bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacologic Stress Testing
Authors: Gupta Ankur , Zoghbi Gilbert J. , Hage Fadi G.
Published: November 2015

Pharmacological stress testing plays an important role in patient management. Pharmacologic stress agents (adenosine, dipyridamole, regadenoson, dobutamine) produce coronary hyperemia, which is at least as high as that achieved by maximal exercise, by a completely different set of mechanisms than that achieved during exercise. Regadenoson, a relatively newer agent, offers ease of administration and fewer side effects than older stress agents and has become the agent of choice in many stress laboratories. The choice of the stress agent should be individualized based on its indications, contraindications and safety profile. The diagnostic accuracy of pharmacological stress testing for significant coronary artery disease detection is comparable to or exceeds that of exercise myocardial perfusion imaging.
Clinical assessment of the patient with renal disease
Authors: Winearls Christopher G.
Published: November 2015

As an overview of chapters covering presentation, history and examination of patients with kidney disease, this chapter lists reasons for referral, necessity for involvement of a nephrologist, and a general approach.
Kidney disease-focused history taking
Authors: Winearls Christopher G.
Published: November 2015

Each referral must be approached with an open mind. No assumptions should be made and every statement should be checked. One should not believe or disbelieve what has been asserted. It is important to note the history of the presenting case. This involves a detailed exploration of the onset, duration, progression, alleviating and aggravating features, and associated symptoms.
Kidney disease-focused features on examination
Authors: Winearls Christopher G.
Published: November 2015

Examination depends on the context and clinical presentation and the emphasis will be different too. Tell-tale signs are often unnoticed in the general examination of the eyes (lecithin cholesterol acyltransferase deficiency, Fabry disease, corneal calcification), the skin (vasculitis, Anderson–Fabry disease), the optic fundus (haemorrhages and exudates, papilloedema), and the hands (nail patella syndrome, splinter haemorrhages of systemic lupus erythematosus, and subacute bacterial endocarditis). Many of these are illustrated.
The regular review of patients on dialysis or with a kidney transplant is also considered.
Urinalysis
Authors: Mutter Walter P.
Published: November 2015

Physicians have examined urine for over 6000 years. Urine microscopy was first employed to diagnose kidney disease in the seventeenth century and remains an indispensable tool. The value of urinalysis for diagnosis and management of renal and genitourinary disease is well accepted. Urinalysis aids in the diagnosis of renal disease especially in cases when a renal biopsy is not immediately available or is contraindicated. It is most informative when done by the treating physician with knowledge of the clinical context. Inspection is done by eye. Routine chemical analysis is done by dipstick but urine microscopy is essential for it may reveal abnormalities even when chemical evaluation is normal. Dysmorphic red cells, red cell casts, white blood cells, renal cells, and specific crystals may be diagnostically important. Urinalysis and microscopy can narrow the differential diagnosis faster than many more complex tests are able to.
Tubular function
Authors: Speeckaert Marijn , Delanghe Joris
Published: November 2015

Assessment of tubular function is more complicated than the measurement of glomerular filtration rate. Different functions may be affecting according to the different segments of tubule involved. Key tests include concentrating and diluting capacity, and fractional excretion of sodium.
Tubular proteinuria occurs when glomerular function is normal, but when the proximal tubules have a diminished capacity to reabsorb and to catabolize proteins, causing an increased urinary excretion of the low-molecular-mass proteins that normally pass through the glomerulus.
Proximal tubular dysfunction is characterized by hypophosphataemia, and a variety of other abnormalities characteristics of the renal Fanconi syndrome. Distinguishing the location of the lesion in Renal Tubular Acidosis is considered in Chapter 35.
Clinical trials
Authors: Haynes Richard , Landray Martin J. , Herrington William G. , Baigent Colin
Published: November 2015

Randomized trials are the best method for identifying and quantifying the benefits and risks of interventions in clinical practice. Nephrology lags behind most specialties in medicine in its evidence base.
Many commonly used therapies are untested and may be ineffective or even cause harm. For trials to provide reliable answers to important clinical questions they must first avoid two sources of error. Firstly, systematic error (or bias) can only be removed by proper randomization. Secondly, random error (the play of chance) can only be removed by the randomization of large numbers of patients (and therefore the accrual of large numbers of trial outcomes).
Following successful large-scale randomization, it is critical that patients’ compliance with their allocated treatment is maintained, relevant study outcomes are systematically ascertained, and appropriate statistical analyses are performed. There is an urgent need to conduct such trials to address the many important clinical questions in nephrology.
An overview of tubular function
Authors: Bailey Matthew A.
Published: November 2015

This chapter provides an overview of transport processes, describing both the membrane proteins that effect transepithelial solute flux and the systems that allow integrated regulation of electrolyte transport. The emphasis is on the physiological mechanisms but links to human diseases are made in order to illuminate fundamental principles of control. The key transport proteins and encoding genes are listed.
First, the major transport pathways and regulatory features for each nephron segment are described. The focus here is on the transepithelial flux of sodium, potassium, and water.
In the second part, other important aspects of renal homeostasis, including urine concentration and acid–base balance, are summarized.
Calcium homeostasis
Authors: Trepiccione Francesco , Capasso Giovambattista
Published: November 2015

Ca2+ homeostasis is achieved through a fine balance among three main organs: the intestine, the kidney, and bone. Blood levels of Ca2+ are accurately tuned through the Ca2+ sensing receptors and regulated by several hormones, including parathyroid hormone (PTH), active vitamin D, and calcitonin.
The most recent findings in Ca2+ handling are described. The role of the Ca2+ sensing receptor, as well as Klotho, a new player participating in Ca2+ homeostasis, are described. Finally, the effects of diuretics, calcineurin inhibitors, and the link between hypertension and Ca2+ metabolism are reviewed.
Approach to the patient with renal tubular acidosis
Authors: Walsh Stephen B.
Published: November 2015

The renal tubular acidoses are a collection of syndromes characterized by defective urinary acidification. These syndromes have classically caused some confusion, and many opine that the widely used numerical system (type 1, 2) should be abandoned. We consider distal renal tubular acidosis and proximal renal tubular acidosis separately, and briefly cover hypoaldosteronism.
Distal (Type 1) renal tubular acidosis is a syndrome of hypokalaemia, metabolic acidosis, kidney stones, nephrocalcinosis, and osteomalacia or rickets. It is caused by failure of the acid secreting α‎‎‎-intercalated cells in the distal nephron.
Proximal (Type 2) renal tubular acidosis is a syndrome of metabolic acidosis that is almost always accompanied by the Fanconi syndrome of glycosuria, phosphaturia, uricosuria, aminoaciduria, and low-molecular-weight proteinuria. It is caused by a failure of bicarbonate reabsorption by the proximal tubular cells.
Type 3 or mixed renal tubular acidosis, as originally described, has vanished (or was originally incompletely described). It is sometimes used to describe a mutation of carbonic anhydrase II, which causes both proximal and distal renal tubular acidosis, as well as cerebral calcification and osteopetrosis.
Type 4 or hypoaldosteronism is a syndrome of hyperkalaemia and mild metabolic acidosis. It is due to a lack of aldosterone or resistance to its action.
The glomerulus and the concept of glomerulonephritis
Authors: Woywodt Alexander , Chiu Diana
Published: November 2015

The key features of glomerular diseases—haematuria, proteinuria, loss of glomerular filtration rate, and hypertension—were recognized in the nineteenth century, and some earlier, but Richard Bright is usually given credit for synthesizing the concepts of renal disease, and glomerulonephritis came under the heading of Bright’s disease for almost a century. Separation into different types was based on first clinical syndromes, but in the early twentieth century, pathological description was improving and with the introduction of percutaneous renal biopsies in the 1950s, in the 1960s histopathological definitions assumed the ascendancy. A unifying classification of glomerular disease remains work in progress.
Current classifications are pathologically based but increasingly include the results of other investigations (including genotype and a variety of immunological and other tests). This chapter follows this pragmatic, hybrid approach, categorizing glomerular disease by pattern on renal biopsy except where aetiological factors are clearly identified (e.g. HIV nephropathy), or associated multisystem disease is defined (e.g. lupus nephritis), or the immunopathogenesis is well characterized (e.g. antiglomerular basement membrane disease).
The renal glomerulus
Authors: Elger Marlies , Kriz Wilhelm
Published: November 2015

The glomerulus performs its functions with three major cell types. Endothelial cells and visceral epithelial cells (podocytes) lie on the inside and outside of the glomerular basement membrane, and together these three structures form the glomerular filtration barrier. Mesangial cells sit in the axial region. Pathologies of all these regions and cell types can be identified. Parietal epithelial cells lining Bowman’s capsule participate in crescent formation, and at the tubular pole some of these cells seem to represent a stem cell population for tubular cells and podocytes. The extraglomerular mesangium and juxtaglomerular apparatus complete the description of the glomerular corpuscle.
The structure of these elements, and how they relate to function, are illustrated in detail.
Postural proteinuria (benign orthostatic proteinuria)
Authors: Turner Neil
Published: November 2015

Postural proteinuria, synonymous with the condition known as benign orthostatic proteinuria, describes increased levels of protein excretion associated with normalization first thing in the morning. It is usually diagnosed in children, for whom it is the most common explanation for proteinuria picked up incidentally on dipstick testing. In children, it generally resolves with age and is thought to have a benign long-term prognosis, with the caveat that numbers with very long follow-up times are few. It is also seen in teenagers but becomes much less common in early adulthood.
Its aetiology is not well understood, although patients with pathological causes for proteinuria and patients with physiological levels of total protein excretion have been shown to exhibit similar diurnal variation. Using currently published limits for daily protein excretion the diagnosis is common. Some examples have been attributed to nutcracker syndrome (compression of the left renal vein), although that is more commonly associated with macroscopic haematuria, and the association remains uncertain.
The condition is best diagnosed by comparing first-in-morning urine samples paired with afternoon samples on several occasions. In childhood, if proteinuria levels are in the normal range in morning samples, and within moderately increased limits later in the day, probably no investigation beyond observation is required.
Most will resolve; very few will evolve into serious renal disease. The simplest mode of long-term monitoring is to measure protein:creatinine or albumin:creatinine ratios in first-in-morning urine samples.
Secondary membranous glomerulonephritis
Authors: Cattran Daniel C. , Reich Heather N.
Published: November 2015

Primary (autoimmune) disease accounts for at least 70% of membranous glomerulonephritis (MGN). The main causes of secondary MGN are lupus, hepatitis B, drugs, and malignancy. Other autoimmune or inflammatory diseases, and some infections, are associated with it less commonly.
Crescentic (rapidly progressive) glomerulonephritis
Authors: Turner Neil
Published: November 2015

Crescent formation refers to the appearance of proliferating cells in Bowman’s space in response to severe glomerular inflammation. Any aggressive ‘nephritic’ diseases that cause basement membrane breaks may provoke this. Specific serum proteins appear to be responsible for provoking crescent formation as it is largely abolished by defibrination in animal models.
The cells in the crescent are initially mostly hypertrophying and proliferating parietal epithelial cells that normally line Bowman’s capsule. Foci of proliferation of these cells (extracapillary proliferation) are the first steps of crescent formation. Monocytes are frequently seen in established crescents. At this stage recovery of glomerular structure and function is possible in many circumstances. However, if Bowman’s capsule is ruptured, fibroblast ingress followed by fibrosis and glomerulosclerosis are likely.
Crescentic nephritis is a histological description, but it fits closely with the clinical picture of rapidly progressive glomerulonephritis (RPGN), in which renal function is lost over days to weeks. The diseases most likely to cause this clinical picture are small vessel vasculitis, anti-GBM disease, lupus nephritis, and post-infectious glomerulonephritis. Any ‘nephritic’ disease may provoke crescent formation, but it is frequently encountered in immunoglobulin A nephropathy/Henoch–Schönlein purpura, and in post-infective glomerulonephritis.
Recognizing the clinical picture is important as aggressive immunosuppression can be effective in saving glomerular function in some of the conditions causing it.
Post-infectious glomerulonephritis
Authors: Rodriguez-Iturbe Bernardo , Haas Mark
Published: November 2015

Post-infectious glomerulonephritis (GN) defines an inflammatory lesion involving exclusively or predominantly the glomeruli that is a consequence of an infectious disease. There are numerous bacterial, viral, and fungal infections associated with GN. This chapter acts as an overview of the following chapters that discuss only post-streptococcal GN, immunoglobulin A-dominant GN associated with staphylococcal infections, GN associated with bacterial endocarditis, with infected ventriculoatrial shunts (‘shunt nephritis’), and GN associated with deep-seated infections (osteomyelitis, visceral abscesses, pleural suppuration, pneumonia).
Drug-induced acute tubulointerstitial nephritis
Authors: Izzedine Hassan , Gueutin Victor
Published: November 2015

Drug-induced acute tubulointerstitial nephritis (ATIN) is the most common aetiology of ATIN and a potentially correctable cause of acute kidney injury (AKI). An interval of 7–10 days typically exists between drug exposure and development of AKI, but this interval can be considerably shorter following re-challenge or markedly longer with certain drugs. It occurs in an idiosyncratic and non-dose-dependent manner. Antibiotics, NSAIDs, and proton pump inhibitors are the most frequently involved agents, but the list of drugs that can induce ATIN is continuously increasing.
The mechanism of renal injury is postulated to involve cell-mediated immunity, supported by the observation that T cells are the predominant cell type comprising the interstitial infiltrate. A humoral response underlies rare cases of ATIN, in which a portion of a drug molecule (i.e. methicillin) may act as a hapten, bind to the tubular basement membrane (TBM), and elicit anti-TBM antibodies.
The classic symptoms of fever, rash, and arthralgia may be absent in up to two-thirds of patients. Diagnostic studies, such as urine eosinophils and renal gallium-67 scanning provide only suggestive evidence. Renal biopsy remains the gold standard for diagnosis, but it may not be required in mild cases or when clinical improvement is rapid after removal of an offending medication. Pathologic findings include interstitial inflammation, oedema, and tubulitis.
The time until removal of such agents and the severity of renal biopsy findings provide the best prognostic value for the return to baseline renal function. Poor prognostic indicators are the long duration of AKI (> 3 weeks), a patient’s advanced age, and the high degree of interstitial fibrosis. Early recognition and appropriate therapy are essential to the management of drug-induced ATIN, because patients can ultimately develop chronic kidney disease. The mainstay of therapy is timely discontinuation of the causative agent, whereas controversy persists about the role of steroids.
Chronic kidney disease
Authors: Upadhyay Ashish , Inker Lesley A. , Levey Andrew S.
Published: November 2015

The conceptual model, definition, and classification of chronic kidney disease (CKD) were first described in the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines in 2002 and have had a major impact on patient care and research. Since this publication there has been an increased recognition that the cause of CKD influences progression and complications. In addition, epidemiologic reports from diverse populations have consistently shown graded relations between higher albuminuria and adverse kidney outcomes and complications, in addition to, and independent of, low GFR. Given these new understanding in risk relationships, Kidney Disease Improving Global Outcomes (KDIGO) updated the original guidelines in 2012. The updated guidelines retain the KDOQI definition of CKD, but recommend classifying CKD by the cause, level of GFR, and level of urinary albumin to creatinine ratio. Specialized nephrology care is recommended for severe reduction in GFR or high albuminuria, uncertain diagnosis, or difficult to manage complications.
Chronic kidney disease in the developed world
Authors: Grams Morgan E. , Coresh Josef
Published: November 2015

Chronic kidney disease is common, increasing in prevalence, and associated with significant morbidity and mortality. A disease of multiple and complex aetiologies, chronic kidney disease is more prevalent among elderly, hypertensive, and diabetic persons—all growing segments of the developed world. This chapter discusses trends in and determinants of chronic kidney disease prevalence, incidence, and prognosis. In addition, advances in chronic kidney disease staging and reporting as well as the discovery of a major genetic locus for hypertensive kidney disease in populations of African ancestry are examined.
Sudden cardiac death in chronic kidney disease
Authors: Hajhosseiny Reza , Khavandi Kaivan , Goldsmith David J.
Published: November 2015

Epidemiological data demonstrate the unique vulnerability of chronic kidney disease (CKD) subjects to cardiovascular disease, the most catastrophic being sudden cardiac death (SCD). In patients with declining kidney function there is a continuum of cardiovascular risk. In those individuals who survive to reach end-stage renal disease (ESRD), the risk of suffering a cardiac event is extremely high. Some of this risk is explained by the common risk factors and traditional cardiovascular events, namely atherosclerotic plaque fissure and rupture, but there is now evidence of a distinct ‘later CKD’ mechanism, notably arrhythmias. This appears particularly true in later stages of CKD and corresponds with the multifaceted range of myocardial and vascular insults operating. The physiological milieu of disordered vessel autoregulation, sequestered vasoprotective agents, loss of conduit and small artery elasticity/compliance, a stiffened and fibrotic myocardium, with calcified and diseased coronary arteries, all within an inflammatory environment, all contribute to arrhythmia generation. The final insult is changes in volume and electrolyte status.
Risk stratification tools would be helpful in guiding clinicians to recognize those subjects likely to benefit from specific interventional strategies. These might include the novel, or emerging serum, haemodynamic, or electrocardiographic biomarkers in CKD. Current tools—such as those used for stratifying risk for SCD and determining the need for ICD implantation—are not valid in ESRD patients.
Beta blockers appear likely to be generally advisable, blood pressure permitting, for patients with significant cardiomyopathy. Evidence for implantable cardiac defibrillators (ICD) is lacking. There is good reason to think that young dialysis patients at high risk of sudden death may benefit, but the risk/benefit ratio for older patients is less likely to be advantageous. These hypotheses need further investigation.
Oxidative stress and its implications in chronic kidney disease
Authors: Vaziri Nosratola D.
Published: November 2015

Reactive oxygen species (ROS) are produced at low levels physiologically and their production conveys signals and has specific functions. Control mechanisms ensure that this does not cause damage. ROS are highly reactive and cytotoxic and are also deliberately produced by inflammatory cells (granulocytes, macrophages) to kill pathogens. If these chemicals are released inappropriately or excessively, or if control mechanisms are under-functioning, bystander or unintended tissue damage may be caused.
The concept of oxidative stress is based on the idea that in certain states, commonly inflammatory states, release of oxygen radicals may be excessive, or control mechanisms weakened, so that tissue damage occurs. In CKD, both overproduction and diminished control may apply. No effective therapies acting via these pathways have been established so far though there remain some candidates.
Abnormal endothelial vasomotor and secretory function
Authors: Speer Thimoteus , Fliser Danilo
Published: November 2015

The endothelium plays a crucial role in the maintenance of vascular integrity and function. Nitric oxide produced by endothelial cells is a key player, inducing relaxation of vascular smooth muscle cells, inhibition of vascular inflammation, and prevention of coagulatory activation. Chronic kidney disease (CKD) is characterized by deterioration of different protective endothelial properties, collectively described as endothelial dysfunction. Several factors such as methylarginines, modified lipoproteins, and other substances that accumulate may be involved in the pathogenesis of endothelial dysfunction of CKD. Endothelial dysfunction is suggested to be the first critical step in the initiation of atherosclerosis. Clinical assessment of endothelial function may become important in recognition of patients with increased cardiovascular risk. Beside several invasive and non-invasive methods to assess endothelial function in vivo, measurement of circulating (bio)markers may be useful for the evaluation of endothelial dysfunction.
Imaging for detection of vascular disease in chronic kidney disease patients
Authors: Raggi Paolo , D’Marco Luis
Published: November 2015

The well-known severity of cardiovascular disease in patients suffering from chronic kidney disease (CKD) requires an accurate risk stratification of these patients in several clinical situations. Imaging has been used successfully for such purpose in the general population and it has demonstrated excellent potential among CKD patients as well. Two main forms of arterial pathology develop in patients with CKD: atherosclerosis, with accumulation of inflammatory cells, lipids, fibrous tissue and calcium in the subintimal space, and arteriosclerosis. The latter is characterized by accumulation of deposits of hydroxyapatite and amorphous calcium crystals in the muscular media of the vessel wall, and is believed to be more closely associated with alterations of mineral metabolism than with traditional atherosclerosis risk factors. The result is the development of what appears to be premature arterial ageing, with loss of elastic properties, increased stiffness, and increased overall fragility of the arterial system. Despite intensifying research and increasing awareness of these issues, the underlying pathophysiology of the aggressive vasculopathy of CKD remains largely unknown. As a consequence, there are currently very limited pathways to prevent progression of vascular damage in CKD. The indications, strengths and weaknesses of several imaging modalities employed to evaluate vascular disease in CKD are described, focusing on coronary arterial circulation and the peripheral arteries, with the exclusion of the intracranial arteries.
Fibroblast growth factor 23, Klotho, and phosphorus metabolism in chronic kidney disease
Authors: Gutiérrez Orlando M.
Published: November 2015

Fibroblast growth factor 23 (FGF23) and Klotho have emerged as major hormonal regulators of phosphorus (P) and vitamin D metabolism. FGF23 is secreted by bone cells and acts in the kidneys to increase urinary P excretion and inhibit the synthesis of 1,25 dihydroxyvitamin D (1,25(OH)2D) and in the parathyroid glands to inhibit the synthesis and secretion of parathyroid hormone. Phosphorus excess stimulates FGF23 secretion, likely as an appropriate physiological adaptation to maintain normal P homeostasis by enhancing urinary P excretion and diminishing intestinal P absorption via lower 1,25(OH)2D. The FGF23 concentrations are elevated early in the course of chronic kidney disease (CKD) and may be a primary initiating factor for the development of secondary hyperparathyroidism in this setting. Klotho exists in two forms: a transmembrane form and a secreted form, each with distinct functions. The transmembrane form acts as the key co-factor needed for FGF23 to bind to and activate its cognate receptor in the kidneys and the parathyroid glands. The secreted form of Klotho has FGF23-independent effects on renal P and calcium handling, insulin sensitivity, and endothelial function. Disturbances in the expression of Klotho may play a role in the development of altered bone and mineral metabolism in early CKD. In addition, abnormal circulating concentrations of both FGF23 and Klotho have been linked to excess cardiovascular disease, suggesting that both play an important role in maintaining cardiovascular health.
Fractures in patients with chronic kidney disease
Authors: Hutchison Alastair J. , Picton Michael L.
Published: November 2015

Patients with any degree of chronic kidney disease (CKD) have a much higher risk of fractures than the general population, and the risk of death at 1 year post hip fracture in a dialysis patient is over 60%, compared to less than 20% for a non-CKD patient. The assessment of fracture risk and diagnosis of the underlying skeletal pathology in CKD patients is a significant clinical challenge. Non-invasive imaging techniques are not totally reliable in the general population, and the presence of advanced CKD (stages 4, 5, and 5D) renders them largely useless. Bone strength is not determined only by quantity of bone, and renal osteodystrophy can significantly affect bone quality, rendering it liable to fracture even in the presence of a normal bone density measurement. Currently, the only reliable method of assessing both quantity and quality of bone is the examination of trans-iliac bone biopsy, which is generally, but probably incorrectly, perceived to be overly invasive. However, identifying the cause of reduced bone strength and fractures may influence the choice of therapy. For example, in the presence of low-turnover states such as adynamic bone, antiresorptive agents may be ineffective. Pharmaceuticals licensed for the treatment of osteoporosis in the general population can be used similarly in patients with CKD 1–3 without dosage alteration. In CKD 4, post-hoc analyses suggest denosumab is effective and safe, based on a 3-year study that included 73 such patients. In CKD 5 and 5D no dependable data exists to guide therapy, and it should probably be reserved for patients who have already suffered and survived a fracture, and are therefore at high risk of death from a second event.
Clinical aspects and overview of renal anaemia
Authors: Macdougall Iain C.
Published: November 2015

Anaemia is an almost ubiquitous complication of chronic kidney disease, which has a number of implications for the patient. It is associated with adverse outcomes, an increased rate of red cell transfusions, poor quality of life, and reduced physical capacity. Severe anaemia also impacts on cardiac function, as well as on platelet function, the latter contributing to the bleeding diathesis of uraemia.
Renal anaemia occurs mainly in the later stages of chronic kidney disease (stages 3B, 4, and 5), and up to 95% of patients on dialysis suffer from this condition. It is caused largely by inappropriately low erythropoietin levels, but other factors such as a shortened red cell survival also play a part.
The anaemia is usually normochromic and normocytic, unless concomitant iron deficiency is present. The latter is also common in renal failure, partly due to low dietary iron intake and absorption, and partly due to increased iron losses.
Prior to the 1990s, treatment options were limited, and many patients (particularly those on haemodialysis) required regular blood transfusions, resulting in iron overload and human leucocyte antigen sensitization. Correction of anaemia requires two main treatment strategies: increased stimulation of erythropoiesis, and maintenance of an adequate iron supply to the bone marrow. Ever since the introduction of recombinant human erythropoietin, it has been possible to boost erythropoietic activity, and both oral and intravenous iron products are available to provide supplemental iron.
In dialysis patients, oral iron is usually poorly absorbed due to upregulation of hepcidin activity, and intravenous iron is often required.
The physiological processes relevant to red cell production are described, as well as the prevalence, characteristics, pathogenesis, and physiological consequences of renal anaemia.
Iron management in renal anaemia
Authors: Macdougall Iain C.
Published: November 2015

Although erythropoiesis-stimulating agent therapy is the mainstay of renal anaemia management, maintenance of an adequate iron supply to the bone marrow is also pivotal in the process of erythropoiesis. Thus, it is important to be able to detect iron insufficiency, and to treat this appropriately. Iron deficiency may be absolute (when the total body iron stores are exhausted) or functional (when the total body iron stores are normal or increased, but there is an inability to release iron from the stores rapidly enough to provide a ready supply of iron to the bone marrow). Several markers of iron status have been tested, but those of the greatest utility are the serum ferritin, transferrin saturation, and percentage of hypochromic red cells. Measurement of serum hepcidin, which is the master regulator of iron homoeostasis, has to date proved disappointing as a means of detecting iron insufficiency, and none of the available iron markers reliably exclude the need for supplemental iron.
Iron may be replaced by either the oral or the intravenous route. In the advanced stages of chronic kidney disease, however, hepcidin is upregulated, and this powerfully inhibits the absorption of iron from the gut. Thus, such patients often require intravenous iron, particularly those on dialysis. Several intravenous (IV) iron preparations are available, and they have in common a core containing an iron salt, surrounded by a carbohydrate shell. The IV iron preparations differ in their kinetics of iron release from the iron–carbohydrate complex. In recent times, several new IV iron preparations have become available, and these allow a greater amount of iron to be given more rapidly as a single administration, without the need for a test dose.
Cutaneous manifestations of end-stage renal disease
Authors: Galperin Timur A. , Leslie Kieron S. , Cronin Antonia J.
Published: November 2015

A broad range of skin diseases occur in patients with end-stage renal disease. Some of these conditions are benign, and make little impact on patients’ lives. Others, however, have a greater impact on quality of life, may be physically disabling, and even life-threatening. Mostly, they result from a combination of factors, such as electrolyte imbalance and co-morbid disease. Uraemic pruritus is the most commonly troublesome and an approach to it is presented. Other non-specific skin manifestations of CKD include skin-colour changes, xerosis, half-and-half nails
Specific manifestations include acquired perforating dermatosis, bullous dermatoses, metastatic calcification, and nephrogenic systemic fibrosis. Pathophysiology, clinical presentation, diagnosis, and treatment options are discussed.
The patient with reduced renal function
Authors: Thor Agustsson Tomas , Carroll Paul
Published: November 2015

Although advances in biochemistry, physiology, cell biology, molecular biology, and genetics have explained many of the mechanisms of endocrine disease and hormone function, the essential subject of endocrinology remains the same—the signaling, by secreted substances, which control and coordinate the function of multiple organs and processes. These processes affect both the precise short-term control of whole body homeostasis and longer-term adaptation and developmental changes.
Health-related quality of life and the patient with chronic kidney disease
Authors: Finkelstein Fredric O. , Finkelstein Susan H.
Published: November 2015

The association of various health-related quality of life (HRQOL) measures with patient morbidity and mortality is well documented, but attention is now being directed at HRQOL assessments as primary outcomes measures themselves. A variety of instruments have been suggested to assess the HRQOL of patients, encompassing a variety of domains. Instruments that are used include generic, disease-specific, and symptom specific instruments. These instruments reply on both subjective and objective information to document the difficulties presented by both the disease itself as well as the treatment of the disease. The challenge for the nephrology community is how to incorporate these assessments into routine care. Additional research needs to be done concerning the optimal way to document patients’ perceptions of their HRQOL and then to develop treatment strategies to improve patients’ perceptions of their quality of life and their care.
Conservative care in advanced chronic kidney disease
Authors: Burns Aine , Murtagh Fliss E. M.
Published: November 2015

Increasing numbers of those with stage 5 chronic kidney disease are older, with multiple co-morbid conditions. There is growing awareness that, while dialysis may provide some survival advantage in this population, there is major disease and treatment burden associated with dialysis, and considerable impact on quality of life. Conservative (non-dialysis) management pathways are therefore increasingly being developed and studied, and more is known about the best ways to optimize quality of life for those managed without dialysis.
In low- and middle-income countries, the resources for dialysis are frequently limited and conservative management is often imposed rather than chosen. However, in high-income countries, dialysis is more widely available, and the decision whether to follow a conservative management pathway or not needs to be carefully weighed. This will include the context of the ageing kidney, the overall prognosis, and the trajectory of illness, to inform the best individual decisions.
Management of those following a conservative management pathway includes detailed communication and advance care planning, actively managing the kidney disease and minimizing complications, and detailed assessment and proactive management of symptoms.
Palliative care in end-stage renal disease
Authors: Vinen Katie , Murtagh Fliss E. M. , Higginson Irene J.
Published: November 2015

The changing demographics of the end-stage renal failure population have necessitated a different focus of care for older or highly co-morbid patients. End-of-life care for this population is best provided by combined nephrological and palliative care input. Honest prognostic information, excellent communication, and understanding the patient’s own priorities lie at the heart of this type of care. Excellent symptom control, a reduction in treatment burdens, and an effective network of professional support can be offered by clinicians. Ensuring a renal patient is able to die well and providing support for their family during and after death are important aspects of nephrological care.
Acidosis in chronic kidney disease
Authors: Yaqoob Muhammad M.
Published: November 2015

Metabolic acidosis becomes increasingly common as chronic kidney disease progresses. It is associated with a number of complications, including bone disease, altered protein synthesis and degradation, skeletal muscle wasting, and lately progressive glomerular filtration rate loss. Experimental and clinical studies suggest a role for alkali therapy to lessen these complications. Recent controlled studies support this notion, and suggest that correction of metabolic acidosis in patients with chronic kidney disease slows the rate of decline of renal function and the development of end-stage renal disease, although more definitive evidence is needed on the long-term benefits of alkali therapy, type of alkali supplements, and the optimal level of serum bicarbonate.
The patient with cryoglobulinaemia
Authors: Fabrizi Fabrizio , Cacoub Patrice
Published: November 2015

Abstract

Cryoglobulinaemia is characterized by the presence in the blood of proteins showing the that precipitate when serum is cooled. Clinically recognised cryoprecipitates are predominantly immunoglobulin-containing. In Type 1 cryoglobulinaemia, the precipitate is formed from a monoclonal paraprotein, usually IgG. In Type 2, a monoclonal IgM binds IgG to form a mixed precipitate. Type 3 cryoglobulins do not contain a monoclonal element.

Type 1 cryoglobulins are a rare cause of renal disease, but cause a membranoproliferative glomerulonephritis (MPGN) with nephrotic syndrome and haematuria and usually with severe cutaneous involvement.

Type 2 is most typically associated with renal disease, again characterized by MPGN and haematuria, with variable cutaneous signs and vasculitis in other organs. Many cases are associated with Hepatitis C virus (HCV) infection – but not all.

Therapeutic approaches include optimal antiviral regimen, immunosuppressive therapy (corticosteroids, rituximab, and cytotoxic agents), and plasma exchange. Treatment of HCV-related mixed cryoglobulinaemia vasculitis should be adjusted according to the clinico-biological presentation.
The patient with vasculitis
Authors: Harper Lorraine , Jayne David
Published: November 2015

The goals of treatment in renal vasculitis are to stop vasculitic activity and recover renal function. Subsequent strategies are required to prevent vasculitis returning and to address longer-term co-morbidities caused by tissue damage, drug toxicity, and increased cardiovascular and malignancy risk.

Cyclophosphamide and high-dose glucocorticoids remain the standard induction therapy with alternative immunosuppressives, such as azathioprine, to prevent relapse. Plasma exchange improves renal recovery in severe presentations. Refractory disease resulting from a failure of induction or remission maintenance therapy requires alternative agents and rituximab has been particularly effective. Replacement of cyclophosphamide by rituximab for remission induction is supported by recent evidence. Methotrexate is effective in non-renal vasculitis but difficult to use in patients with renal impairment. Mycophenolate mofetil seems to be effective but there is less long-term evidence.

Drug toxicity contributes to co-morbidity and mortality and has led to newer regimens with reduced cyclophosphamide exposure. Glucocorticoid toxicity remains a major problem with controversy over the rapidity with which glucocorticoids can be reduced or withdrawn.

Disease relapse occurs in about 50% of patients. Early detection is less likely to lead to an adverse affect on outcomes. Rates of cardiovascular disease and malignancy are higher than in control populations but strategies to reduce their risk, apart from cyclophosphamide-sparing regimens, have not been developed. Thromboembolic events occur in 10% and may be linked to the recently identified autoantibodies to plasminogen and tissue plasminogen activator.

Renal impairment at diagnosis is a strong predictor of patient survival and renal outcome. Other predictors include patient age, antineutrophil cytoplasmic antibody subtype, disease extent and response to therapy. Chronic kidney disease can stabilize for many years but the risks of end-stage renal disease are increased by acute kidney injury at presentation or renal relapse. Renal transplantation is successful with similar outcomes to other causes of end-stage renal disease.
The patient with systemic lupus erythematosus
Authors: Condon Marie , Dodd Philippa , Lightstone Liz
Published: November 2015

Abstract

Systemic lupus erythematosus (SLE) is a chronic, relapsing, inflammatory, often febrile multisystemic disorder, characterized by involvement of the skin, joints, visceral organs, and serosal membranes. Symptoms and manifestations vary widely over an unpredictable relapsing and remitting course.

The presentation of SLE can range from mild forms to severe disease requiring hospitalization. Most commonly it manifests as a combination of constitutional symptoms, particularly fatigue and fever, with cutaneous, musculoskeletal, mild haematological, and serological involvement; however, when renal, haematological or central nervous system disease predominate it can be more severe, even life-threatening. There is a tendency for the disease pattern present at the time of onset to prevail during subsequent exacerbations.

Investigating SLE depends to an extent on the presentation of the individual. However a number of haematological, biochemical and immunological investigations provide useful diagnostic information, either for the disease itself or in context of organ system involvement, and should be performed routinely.

The presence of lupus nephritis should be considered in any lupus patient with impaired kidney function, proteinuria, hypertension, or an active urine sediment; the gold standard investigation in this context is a kidney biopsy. Glomerular immune complex deposition is the hallmark of lupus nephritis and underpins the International society of Nephrology/Renal Pathology Society classification of lupus nephritis.

The diagnosis of SLE is based upon the presence of clinical and/or laboratory features and immunological markers that meet the various published diagnostic criteria. In 2012, lupus nephritis identified on kidney biopsy became an independent diagnostic criterion.

This chapter goes through the clinical manifestations, investigations (including a detailed look at the kidney biopsy) and a review of the latest published diagnostic criteria.
The patient with antiphospholipid syndrome with or without lupus
Authors: Alchi Bassam , Jayne David
Published: November 2015

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent arterial or venous thrombosis and/or pregnancy loss, accompanied by laboratory evidence of antiphospholipid antibodies (aPL), namely anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed against beta-2 glycoprotein 1 (β‎‎‎2GP1). APS may occur as a ‘primary’ form, ‘antiphospholipid syndrome,’ without any known systemic disease or may occur in the context of systemic lupus erythematosus (SLE), ‘SLE-related APS’. APS may affect any organ system and displays a broad spectrum of thrombotic manifestations, ranging from isolated lower extremity deep vein thrombosis to the ‘thrombotic storm’ observed in catastrophic antiphospholipid syndrome. Less frequently, patients present with non-thrombotic manifestations (e.g. thrombocytopaenia, livedo reticularis, pulmonary hypertension, valvular heart disease, chorea, and recurrent fetal loss).

The kidney is a major target organ in both primary and SLE-related APS. Renal involvement is typically caused by thrombosis occurring at any location within the renal vasculature, leading to diverse effects, depending on the size, type, and site of vessel involved. The renal manifestations of APS include renal artery stenosis and/or renovascular hypertension, renal infarction, APS nephropathy (APSN), renal vein thrombosis, allograft vasculopathy and vascular thrombosis, and thrombosis of dialysis access.

Typical vascular lesions of APSN may be acute, the so-called thrombotic microangiopathy, and/or chronic, such as arteriosclerosis, fibrous intimal hyperplasia, tubular thyroidization, and focal cortical atrophy. The spectrum of renal lesions includes non-thrombotic conditions, such as glomerulonephritis. Furthermore, renal manifestations of APS may coexist with other pathologies, especially proliferative lupus nephritis.

Early diagnosis of APS requires a high degree of clinical suspicion. The diagnosis requires one clinical (vascular thrombosis or pregnancy morbidity) and at least one laboratory (LA, aCL, and/or anti-β‎‎‎2GP1) criterion, positive on repeated testing.

The aetiology of APS is not known. Although aPL are diagnostic of, and pathogenic in, APS, a ‘second hit’ (usually an inflammatory event) may trigger thrombosis in APS. The pathogenesis of the thrombotic tendency in APS remains to be elucidated, but may involve a combination of autoantibody-mediated dysregulation of coagulation, platelet activation, and endothelial injury.

Treatment of APS remains centred on anticoagulation; however, it has also included the use of corticosteroids and other immunosuppressive therapy. The prognosis of patients with primary APS is variable and unpredictable. The presence of APS increases morbidity (renal and cerebral) and mortality of SLE patients.