Dwomoa Adu

Primary systemic vasculitis

Systemic vasculitides are multisystem diseases characterised pathologically by necrotising inflammation of blood vessels. The clinical presentation of vasculitis depends on the vessels involved. Classification of such diseases is now by the size of the affected vessel. This review focuses predominantly on the small vessel vasculitides shown to be associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA), that is Wegeners granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. It will examine the clinical characteristics of these diseases, the use of ANCA in diagnosis and monitoring of disease along with current and novel treatment strategies. The immunopathology of the ANCA-associated vasculitides will also be explored reviewing the roles of ANCA, neutrophils, T cells and apoptosis in the production of disease.

Treatment of Acute Renal Failure Secondary to Multiple Myeloma with Chemotherapy and Extended High Cut-Off Hemodialysis

BACKGROUND AND OBJECTIVES Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS An open-label study of the relationship between free light chain levels and clinical outcomes in 19 patients treated with standard chemotherapy regimens and HCO-HD. RESULTS There were sustained early reductions in serum free light chain concentrations (median 85% [range 50 to 97]) in 13 patients. These 13 patients became dialysis independent at a median of 27 d (range 13 to 120). Six patients had chemotherapy interrupted because of early infections and did not achieve sustained early free light chain reductions; one of these patients recovered renal function (at 105 d) the remaining 5 patients did not recover renal function. Patients who recovered renal function had a significantly improved survival (P < 0.012). CONCLUSION In dialysis-dependent acute renal failure secondary to myeloma kidney, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum free light chain concentrations and recovered independent renal function.

Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake.

Copy number (CN) variation (CNV) has been shown to be common in regions of the genome coding for immune-related genes, and thus impacts upon polygenic autoimmunity. Low CN of FCGR3B has recently been associated with systemic lupus erythematosus (SLE). FcγRIIIb is a glycosylphosphatidylinositol-linked, low affinity receptor for IgG found predominantly on human neutrophils. We present novel data demonstrating that both in a family with FcγRIIIb-deficiency and in the normal population, FCGR3B CNV correlates with protein expression, with neutrophil uptake of and adherence to immune complexes, and with soluble serum FcγRIIIb. Reduced FcγRIIIb expression is thus likely to contribute to the impaired clearance of immune complexes, which is a feature of SLE, explaining the association between low FCGR3B CNV and SLE that we have confirmed in a Caucasian population. In contrast, antineutrophil cytoplasmic antibody–associated systemic vasculitis (AASV), a disease not associated with immune complex deposition, is associated with high FCGR3B CN. Thus, we define a role for FCGR3B CNV in immune complex clearance, a function that may explain why low FCGR3B CNV is associated with SLE, but not AASV. This is the first report of an association between disease-related gene CNV and variation in protein expression and function that may contribute to autoimmune disease susceptibility.

HYPERKALAEMIA IN CYCLOSPORIN-TREATED RENAL ALLOGRAFT RECIPIENTS

Mean serum potassium levels were significantly higher for 9 months in renal allograft recipients receiving cyclosporin than in those receiving prednisolone and azathioprine. Sustained hyperkalaemia (serum potassium 6.0-7.1 mmol/l) inappropriate for their renal function (glomerular filtration rate 21-36 ml/min) developed in seven of forty-three cyclosporin-treated patients. All seven patients had hyperchloraemic acidosis; four were able to acidify their urine to pH less than or equal to 5.4. Six of the seven patients were hypertensive and receiving beta-blockers; one had had bilateral nephrectomy. Despite hyperkalaemia, plasma aldosterone levels were within the normal range in five patients and raised in two. During moderate sodium restriction, plasma renin activity was low or low-normal in five of the seven patients. In these patients a combination of hypoaldosteronism and renal tubular damage leading to a tubular defect of potassium and hydrogen ion secretion is the apparent cause of the hyperkalaemia and hyperchloraemic acidosis. Hyporeninaemia caused by beta-blockade probably blunts the aldosterone response to hyperkalaemia, thereby worsening it.

The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease

To assess the relationship between interstitial capillary density and interstitial macrophages we prospectively measured these factors in situ in 110 patients with chronic kidney disease. Macrophage numbers and urinary MCP-1/CCL2 levels significantly correlated inversely with capillary density which itself significantly correlated inversely with chronic damage and predicted disease progression. In 54 patients with less than 20% chronic damage, there was a significant correlation between the urinary albumin to creatinine ratio and MCP-1/CCL2, and MCP-1/CCL2 and macrophages but not between MCP-1/CCL2 and capillary density. Conversely, in 56 patients with over 20% chronic damage there was no correlation between MCP-1/CCL2 and macrophages but there were significant inverse correlations between capillary density and both macrophages and chronic damage. The expression of VEGF mRNA significantly correlated with macrophage infiltration, capillary density and chronic scarring. In an ischemic-hypertensive subgroup there was upregulation of the hypoxia marker carbonic anhydrase IX and with over 20% chronic damage an increased macrophage to CCR2 ratio. Our study shows that proteinuria and MCP-1/CCL2 are important for macrophage recruitment in early disease. As renal scarring evolves, alternative pathways relating to progressive tissue ischemia secondary to obliteration of the interstitial capillary bed predominate.

Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy

The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.

Calcineurin inhibitor sparing with mycophenolate in kidney transplantation: a systematic review and meta-analysis

Background. Limiting the exposure of kidney transplant recipients to calcineurin inhibitors (CNIs) has potential merit, but there is no clear consensus on the utility of current strategies. In an attempt to aid clarification, we conducted a systematic review and meta-analysis of randomized trials that assessed CNI sparing (minimization or elimination) with mycophenolate as sole adjunctive immunosuppression. Methods. The search strategy identified trials where CNI sparing was accompanied by the continuation of, or conversion to, mycophenolate and compared with standard or higher dose CNI therapy. Two investigators independently examined each trial for eligibility, quality, and outcome measures. Additional subgroup analyses were assessed: (1) de novo CNI sparing; (2) elective CNI sparing beyond 2 months posttransplantation; and (3) CNI sparing for transplant dysfunction. Results. Nineteen randomized controlled trials met the inclusion criteria permitting analysis of 3312 renal transplant recipients with median follow-up of 12 months. CNI sparing significantly improved glomerular filtration rate (weighted mean difference 4.4 mL/min, 95% confidence interval [CI] 2.9–5.9, P<0.001); with some evidence, albeit weak, of improved graft survival (odds ratio 0.72, 95% CI 0.52–1.01, P=0.06). Acute rejection rates were only increased after elective CNI elimination (odds ratio 2.23, 95% CI 1.57–3.17, P<0.001). There were no significant differences in mortality, malignancy or incidence of infections. Conclusions. CNI sparing strategies with adjunctive mycophenolate may play an important role in kidney transplant recipients. Improvements in short-term graft function, and possibly graft survival, are achievable. Longer term studies are needed to substantiate the short-term benefits, and refining elective CNI elimination protocols may help to reduce the risk of rejection.

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

Hypertension and chronic kidney disease (CKD) have a significant impact on global morbidity and mortality. The Low Birth Weight and Nephron Number Working Group has prepared a consensus document aimed to address the relatively neglected issue for the developmental programming of hypertension and CKD. It emerged from a workshop held on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology. Through multidisciplinary engagement, the goal of the workshop was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. The recommendations for action of the consensus workshop are the results of combined clinical experience, shared research expertise, and a review of the literature. They highlight the need to act early to prevent CKD and other related noncommunicable diseases later in life by reducing low birth weight, small for gestational age, prematurity, and low nephron numbers at birth through coordinated interventions. Meeting the current unmet needs would help to define the most cost-effective strategies and to optimize interventions to limit or interrupt the developmental programming cycle of CKD later in life, especially in the poorest part of the world.

A developmental approach to the prevention of hypertension and kidney disease: a report from the Low Birth Weight and Nephron Number Working Group

In 2008, the World Health Assembly endorsed the Global Noncommunicable Disease (NCD) Action Plan based on the realization that NCDs caused more deaths than communicable diseases worldwide. 1 This plan strongly advocates prevention as the most effective strategy to curb NCDs. The “Life Course Approach”, also recently highlighted in the Minsk Declaration, reflects the increasing recognition that early development impacts later-life health and disease. 1,2 Optimization of early development offers the opportunity for true primary prevention of NCDs. Developmental programming in the kidney has been recognized for over 2 decades but its contribution to the global burden of kidney diseases remains underappreciated by policy makers. 3 Given the many factors known to impact fetal kidney development, including maternal health and nutrition, exposure to stress, poverty, pollutants, drugs and infections during gestation, 3 a holistic strategy to prevent such programming effects is consistent with the “Life-Course” approach and aligns with the United Nations Sustainable Development Goals (SDG) to foster health. 2,4 Chronic kidney disease (CKD) is an important contributor to the NCD burden that has been relatively neglected in the Global NCD Action Plan, despite CKD being a major cause of hypertension, and a major risk multiplier of cardiovascular disease 1,5 While the prevalence of CKD in many lower-income countries remains unknown, CKD is more prevalent among disadvantaged populations within industrialized nations, e.g. African Americans and Aboriginal Australians. 6 People receiving dialysis or transplantation are projected to double from 2.6 million in 2010 to 5.4 million in 2030. 7 Between 2.3 and 7.1 million adult people died from lack of access to dialysis and transplantation in lower-income countries in 2010. 7 Given the clinical consequences and often prohibitively high costs of treatment, prevention and early detection are the only sustainable solutions to address this growing global burden. To address the neglected issue of developmental programming of kidney disease and hypertension, a multidisciplinary workgroup, including international expert obstetricians, neonatologists and nephrologists (see Appendix), was convened. We argue that the Global NCD Action Plan does not adequately address the impact of developmental origins of NCDs which is globally but is particularly important in low- and middle-income countries (LMICs) where developmental risk is highest and the burden of NCDs is growing fastest. 8 The working group identified the need to raise awareness of the role of developmental programming in renal disease, and suggests locally adapted preventive strategies that could have long-term benefits on health and heath cost savings worldwide, integrating obstetrical, neonatal and nephrology perspectives.

Holiday haemodialysis and imported hepatitis C virus infection: A series of sixteen cases in two large haemodialysis units

BACKGROUND Patients in haemodialysis units are at an increased risk of blood borne virus infections. Birmingham city (West Midlands, UK) has a large number of its population from an ethnic origin other than white (30%). Recently due to the increase in number of haemodialysis centres abroad and particularly in the Indian Subcontinent, a large number of haemodialysis patients from these ethnic minorities are encouraged to take holidays in their countries of origin. OBJECTIVES To present the data on a series of cases of holiday haemodialysis acquired hepatitis C virus (HCV) infections from two large dialysis units in Birmingham. STUDY DESIGN In this retrospective study we have reviewed the case records of all patients in two large dialysis units who had holiday dialysis abroad and developed HCV infection after returning to the UK. RESULTS A total of 16 patients from two large dialysis units in Birmingham who developed HCV infection after haemodialysing abroad mainly in the Indian Subcontinent are being described. This constituted 44% of the total HCV positive patients in the two haemodialysis units (16/36). The cases occurred over a period of 9 years between 2000 and 2008. The last twelve of these fifteen cases had been diagnosed in the past 17 months. There were 10 male patients with a mean age 62.8 years (range 26-84 years) and 6 female patients with a mean age of 57 years (range 44-68 years). HCV genotypes 1, 3 and 4 were found in 9, 4 and 3 patients, respectively. CONCLUSION These cases underline the importance of enhanced surveillance and infection control procedures in haemodialysis units for patients who return after dialysing in resource poor countries. To the best of our knowledge this represents the largest series of imported HCV infection after holiday haemodialysis, and demonstrates clearly the significance of the perceived risk with increasing number of incident infections.