bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging Patients with Chest Pain in the Emergency Department
Authors: Soman Prem , Udelson James E.
Published: November 2015

The six-to-eight million people who present to emergency departments (EDs) across the U.S. each year for the evaluation of chest pain present a unique challenge to physicians.(1) Less than a third of these patients are eventually diagnosed with coronary artery disease (CAD).(2,3) However, a small percentage of patients with acute cardiac ischemia and an acute coronary syndrome (ACS) are inadvertently discharged, with potential adverse consequences.(2,4-6) Concerns about patient safety and malpractice litigation has resulted in the adoption of a practice paradigm that involves observation and testing that is associated with high cost. In this chapter we review the current approaches to risk stratification of chest pain patients, the utility of myocardial perfusion imaging for this purpose and, the ongoing investigation of potential new approaches in this area.
Role of PET in Diagnosis and Risk Assessment in Patients with Known or Suspected CAD
Authors: Mc Ardle Brian A. , Renaud Jennifer M. , deKemp Robert A. , Beanlands Rob S. B.
Published: November 2015

Cardiac PET enables evaluation of multiple aspects of myocardial perfusion, metabolism, cell signaling and function that are of value both for diagnosis and prognostication in patients with known or suspected CAD and its use has increased in the past three decades. PET myocardial perfusion imaging (MPI) offers several technological advantages over SPECT including; higher photon energy, higher count sensitivity, more consistent attenuation correction and the ability to measure myocardial blood flow in absolute terms. These result in faster imaging times, lower patient radiation exposure and increased diagnostic accuracy. However the availability of PET MPI remains limited, predominantly due to expense. Efforts are underway to expand the use of PET MPI beyond larger centers, with lower-cost scanners and more widely available radiotracers. In this chapter we describe the latest advances in PET camera technology and image reconstruction as well as potential image artifacts specific to PET MPI. We go on to discuss diagnostic accuracy and prognostic value of PET MPI as well as its role in clinical practice.
Phase Analysis for Dyssynchrony by MPI and MUGA
Authors: Chen Ji
Published: November 2015

Fourier phase analysis can be used to assess dyssynchrony from nuclear images, such as multi-gated acquisition (MUGA) radionuclide angiography, gated blood-pool SPECT, and gated SPECT myocardial perfusion imaging. This chapter reviews the technical background of Fourier phase analysis with these imaging modalities and demonstrates how it measures ventricular dyssynchrony. The major clinical application of ventricular dyssynchrony assessment is to improve response to cardiac resynchronization (CRT) in patients with heart failure. This chapter introduces the current practice of CRT and the potential factors related to CRT response, and then reviews the clinical studies of the above phase analysis techniques for increasing CRT response.
Imaging of Myocardial Innervation
Authors: Masuda Atsuro , Naya Masanao , Yoshinaga Keiichiro , Tamaki Nagara
Published: November 2015

Cardiac autonomic innervation imaging has been focused on assessing molecular, electrophysiologic, and pathophysiologic processes of various cardiac disorders. Iodine radiotracer (I-123)-labeled metaiodobenzylguanidine (MIBG), as a marker of adrenergic neuron function, plays an important role in risk stratification and treatment monitoring of heart failure patients. In addition, MIBG has a potential value for predicting fatal arrhythmias that may require implantable cardioverter-defibrillator treatment. Among various positron emission tomography (PET) tracers for probing autonomic neuronal function, C-11 hydroxyephedrine (HED), has been used for precise assessment of heart failure and arrhythmias, similar to MIBG. More studies are needed to confirm the clinical utility of these molecular imaging modalities for the management of patients with heart failure, coronary artery disease and arrhythmias.
Image-Based Measurements of Myocardial Blood Flow
Authors: Schelbert Heinrich R.
Published: November 2015

Image-based measurements of myocardial blood flow afford the assessment of coronary circulatory function. They reflect functional consequences of coronary stenoses, diffuse epicardial vessel disease and microvascular dysfunction and structural changes and thus provide a measure of the total ischemic burden. Measured flows contain therefore clinically important predictive information. Fundamental to flow measurements are the tissue tracer kinetics, their description through tracer kinetic models, high spatial and temporal resolution imaging devices and accurate extraction of radiotracer tissue concentrations from dynamically acquired images for estimating true flows from the tissue time activity curves. A large body of literature on measurements of myocardial blood flow exists for defining in humans normal values for flow at baseline and during hyperemic stress as well as for the myocardial flow reserve. The role of PET for flow measurements has been well established; initial results with modern SPECT devices are encouraging. Responses of myocardial blood flow to specific challenges like pharmacologic vasodilation and to sympathetic stimulation can uncover functional consequences of focal epicardial coronary stenoses, of conduit vessel disturbances and disease and impairments of microvascular function. Apart from risk stratification, flow measurements may allow detection of early preclinical disease, influence treatment strategies and identify therapy responses.
Imaging of Myocardial Metabolism
Authors: Gropler Robert J.
Published: November 2015

Abnormalities in myocardial substrate metabolism play a key role in the pathogenesis of a host of cardiac disease processes. The importance is highlighted by the routine clinical use of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) to measure myocardial glucose metabolism to detect viable tissue in patients with ischemic cardiomyopathy and the development of novel therapies designed to modulate myocardial metabolism. Our understanding of myocardial metabolism has benefitted from the application of advanced molecular biologic techniques and the development of elegant genetic models to of myocardial metabolic disease resulting in a greater appreciation for the pleiotropic actions of cellular metabolism. In parallel, there have been significant advances in radionuclide-based metabolic imaging techniques in terms instrumentation design, radiopharmaceutical development and small animal imaging. These advances have further ensconced radionuclide metabolic imaging techniques as tools to further our understanding of various forms of cardiovascular disease and potentially improve the care of the cardiac patient. In this chapter several of key advances in metabolic imaging will be described, their potential new clinical applications are reviewed and contribution to cardiovascular research highlighted.
Radionuclide Imaging in Heart Failure
Authors: Soman Prem
Published: November 2015

Heart Failure is a clinical syndrome characterized by symptoms and signs of systemic or pulmonary congestion, associated with elevated intracardiac filling pressures. The structural and functional abnormalities of the myocardium which characterize the heart failure state can be explored by various imaging approaches. Hence cardiac imaging plays an integral part in the evaluation the heart failure patient. Radionuclide imaging techniques may be uniquely suited to address several important clinical questions in heart failure related to etiology, the quantification and serial evaluation of LV function, and the selection of patients for therapies including coronary revascularization, implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT).
Hybrid Cardiac Imaging
Authors: Kaufmann Philipp A. , Gaemperli Oliver
Published: November 2015

Assessment of both coronary anatomy and myocardial perfusion are equally important for the appropriate treatment of patients with stable coronary artery disease. Cardiac hybrid imaging allows integration of coronary anatomy and perfusion in one all-in-one image, thereby avoiding mental integration of findings. In selected subgroups of patients, cardiac hybrid imaging has demonstrated superior diagnostic accuracy compared to single modalities. The combination of coronary anatomy and function provides incremental prognostic information and improves risk stratification of patients with suspected or known CAD. Aside from CT coronary angiography, coronary artery calcium score (CACS) scans obtained from native ECG-triggered CT are used for hybrid imaging. They are used either for attenuation correction, or can be combined with radionuclide information to improve CAD detection and risk stratification. A large number of integrated hybrid scanners are commercially available and offer advantages for cardiac hybrid imaging. However, these devices are not mandatory, and hybrid imaging is perfectly feasible from two separate datasets using appropriate image fusion software. Cardiac magnetic resonance has entered the arena of hybrid imaging and several integrated PET/MRI devices are already commercially available. Its advantages include the lack of ionizing radiation and a high spatial resolution, particularly for soft tissue structures. In research, hybrid imaging moves beyond its conventional borders of perfusion imaging to target specific molecular or biological pathways that underlie cardiac disease, a concept known as molecular imaging. The combination of radionuclide imaging with CT or MRI offers attractive features to co-localize biological signals from radiolabeled targeted compounds with microanatomical structures.
Cost Effectiveness of Imaging with Nuclear Cardiology
Authors: Phillips Lawrence M. , Shaw Leslee J.
Published: November 2015

This chapter focuses on the economic data available for cardiovascular (CV) imaging. The total costs of testing are substantively lower than those associated with invasive procedures. There are several ongoing randomized trials, such as the PROMISE trial, that may further add to our evidence base on the cost implications of CV imaging. Data for stress nuclear cardiology supports its utility in terms of a high prognostic accuracy and that this test is economically attractive; notably for patients with a high likelihood of coronary artery disease. Data also supports that this benefit does not only include patients with known coronary artery disease but also the high likelihood subsets of the elderly or functionally impaired where ischemic findings play a fundamental role in ischemia-guided management. Importantly, more recent data support that alternative testing strategies have reduced cost in subsets of patients including lower risk women with stable chest pain and in the acute evaluation of low risk chest pain in the ED. Negative evidence is extremely important for the field of CV imaging and this more recent data should be embraced as defining our limitations in nuclear cardiology.
Presentations of renal disease
Authors: Winearls Christopher G.
Published: November 2015

Patients are referred to nephrologists either because they are found incidentally to have clinical or laboratory abnormalities that may point to renal disease, or they have an illness that is likely to be caused by renal disease, or in the case of systemic disorders known to be complicated by renal injury. An overview of these presentations is given.
Approach to the patient with hyponatraemia
Authors: Hoorn Ewout J. , Zietse Robert
Published: November 2015

Hyponatraemia is the most common electrolyte disorder in hospitalized patients and is primarily a water balance disorder. Therefore, hyponatraemia is due to a relative excess of water in comparison with sodium in the extracellular fluid volume. Hyponatraemia is usually due to the release of vasopressin despite hypo-osmolality; this secretion is either ‘appropriate’ (i.e. due to a low intravascular volume) or ‘inappropriate’.
The diagnostic approach to hyponatraemia relies on the assessment of the time of development, symptoms, and volume status, along with laboratory parameters such as urine sodium and urine osmolality. Complications are mainly neurological and usually depend on the rate of development and correction.
If hyponatraemia develops acutely, treatment should be directed towards counteracting the water shift to or brain cells. Conversely, in more chronic cases of hyponatraemia, treatment should be directed at the underlying cause, while avoiding over-correction.
Clinical use of diuretics
Authors: Ellison David H. , Subramanya Arohan R.
Published: November 2015

Diuretics are widely employed to treat extracellular fluid volume expansion caused by heart failure, cirrhosis of the liver, nephrotic syndrome, and chronic kidney disease. Major classes of diuretic inhibit sodium reabsorption along the proximal tubule, the loop of Henle, the distal convoluted tubule, and the connecting and collecting tubules.
Loop diuretics have the highest ceiling of action and often form the cornerstones of diuretic treatment of oedema. Members of this class are short-acting drugs, with different bioavailabilities, the specifics of which contribute importantly to a rational and effective approach to their use. They are not filtered substantially because they are all protein bound. They enter tubules by secretion along the proximal tubule, thereby gaining access to the Na-K-2Cl cotransporter of the thick ascending limb. Their dose–response curves are sigmoidal and altered by several disease processes. Chronic administration can elicit adaptive processes along the nephron that limit their efficacy.
Distal convoluted tubule diuretics, such as the thiazides, inhibit NaCl absorption along the distal convoluted tubule. While used predominantly to treat hypertension, they are also useful to treat oedema, especially when combined with loop diuretics.
Drugs acting along the connecting tubule and collecting duct either inhibit Na+ channels directly or block mineralocorticoid receptors. These drugs are effective in states of very high aldosterone secretion, and can also be used to reduce the hypokalaemia caused by other classes of diuretics.
An evidence-based approach to treating the oedematous patient is described.
Approach to the patient with hypo-/hyperphosphataemia
Authors: Blaine Judith , Giral Hector , Jelen Sabina , Levi Moshe
Published: November 2015

Phosphate is the most abundant anion in the human body and has an indispensable role in numerous biological functions, including energy metabolism, bone formation, signal transduction, and as a constituent of phospholipids and nucleic acids. Only 1% is in extracellular fluid, but serum phosphate (Pi) levels are subject to fine tuning involving several hormones modulating renal tubular reabsorption, intestinal absorption, and bone homeostasis to maintain a normal range from 0.81 to 1.45 mmol/L (2.5–4.5 mg/dL) in adulthood and higher levels during infancy and childhood.
An approach to the diagnosis of low and high phosphate levels is described.
Nutcracker syndrome and phenomenon
Authors: Neary John , Turner Neil
Published: November 2015

Nutcracker syndrome describes symptomatology associated with obstruction to the left renal vein caused by pressure from the overlying superior mesenteric artery. Modern imaging methods show that some degree of left renal vein obstruction may be a common incidental finding in asymptomatic patients so it is better described as ‘nutcracker phenomenon’, NCP. The association of NCP with symptoms and signs is often speculative. NCP may be seen at any age but most patients with symptoms attributed to it are teenagers or young adults.
The strongest evidence is for association with episodic macroscopic haematuria. There is weak evidence that it may in some circumstances account for orthostatic (postural) proteinuria, microscopic haematuria, or pain syndromes. Apart from rare examples of extreme haemorrhage the syndrome has not been associated with life-threatening features other than through complications of treatment.
Various interventions have been employed, recently most commonly endovascular or extravascular approaches to stenting the vein, but serious adverse consequences from stent migration and thrombosis have been described.
Alport post-transplant antiglomerular basement membrane disease
Authors: Cui Zhao , Turner Neil , Zhao Ming-hui
Published: November 2015

Alport antiglomerular basement membrane (anti-GBM) disease is a rare example of disease caused by allo-sensitization after renal transplantation, first described in 1992. Because the recipient lacks a specific glomerular basement membrane (GBM) protein, they can become sensitized to the normal molecule present in the GBM of the donor kidney. The disease is restricted to the allograft. Interestingly severe disease arises from this only arises rarely, certainly less than 1 in 20, probably closer to 1 in 50.
It characteristically causes late graft loss in a first transplant with accelerated tempo in later allografts, and in its most extreme form recurs within days. However, inexplicably some subsequent transplants do not provoke aggressive recurrence.
Treatment of the most aggressive disease is difficult and in most cases has been ultimately unsuccessful. Lower levels of immune response, marked by linear binding of immunoglobulin-G to GBM without glomerular disease, are not uncommon in Alport patients after transplantation and should not lead to altered treatment. Immunoassays for anti-GBM antibodies can be misleading as in most cases the target of antibodies is the α‎‎‎5 chain of type IV collagen, rather than the α‎‎‎3 chain which is the target in spontaneous anti-GBM disease.
Overall the outcome of transplantation in Alport syndrome is better than average. This complication is more likely in patients with partial or total gene deletion rather than point mutations, but no other predictive features have been identified.
Fibrillary and immunotactoid glomerulopathy
Authors: Korbet Stephen M. , Schwartz Melvin M. , Lewis Edmund J.
Published: November 2015

Fibrillary or immunotactoid nephropathy is a rare deposition disease of unknown cause in which highly organized deposits containing immunoglobulin and complement are found in the glomerular basement membrane and mesangium. These deposits are not amyloid fibrils and do not stain with Congo red. They are usually polyclonal and are not associated with monoclonal paraproteins, or with cryoglobulins or systemic lupus, distinguishing them from other non-amyloid fibrillary glomerulopathies.
There is debate about whether there is a useful distinction between distinct fibrillary and rarer immunotactoid variants, the rarer immunotactoid variety being associated with larger, more organized, microtubular fibrils and possibly more commonly associated with malignancy (usually lymphoproliferative). However, clinically the conditions are similar.
Patients usually present with heavy proteinuria or nephrotic syndrome. Microscopic haematuria is common and many have reduced glomerular filtration rate at presentation. Fifty per cent reach end-stage renal failure in 3–5 years and there is no convincing evidence that any treatment is effective in altering this outcome. Other organs appear to be affected only rarely (lung, liver). The disease may recur post-transplant but not always and usually more slowly, so does not preclude transplantation.
Other toxic acute tubulointerstitial nephritis
Authors: Freda Benjamin J. , Braden Gregory L.
Published: November 2015

Chronic kidney disease (CKD) is often the result of incomplete recovery of renal function from a variety of causes of acute tubulointerstitial injury. Exposure to ethylene glycol, chlorinated hydrocarbons, paraquat, or toxic mushrooms often causes severe acute kidney injury (AKI), leading to chronic tubulointerstitial nephritis (TIN) and CKD, including end-stage renal disease. Ethylene glycol intoxication often leads to chronic TIN and CKD from direct renal tubular toxicity and from interstitial calcium oxalate deposition. Chlorinated hydrocarbon exposure can cause dialysis-dependent AKI, but only rarely causes CKD from interstitial calcium deposition. Paraquat intoxication causes dose-dependent AKI and often Fanconi syndrome in up to 50% of patients, but only 15% of these patients survive, so CKD is rarely seen as a complication. The toxic mushrooms Cortinarius and Amanita phalloides often cause delayed AKI leading to CKD, chronic dialysis, or renal transplantation.
Drug-induced chronic tubulointerstitial nephritis
Authors: Izzedine Hassan , Gueutin Victor
Published: November 2015

The chronic form of drug-induced tubulointerstitial nephritis (CTIN) is an insidious disease and most probably represents the common final response pattern of the kidney to a variety of agents (including analgesics, lithium, antineoplastic chemotherapeutic agents, like cisplatin and nitrosoureas, and immunosuppressive drugs, such as ciclosporin and tacrolimus). Drug-induced CTIN is usually asymptomatic, presenting with slowly progressive renal impairment. Because of its insidious nature, CTIN is often diagnosed incidentally on routine laboratory screening or evaluation of CKD.
The diagnosis of drug-induced CTIN largely depends on the history of exposure to a nephrotoxic drug.
Clinical investigations may show modest elevation in serum creatinine, evidence of tubular dysfunction (e.g. renal tubular acidosis), or Fanconi syndrome (i.e. aminoaciduria, glycosuria, hypophosphataemia, and hypouricaemia). Urinalysis may be normal or show low-grade proteinuria (< 1.5 g/day) and/or pyuria. Diagnosis depends on renal biopsy, which reveals variable cellular infiltration of the interstitium, tubular atrophy, and fibrosis.
Analgesic nephropathy is possibly still the most common category of CTIN worldwide. The amount of phenacetin-acetaminophen combination required to cause CTIN has been estimated to be at least 2–3 kg over many years. Lithium-induced CTIN occurs in a small subset of patients receiving long-term lithium therapy, who have had repeated episodes of lithium toxicity, with high serum drug levels. CTIN induced by ciclosporin or tacrolimus is common among patients receiving kidney, heart, liver, and pancreas transplants. The mechanism appears to be dependent largely on the potent vasoconstrictive effects of these drugs.
The recognition of a potential association between a patient’s renal disease and exposure to a drug is crucial, because, unlike many other forms of renal disease, drug-induced CTIN can be prevented and even reversed, by avoiding additional drug exposure.
Aristolochic acid nephropathy caused by ingestion of herbal medicinal products
Authors: Gökmen M. Refik , Lord Graham M.
Published: November 2015

Aristolochic acid nephropathy (AAN) is a rapidly progressive renal disease caused by the ingestion of plant products containing aristolochic acid (AA), first described in connection with the use of Chinese herbal medicines. Although the true worldwide extent of this disease is unknown, it is likely to represent a significant cause of chronic kidney disease (CKD) in many parts of the world. Furthermore, recent data have also demonstrated that AA is also the primary aetiological agent in Balkan endemic nephropathy. AAN is notable in its association with urothelial malignancy, with the mechanisms of carcinogenesis now well characterized.
Aside from a possible role for corticosteroid therapy in slowing disease progression in selected patients, no disease-specific treatments have yet been shown to alter the course of this nephropathy. Therefore, prevention of exposure to AA and, in affected patients, effective management of the risk of malignancy are key principles in the approach to this condition.
Although preparations containing Aristolochia spp. and herbs that can be confused or substituted for Aristolochia have been banned in many countries, other herbal products containing AA have continued to be available to consumers long after these bans have been instituted, highlighting the ongoing need for awareness of this disease.
Urate nephropathy
Authors: Kang Duk-Hee , Kanbay Mehmet
Published: November 2015

Gout is a disorder of purine metabolism, characterized by hyperuricaemia and urate crystal deposition within and around the joints. The recognition of increased comorbidity burden in patients with gout rendered it as a systemic disorder rather than simply a musculoskeletal condition. Gout nephropathy (also known as chronic uric acid nephropathy or urate nephropathy) is a form of chronic tubulointerstitial nephritis, induced by deposition of monosodium urate crystals in the distal collecting ducts and the medullary interstitium, associated with a secondary inflammatory reaction. Other renal histologic changes include arteriolosclerosis, glomerulosclerosis, and tubulointerstitial fibrosis. In patients with urate nephropathy, hypertension is common, but usually there is only mild proteinuria and a slight increase in serum creatinine.
The reduction of serum uric acid, using xanthine oxidase inhibitors and perhaps low-purine diet, is the mainstay of therapy.
There is current research around the question of whether it is beneficial to lower serum uric acid in asymptomatic patients with renal disease or with cardiovascular risk factors.
Lipid disorders of patients with chronic kidney disease
Authors: Jardine Alan G. , Patel Rajan K.
Published: November 2015

The risk of developing cardiovascular (CV) disease is increased in patients with chronic kidney disease (CKD) and although dyslipidaemia is a major contributory factor to the development of premature CV disease, the relationship is complex. Changes in lipid fractions are related to glomerular filtration rate and the presence and severity of proteinuria, diabetes, and other confounding factors. The spectrum of CV disease changes from lipid-dependent, atheromatous coronary disease in early CKD to lipid-independent, non-coronary disease, manifesting as heart failure, and sudden cardiac death in advanced and end-stage renal disease.
Statin-based lipid-lowering therapy is proven to reduce coronary events across the spectrum of CKD. The relative reduction in overall CV events, however, diminishes as CKD progresses and the proportion of lipid-dependent coronary events declines. There is nevertheless a strong argument for the use of statin-based therapy across the spectrum of CKD. The argument is particularly strong for those patients with progressive renal disease who will eventually require transplantation, in whom preventive therapy should start as early as possible. The SHARP study established the benefits and endorses the use of lipid-lowering therapy in CKD 3-4 but uncertainty about the value of initiation of statin therapy in CKD 5 remains. There is, however, no rationale for stopping agents started earlier in the course of the illness for compelling indications, particularly in those who will ultimately be transplanted.
The place of high-density lipoprotein-cholesterol raising and triglyceride lowering therapy needs to be assessed in trials.
Modifying dyslipidaemia in CKD has demonstrated that lipid-dependent atheromatous cardiovascular disease is only one component of the burden of CV disease in CKD patients, that this is proportionately less in advanced CKD, and that modification of lipid profiles is only one part of CV risk management.
Analytical aspects of measurements and laboratory values in kidney disease
Authors: Lamb Edmund J. , MacKenzie Finlay
Published: November 2015

This chapter explains the essential principles that must underlie meaningful laboratory data in terms of the production of an accurate result and an intelligent interpretation of its significance. These principles are illustrated by reference to three measurements that nephrologists commonly request: serum creatinine (Jaffe to creatinase); urinary albumin and total protein (Lowry and tetrabromphenol blue to immunoassay); and parathyroid hormone (first to third generation immunoassays). These analytes are placed in their historical and clinical context, and the progress that has been made, and that still needs to be made, in terms of obtaining trueness is outlined.
The aim is to provide an understanding of the production of laboratory data, and of some of the pitfalls in its interpretation.
Spectrum of bone pathologies in chronic kidney disease
Authors: Sprague Stuart M. , Pullman James M.
Published: November 2015

Histologic bone abnormalities begin very early in the course of chronic kidney disease. The KDIGO guidelines recommend that bone disease in patients with chronic kidney disease should be diagnosed on the basis of bone biopsy examination, with bone histomorphometry. They have also proposed a new classification system (TMV), using three key features of bone histology—turnover, mineralization, and volume—to describe bone disease in these patients. However, bone biopsy is still rarely performed today, as it involves an invasive procedure and highly specialized laboratory techniques. High-turnover bone disease (osteitis fibrosa cystica) is mainly related to secondary hyperparathyroidism and is characterized by increased rates of both bone formation and resorption, with extensive osteoclast and osteoblast activity, and a progressive increase in peritrabecular marrow space fibrosis. On the other hand, low-turnover (adynamic) bone disease involves a decline in osteoblast and osteoclast activities, reduced new bone formation and mineralization, and endosteal fibrosis. The pathophysiological mechanisms of adynamic bone include vitamin D deficiency, hyperphosphataemia, metabolic acidosis, inflammation, low oestrogen and testosterone levels, bone resistance to parathyroid hormone, and high serum fibroblast growth factor 23. Mixed uraemic osteodystrophy describes a combination of osteitis fibrosa and mineralization defect. In the past few decades, an increase in the prevalence of mixed uraemic osteodystrophy and adynamic bone disease has been observed.
Mechanisms of progression of chronic kidney disease
Authors: Turner Neil
Published: November 2015

Three major hypotheses attempt to explain progressive kidney disease following diverse diseases and injuries. To varying degrees they can explain the observed risk factors for progression and the ability of interventions to lower risk. The hyperfiltration hypothesis argues that progression is due to stress on residual nephrons leading to injury and damage to remaining glomeruli. The toxicity of proteinuria hypothesis proposes that serum proteins or bound substances are toxic to tubular or tubulointerstitial cells. This sets up cycles of damage which lead to tubulointerstitial scarring. The podocyte loss hypothesis contends that proteinuria is simply a biomarker for damaged or dying podocytes, and that it is further podocyte loss that leads to progressive glomerulosclerosis. Renoprotective strategies might have direct effects on podocytes. Importantly these different hypotheses suggest different therapeutic approaches to protecting the function of damaged kidneys. Differences between repair mechanisms may explain why some injuries lead to recovery and others to progressive disease, and may suggest new targets for protective therapy.
Proteinuria as a direct cause of progression
Authors: Hughes Jeremy
Published: November 2015

Proximal tubular cells reabsorb any filtered proteins during health via cell surface receptors such as megalin and cubulin so that very low levels of protein are present in the excreted urine. Significant proteinuria is a common finding in patients with many renal diseases. Proteinuria is a marker of glomerular damage and podocyte loss and injury in particular. The degree of proteinuria at presentation or during the course of the disease correlates with long-term outcome in many renal diseases. Proteinuria per se may be nephrotoxic and thus directly relevant to the progression of renal disease rather than simply acting as a marker of the severity of glomerular injury and podocytes loss.
Seminal studies used the atypical renal anatomy of the axolotl to instill proteins directly into the tubular lumen without requiring passage through the glomerulus. This indicated that tubular protein could be cytotoxic and induce interstitial inflammation and fibrosis in the peritubular region. Cell culture studies demonstrate that exposure to proteins results in proximal tubular cell activation and the production of pro-inflammatory and pro-fibrotic mediators. Proximal tubular cell death occurred in some studies reinforcing the potential of protein to exert cytotoxic effects via oxidative stress or endoplasmic reticulum stress. Analysis of renal biopsy material from both experimental studies using models of proteinuric disease or patients with various proteinuric diseases provided evidence of activation of transcription factors and production of chemokines and pro-inflammatory mediators by proximal tubular cells. These data strongly suggest that although proteinuria is the result of glomerular disease it also represents an important cause of progression in patients with chronic kidney disease associated with proteinuria.
Nephron numbers and hyperfiltration as drivers of progression
Authors: Luyckx Valerie A.
Published: November 2015

The relationship between low birth weight (LBW) and subsequent increased risk of hypertension and renal disease in humans is now well established. The initial hypothesis suggested that an adverse intrauterine environment, reflected by LBW, would impact renal development, resulting in a low nephron number and predisposition to hypertension and renal disease. Studies in various populations have shown a direct correlation between birth weight and nephron number, and in infants, nephron numbers are reduced in those of LBW. Among Caucasian and Australian Aboriginal adults, lower nephron numbers are associated with higher blood pressure, whereas higher nephron numbers appear to protect against hypertension. LBW is currently the best clinical surrogate for low nephron number and has been independently associated with higher blood pressure from infancy through to adulthood in many populations, as well as an increased risk of proteinuria, reduced glomerular filtration rate, chronic kidney disease, and end-stage renal disease in later life. The pathophysiology is analogous to that in other chronic kidney diseases where surviving nephrons are subject to hyperfiltration early on, resulting in glomerular hypertrophy, proteinuria, and eventually, especially in the setting of other renal disease risk factors, glomerulosclerosis, and loss of renal function.
Mean nephron number varies by up to 13-fold in certain populations, however, therefore nephron number is unlikely the sole developmentally programmed risk factor for renal disease in later life, but may be a first ‘hit’ impacting an individual’s susceptibility to or resistance to superimposed renal injury. Augmentation of nephron number perinatally has only been addressed in experimental settings.
In humans, therefore optimization of nephron number is likely best achieved through good perinatal care and adequate postnatal nutrition. Cardiovascular disease and diabetes are also developmentally programmed and therefore likely coexist in subjects with LBW and low nephron numbers. Awareness of an individual’s birth weight should serve to highlight the possibility of low nephron number and potential risk for future hypertension and renal disease, which may be attenuated by optimization of early nutrition, lifestyle choices, and management of other risk factors for renal disease.
Podocyte loss as a common pathway to chronic kidney disease
Authors: Kriz Wilhelm
Published: November 2015

Experimental studies show that podocyte death first causes focal scars, but beyond approximately 40% loss is lethal to a glomerulus. Podocytes have limited ability to regenerate, although some degree of replacement may occur from stem cells located near the urinary pole of Bowman’s capsule. It is not yet known whether this plays a significant part in ameliorating damage in disease processes. In one interpretation, foot process effacement may be seen as an adaptation by the podocyte to remain attached to the glomerular basement membrane after injury, at the expense of proteinuria. Podocyte dysfunction is closely associated with proteinuria, which in turn is strongly associated with progressive loss of glomerular filtration rate. Continuing podocyte damage and loss could therefore account for progressive renal disease. In this hypothesis, drugs that protect against progression of renal disease may have their primary protective effects on podocytes themselves, rather than or as well as on haemodynamic factors or on fibrotic processes.
Choices and considerations for in-centre versus home-based renal replacement therapy
Authors: Tennankore Karthik K. , Chan Christopher T.
Published: November 2015

There has been a renewed global interest in expanding home dialysis (both peritoneal dialysis (PD) and home haemodialysis (HHD)), but the majority of patients are maintained on in-centre haemodialysis (HD). While the importance of in-centre haemodialysis cannot be overlooked, home dialysis has many advantages. If so, why are so few patients maintained on home dialysis therapies?
From the perspective of the patient, both inadequate modality education and self-perceived barriers limit selection of home dialysis. Physicians are less likely to consider elderly frail patients as candidates for home therapies. In addition, inadequate training and poor reimbursement for home dialysis are important physician barriers.
From the facility perspective, the limited availability of personnel and physical resources to maintain a home unit are important barriers. However, while there are many obstacles to home dialysis, they can be overcome. Improved patient education, home support for elderly dialysis patients, and financial incentives may be effective measures. In addition, at the facility level, an emphasis needs to be placed on infrastructure development. Overall, while the appropriate balance of in-centre versus home-based renal replacement therapy has not been determined, maximizing the number of patients on home therapies is a reasonable target.
The patient with amyloidosis
Authors: Lachmann Helen J. , Merlini Giampaolo
Published: November 2015

Amyloidosis is a disorder of protein folding in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal insoluble fibrillar form. The process of amyloid formation and deposition causes cytotoxicity and progressive organ dysfunction. Amyloid is remarkably diverse and can be hereditary or acquired, localized or systemic, and lethal or merely an incidental finding. The most important numerically are AL amyloidosis, in which the fibrils are composed of monoclonal immunoglobulin light chains, and AA amyloidosis, in which the acute phase reactant Serum Amyloid A component forms the fibrils.

The kidney is involved in 75% of patients with systemic amyloidosis. Heavy proteinuria or nephrotic syndrome is characteristic of most amyloid variants.

Without treatment, systemic disease is usually fatal but measures that reduce the supply of amyloid fibril precursor proteins can result in regression of amyloid deposits, prevention of organ failure, and improved quality of life and survival. Early diagnosis, before irreversible organ damage has occurred, is the key to effective treatment. Recent advances in diagnosis and therapy have much improved the outlook of patients with AL amyloidosis, but agents with broader promise are under investigation.
The obese patient (metabolic syndrome)
Authors: Korkeila Maarit , Lindholm Bengt , Stenvinkel Peter
Published: November 2015

Overweight and obesity cause pathophysiological changes in renal function and increase the risk for chronic kidney disease in otherwise healthy subjects. This should not be a surprise as the risk factors for metabolic syndrome largely overlap with those for chronic kidney disease. Intentional weight loss has beneficial effects on risk factors, but long term effects are less clear. Bariatric surgery does seem to achieve rapid benefits on blood pressure and proteinuria as well as on other aspects of metabolic syndrome, but its long term implications for kidney function are less clear cut as there may be an increased risk of nephrolithiasis, and possibly AKI and other complications.

Obesity in haemodialysis patients is one of those paradoxical examples of reverse epidemiology where a factor associated with negative outcomes in the general population is associated with better outcomes in dialysis patients. The same is true for high blood cholesterol values. Interpretation is complicated by complex competing outcomes and confounders.
Kidney/ear syndromes
Authors: Goodyer Paul
Published: November 2015

Malformations of the external ear may signal renal disease, but it is actually the disorders of the inner ear which reflect molecular pathways that are also crucial for kidney development. In a number of monogenic renal diseases, renal dysplasia is associated with deafness. Disorders of the kidney and inner ear are also linked in complex syndromes such as the human ciliopathies. In some cases, the loss of specific genes affects shared transport physiology, basement membrane assembly, or energy metabolism.

The kidney and cochlea have a common susceptibility to toxins that are selectively concentrated by comparable uptake mechanisms in the two tissues.

This chapter provides an overview of the many ways in which pathologies of the two organs are linked.
Urinary tract infection in a patient with a kidney transplant
Authors: Harber Mark
Published: November 2015

Urinary tract infection is the commonest bacterial infection and cause of septicaemia post kidney transplant, accounting for 40–50% of all infectious post-transplant complications. The risk of a urinary tract infection post transplant is very high with most studies recording at least 50%, and rates as high as 86% have been reported. Clinically overt urinary tract infections are a major cause of morbidity post transplant and are associated with worse graft outcome and increased mortality. This chapter discusses the epidemiology, aetiology, pathology, clinical presentation, investigations, consequences, treatment, and prophylaxis of post-transplant urinary tract infections.
Leptospirosis
Authors: Burdmann Emmanuel A.
Published: November 2015

Leptospirosis is one of the most prevalent zoonotic diseases worldwide. Pathogenic spirochaetes are shed in the urine of infected mammals to the environment. Humans are infected through contact with contaminated material. Leptospirosis is more prevalent in tropical and subtropical areas, but exists in all continents except Antarctica. The disease is difficult to diagnose and hence frequently neglected. Its clinical picture ranges from a mild flu-like disease to a life-threatening form with pulmonary haemorrhage, liver failure and acute kidney injury (AKI), called Weil disease, which may affect 10% of those with clinical disease. Typically, fever, myalgia and headache progress to nausea and vomiting, jaundice, red eyes, and other manifestation affecting skin, brain, and other organs.

Kidney involvement, characterized by acute tubulointerstitial nephritis, is nearly universal. It may be clinically manifested as a tubulopathy with urinary electrolytes wasting, hypokalaemia and hypomagnesaemia and/or as AKI, which is more frequently non-oliguric. Antibiotic therapy may reduce hospitalization time and AKI frequency. Otherwise management is supportive, including timely and adequate dialysis support.
Mycobacterial infections
Authors: Eastwood John , Corbishley Cathy , Grange John
Published: November 2015

Mycobacterium leprae, the causative agent of leprosy, is one of over a hundred species of Mycobacteria. The many other species are environmental saprophytes, present particularly in free and piped water sources, and some species are causes of opportunist disease in humans, especially in those who are immune compromised.

In 2009, world-wide notifications of leprosy amounted to 244,796 new cases, a significant fall compared with 514,718 in 2003. Elimination of leprosy as a public health problem, defined as a prevalence of registered cases of under 1 per 10,000 population, has been achieved in many countries where leprosy was once highly endemic, and most others are close to reaching this stage.

Direct bacterial invasion of the kidney is rare in leprosy but renal amyloidosis and various forms of glomerulonephritis are common, especially those with multibacillary forms of the disease.

Renal disease due to environmental mycobacteria is very rare but as these bacteria are frequently present as contaminants of the lower urethra and external genitalia, care is required to distinguish disease from contamination of urine samples.

The risk of generalized disease due to environmental mycobacteria is increased by any form of immune compromise including renal failure and post-renal transplant immunosuppression.
Renal artery stenosis
Authors: Ritchie James , Green Darren , Chrysochou Constantina , Kalra Philip A.
Published: November 2015

Renovascular disease refers to a narrowing of a main or branch renal artery. Consequences include loss of functional renal tissue and renovascular hypertension, with other manifestations depending on the underlying cause. Worldwide the most common cause is atherosclerotic narrowing, with other causal pathologies including fibromuscular disease (FMD) and inflammatory conditions. FMD occurs much more frequently in women than in men, and is associated with smoking but genetic predisposing factors are also suspected. In South East Asia, Takayasu arteritis is an important cause.

Takayasu disease often presents in a non-specific syndromic manner with fatigue and malaise. FMD often presents with early-onset hypertension. Atherosclerotic renal artery stenosis is often clinically silent with suspicion raised due to the existence of other cardiovascular pathology with the more dramatic presentations of acute decompensated heart failure or acute kidney injury less common. Clinical criteria can identify patients at risk.
Fluid overload in acute kidney injury
Authors: Jörres Achim , Hasper Dietrich , Oppert Michael
Published: November 2015

A central objective in the management of acute kidney injury is the restoration and maintenance of adequate systemic and renal perfusion, often requiring the parallel administration of fluids and vasoactive drugs. However, hypovolaemia and fluid overload may both predispose the patient to complications and poor outcomes. Therefore, body weight and daily fluid intake/output should be recorded, patients should continuously be assessed for clinical signs of under- or over-hydration, and adequate monitoring of haemodynamic parameters should be performed. Together these parameters constitute the basis for individualized fluid therapy that needs to be initiated promptly and should be re-evaluated at least on a daily basis.
Continuous renal replacement therapy
Authors: Schetz Miet , Davenport Andrew
Published: November 2015

After its introduction, continuous renal replacement therapy (CRRT) has found widespread acceptance amongst physicians taking care of critically ill patients. Various modalities (haemofiltration, haemodialysis, haemodiafiltration) are used. As for all types of renal replacement therapy, a good functioning vascular access is an absolute requirement. Whether CRRT is to be preferred over intermittent haemodialysis remains a matter of debate, but haemodynamic instability and risk of cerebral oedema are generally considered indications for CRRT. Whereas under-dosing should certainly be avoided, increasing the dose over an actually delivered effluent flow of 20–25 mL/kg/hour does not appear to improve outcome.

One of the major drawbacks of CRRT is the requirement for continuous anticoagulation. Citrate anticoagulation is gaining popularity and represents a valuable alternative, especially in patients with bleeding risk. Other potential complications of CRRT include thermal, nutrient, and drug losses, and acid–base and electrolyte disturbances.