NephroShotz Book 1 PDF

ME nhnnHMdn athepeanutkidney 1 s B00K 1 M i n i m a l c h a n g e // F S G S // I m m u n o s u p p r e s s i o n // M e m b r a n o u s n e p h r o p a t h y / / H a e m a t u r i a // P r o t e i n u r i a // D i a b e t i c n e p h r o p a t h y H...

ME nhnnHMdn athepeanutkidney 1 s B00K 1 M i n i m a l c h a n g e // F S G S // I m m u n o s u p p r e s s i o n // M e m b r a n o u s n e p h r o p a t h y / / H a e m a t u r i a // P r o t e i n u r i a // D i a b e t i c n e p h r o p a t h y HIGH YIELD HEPHROIOGYFOR THEREHAI SPECIALTY CERTIFICATE EXAM John Booth  About this book Hello, and welcome to the first book in a new series of Renal Medicine titles – NephroShotz! I am writing these books with several aims in mind. Foremost, is to create a comprehensive learning tool for the MRCP’s renal specialty certificate exam (recently rebranded as the European Specialty Examination in Nephrology, ESENeph), by covering the breadth of the training curriculum, and supporting the practical knowledge which can only be obtained by meeting and treating patients in the hospital. At the same time, I am also endeavouring to make the books a succinct and practical guide to contemporary real-world nephrology (or at least the brand I try to practise!) by focusing on the mechanisms of disease, key basic science findings, clinical trials and guidelines which inform day-to-day practice, without becoming bogged down in minutia, speculation or superfluous detail. In essence, this is my attempt to ‘download’ on to paper the mental framework which I use to practice nephrology, and I hope that you will find many of the tables, figures and boxes to be useful ‘desk references’, pulling together practical clinical information and ‘pearls’ which are often not quite so accessible in weightier textbooks! Although the questions at the start of each chapter are written in an MRCP best-of-five style, and do give insight into the way questions are formulated in the exam, I have included them more as a problem-based ‘spark’ or springboard to the topic, than as a ‘mock question’. The questions are drawn from the series of in-house renal SCE lectures I give to renal trainees at the Royal London Hospital, and are designed to signpost ‘silos of knowledge’ from across the renal specialty curriculum; detailed answers are provided at the end of the chapter with reflections on the relevant knowledge required to select the correct response. I make no apology for the slightly chatty writing style, which is one of the definite plus-points of writing, editing and self-publishing your own work! The ‘Nephroshotz’ title reflects the fact that I’ve chosen to publish the course in concise ‘high yield’ chunks (‘shots’) rather than one mega- tome – both to make the learning experience more flexible and less daunting, and to allow me to write and publish quicker (let’s face it, a full-time NHS job does not leave that much free time for text book writing, so you might be waiting a while for me to finish the complete course!). Although ultimately I intend these books to cover the knowledge base of the entire renal training curriculum, I am writing with the intention that the 21st Century reader will be able to support the text and hand-drawn figures by judicious ‘googling’ of representative clinical images! Most importantly, I hope you find the books as engaging and enjoyable to read as I am finding them to write. Please do let me know via Twitter if you think there is a factual inaccuracy, or you want me to try and clarify something equivocal! JB @thepeanutkidney July 2020  About the author Dr John Booth is an NHS Consultant Nephrologist at the Royal London Hospital, Barts Health NHS Trust, in London, UK. He trained at Oxford University and UCL medical schools, gaining a ‘Prize First’ in Physiological Sciences and qualifying in Medicine with distinction and as first runner up to the University of London Gold Medal in 2004. He considers himself as something of an ‘exam expert’ – and with academic prizes in every year at school and University, including five for the final MBBS exams, and no B’s in sight on his CV, this is probably with some justification. As such, he prides himself on both his ability to organise knowledge and on his knack to pick out relevant, ‘high yield’ and testable information. John was awarded a PhD from UCL in 2013 for research into disease mechanisms of diabetic nephropathy. His main clinical interests now are glomerular disorders and the interface between HIV and the kidney, although his clinical brief is broad, and day-to-day work includes dialysis, transplantation and the full scope of acute nephrology. He runs a popular weekly internal teaching course for renal trainees at Barts Health, covering the breadth of the renal specialty curriculum, which is the inspiration for these books. In his spare time he is a keen runner, bird- watcher (yes, really), Netflix-consumer and Spanish student. He is also active in the nephrology social media sphere, tweeting as the salty-snack alias @thepeanutkidney!  Notice This book is written as an exam-preparation tool, and is not intended as a manual for clinical practice. It is the responsibility of clinical practitioners to use their own experience and knowledge to evaluate information or methods described within this text. While the author has made every effort to ensure drug doses are correct, it is still possible that errors have been missed, and the reader is advised to consult the summary of product characteristics for full and updated information on any medicine or drug described prior to prescribing, and to use their own experience, knowledge and prescribing resources when determining dosages and treatments for any individual patient. Likewise, national and international guidelines are being continuously revised and updated, and the reader is advised to consult the source guideline document to verify the presented information remains as described. To the full extent of the law, the author does not assume liability for any injury or damage to persons or property resulting from any use of methods, products, instructions or ideas contained within this book. Version History Version 1: July 2020 Contents About this book About the author Question 1 - Minimal change 1 Question 2 - Minimal change 2 Question 3 - Minimal change 3 Question 4 - FSGS 1 Question 5 - FSGS 2 Question 6 - FSGS 3 Question 7 - Immunosuppression 1 Question 8 - Immunosuppression 2 Question 9 - Membranous nephropathy 1 Question 10 - Membranous nephropathy 2 Question 11 - Membranous nephropathy 3 Question 12 - Membranous nephropathy 4 Question 13 - Nephrotic syndrome complications Question 14 - Haematuria Question 15 - Proteinuria 1 Question 16 - Proteinuria 2 Question 17 - Diabetic nephropathy 1 Question 18 - Diabetic nephropathy 2  Question 1 An 18-year-old Chinese woman presents with a 1-month history of intermittent fever, malaise, swelling in the neck and ankle oedema. On examination, her blood pressure is 115/73, she has clinical evidence of lymph node enlargement in the left anterior cervical chain and left axilla, together with facial puffiness and marked ankle swelling. Investigations: Haemoglobin 97 g/l (115-165) Total white blood cells 9.2 x 109 /L (3.6-11) Eosinophils 1.3 x 109 / L (0.1-0.4) Serum creatinine 85 µmol/L (45–84) Serum albumin 18 g/L (35–50) Urinary protein : creatinine ratio 750 mg/mmol (3g per 24 hours), hypoalbuminaemia (50% of African-American patients with FSGS carry two risk alleles for the APOL1 gene (encoding apolipoprotein L1), which predicts a younger onset and more rapid decline in renal function than in patients carrying only 1 or 0 risk alleles. While APOL1 is not specific in conferring risk for FSGS (it also confers considerable risk to development of HIVAN in patients with HIV, and hypertensive nephropathy), it appears to represent an important cofactor in FSGS progression in patients of black ethnicity. It is worth noting that the proportion of patients responding to steroid therapy appears to be the same, regardless of the number of risk alleles a patient possesses, supporting the notion that APOL1 is a modifier of progression, rather than the root cause. Selecting adult patients with FSGS for genetic testing remains a contentious issue. In the UK, the Bristol genetics laboratory offers a gene panel for steroid resistant nephrotic syndrome, which currently includes 69 genes at the time of writing. Critics argue that the ‘pick up’ rate of genetic testing is low in sporadic adult disease, and the result unlikely to immediately change outcome (as some genetic forms of FSGS do, somewhat unpredictably, respond to immunosuppression). Advocates, on the other hand, argue that making a genetic diagnosis may help to limit immunosuppression exposure, and also help triage risk of disease recurrence after transplantation as well as direct investigation of potential kidney donors if a mutation is identified. Current KDIGO guidance is not to ‘routinely perform genetic testing’, which is clearly open to some interpretation! Logical scenarios in which to consider it are in patients with a family history of nephrotic syndrome, evidence of a wider genetic ‘syndrome’, primary steroid resistance, or an ‘adaptive FSGS’ picture (no overt nephrotic syndrome, patchy foot process effacement on EM) in the absence of an identifiable ‘secondary cause’. Answer discussion: In this case vignette, the young woman in question is presenting with nephrotic syndrome; the history of disease in her father is suggestive of an autosomal dominant pattern of inheritance. A: APOL1 risk alleles are exceedingly rare in patients other than those of black ethnicity.  Even then APOL1 is likely a co-factor in disease progression (rather than root cause) and behaves as an autosomal recessive trait, due to the need for 2 risk alleles. B: Nephrin mutations are the commonest cause of monogenic nephrotic syndrome in children, but are rarely identified in children presenting over the age of 1, and are inherited in an autosomal recessive fashion. C: Although statistically mutations in podocin are the most commonly identified genetic abnormality in adult onset nephrotic syndrome, patients are typically compound heterozygote and thus display an AR pattern of inheritance D: Best answer E: suPAR has been suggested as the circulating permeability factor in 'primary' FSGS, but has not been linked to genetic disease. References and further reading Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach. De Vriese et al, 2018. JASN, 29:759-774. A logical and well thought-out discussion of FSGS, focusing on contemporary classification, and also offering opinion on when genetic testing is justified in adults. Authored by glomerular big-hitters (including Sanjeev Sethi, Dick Glassock and Fernando Fervenza). Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults. Lepori N et al, 2018. Clin Kidney J 11:179-190. Comprehensive review of genetic- FSGS. RareRenal clinician info on FSGS. https://rarerenal.org/clinician-information/nephrotic- syndrome-clinician-information/. Provides signposts to the Bristol SRNS genetic testing panel, and information about ongoing clinical studies (e.g. NephroS, investigation epidemiological and clinical features of nephrotic syndrome).  Question 6 A 27 year-old Black male presents with a 3 month history of worsening leg oedema. Past medical history is notable for mild asthma only. He takes no medications aside from an over the counter multi-vitamin. His father suffers from type 2 diabetes mellitus. Blood pressure at presentation was 125/72. Examination revealed symmetrical pitting oedema to the knees. Initial investigations showed: serum creatinine 130 µmol/L (59–104) serum albumin 26 g/L (35–50) urinary protein : creatinine ratio 496 mg/mmol (10g. All men should be counselled for risk of permanent infertility, and offered sperm storage before treatment whenever possible Malignancy Particular risks include myelodysplasia, haematologic malignancies (including leukaemia and lymphoma) and bladder cancers Genotoxicity Cyclophosphamide is a powerful teratogen and is contraindicated in women in all trimesters of pregnancy. Two forms of effective contraception should be used during treatment and for 6-12 months after stopping  May also cause mutations in male germ cells, and men are recommended not to father a child either during treatment or for 6 months afterwards Other organ toxicities Pneumonitis and pulmonary fibrosis are both well recognised, and may be delayed in onset Acute myocarditis may be seen with high dose therapy Veno-occlusive liver disease (VOLD) is rare, and typically reported in high dose bone marrow conditioning regimes Table 8.1. Potential adverse effects of cyclophosphamide Rituximab The B lymphocyte depleting anti-CD20 monoclonal antibody rituximab, continues to find new uses in the field of nephrology. Current indications include transplantation (ABOi incompatible transplants), induction regimens for vasculitis and lupus nephritis, idiopathic membranous nephropathy (off the back of the recent MENTOR study), cryoglobulinaemia and minimal change nephropathy in children and adolescents. Second generation anti-CD20 drugs resulting in ‘deeper’ depletion of tissue B cells (eg obinutuzumab) are also progressing through clinical trials for renal disease. Rituximab is often an attractive option compared to continuous oral therapies due to its prolonged duration of action (often in excess of 6 months) after just one or two intravenous infusions, sometimes obviating the need for other oral medications entirely. On the whole, it is also well tolerated by patients, although it too has a number of important potential adverse effects which require careful discussion and consent (table 8.2). Effictiveness and duration of circulating B lymphocyte depletion can be tracked by monitoring CD19 positive lymphocyte levels in blood (CD19 is co-expressed on lymphocytes with CD20 – CD20 cannot be measured as rituximab blocks the antibody binding site and thus interferes with the assay); B cell reappearance does not, however, always correlate well with behaviour of clinical disease. Adverse effect Notes Infection Pneumocystis pneumonia (PCP or PJP) is a well- recognised complication in rituximab-treated patients, although risk is highest in those receiving additional immunosuppressive agents Some units chose to give routine PCP prophylaxis (e.g. co-trimoxazole); others individually risk assess Infusion reactions Typically mild and usually respond to suspension of infusion and re-initiation at a slower rate, although serious (even fatal) reactions have been reported Reaction frequency may be reduced by pre- medicating with anti-histamine +/- steroid Hypogammaglobulinaemia Severe hypogammaglobulinaemia (IgG 4 g / day And Urine protein remains > 50% of the baseline value And There is no evidence of progressive decline in proteinuria over the 6-month period with ACEi / ARB alone Or The patient is experiencing severe or life-threatening complications of nephrotic syndrome Or The patient has evidence of progressive CKD (defined as > 30% rise in creatinine over 6-12 months, not due to super-imposed complications) As you can see, these guidelines are carefully crafted to minimise the chance that immunosuppression will be commenced either in a patient who is already demonstrating signs of spontaneous remission, or in whom the risk of developing progressive CKD is low. KDIGO also recommend withholding immunosuppressive therapy in patients where this is likely to be futile due to the presence of advanced and irreversible CKD (i.e. patients who are beyond the ‘point of no return’). KDIGO define this cut-off as a creatinine persistently more than 3.5 mg/dl (309 µmol/l), or an eGFR 30g/l), nor has there been a > 30% rise in creatinine. As such, in the absence of other severe complications of nephrotic syndrome, she does not meet the criteria to commence immunomodulatory therapy. A – D All incorrect as patient does not meet the KDIGO guidelines criteria for starting immunosuppression E. Best answer (i.e. continue with conservative treatment) Relevant Guidelines KDIGO Clinical Practice Guidelines for glomerulonephritis, 2012. Kidney Int Supplements, Vol 2, Issue 2, 2012, or online at www.kdigo.org Further reading: Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis. Pei Y, Cattran D and Greenwood C. Kidney Int 1992; 42:960-6. Seminal paper modelling risk of progressive CKD in patients with idiopathic MN and still the cornerstone of evidence underpinning treatment-selection algorithms.  Question 12 A 54-year old man was evaluated after admission to hospital with an acute massive pulmonary embolus 14 days previously, requiring treatment with intravenous thrombolysis. On direct questioning, he reported a history of gradually worsening ankle oedema over the preceding 9 months. His past medical history comprised angina and hypertension, both of which were well controlled taking bisoprolol 5mg once daily and ramipril 10mg once daily. He was now anticoagulated with apixaban. On examination, his blood pressure was 122/75 and jugular venous pressure was not elevated. He had moderate ankle oedema. Urinalysis showed protein 4+. Investigations Serum creatinine 156 µmol/L (59-104) Serum albumin 22 g/l (35-50) Urine protein : creatinine ratio 1230 mg/mmol (