bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic kidney disease long-term outcomes
Authors: Beaulieu Monica , Weber Catherine , Zalunardo Nadia , Levin Adeera
Published: November 2015

Chronic kidney disease (CKD) is associated with a variety of outcomes, some of which are directly and indirectly related to kidney disease, but which ultimately impact on patients’ quality of life and long-term outcomes. The events to which people with CKD are exposed ultimately determine their risk and prognosis of both progression to needing renal replacement therapy, or other morbidities and mortalities. The notion of competing risk is important.
The five major outcomes of CKD are: progression of CKD, progression to ESRD (either dialysis or transplantation); death; cardiovascular events; infections; and hospitalizations. Where data is available, not only the risk of the specific outcome, but the factors which may predict those outcomes are described. Each section describes what is currently known about the frequency of the outcome, the limitations of that knowledge, the risk factors associated with outcome, and implications for care and future research.
Available published literature often describes outcomes in CKD populations as if it is a homogenous group of patients. But it is well documented that outcomes in those with CKD differ depending on stage or severity, and whether they are or are not known to specialists. Where possible, each section ensures that the specific CKD cohort(s) from which the information is derived is clearly described.
Cardiovascular disease and chronic kidney disease
Authors: Goldsmith David J.
Published: November 2015

Even after as full a statistical adjustment as can be made for traditional cardiovascular risk factors has been undertaken, impaired kidney function and raised concentrations of albumin in urine each increase the risk of cardiovascular disease (CVD) by two- to fourfold, the degree increasing with severity. If the patient is also suffering from diabetes (as either the cause of CKD or a complication of it), the risks of CVD increase two- to fourfold again. CKD patients should, therefore, be acknowledged as having perhaps the highest cardiovascular risk of any patient cohort. CVD is underdiagnosed and undertreated in these patients.
In early CKD the manifestations of CVD are similar to those of other patients. In late CKD and particularly in patients on dialysis the epidemiology is different. Left ventricular hypertrophy is very common and sudden cardiac death is greatly increased in incidence. Heart failure is a common complication. Calcification of valves and vessels becomes increasingly common and bad CVD outcomes are associated with hyperphosphataemia and other manifestations.
The mechanisms by which risks are increased are not fully understood. The evidence base for the effectiveness of established therapies for CVD is relatively light in patients with CKD, but there is evidence for benefit of lipid-lowering therapies and most nephrologists believe that blood pressure and volume control are important for good long-term outcomes. Evidence of impact on CVD of interventions to alter mineral bone disease is disappointingly weak.
Hypertension as a cause of chronic kidney disease
Authors: Tandon Teena , Agarwal Rajiv
Published: November 2015

There is a strong association between hypertension and progressive renal disease, and it has long been assumed that a variable but often large proportion of end-stage renal disease is caused by essential hypertension damaging the kidney. While it is clear that malignant hypertension can cause renal damage, several lines of evidence cast doubt on the idea that more moderate blood pressures are commonly a primary cause of renal disease. These include (a) observational studies showing that microalbuminuria precedes hypertension; (b) morphological studies in animals and man suggest that changes traditionally described as due to hypertension correlate poorly with blood pressure; and (c) mutations in or near the APOL1 gene appear to underlie the development of renal disease in many black Americans previously labeled as suffering from hypertensive renal disease. The same mutations strongly predispose to focal segmental glomerulosclerosis. The mechanism of the association with ‘hypertensive’ renal disease is not established but it may act as a risk factor for progression of renal disease. Hypertension is associated with reduced renal mass. It is described as a consequence of renal cysts, simple as well as multiple. Obesity may be associated with accumulation of fat in the renal sinus and with hypertension.
The role of inflammation in chronic kidney disease
Authors: Carrero Juan Jesús , Stenvinkel Peter
Published: November 2015

Low-grade persistent inflammation is a common feature of chronic kidney disease. This chapter provides an overview of the pathogenesis and clinical consequences of elevated pro-inflammatory cytokines in the uraemic milieu with an emphasis on dialysis stages. It reviews the multifactorial dialysis- and non-dialysis-related causes of inflammation and its purported role in the development of protein energy wasting, vascular calcification, endocrine disorders, and depression.
The chapter also discusses the use and the need of monitoring C-reactive protein levels regularly in the clinical setting and comments on possible therapeutic approaches to reduce inflammation in these patients.
Vascular stiffness in chronic kidney disease
Authors: Townend Jonathan N. , Ferro Charles J.
Published: November 2015

Increased arterial stiffness is a hallmark of chronic kidney disease and is associated with adverse alterations in cardiac structure and function that predispose to an increased risk of cardiovascular death. These changes are already apparent in early kidney disease, which is common in the ageing population in the developed world. The mechanisms underlying increased arterial stiffness in chronic kidney disease are complex, but some are alterable by therapies, for instance those that affect the endothelium or renin-angiotensin system. This may contribute to lowering cardiovascular risk in chronic kidney disease.
Pathophysiology of chronic kidney disease-mineral and bone disorder
Authors: Voinescu Alexandra , Wasi Iqbal Nadia , Martin Kevin J.
Published: November 2015

Chronic kidney disease is associated with the inability to control normal mineral homeostasis, resulting in abnormalities in serum levels of calcium, phosphorus, parathyroid hormone, fibroblast growth factor 23 (FGF23) and vitamin D metabolism. These disturbances lead to the development of secondary hyperparathyroidism, skeletal abnormalities, vascular calcifications, and other systemic manifestations. Traditionally, mineral and bone abnormalities seen in chronic kidney disease were included in the term ‘renal osteodystrophy’. More recently, the term chronic kidney disease-mineral and bone disorder was introduced to define the biochemical abnormalities of phosphorus, parathyroid hormone, FGF23, calcium, or vitamin D metabolism, abnormalities in bone remodelling and mineralization, and vascular or other soft tissue calcifications.
Erythropoiesis-stimulating agents in chronic kidney disease
Authors: Macdougall Iain C.
Published: November 2015

The advent of recombinant human erythropoietin (epoetin) in the late 1980s transformed the management of renal anaemia, liberating many dialysis patients from lifelong regular blood transfusions, in turn causing severe iron overload and human leucocyte antigen sensitization. Epoetin can be administered either intravenously or subcutaneously, but the half-life of the drug is fairly short at around 6–8 hours, necessitating frequent injections. To circumvent this problem, two manipulations to the erythropoietin molecule were engineered. The first of these was to attach an extra two carbohydrate chains to the therapeutic protein hormone (to make darbepoetin alfa), and the second was to attach a large pegylation chain to make continuous erythropoietin receptor activator. Both of these strategies prolonged the circulating half-life of the erythropoietin analogue. The next erythropoietic agent to be produced was peginesatide, a peptide-based agent which had no structural homology with native or recombinant erythropoietin, but shared the same biological and functional characteristics. Future strategies include stabilization of hypoxia-inducible factor, by orally active inhibitors of the prolyl hydroxylase enzyme, and advanced clinical trials are underway. In the meantime, several large randomized controlled trials have highlighted the potential harm in targeting a near normal haemoglobin of 13–14 g/dL (with an increased risk of cardiovascular complications), and sub-normal correction of anaemia is now advised. Some patients may show mild or severe resistance to erythropoiesis-stimulating agent (ESA) therapy, and common causes include iron insufficiency, infection, and underlying inflammation. Very rarely, patients may produce antibodies against their ESA, which neutralize not only the ESA, but also endogenous erythropoietin, causing pure red cell aplasia.
Immunity
Authors: Afzali Behdad , Kemper Claudia
Published: November 2015

Immunological health relies on a balance between immune responsiveness to foreign pathogens and tolerance to self-components, commensals, food-derived components, and semi-allogeneic fetal antigens. Disruptions of this balance are hallmarks of immunodeficiency diseases, autoimmune diseases, and pregnancy failure. Patients with chronic kidney disease are immunologically unique in demonstrating features of both chronic inflammation and acquired immunodeficiency—predisposing these individuals to the two commonest causes of death, namely cardiovascular disease and sepsis. Defects and abnormalities in almost all components of the immune system can be observed, although it is difficult to say whether the observations denote mechanism or effect. This chapter reviews, briefly, measurable immune system abnormalities in chronic kidney disease and some of the potential underlying mechanisms.
Sexual dysfunction
Authors: Thor Agustsson Tomas , Carroll Paul
Published: November 2015

Sexual problems in patients with chronic renal failure are both common and varied and have been shown to significantly impair quality of life. Sexual dysfunction is found in at least two-thirds of both haemodialysis and peritoneal dialysis patients and numerous factors both physical and psychological may contribute. It is probably less frequent in transplant patients but still affects at least half. This chapter describes the most clinically relevant physical and psychological factors which may play a role in the pathophysiology of sexual dysfunction and summarizes several therapeutic approaches to these problems.
Disordered scarring and failure of repair
Authors: Duffield Jeremy S.
Published: November 2015

Scarring is the name given to fibrous tissue accumulation in the skin, which, when it forms elsewhere, is known as fibrosis, but the terms are frequently used interchangeably. The scientific study of fibrosis or scarring was established and developed in skin wounding, as a part of the normal repair response, long before it was appreciated that pathological fibrosis or scarring occurs as a consequence of sustained or iterative injury to internal organs. Increasing experimental evidence indicates that the process of skin wounding with scarring is very similar to the process of organ injury with fibrosis detected in vital organs including the kidney. Kidney fibrosis develops in glomeruli, where it is known as glomerulosclerosis (literally hardening of glomeruli due to fibrotic tissue), or in the interstitial virtual space between tubules and peritubular capillaries, known as interstitial fibrosis. Increasingly fibrosis of the kidney and the cells that make fibrous tissue are seen as targets for therapeutic intervention in chronic diseases of the kidney.
Kidney involvement in plasma cell dyscrasias
Authors: Ronco Pierre M.
Published: November 2015

Monoclonal proliferations of the B-cell lineage are characterized by abnormal and uncontrolled expansion of a single clone of B cells at different maturation stages, with a variable degree of differentiation to immunoglobulin-secreting plasma cells. Therefore, they are usually associated with the production and secretion in blood of a monoclonal immunoglobulin and/or a fragment thereof which may become deposited in tissues. These deposits can take the form of casts (in myeloma cast nephropathy), crystals (in myeloma-associated Fanconi syndrome), fibrils (in light-chain and exceptional heavy-chain amyloidosis), or granular precipitates (in monoclonal immunoglobulin deposition disease). They may disrupt organ structure and function, inducing life-threatening complications. All of the pathologic entities related to immunoglobulin deposition principally involve the kidney, which is not only explained by the high levels of renal plasma flow and glomerular filtration rate, but also by the sieving properties of the glomerular capillary wall and by the prominent role of the renal tubule in LC handling and catabolism.

The different renal (and other) manifestations are related to the unique physicochemical characteristics of each paraprotein or immunoglobulin fragment, and the rate of their production.
The patient with sarcoidosis
Authors: Rajakariar Ravindra , Yaqoob Muhammad M.
Published: November 2015

Renal involvement in sarcoidosis is common and often under-recognized. The most frequent manifestation is acute kidney injury secondary to hypercalcaemia and granulomatous tubulointerstitial nephritis. The latter can lead to both acute kidney injury and to slowly progressive chronic renal impairment with concomitant chronic damage seen on histology. This chapter describes the types of renal disease that may occur in sarcoidosis and the pathogenesis, clinical presentation, diagnosis, and treatment of the patient with sarcoidosis. Corticosteroid therapy is the cornerstone of therapy. In patients with granulomatous tubulointerstitial nephritis, the authors recommend long-term, low-dose maintenance steroids.
The patient with vasculitis
Authors: Heeringa Peter , Stegeman Coen A.
Published: November 2015

Vasculitis is an inflammatory destructive process affecting blood vessels resulting in fibrinoid necrosis of the vessel wall that eventually can lead to occlusion of the vascular lumen and organ failure. Vasculitis may be the primary manifestation of a disease, or be a secondary manifestation of another underlying disease.

The pathogenesis of vasculitis is complex, involving innate and adaptive immune effector mechanisms that range from cell-mediated inflammation, immune-complex-mediated inflammation, and inflammation triggered by autoantibodies. Here it is discussed with respect to general pathogenic patterns and more disease-specific pathogenic pathways related to primary and secondary vasculitic syndromes.
The patient with scleroderma
Authors: Lynch Bernadette , Burns Aine
Published: November 2015

Scleroderma is tightness, thickening, and non-pitting induration of skin. Two forms of the skin disease are described. Limited cutaneous systemic sclerosis (lcSSc) which occurs distal to the wrists (or ankles) and/or over the face and neck, often associated with longstanding Raynaud’s phenomenon, and diffuse cutaneous systemic sclerosis (dcSSc) where truncal as well as acral skin involvement occurs as well as tendon friction rubs. In this latter condition the onset of the skin changes occurs within 1 year of onset of Raynaud’s phenomenon; however, the skin involvement may precede onset of vascular symptoms.

The skin manifestations are the outward manifestation of a systemic disease, systemic sclerosis. Lung, heart, and gut involvement are frequent. Scleroderma renal crisis, usually presenting as accelerated hypertension and acute kidney injury, is one of the most severe complications of this disease. Autoantibodies against RNA polymerase are associated with scleroderma renal crisis. It occurs in 12% of dcSSc and 2% of lcSSc patients (men and women) and carries a high morbidity and mortality although careful supportive care and blood pressure management using angiotensin converting enzyme inhibitors (ACEI) or angiotensin-II receptor blockers have improved short-term outcomes. In general, beta blockers should be avoided in the early management.

Approximately two-thirds of patients require dialysis, of these many recover enough function to come off dialysis. Higher blood pressure and younger age at presentation have a better prognosis. ACEIs should be continued even after dialysis is established as the latter increases the chance of late recovery. Average time to coming off dialysis is 11 months but recovery is uncommon after 24 months. After a crisis renal function continues to improve for several years.
The patient with rheumatoid arthritis, mixed connective tissue disease, Sjögren syndrome, or polymyositis
Authors: Bissell Lesley-Anne , Adu Dwomoa , Emery Paul
Published: November 2015

Renal disease is a well-recognized cause of ill health and death in rheumatoid arthritis. Three broad categories of renal disease occur. The first—and by far the most common—arises from the nephrotoxicity of the drugs used in the treatment of arthritis, particularly with non-steroidal anti-inflammatory drugs. Disease-modifying antirheumatic drugs such as gold and D-penicillamine may lead to proteinuria and a glomerulonephritis in 10–30% of patients. Ciclosporin is associated with significant nephrotoxicity and hypertension. A second major but diminishing cause of renal disease in rheumatoid arthritis is amyloidosis. Thirdly, rheumatoid arthritis may be associated with the development of glomerulonephritis. The main types described are a mesangial proliferative glomerulonephritis with or without immunoglobulin A deposits, a membranous nephropathy, and a focal segmental necrotizing glomerulonephritis of the vasculitic type.

Renal disease in mixed connective tissue disease and polymyositis is infrequent, but the former can be associated with a membranous and mesangial proliferative glomerulonephritis.

Sjögren syndrome is rarely associated with clinically significant renal disease, but patients can present with proteinuria, acidosis, or hyperchloraemia. Interstitial nephritis and immune complex glomerulonephritis reflect the exocrinopathy and circulating immune complex disease pathognomonic of Sjögren syndrome. Evidence for effective treatment of the renal complications is lacking. Corticosteroids and cyclophosphamide are most commonly used, with newer biological drugs, such as rituximab, showing promise.
The patient with sickle cell anaemia
Authors: Haymann Jean-Philippe , Lionnet Francois
Published: November 2015

In sickle cell anaemia (SCA) a single mutation in the haemoglobin beta-globin gene is responsible for a pleomorphic phenotype leading to acute and chronic life-threatening complications. Healthcare management programmes, patient and family education, infection prophylaxis (especially in childhood), and long-term treatment for some patients (such as hydroxyurea) have significantly improved survival, giving rise to some new long-term issues.

Sickle cell-associated nephropathy (SCAN) leads in some cases to chronic renal failure with a significant impact on survival. SCAN is characterized by an increased effective plasma renal flow and glomerular filtration rate, glomerular hypertrophy, and damaged vasa recta system leading to albuminuria and impaired urinary concentration.

Early onset of hyperfiltration occurs in 60% of SCA patients often associated with microalbuminuria. SCAN risk factors are still under investigation, but may be related to chronic haemolysis at an early time point. Other lesions in patients with sickle cell anaemia include papillary necrosis, and recurrent acute kidney injury in association with crises or infections.

ACEI are recommended if there is proteinuria. There is no current agreement on whether angiotensin-converting enzyme inhibitors (ACEI) should be introduced earlier, but systematic screening for microalbuminuria and hypertension, and avoidance of nephrotoxic agents are strongly advised.

Patients with sickle cell trait (carriers for sickle cell anaemia) are prone to microscopic haematuria and abnormalities of the vasa recta have been described. A very rare tumour, renal medullary carcinoma, is largely restricted to this group (in whom it is still extremely rare). Increased risk of other renal problems is still largely hypothetical rather than proven.

The prevalence of nephropathies in other sickle cell diseases (in particular haemoglobin SC disease) is much lower.
Mycobacterial infections
Authors: Eastwood John , Corbishley Cathy , Grange John
Published: November 2015

The genus Mycobacterium contains over a hundred species including the M. tuberculosis complex and M. leprae, the causative agents of, respectively, tuberculosis and leprosy. 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.

The genitourinary tract is a common site of both primary and post-primary tuberculosis. In most cases of renal tuberculosis there are gross lesions consisting of caseating granulomas from which tubercle bacilli enter the urinary tract, often with the development of secondary lesions in the ureters, bladder, epididymis, and testis. Tuberculous interstitial nephritis is a less common condition with an insidious course and may result in renal failure. The urine is often negative for tubercle bacilli, emphasizing the need for biopsy in those with renal insufficiency.

The risk of developing pulmonary or disseminated tuberculosis after infection is greatly enhanced by any form of immune compromise including renal failure and post-renal transplant immunosuppression.
Tubuloglomerular feedback, renal autoregulation, and renal protection
Authors: Endlich Karlhans , Loutzenhiser Rodger
Published: November 2015

Vascular tone of glomerular blood vessels is controlled dynamically in response to a number of stimuli of which tubuloglomerular feedback and blood flow (and glomerular filtration rate) autoregulation are the most prominent. Both tubuloglomerular feedback- and myogenic-mediated pre-glomerular vasoconstriction are important in the response to reduced pressure. The renal myogenic mechanism, which has the potential to adjust steady-state tone in response to the oscillating systolic pressure signal, additionally plays an essential role in protecting the kidney from the damaging effects of hypertension.
Renal artery stenosis
Authors: Ritchie James , Green Darren , Chrysochou Constantina , Kalra Philip A.
Published: November 2015

In fibromuscular disease (FMD), renal artery occlusion seems to be rare. Balloon angioplasty appears moderately successful in the medium term in controlling hypertension, at least in younger patients. In more complicated circumstances, medical therapy may be preferred. Similar approaches have been used in Takayasu disease but with less information about lasting outcomes.

In atherosclerotic renal disease, the risk of renal artery occlusion and loss of renal function seems higher, but so are the complications of invasive management. Randomized clinical studies have not shown better blood pressure control or renal outcomes between medical therapy and percutaneous revascularization. As a consequence, modern management of atherosclerotic renovascular disease is primarily pharmacological, with interventional techniques reserved for selected presentations such as rapidly declining therapy, acute occlusion, or characteristic ‘flash’ pulmonary oedema.

Whilst this approach is widely accepted, long-term outcome data are scant and there is ongoing research interest into specific disease phenotypes, refined interventional techniques, and novel treatment strategies aimed at preserving the renal microcirculation.
Malignant hypertension
Authors: Whitworth Caroline , Fleming Stewart
Published: November 2015

Malignant hypertension (MH) is recognized clinically by elevated blood pressure together with retinal haemorrhages or exudates with or without papilloedema (grades III or IV hypertensive retinopathy); and may constitute a hypertensive emergency or crisis when complicated by evidence of end-organ damage including microangiopathic haemolysis, encephalopathy, left ventricular failure, and renal failure. Though reversible, it remains a significant cause of end-stage renal failure, and of cardiovascular and cerebrovascular morbidity and mortality in developing countries.

MH can complicate pre-existing hypertension arising from diverse aetiologies, but most commonly develops from essential hypertension. The absolute level of blood pressure appears not to be critical to the development of MH, but the rate of rise of blood pressure may well be relevant in the pathogenesis. The pathogenesis of this transformation remains unclear.

The pathological hallmark of MH is the presence of fibrinoid necrosis (medial vascular smooth muscle cell necrosis and fibrin deposition within the intima) involving the resistance arterioles in many organs. Fibrinoid necrosis is not specific to MH and this appearance is seen in other conditions causing a thrombotic microangiopathy such as haemolytic uraemic syndrome, scleroderma renal crisis, antiphospholipid syndrome, and acute vascular rejection post transplant. MH can both cause a thrombotic microangiopathy (TMA) but can also complicate underlying conditions associated with TMA.

The pathophysiological factors that interact to generate and sustain this condition remain poorly understood. Risk factors include Afro-Caribbean race, smoking history, younger age of onset of hypertension, previous pregnancy, and untreated hypertension associated with non-compliance or cessation of antihypertensive therapy.

Evidence from clinical studies and animal models point to a central role for the intrarenal renin–angiotensin system (RAS) in MH; there is good evidence for renal vasoconstriction and activation of the renal paracrine RAS potentiating MH once established; however, there may also be a role in the predisposition of MH suggested by presence of increased risk conferred by an ACE gene polymorphism in humans and polymorphisms for both ACE and AT1 receptor in an animal model of spontaneous MH. Other vasoactive mediators such as the endothelin and the inflammatory response may be important contributing to and increasing endothelial damage. There have been no randomized controlled trials to define the best treatment approach, but progressive lowering of pressures over days is considered safest unless made more urgent by critical clinical state. It seems logical to introduce ACE inhibition cautiously and early, but in view of the risk of rapid pressure lowering some recommend delay.
Pathophysiology of acute kidney injury
Authors: Goligorsky Michael S. , Maizel Julien , Vasko Radovan , Rabadi May M. , Ratliff Brian B.
Published: November 2015

In the intricate maze of proposed mechanisms, modifiers, modulators, and sensitizers for acute kidney injury (AKI) and diverse causes inducing it, this chapter focuses on several common and undisputable strands which do exist.

Structurally, the loss of the brush border, desquamation of tubular epithelial cells, and obstruction of the tubular lumen are commonly observed, albeit to various degrees. These morphologic hallmarks of AKI are accompanied by functional defects, most consistently reflected in the decreased glomerular filtration rate and variable degree of reduction in renal blood flow, accompanied by changes in the microcirculation. Although all renal resident cells participate in AKI, the brunt falls on the epithelial and endothelial cells, the fact that underlies the development of tubular epithelial and vascular compromise.

This chapter further summarizes the involvement of several cell organelles in AKI: mitochondrial involvement in perturbed energy metabolism, lysosomal involvement in degradation of misfolded proteins and damaged organelles, and peroxisomal involvement in the regulation of oxidative stress and metabolism, all of which become defective. Common molecular pathways are engaged in cellular stress response and their roles in cell death or survival. The diverse families of nephrotoxic medications and the respective mechanisms they induce AKI are discussed. The mechanisms of action of some nephrotoxins are analysed, and also of the preventive therapies of ischaemic or pharmacologic pre-conditioning.

An emerging concept of the systemic inflammatory response triggered by AKI, which can potentially aggravate the local injury or tend to facilitate the repair of the kidney, is presented. Rational therapeutic strategies should be based on these well-established pathophysiological hallmarks of AKI.
Renal failure in cirrhosis
Authors: Arroyo Vicente , Guevara Mónica , Fernández Javier
Published: November 2015

A major event in liver cirrhosis is the development of a progressive deterioration of circulatory function due to splanchnic arterial vasodilation and impairment in cardiac function. This feature determines a homeostatic activation of the renin–angiotensin–aldosterone system, sympathetic nervous system, and antidiuretic hormone. The splanchnic microcirculation is resistant to the vasoconstrictor effect of these systems. Therefore, the homeostasis of arterial pressure in cirrhosis occurs in the extrasplanchnic, mainly renal circulation. The activation of these systems produces renal fluid retention, which accumulates as ascites, and water retention and dilutional hyponatraemia. In the latest phase of cirrhosis, when circulatory dysfunction is severe, renal vasoconstriction is intense and patients develop type 2 hepatorenal syndrome (HRS) and refractory ascites.

Type 1 HRS is an acute and rapidly progressive renal failure that occurs in the setting of a precipitating event, commonly an infection. Patients with type 1 HRS also present with rapid deterioration of liver function (encephalopathy, jaundice) and relative adrenal insufficiency. The mechanism of this multiorgan failure is an acute deterioration in circulatory function due to both an accentuation of arterial vasodilation and of cardiac dysfunction.

There is no specific test for the diagnosis of HRS. The most accepted diagnostic criteria are those proposed by the International Ascites Club which are based on the exclusion of other types of renal failure. The course of renal failure following treatment of the precipitating event of HRS is another important diagnostic feature.

The treatment of choice of tense ascites in cirrhosis is paracentesis associated with intravenous albumin infusion. Moderate sodium restriction and diuretics (spironolactone alone or associated with furosemide) are subsequently given to prevent re-accumulation of ascites. Diuretics are the treatment of choice in patients with moderate ascites. Patients with type 2 HRS and refractory ascites (not responding to diuretics) could be treated by frequent paracentesis or by the insertion of a transjugular intrahepatic portosystemic shunt (TIPS).

Terlipressin plus albumin is the treatment of choice in type 1 HRS
Haemodialysis
Authors: Himmelfarb Jonathan
Published: November 2015

This chapter provides an overview of haemodialysis, a medical procedure where the blood volume circulates extracorporeally through a dialysis membrane and is returned to the patient via the vasculature, during which time there is diffusion of molecules in solution along an electrochemical concentration gradient. In clinical haemodialysis, the semipermeable dialysis membrane separates the blood from a solution of prescribed electrolyte composition known as the dialysate. The use of long-term dialysis for treatment of irreversible kidney failure and amelioration of the uraemic syndrome dates back to the 1960s, when Belding Scribner and colleagues developed a repeatedly usable vascular access device using Teflon-coated plastic tubes. These and many other pioneering advances led to early successes in carefully selected populations of predominantly young, relatively fit patients with kidney failure. This in turn prompted a dramatic expansion of the use of haemodialysis as a life-sustaining treatment, and today haemodialysis is the most frequently used treatment for end-stage kidney disease in the United States, Europe, and worldwide. The expanded use of haemodialysis as kidney replacement therapy transformed the profession of nephrology and the care of people living with severe kidney disease, and also created a new field of medical science, which has been referred to as ‘the physiology of the artificial kidney’.
Haemodialysis
Authors: Allon Michael
Published: November 2015

Delivery of haemodialysis is dependent on having a vascular access that can reproducibly deliver an adequate blood flow thrice weekly. None of the three types of vascular access is perfect; each has potential advantages and drawbacks. Fistulas are the preferred type of vascular access because they have the longest cumulative survival and require the fewest interventions to maintain their long-term patency, once they achieve suitability for dialysis. However, fistulas have a fairly high non-maturation rate, frequently require revisions to achieve suitability for dialysis, and often are associated with prolonged catheter dependence until they are ready to cannulate. In contrast, grafts have a lower primary failure rate, are usually ready to use within 2–3 weeks of creation, and are therefore associated with a shorter duration of catheter dependence. However, the cumulative survival of grafts is shorter than that of fistulas, and they require more frequent interventions (angioplasty, thrombectomy, or surgical revisions) to maintain their patency for dialysis. The major advantage of dialysis catheters is that they are suitable for use as soon as they are placed. However, catheter use is associated with frequent complications, including catheter-related bacteraemia, dysfunction, and central vein stenosis. Many patients require a tunnelled dialysis catheter as a bridge, until they have a mature fistula or graft. Optimal management of vascular access is extremely challenging, and requires close collaboration among multiple medical disciplines, advance planning, and treatment or prophylaxis of their frequent complications.
The evolution of kidney transplantation
Authors: Morris Peter J. , Chapman Jeremy R.
Published: November 2015

The history of kidney transplantation starts in 1902 with Ullman transplanting kidneys between dogs, and Carrel’s development of vascular anastomotic techniques. The developments in the 1950s in Boston, Paris, and the laboratories of Medawar and others demonstrated both proof of the principle and some of the barriers to clinical kidney transplantation. The 1960s laid the groundwork for organ preservation, immunosuppression, and histocompatibility leading to the creation of transplant units in many countries. In the 1970s, there was steady progress in understanding the immunology of allograft rejection and its suppression. The advent of azathioprine used with steroids in the early 1960s resulted in 1-year graft survival rates of around 60% and patient survival of 90% in good units. However, with the introduction of ciclosporin in the early 1980s, renal transplantation became an even more reliable renal replacement option as there was a dramatic reduction in the incidence of irreversible acute rejection. The 1990s saw the introduction of both better immunosuppression and better infection prophylaxis, which further improved patient outcomes. The first decade of the twenty-first century has been characterized by the promise of new technologies in many areas, only some of which have delivered clinical benefit. Molecular human leucocyte antigen (HLA) typing and detection of antibodies to HLA antigens, standardized immunosuppression and anti-infective prophylaxis, surveillance biopsy, and developing systems for increasing donation rates are delivering major benefits. Gene biomarkers, stem cell therapy, and tolerance protocols have yet to make an impact. This chapter describes the historical development of transplantation and how it has yielded the results delivered in clinical practice today.
Immunology, sensitization, and histocompatibility
Authors: Muthukumar Thangamani , Dadhania Darshana , Hartono Choli , Suthanthiran Manikkam
Published: November 2015

Allograft rejection of the histo-incompatible allograft involves a highly orchestrated action of multiple cell types and mediators, with lymphocytes responsible for the identification of the foreignness of the allograft. The immune response directed against the donor is primarily, but not exclusively, directed at the donor’s major histocompatibility complex region class I and class II proteins. This chapter describes the immunobiology of the T cell and the role of human leucocyte antigens in clinical transplantation, thus identifying the targets for manipulation of the immune response by immune suppressants and through strategies designed to create a state of tolerance of the allograft.
Growth and development
Authors: Rees Lesley
Published: November 2015

Enabling achievement of full height potential in a child with chronic kidney disease (CKD) is one of the major and most challenging goals for the paediatric nephrologist. Short stature is associated with psychological maladjustment and with increased morbidity and mortality. The causes of poor growth are multifactorial and include poor nutrition, and metabolic, haematological, and endocrine disturbances. The most vulnerable times are the periods of most rapid growth, that is, infancy and puberty. Growth during infancy is principally dependent on nutrition so many infants need supplemental enteral feeding. Growth delay correlates with severity of CKD, with those on dialysis faring the worst such that by CKD stage 5, approximately 25% of patients are below the normal range for height. Height achieved post transplant is dependent on graft function and is better in younger children and those who have the best height attainment pre transplant. The use of steroid-free immunosuppressive regimens is encouraging. The prognosis for final height is improving.
Acute kidney injury in pregnancy
Authors: Wiles Kate , Nelson-Piercy Catherine
Published: November 2015

The diagnosis of acute kidney injury in pregnancy is complicated by physiological changes to both kidney and circulation; although a serum creatinine of higher than 90 μ‎‎‎mol/L is considered diagnostic of kidney injury in pregnancy. The aetiology of acute kidney injury in pregnancy mirrors that of the non-pregnant patient with the addition of pregnancy-specific conditions such as pre-eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes, low platelets), post-partum haemorrhage, and acute fatty liver of pregnancy. In early pregnancy, the major additional concerns are septic abortion and hyperemesis. Urinary tract infection is common in pregnancy. Surveillance and treatment thresholds reflect the recognized association between urinary tract infection and adverse pregnancy outcome. Obstructive nephropathy is difficult to diagnose in pregnancy due to a physiological dilatation of the renal tract. Radiological assessment and intervention to the renal tract in pregnancy are also discussed in this chapter.
Specific renal conditions in pregnancy
Authors: Bramham Kate , Nelson-Piercy Catherine
Published: November 2015

Pre-pregnancy glomerular filtration rate, proteinuria, and blood pressure are usually more important in determining the risk of pregnancy in patients with chronic kidney disease, but some diseases may be exacerbated in pregnancy, or appear more liable to complications. This chapter considers immunoglobulin A nephropathy, systemic lupus erythematosus (which may also be associated with some manifestations in the infant), diabetic nephropathy, polycystic kidney disease, reflux nephropathy, single kidney, urological disorders, and angiomyolipomata. Distinguishing underlying renal disease exacerbation from pre-eclampsia and other complications of pregnancy can be challenging. Renal biopsy is sometimes indicated.
Autosomal recessive polycystic kidney disease
Authors: Bergmann Carsten , Zerres Klaus
Published: November 2015

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality with variable disease expression. Many patients manifest peri- or neonatally with a mortality rate of 30–50%, whereas others survive to adulthood with only minor clinical features. ARPKD is typically caused by mutations in the PKHD1 gene that encodes a 4074-amino acid type 1 single-pass transmembrane protein called fibrocystin or polyductin. Fibrocystin/polyductin is among other cystoproteins expressed in primary cilia, basal bodies, and centrosomes, but its exact function has still not been fully unravelled. Mutations were found to be scattered throughout the gene with many of them being private to single families. Correlations have been drawn for the type of mutation rather than for the site of the individual mutation. Virtually all patients carrying two truncating mutations display a severe phenotype with peri- or neonatal demise while surviving patients bear at least one hypomorphic missense mutation. However, about 20–30% of all sibships exhibit major intrafamilial phenotypic variability and it becomes increasingly obvious that ARPKD is clinically and genetically much more heterogeneous and complex than previously thought.
Alport syndrome
Authors: Heidet Laurence , Knebelmann Bertrand , Claire Gubler Marie
Published: November 2015

Alport syndrome is an inherited renal disorder characterized by early haematuria, progressing to proteinuria, sensorineural hearing loss, and progressive renal failure typically in the third or fourth decade but with wide variation. It is responsible for about 1% of end-stage renal failure. Over 80% of cases are X-linked and young men are most affected, but heterozygous carriers of the abnormal gene are also at significantly increased risk of end-stage renal failure in their lifetime. Those affected by the autosomal recessive variant are phenotypically very similar. It is caused by mutations in tissue-specific isoforms of basement membrane (type IV) collagen encoded by COL4A5 (X chromosome), COL4A3, and COL4A4 (chromosome 2).
Mitochondrial diseases and the kidney
Authors: Hall Andrew , Rahman Shamima
Published: November 2015

Mitochondrial disease can affect any organ in the body including the kidney. As increasing numbers of patients with mitochondrial disease are either surviving beyond childhood or being diagnosed in adulthood, it is important for all nephrologists to have some understanding of the common renal complications that can occur in these individuals. Mitochondrial proteins are encoded by either mitochondrial or nuclear DNA (mtDNA and nDNA, respectively); therefore, disease causing mutations may be inherited maternally (mtDNA) or autosomally (nDNA), or can arise spontaneously. The commonest renal phenotype in mitochondrial disease is proximal tubulopathy (Fanconi syndrome in the severest cases); however, as all regions of the nephron can be affected, from the glomerulus to the collecting duct, patients may also present with proteinuria, decreased glomerular filtration rate, nephrotic syndrome, water and electrolyte disorders, and renal tubular acidosis. Understanding of the relationship between underlying genotype and clinical phenotype remains incomplete in mitochondrial disease. Proximal tubulopathy typically occurs in children with severe multisystem disease due to mtDNA deletion or mutations in nDNA affecting mitochondrial function. In contrast, glomerular disease (focal segmental glomerulosclerosis) has been reported more commonly in adults, mainly in association with the m.3243A<G point mutation. Co-enzyme Q10 (CoQ10) deficiency has been particularly associated with podocyte dysfunction and nephrotic syndrome in children. Underlying mitochondrial disease should be considered as a potential cause of unexplained renal dysfunction; clinical clues include lack of response to conventional therapy, abnormal mitochondrial morphology on kidney biopsy, involvement of other organs (e.g. diabetes, cardiomyopathy, and deafness) and a maternal family history, although none of these features are specific. The diagnostic approach involves acquiring tissue (typically skeletal muscle) for histological analysis, mtDNA screening and oxidative phosphorylation (OXPHOS) complex function tests. A number of nDNA mutations causing mitochondrial disease have now been identified and can also be screened for if clinically indicated. Management of mitochondrial disease requires a multidisciplinary approach, and treatment is largely supportive as there are currently very few evidence-based interventions. Electrolyte deficiencies should be corrected in patients with urinary wasting due to tubulopathy, and CoQ10 supplementation may be of benefit in individuals with CoQ10 deficiency. Nephrotic syndrome in mitochondrial disease is not typically responsive to steroid therapy. Transplantation has been performed in patients with end-stage kidney disease; however, immunosuppressive agents such as steroids and tacrolimus should be used with care given the high incidence of diabetes in mitochondrial disease.
Human kidney development
Authors: Winyard Paul
Published: November 2015

The kidneys perform diverse functions including excretion of nitrogenous waste products, homeostasis of water, electrolytes and acid–base balance, and hormone secretion. The simplest functional unit within the kidneys is the nephron, which consists of specialized segments from glomerulus, through proximal tubule, loop of Henle, and distal tubule. Human nephrogenesis starts with two stages of transient kidneys, termed the pronephros and mesonephros, and ends with development of a permanent organ from the metanephros on each side. The latter consists of just a few hundred cells when it is formed in the fifth week of pregnancy but progresses to a nephron endowment of between 0.6 to 1.3 million by the time nephrogenesis is completed at 32–36 weeks of gestation. Key events during this process include outgrowth of the epithelial ureteric bud from the mesonephric duct, interactions between the bud and the metanephric blastema (a specific region of mesenchyme) that cause the bud to branch and mesenchyme to condense, epithelialization of the mesenchyme to form proximal parts of the nephron, and differentiation of segment specific cells. Molecular control of these events is being unpicked with data from human genetic syndromes and animal models, and this chapter highlights several of the most important factors/systems involved. Increased understanding of development is not just relevant to congenital kidney malformations, but may also be important in designing rational therapies for diseases of the mature kidney where recapitulation of developmental pathways is common.
Congenital solitary functioning kidney
Authors: Schreuder Michiel F.
Published: November 2015

The main cause for unilateral non-formation or non-functioning of a kidney can be found in renal agenesis/aplasia and multicystic dysplastic kidney. Even though kidney donation at adult age is considered safe, studies in recent years have shown that this may be different in congenital solitary functioning kidneys. Whether this is based on dysplasia in the remaining kidney or based on glomerular hyperfiltration damage, follow-up has shown renal injury, defined as hypertension and/or proteinuria, in up to 32% of children with a congenital solitary functioning kidney. Therefore, long-term infrequent follow-up of all patients with a congenital solitary functioning kidney seems to be indicated.