent investigation revealed no evidence of monoclonal gammopathy as assessed by serum and urine electrophoresis and immunofixation, or by serum-free light chain assay. Bone marrow aspirate and trephine did not reveal a monoclonal plasma cell population and the Congo red stain was negative for amyloid. Electrocardiogram was normal. Serum NT-proBNP was 26 pmol/L (normal ,40 pmol/L). Transthoracic echocardiogram demonstrated normal left ventricular size and function with mild to moderate left ventricular hypertrophy. The interventricular septum was 13 mm thick (normal 7–11 mm). There was no diastolic dysfunction, valve thickening or atrial dilatation. Skeletal survey was normal. In view of the absence of demonstrable monoclonal paraprotein and the non-diagnostic histopathology, further opinion was sought from the United Kingdom National Amyloidosis Centre. Their review confirmed substantial

Myelodysplasia with myelofibrosis — A distinct subgroup within the myelodysplastic syndromes

&NA; A case of myelodysplastic syndrome with myelofibrosis is presented in an attempt to highlight pitfalls in the current French‐American‐British (FAB) classification of the myelodysplastic syndromes.