Leo Francis

Calcific uremic arteriolopathy in peritoneal dialysis populations.

Calciphylaxis or calcific uremic arteriolopathy is an infrequent complication of end stage kidney disease. It is characterized by arteriolar medial calcification, thrombotic cutaneous ischemia, tissue necrosis often leading to ulceration, secondary infection and increased mortality rates. Current, multimodality treatment involves local wound care, well-controlled calcium, phosphate and parathyroid hormone levels and combination therapy with sodium thiosulfate and hyperbaric oxygen therapy. This combination therapy may be changing the historically poor prognosis of calcific uremic arteriolopathy reported in the literature. Peritoneal dialysis is considered a risk factor based on limited publications, however this remains to be proven. Clinical presentation, diagnosis, pathogenesis and treatment of calcific uremic arteriolopathy in these patients are no different from other patients manifesting with this condition.

Laser Capture Microdissection and Multiplex-Tandem PCR Analysis of Proximal Tubular Epithelial Cell Signaling in Human Kidney Disease

Interstitial fibrosis, a histological process common to many kidney diseases, is the precursor state to end stage kidney disease, a devastating and costly outcome for the patient and the health system. Fibrosis is historically associated with chronic kidney disease (CKD) but emerging evidence is now linking many forms of acute kidney disease (AKD) with the development of CKD. Indeed, we and others have observed at least some degree of fibrosis in up to 50% of clinically defined cases of AKD. Epithelial cells of the proximal tubule (PTEC) are central in the development of kidney interstitial fibrosis. We combine the novel techniques of laser capture microdissection and multiplex-tandem PCR to identify and quantitate “real time” gene transcription profiles of purified PTEC isolated from human kidney biopsies that describe signaling pathways associated with this pathological fibrotic process. Our results: (i) confirm previous in-vitro and animal model studies; kidney injury molecule-1 is up-regulated in patients with acute tubular injury, inflammation, neutrophil infiltration and a range of chronic disease diagnoses, (ii) provide data to inform treatment; complement component 3 expression correlates with inflammation and acute tubular injury, (iii) identify potential new biomarkers; proline 4-hydroxylase transcription is down-regulated and vimentin is up-regulated across kidney diseases, (iv) describe previously unrecognized feedback mechanisms within PTEC; Smad-3 is down-regulated in many kidney diseases suggesting a possible negative feedback loop for TGF-β in the disease state, whilst tight junction protein-1 is up-regulated in many kidney diseases, suggesting feedback interactions with vimentin expression. These data demonstrate that the combined techniques of laser capture microdissection and multiplex-tandem PCR have the power to study molecular signaling within single cell populations derived from clinically sourced tissue.

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

Current concepts in C3 glomerulopathy.

Complement component 3 glomerulopathy (C3G) is a recently defined entity comprising of dense deposit disease and C3 glomerulonephritis. The key histological feature is the presence of isolated C3 deposits without immunoglobulins. Often masqueradng as some of the common glomerulonephritides this is a prototype disorder occurring from dysregulated alternate complement pathway with recently identified genetic defects and autoantibodies. We review the pathophysiology, clinical features, and diagnostic and treatment strategies.

Epidemiology of biopsy-proven glomerulonephritis in Queensland adults.

There is a paucity of data pertaining to the incidence of biopsy‐proven glomerulonephritis (GN) in Australia. This retrospective study aims to review the data from all adult native renal biopsies performed in the state of Queensland from 2002 to 2011 – comparing results with centres from across the world.

Coincident Iga Nephropathy in An Australian Patient with Fabry'S Disease

We report a male infant with onset of an extensive bullous eruption at the age of 45 days. Staphylococcal scalded skin syndrome (SSSS) was suspected. Bullous mastocytosis was diagnosed by cytodiagnosis and confirmed by histologic examination. Three serious relapses were noted in a 2-year follow-up, and SSSS was again suspected because of high fever and leukocytosis with neutrophilia in an infectious context. Cytodiagnosis revealed the presence of mast cells and permitted rapid diagnosis of recurrences of bullous mastocytosis. Systemic corticotherapy dramatically improved the cutaneous lesions and general symptoms. This case report emphasizes the utility of cytodiagnosis in extensive blistering diseases in infancy and the possibility of obtaining rapid healing by using steroids. Mastocytosis is defined as mast cell infiltration of various tissues. It encompasses different clinical pictures ranging from indolent cutaneous forms to systemic and malignant conditions (1). Molecular biology can offer some clues concerning the pathogenesis of mastocytosis. Dysfunction of the KIT receptor (a tyrosine kinase that is a receptor for the mast cell growth factor) as well as elevated levels of mast cell growth factor (MCGF) have been demonstrated as mechanisms involved in mastocytosis (2). It becomes evident that clinical diversity corresponds to genetic heterogeneity, and proper classification of mastocytosis must also include molecular genetic criteria. Longley et al (3) have studied the c-Kit gene encoding KIT in patients with various clinical forms of mastocytosis. They differentiated three groups of pediatric patients. Extensive and persistent sporadic forms, atypical in children, were correlated with activating codon 816 somatic mutations. In the second group, with typical pediatric mastocytosis, a dominant inactivating mutation in codon 839 was present, but its role in the pathogenesis is not yet completely understood. In the third group, no c-Kit mutations were identified. Childhood mastocytosis is frequently benign, presenting as mastocytoma, urticaria pigmentosa, or the more extensive, diffuse cutaneous mastocytosis. CASE REPORTS Pediatric Dermatology Vol. 19 No. 3 220–223, 2002 Address correspondence to Laurent Misery, M.D., Ph.D., Service de Dermatologie, CHU Morvan, 29609 Brest cedex, France, or e-mail: laurent.misery@chu-brest.fr.

Sustained remission of systemic lupus erythematosus related calciphylaxis

Calciphylaxis continues to present a clinical challenge for patient management. As in this case, it can be associated with connective tissue disease (CTD) such as systemic lupus erythematosus (SLE). Unlike previous reported cases, long-term remission has been attained. This provides some insight into methods of therapy as well as potential pathogenic models for this disease.

Nurses Perspectives On the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA)

Aim: To access the determinants of infra-renal aortic calcifi cation in patients with Chronic Kidney disease (CKD). Background: Infra-renal aortic calcification is associated with increased cardiovascular morbidity. Few studies have investigated this in CKD patients with most reports failing to use validated methods of quantifying calcification severity. Methods: We estimated infra-renal aortic calcification in 58 CKD patients (39 dialysis, 19 non dialysis) who had undergone abdominal aortic Computed Tomography. Infra-renal aortic calcification volume was estimated using a previously validated highly reproducible semi automated method. Clinical risk factors and co-morbidities (age, atherosclerotic risk factors, medications), serum creatinine, corrected serum calcium and phosphate concentrations were assessed. The association of these risk factors with aortic calcification was analyzed using both univariate and multivariate statistical tests. Results: In all 58 patients aortic calcification severity was strongly correlated with age (Spearman correlation coefficient (r) = 0.680, P < 0.001), but only weakly correlation with eGFR (r = 0.218, P = 0.103) and serum creatinine (r = −0.231, P = 0.084). Patients that required dialysis were much younger [n = 39, median age 58 years, IQR 49–67] than those not on dialysis [n = 19, median age 73 years IQR 66–78] and thus were analyzed separately. In patients receiving dialysis use of calcium based phosphate binders was associated with less calcification [median calcification volume 14 cm3, IQR 0–361, compared to 570 cm3, 2–2468, P = 0.022]. On regression analysis the only factors associated with aortic calcification were age (beta 0.482, P = 0.004) and corrected serum calcium concentrations (beta 0.368, P = 0.012). Conclusion: In this study the principle risk factor for aortic calcification was age. Serum calcium concentrations and use of calcium based phosphate binders may also influence calcification in patients on dialysis but larger studies are required to better assess this.

The Use of Acetic Acid in Magnification Colonoscopy

The Use of Acetic Acid in Magnification Colonoscopy Kazutomo Togashi, David G. Hewett, David A. Whitaker, Georgia E. Hume, Leo Francis, Mark N. Appleyard Background: Staining dyes can provide a clear image in magnification colonoscopy, but not instantly. Indigocarmine (IC) shows contrast effect instantly, but this effect is not as reliable as the staining dyes. Acetic acid (AA) is cheap, easily available and safe. AA has been used in the evaluation of cervical and oesophageal mucosa, but its use has not been evaluated in magnification colonoscopy. The aim of this study was to evaluate the role of AA dye spray during magnification colonoscopy alone and in combination with IC dye. Methods: In one institution, 46 patients (F22, M24; age 56617) entered into a prospective study of magnification colonoscopy, performed by a single endoscopist. The 46 consecutive patients were divided alternately into 2 groups; A (n=23) andB (n=23). InGroup A, 1.5%AAwas initially sprayed on to all detected lesions, followed by spray with 0.2% IC. In Group B, the order was reversed, with IC preceding AA. Pit pattern image was assessed in real time after the spraying of each consecutive dye. Pit patterns were evaluated based upon Kudo’s classification. The time required to obtain a clear image after the first dye spray wasmeasured. The effect of the second dye was evaluated based upon whether the pit pattern image following additional dye spray was clearer than that after the first dye alone. Results: 37 adenomas (AD), 36 hyperplastic polyps (HP), 5 normalmucosa, 4 inflammatory polyps and 1 serrated adenoma were detected. The 73 lesions comprised of AD and HP alone were subjected to further analysis. In group A, 20 AD and 23 HP were detected, and accuracies after AA spray were 95% with AD and 96% with HP. After subsequent IC spray, 37% showed enhanced images, and accuracies increased to 100% in AD and 97% in HP. In group B, 17 AD and 13 HP were detected, and accuracies after IC spray were 76% with AD and 92% with HP. After subsequent AA spray, images were enhanced in 70%with increases in accuracy to 94% in AD and 100% in HP. In both groups, the mean time required to obtain an initial clear image was 14 seconds. Conclusion: The use of AA spray instantly improves pit pattern image during magnification chromo-colonoscopy and improves the accuracy of histological prediction of colorectal polyps. This method could be easily applied to routine magnification colonoscopy. **267 Prevalence and Characteristics of Flat and Depressed Colorectal Neoplasms in a Western Population: A Prospective Study by a Japanese Trained Endoscopist Noriko Suzuki, Nicola C. Palmer, Brian P. Saunders Background: Flat and depressed colorectal neoplasms have been widely investigated in Japan and recently inWestern countries with incidence rate of 6.8%48.5%. This wide variation reflects differences in population characteristics or colonoscopic technique. The aim of this study was to determine the prevalence of flat neoplasms in a UK population by a colonoscopist trained in Japan. Methods: A prospective analysis of 1000 consecutive colonoscopies was performed. Macroscopically the lesions were classified according to the classification described by Japanese Society for Cancer of the Colon and Rectum and histological diagnosis was made based on WHO system. Result: Total colonoscopy (adjusted) was achieved in 98% of patients. Indications for colonoscopy were: neoplasia surveillance (211), change in bowel habit (179), bleeding (160), assessment of IBD (141), family history of colorectal neoplasms (106), anaemia (86), and others (117). In total 1075 polyps were found in 412 patients, which includes 25 cases of advanced cancer. 758 polyps were histologically proven to be neoplastic. Of these, 617 were classified as polypoid (81%) and 141 flat (IIa, IIb, IIc)(19%). A higher incidence of advanced pathology (severe dysplasia or Dukes’A adenocarcinoma) was observed in flat and depressed neoplasms (0% in IIa, 14% in IIb,IIc) than in polypoid ones (2%). Conclusion: A Japanese trained endoscopist found flat neoplasms represented 19 % of all adenomas (flat/ depressed 3% in a western population. Flat elevated (IIa) and polypoid lesions appeared to have similar characteristics, while flat (IIb) or depressed lesions (IIc) contain more advanced pathology. Flat and depressed neoplasms are rare finding but exist in a Western population.

Gastrointestinal mucormycosis in an immunocompromised host

A surgical consultation was requested for a 61-year-old immunocompromised male with worsening abdominal pain and increasing abdominal distension. This was in the setting of myelodysplastic syndrome treated with an allogenic haematopoietic stem cell transplant, complicated by graft versus host disease. There was no other surgical history. Upon review, the patient was haemodynamically stable and afebrile. A multiphase abdominal computed tomography scan was performed, which was suggestive of non-enhancing loops of distal ileum with associated mesenteric stranding and free fluid, concerning for ischaemia/infarction (Fig. 1). The remainder of small bowel was pathologically dilated, indicating obstruction. A laparoscopy was performed, which showed patchy necrosis of the small bowel and perforation of the distal ileum. A laparotomy was performed (Fig. 2) with resection of 110 cm of distal ileum; the ends were left stapled with a view to re-look in 48 h and reassess the remaining bowel to assure viability. At re-exploration, a further 50 cm of necrotic small bowel was resected and an end ileostomy and mucus fistula were fashioned. Histopathology revealed angioinvasive fungal organisms scattered amongst areas of necrotic bowel, with hyphae extending into the walls of regional blood vessels, with associated intestinal transmural infarction (Fig. 3). Tissue culture confirmed a diagnosis of mucormycosis secondary to Rhizopus species and amphotericin B was commenced. Two weeks following the operation, the patient developed worsening abdominal pain, vomiting and confusion. Computed tomography showed extensive small bowel ischemia, perforation and intra-abdominal free fluid. Given his complications from immunosuppression and the need for extensive bowel resection, the treating team and family decided against further surgical or therapeutic interventions. The patient was palliated and passed away several days later. We have reported a rare case of gastrointestinal mucormycosis, which clinically appeared to be ischaemic bowel, and have provided intraoperative, histological and radiological images. Risk factors, diagnosis and principles of treatment will be discussed. Mucormycosis refers to angioinvasive infections caused by fungi in the order of Mucorales. Of these, the most common genera are Rhizopus and Mucor, with Rhizopus oryzae being the most common pathogen accounting for more than 70% of cases. Mucormycosis is characterized by the invasion of blood vessels by fungal hyphae, leading to necrosis and infarction. Infection typically occurs in the presence of immunosuppression, including patients with haematological malignancies, uncontrolled diabetes and diabetic ketoacidosis, haematopoietic stem cell transplants and solid organ transplants. In haematopoietic stem cell transplants recipients, graft versus host disease and voriconazole therapy further increases the risk. Other predisposing factors include iron overload, especially those receiving desferrioxamine therapy; and wound contamination in the setting of penetrating trauma and blast injuries, which may present with a cutaneous manifestation of mucormycosis. Gastrointestinal involvement is rare and usually involves the stomach, colon or ileum. It is associated with a significant risk of mortality, which is up to 85%. Gastrointestinal cases may present with abdominal pain, gastrointestinal bleeding, perforation or unexplained sepsis. As this disease typically affects the