Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease.

Calciprotein particles (CPP) are nanoscale mineralo-protein aggregates that help stabilize excess mineral in the circulation. We examined the relationship between CPP and bone mineral density in Fabry disease patients. We found an inverse correlation with total hip and femoral neck density, but none with lumbar spine. PURPOSE: Calciprotein particles (CPP) are colloidal mineral-protein complexes made up primarily of the circulating glycoprotein fetuin-A, calcium, and phosphate. They form in extracellular fluid and facilitate the stabilization, transport, and clearance of excess minerals from the circulation. While most are monomers, they also exist in larger primary (CPP-I) and secondary (CPP-II) form, both of which are reported to be raised in pathological states. This study sought to investigate CPP levels in the serum of patients with Fabry disease, an X-linked systemic lysosomal storage disorder that is associated with generalized inflammation and low bone mineral density (BMD). METHODS: We compared serum CPP-I and CPP-II levels in 59 patients with Fabry disease (37 female) with levels in an age-matched healthy adult cohort (n=28) and evaluated their association with BMD and biochemical data obtained from routine clinical review. RESULTS: CPP-I and CPP-II levels were higher in male Fabry disease patients than female sufferers as well as their corresponding sex- and age-matched controls. CPP-II levels were inversely correlated with BMD at the total hip and femoral neck, but not the lumbar spine. Regression analyses revealed that these associations were independent of common determinants of BMD, but at the femoral neck, a significant association was only found in female patients. CONCLUSION: Low hip BMD was associated with high CPP-II in patients with Fabry disease, but further work is needed to investigate the relevance of sex-related differences and to establish whether CPP measurement may aid assessment of bone disease in this setting.

Management of refractory lupus nephritis: challenges and solutions.

Refractory lupus nephritis, broadly defined as failure to attain clinical remission after appropriate induction immunosuppressive therapy, is associated with an increased risk of progression to end-stage kidney disease and mortality. This is a challenging issue in clinical practice, as modern induction therapy despite proven efficacy can still be associated with treatment failure. Moreover, newer therapies have failed in recent years to displace or even match existing protocols for effective induction of remission. Refractory disease is generally assessed on the basis of clinical parameters, which may be unreliable, and renal biopsy, which is often not performed in a standard or timely fashion. Persisting histological inflammation in 30%-50% of patients who have attained clinical remission highlights the disparity between clinical and immunological response to therapy. The lack of an international consensus regarding what constitutes refractory lupus nephritis compounds clinician indecision regarding optimal management for these patients. Moreover, non-adherence to prescribed therapy versus primary treatment failure can be challenging to discriminate, and the time point at which non-response becomes treatment failure is unclear. In this review, we assess the key published evidence for the treatment of refractory lupus nephritis and provide practical recommendations based around the use of adjunctive therapies. These agents include rituximab and calcineurin inhibitors, with evidence consisting largely of observational or uncontrolled studies, as well as some of the biologic therapies currently under investigation through prospective clinical trials. The poor prognosis of refractory lupus nephritis demands regular review of patient response and the flexibility to switch or augment therapy.

Giri-nya-la-nha (talk together) to explore acceptability of targeted smoking cessation resources with Australian Aboriginal women.

OBJECTIVES: To engage with health providers and Aboriginal women to understand what educational resources they want and need to support quit smoking attempts during pregnancy in order to develop a comprehensive evidence-based intervention. STUDY DESIGN: Resources were developed in partnership with Aboriginal people, communities and academics with the aim to be inclusive of diverse communities. We then recruited Aboriginal women of various ages for yarning circles (focus groups) held in three Australian states to explore the acceptability of the resources and seeking further guidance as to the needs of Aboriginal women to support smoking cessation during pregnancy. METHODS: Yarning circles were recorded and transcribed, and data were analysed independently by two researchers. Responses were coded using predetermined themes and further general inductive analysis for emergent themes. RESULTS: Twenty-four Aboriginal women reflected on the resources they included: one pregnant woman, 15 mothers and eight elders. Predetermined themes of attraction, comprehension, cultural acceptability, graphics and layout, persuasion and self-efficacy were explored. Women suggested the following: resources need to be visually attractive and interactive to enhance self-efficacy; additional scientific content on health consequences of smoking and combining with non-pharmacological approaches to quitting. CONCLUSION: Indigenous peoples prefer culturally targeted messages. However, developing effective Aboriginal health promotion requires more than a 'culturally appropriate' adaptation of mainstream resources. Consideration needs to be given to the diversity of Aboriginal communities when developing effective, evidence-based interventions. Aboriginal women are calling for innovative and interactive resources that enhance self-efficacy; the use of videos to explain medical and informational brochure content is well received. Requests for non-pharmacological cessation options were reported in New South Wales and Queensland and should be further explored.

Safety and efficacy of a novel short occlusive regimen of imiquimod for selected non-melanotic skin lesions in renal transplant patients.

Australian patients remain at very high risk of non-melanotic skin cancer after renal transplantation. Surgical excision offers a cure but destroys tissue and may jeopardise function and cosmesis. We report excellent safety and efficacy using topical imiquimod in a novel short intensive regimen in 10 renal transplant patients with superficial basal cell carcinomas, Bowen disease or actinic keratosis. Outcomes compare well to those reported with extended-use imiquimod protocols.

Adoptive T cell immunotherapy for treatment of ganciclovir-resistant cytomegalovirus disease in a renal transplant recipient.

Cytomegalovirus (CMV) is a significant cause of morbidity, mortality and graft loss in solid organ transplantation (SOT). Treatment options for ganciclovir-resistant CMV are limited. We describe a case of ganciclovir-resistant CMV disease in a renal transplant recipient manifested by thrombotic microangiopathy-associated glomerulopathy. Adoptive T cell immunotherapy using CMV-specific T cells from a donor bank was used as salvage therapy. This report is a proof-of-concept of the clinical and logistical feasibility of this therapy in SOT recipients.

A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects.

BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally every other day (QOD) to females with FD. METHODS: This was an open-label, uncontrolled, Phase 2 study of 12 weeks with extension to 48 weeks in nine females with FD. Doses of 50mg, 150 mg and 250 mg were given QOD. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Each individual GLA mutation was retrospectively categorized as being amenable or not to migalastat HCl based on an in vitro α-Gal A transfection assay developed in human embryonic kidney (HEK)-293 cells. RESULTS: Migalastat HCl was generally well tolerated. Patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250 mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peri-tubular capillaries. CONCLUSIONS: Migalastat HCl is a candidate oral pharmacological chaperone that provides a potential novel genotype-specific treatment for FD. Treatment resulted in GL-3 substrate decrease in female patients with amenable GLA mutations. Phase 3 studies are ongoing.

Ethnicity and lupus nephritis: an Australian single centre study.

BACKGROUND: The clinical impression of Australian physicians is that systemic lupus erythematosus (SLE) is more prevalent and more severe in Asian patients than in their Caucasian counterparts. The presence and severity of lupus nephritis is a major determinant of prognosis in SLE, and largely determines disease impact. AIM: To analyse the relationships between ethnicity and the prevalence and severity of lupus nephritis (LN) in patients attending a tertiary referral centre (The Royal Melbourne Hospital (RMH)). METHODS: The ethnicity of all known patients with biopsy-proven LN was determined according to three definitions of ethnicity - ancestry, country of origin and primary language spoken. The prevalence of Asian ethnicity in the LN cohort was analysed across severity class, and was compared with the prevalences of Asian ethnicity in the general population within the hospital's geographic area, and with that in the relevant RMH cohorts of inpatients and outpatients, over the same time period. RESULTS: Within this single tertiary centre, Asian patients were disproportionately represented in both the systemic lupus erythematosus (SLE) and the LN patient groups, although the distribution of histological severity of LN was not significantly different from Caucasian patients. CONCLUSION: This study supports the common clinical impression that SLE is more common and more severe in the Asian-Australian population. Asian patients with SLE were more commonly diagnosed with LN. However, the spectrum of histological severity of LN was similar in Asian and Caucasian patients.

Cardiovascular testing in Fabry disease: exercise capacity reduction, chronotropic incompetence and improved anaerobic threshold after enzyme replacement.

AIM: The aim of this study was to document exercise capacity and serial electrocardiogram and echocardiograph findings in a cohort of Australian patients with Fabry disease, in relation to their history of enzyme replacement therapy (ERT). BACKGROUND: Fabry disease has multifactorial effects on the cardiovascular system. Most previous studies have focused on electrocardiographic and echocardiographic parameters. Exercise capacity can be used as an integrated measure of cardiovascular function and allows the effects of treatment to be monitored. METHODS: A total of 38 patients (30 men and 8 women) with Fabry disease were monitored by 12-lead electrocardiograms every 6-12 months, and by annual standardized-protocol echocardiograms. Bicycle stress tests with VO(2) max measurement and once-only 6 minutes' walk tests were also carried out in subsets of patients whose general health status allowed testing. RESULTS: Seventy per cent of patients met electrocardiogram criteria for left ventricular hypertrophy. Left ventricular hypertrophy on echocardiograph was present in 64% of patients (80% of men). Exercise capacity was reduced in patients with Fabry disease compared with that predicted from normative population data. Mild improvement in anaerobic threshold was seen in the first year of ERT (14.1 +/- 3.0 to 15.8 +/- 3.0, P = 0.02), but no consistent further increase was seen beyond the first year. Most patients had resting bradycardia, with impaired ability to increase heart rate during exercise. Serial testing on ERT showed an improvement in anaerobic threshold but no significant change in VO(2) max. CONCLUSIONS: Male patients with Fabry disease were unable to attain predicted maximal heart rate on exercise or to achieve normal exercise levels. ERT was associated with a small improvement in anaerobic threshold over the first year.

Neurology of Fabry disease.

BACKGROUND: Fabry disease has diverse neurological manifestations, many of which influence morbidity and quality of life. AIMS: The aim of the study was to document the clinical and subclinical neurological manifestations in a cohort of Australian patients with Fabry disease, using multiple clinical tools and a multidisciplinary approach. METHODS: Participants completed focused questionnaires and underwent clinical neurological examination, Neurocognitive testing using Mini Mental State Examination and Neuropsychiatry Unit Cognitive Screen, Quantitative Sensory Testing (QST), autonomic assessment using RR interval variation, intracranial magnetic resonance imaging (MRI) and audiology. In subsets of patients who had previously undergone QST and/or prospective serial quality-of-life assessments over the previous 5 years, results before and after enzyme replacement therapy were compared. RESULTS: Twenty hemizygotes and two heterozygotes were recruited. The age (mean +/- standard deviation (SD)) of male participants was 40.4 +/- 11.9 years (range 20-62 years); the women were aged between 20 and 56 years. Increasing age was strongly associated with increasing neurological disability. Clinical peripheral neuropathy predominantly affected thermal sensation in all patients, with variable involvement of pinprick and light touch. QST confirmed these findings. Clinical cerebellar tests were commonly abnormal: this has not been previously reported in the absence of symptomatic cerebrovascular disease. There was hearing loss was in 90% of patients and no patient older than 44 years had normal hearing. MRI lesion prevalence increased with age. Despite neurological complications being common, formal cognitive testing was basically normal. QST thresholds for pain showed a significant change after enzyme replacement therapy. CONCLUSIONS: Neurological complications in Fabry disease are common, complex and may be devastating. All patients studied had neurological involvement, with protean and diverse manifestations.

Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

Intermittent claudication -- atypical presentation, diagnosis and treatment.

A unique case of a man with Fabry's disease and associated small vessel vasculopathy manifesting as recurrent episodes of intermittent claudication is described. The case highlights the concept that microvascular involvement due to local accumulation of glycosphingolipid in the smooth muscle fibres of vessel walls may be responsible for claudicant symptoms in such patients rather than the more classical macrovascular insufficiency.

Sirolimus: a single center experience in combination with calcineurin inhibitors.

A retrospective survey was performed to establish patient and graft outcome for all 41 patients at our centre receiving sirolimus (SRL) in combination with calcineurin inhibition (CNI) as primary therapy for the 6 years prior to March 2002. Patient mortality [12%; n = 5 (TTP, lymphoma, mucormycosis, and small bowel perforation] was significantly higher at 3 months compared with those not receiving SRL, but not thereafter. 12.8% had delayed graft function and 33% had one or more episodes of rejection in the first 6 months. Mean GFR at 12 months was significantly lower (47.3 mL/min) in the SRL group compared with those not receiving SRL (51.3 mL/min). Twenty-two patients had a 12-month protocol biopsy; CNI toxicity was present in 36%. SRL was associated with significant hyperlipidaemia (serum cholesterol, 5.2 +/- 1.4 at baseline vs 7.3 +/- 1.7 mmol/L at 3 months, P <.001; triglycerides, 2.3 +/- 1.4 at baseline vs 2.7 +/- 1.1 mmol/L at 3 months, P <.05). Mild thrombocytopenia occurred in 23% but was not associated with haemorrhagic events. LDH increased by 62%, remaining elevated out to 2 years post engraftment. Seven patients developed insulin requiring diabetes mellitus, similar to the rate observed in our general transplant population.Thus, in this early experience, SRL in combination with CNI was associated with significant mortality and morbidity including CNI toxicity, presumably a reflection of a heavy burden of immunosuppression. However, 1-year graft survival on SRL was similar to the mean Australia-wide graft survival regardless of immunosuppression. The future use of SRL may center around CNI sparing and avoidance type protocols.

Describing randomisation: patients' and the public's preferences compared with clinicians' practice.

Explaining the concept of randomisation in simple terms to patients during the discussion of randomised clinical trials can be a difficult task for many health care professionals. We report the results of a questionnaire-based survey, using seven descriptions of randomisation taken from Corbett's study. We examined the preferences of the general public and patients towards the descriptions and compared the results with the clinicians' choice. Participants in the survey were 341 lay people without cancer, 200 patients with cancer and 200 oncologists from cancer centres throughout the UK. It was difficult to identify 'the best' way to describe the process of randomisation. The two most favoured statements for patients and members of the public included a very explicit statement that mentioned 'a computer', 'chance' and 'not the doctor's or patient's decision' and a succinct statement that played down the role of 'chance'. Clinicians chose neither of these statements as closely resembling their own practice. Patients and members of the public most disliked the statement 'a computer will perform the equivalent of tossing a coin to allocate you to one of two methods of treatment'. This analogy used by 26% of oncologists, was viewed as trivialising and upsetting in the context of determining treatment for life threatening disease.

Clinical features of Fabry's disease in Australian patients.

BACKGROUND: Anticipating the prospect of specific treatment, we studied a large group of Australians with Fabry's disease. AIMS: We aimed to: (i) document the clinical features of Fabry's disease in Australian patients, (ii) test the hypothesis that clinical features vary with specific mutation and blood group and (iii) assess small-fibre peripheral nerve function. METHODS: A questionnaire was forwarded to all Australian patients known to us. Patients were invited to attend for clinical, renal cardiac, ophthalmological and neurological assessment. RESULTS: Sixty-seven patients (29 men and 38 women) from 18 families participated. Diagnosis in index cases was delayed by > or = 10 years in nearly all families. Common clinical features are: (i) episodic acroparaesthesia (100% of hemizygotes; 53% of heterozygotes), (ii) anhydrosis (93%; 1%), (iii) characteristic rash (93%; 13%), (iv) renal disease (69%; 21%), (v) ischaemic heart disease (28%; 26%), (vi) palpitations (62%; 29%), (vii) mitral valve murmurs (37%; 23%) and (viii) premature cerebrovascular disease (31%; 5%). Ophthalmic findings of cornea verticillata (96%; 76%) and anterior cataract (48%; 14%) were common. Findings were variable within and between families. In women, anhydrosis reliably predicts the presence of significant Fabry's renal disease. Small nerve fibre testing using quantitative sensory testing was clearly abnormal in 95% of male patients, and in those female patients with paraesthesiae. CONCLUSIONS: Symptoms of anhydrosis, acroparaesthesiae, rash and renal disease suggest diagnosis of Fabry's. Women are commonly symptomatic, and the advent of therapy highlights the practical advantage of earlier diagnosis.

Impact of acute rejection therapy on infections and malignancies in renal transplant recipients.

BACKGROUND: Infections and malignancies are important causes of mortality and morbidity in renal allograft recipients. Their risk increases with increasing immunosuppression. METHODS: In an attempt to quantitate the increase in the risk of these complications in association with antirejection therapy, we reviewed the records of all renal allograft recipients of our center transplanted during the cyclosporin era. We sub-divided the patients into three groups based on acute rejection episodes during the first 6 months posttransplant, and the treatment for acute rejection: those who did not develop AR--group 1 (n=168); those who had one or more episodes of acute rejection and were treated with high dose corticosteroids --group 2 (n=169); those who in addition to corticosteroids required cytolytics (OKT3) and/or other drugs--group 3 (n=141). RESULTS: 52% patients in group 1, 71% patients in group 2 and 86% patients in group 3 had one or more episodes of infection during the first 6 months posttransplantation. Relative risk for group 2 and 3 were 1.56 (P=0.0002) and 2.98 (P<0.00001), respectively. Infection/patient rates at 6 months were 0.67, 1.23, and 2.79 in groups 1, 2, and 3 respectively. Groups 1 and 2 had a similar number of cases with squamous and basal cell carcinoma, however, there were few cases with these malignancies in group 3. No case of lymphoma was seen in group 1; there were four cases in group 2 and nine in group 3. There was no significant difference in patient survival in group 1 and 2, however, patients in group 3 had a reduced patient survival (1 vs. 3 P<0.001, 2 vs. 3 P=0.067). Graft survival was best in group 1 and worst in group 3 (1 vs. 2 P<0.05; 1 vs. 3 P<0.00001; 2 vs. 3 P<0.01). CONCLUSIONS: In renal transplant recipients the risk of infections and lymphoma increases with increasing immunosuppression and hence mortality and morbidity associated with it. When adding a potent immunosuppressive agent to rescue a kidney one needs to consider the serious and at times fatal side effects given the modest beneficial effect on long-term outcome.

Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study.

We conducted a 3-year randomized placebo-controlled double-blind study to determine the effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the progress of renal function and histology in subjects with diabetes and microalbuminuria. Forty non-insulin-dependent (NIDDM) and insulin-dependent (IDDM) diabetic subjects, either normotensive or hypertensive, were randomly assigned to receive PE (n = 20) or placebo (n = 20). A percutaneous renal biopsy was performed initially in all patients and repeated in 29 patients after 3 years. The mean glomerular volume, glomerular basement membrane (GBM) thickness, interstitial fibrosis, sclerosed glomeruli, and volume fraction of capillary lumina were measured histomorphometrically. Before treatment, both groups had similar clinical characteristics, blood pressure, glycosylated hemoglobin (Hb), albumin excretion rate, glomerular filtration rate (GFR), serum creatinine, and renal structural damage. Blood pressure was well controlled in both groups. After 3 years' therapy, there was no significant change in renal function and albuminuria in the PE or placebo groups. The increase in GBM thickness in nine paired biopsies was significantly less in PE-treated subjects (P = .0275). Interstitial fibrosis tended to increase less in the PE group, although this did not reach statistical significance. This study indicates that long-term therapy with PE may decrease or delay the progression of structural glomerular damage in microalbuminuric diabetic subjects.

Myofibroblasts and arteriolar sclerosis in human diabetic nephropathy.

We examined the biopsy specimens of 62 patients with diabetic nephropathy to establish whether the myofibroblast (MF) has a role in progressive interstitial fibrosis and to ascertain whether a relationship existed between MF activity and severity of arteriolosclerosis. MF were identified by morphology and alpha smooth muscle actin (alpha SMA) immunostaining. Analysis of vascular injury was performed by counting the number of interstitial arterioles after staining endothelial cells with von Willebrand factor (VWF) antibody. Arteriosclerosis was quantified by using a computer-aided image analyzer to measure the arteriolar wall surface and total arteriolar surface area, and the ratio of wall to total surface area was expressed as the index of arteriosclerosis (IA). Fractional area of interstitium (IFA), alpha SMA, and collagen III (Coll III) were quantitated by point counting. Results were related to structural and functional parameters using rank correlation coefficients. There was a strong correlation between IFA and Coll III staining (r = 0.83; P < 0.001). The alpha SMA staining correlated with IFA (r = 0.56; P < 0.001) and Coll III (r = 0.47; P < 0.001), and there were significant correlations between alpha SMA and total urinary protein (r = 0.47; P < 0.001), renal function (plasma creatinine) at time of biopsy (r = 0.51; P < 0.001), and the percent change in plasma creatinine after 4 years (delta Cr) (r = 0.37; P = 0.01). The IA correlated significantly with Coll III (r = 0.29; P = 0.02), glomerular filtration rate (GFR) (r = 0.39; P = 0.008), and creatinine (r = 0.33; P = 0.01), but no correlation was observed between alpha SMA and IA (r = 0.16; P = 0.23) or IA and delta Cr (r = -0.04; P = 0.6). Strong correlations could be shown between arteriolar density, IFA (r = 0.75; P < 0.001), alpha SMA (r = -0.36; P = 0.034), and Coll III (r = -0.66; P < 0.0001). The MF appears to have a significant role in the progression of diabetic nephropathy. Ischemia secondary to arteriosclerosis may contribute to interstitial fibrosis through fibroblast modulation into MF.