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Journal: Nature reviews. Nephrology

37

Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.

Concepts: Nephrology, Corticosteroid, Systemic lupus erythematosus, Glomerulonephritis, Immunosuppressive drug, Lupus nephritis, Cyclophosphamide, Mycophenolic acid

32

The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARĪ± agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Nutrition, Glomerulus, Obesity, Renal physiology

28

Hyponatraemia-the most common serum electrolyte disorder-has also emerged as an important marker of the severity and prognosis of important diseases such as heart failure and cirrhosis. Acute hyponatraemia can cause severe encephalopathy, but the rapid correction of chronic hyponatraemia can also profoundly impair brain function and even cause death. With the expanding elderly population and the increased prevalence of hyponatraemia in this segment of society, prospective studies are needed to examine whether correcting hyponatraemia in the elderly will diminish cognitive impairment, improve balance and reduce the incidence of falls and fractures. Given that polypharmacy is also common in the elderly population, the various medications that may stimulate arginine vasopressin release and/or enhance the hormone’s action to increase water absorption must also be taken into consideration. Whether hyponatraemia in a patient with cancer is merely a marker of poor prognosis or whether its presence may alter the patient’s quality of life remains to be examined. In any case, hyponatraemia can no longer be considered as just a biochemical bystander in the ill patient. A systematic diagnostic approach is necessary to determine the specific aetiology of a patient’s hyponatraemia. Therapy must then be dictated not only by recognized reversible causes such as advanced hypothyroidism, adrenal insufficiency, diuretics or other medicines, but also by whether the hyponatraemia occurred acutely or chronically. Information is emerging that the vast majority of cases of hyponatraemia are caused by the nonosmotic release of arginine vasopressin. Now that vasopressin V2-receptor blockers are available, a new era of clinical investigation is necessary to examine whether hyponatraemia is just a marker of severe disease or whether correction of hyponatraemia could improve a patient’s quality of life. Such an approach must involve prospective randomized studies in different groups of patients with hyponatraemia, including those with advanced heart failure, those with cirrhosis, patients with cancer, and the elderly.

Concepts: Medicine, Disease, Causality, Death, Patient, Vasopressin, Hepatic encephalopathy, Hyponatremia

28

Relapses or flares of systemic lupus erythematosus (SLE) are frequent and observed in 27-66% of patients. SLE flares are defined as an increase in disease activity, in general, requiring alternative treatment or intensification of therapy. A renal flare is indicated by an increase in proteinuria and/or serum creatinine concentration, abnormal urine sediment or a reduction in creatinine clearance rate as a result of active disease. The morbidity associated with renal flares is derived from both the kidney damage due to lupus nephritis and treatment-related toxic effects. Current induction treatment protocols achieve remission in the majority of patients with lupus nephritis; however, few studies focus on treatment interventions for renal flares in these patients. The available data, however, suggest that remission can be induced again in a substantial percentage of patients experiencing a lupus nephritis flare. Lupus nephritis flares are independently associated with an increased risk of deterioration in renal function; prevention of renal flares might, therefore, also decrease long-term morbidity and mortality. Appropriate immunosuppressive maintenance therapy might lead to a decrease in the occurrence of renal and extrarenal flares in patients with SLE, and monitoring for the early detection and treatment of renal flares could improve their outcomes.

Concepts: Nephrology, Renal physiology, Rheumatology, Nephrotic syndrome, Systemic lupus erythematosus, Lupus erythematosus, Glomerulonephritis, Lupus nephritis

28

Acute metabolic acidosis is associated with increased morbidity and mortality because of its depressive effects on cardiovascular function, facilitation of cardiac arrhythmias, stimulation of inflammation, suppression of the immune response, and other adverse effects. Appropriate evaluation of acute metabolic acidosis includes assessment of acid-base parameters, including pH, partial pressure of CO(2) and HCO(3)(-) concentration in arterial blood in stable patients, and also in central venous blood in patients with impaired tissue perfusion. Calculation of the serum anion gap and the change from baseline enables the physician to detect organic acidoses, a common cause of severe metabolic acidosis, and aids therapeutic decisions. A fall in extracellular and intracellular pH can affect cellular function via different mechanisms and treatment should be directed at improving both parameters. In addition to supportive measures, treatment has included administration of base, primarily in the form of sodium bicarbonate. However, in clinical studies of lactic acidosis and ketoacidosis, bicarbonate administration has not reduced morbidity or mortality, or improved cellular function. Potential explanations for this failure include exacerbation of intracellular acidosis, reduction in ionized Ca(2+), and production of hyperosmolality. Administration of tris(hydroxymethyl)aminomethane (THAM) improves acidosis without producing intracellular acidosis and its value as a form of base is worth further investigation. Selective sodium-hydrogen exchanger 1 (NHE1) inhibitors have been shown to improve haemodynamics and reduce mortality in animal studies of acute lactic acidosis and should also be examined further. Given the important effects of acute metabolic acidosis on clinical outcomes, more intensive study of the pathogenesis of the associated cellular dysfunction and novel methods of treatment is indicated.

Concepts: Immune system, Better, Blood, PH, Acid-base homeostasis, Metabolic acidosis, Anion gap, Acidosis

28

Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. Primary MPGN was further classified into three types-type I, type II, and type III-based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies.

Concepts: Complement system, Classical complement pathway, Membranoproliferative glomerulonephritis

26

Many transplant recipients are not protected against vaccine-preventable illnesses, primarily because vaccination is still an underutilized tool both before and after transplantation. This missed opportunity for protection can result in substantial morbidity, graft loss and mortality. Immunization strategies should be formulated early in the course of renal disease to maximize the likelihood of vaccine-induced immunity, particularly as booster or secondary antibody responses are less affected by immune compromise than are primary or de novo antibody responses in naive vaccine recipients. However, live vaccines should be avoided in immunocompromised hosts. Although some concern has been raised regarding increased HLA sensitization after vaccination, no clinical data to suggest harm currently exists; overall, non-live vaccines seem to be immunogenic, protective and safe. In organ transplant recipients, some vaccines are indicated based on specific risk factors and certain vaccines, such as hepatitis B, can protect against donor-derived infection. Vaccines given to close contacts of renal transplant recipients can provide an additional layer of protection against infectious diseases. In this article, optimal vaccination of adult transplant recipients, including safety, efficacy, indication and timing, is reviewed.

Concepts: Immune system, Kidney, Infectious disease, Vaccine, Vaccination, Immunology, Organ transplant, Smallpox

26

The immune management of organ transplant recipients is imperfect. Beyond general dosing guidelines for immunosuppressive agents and clinical diagnostic tests for rejection or infection, there are few objective tools to determine the aggregate status of a patient’s alloimmune response or protective immune capacity. The lack of prognostic precision significantly contributes to patient morbidity and reduces long-term allograft survival after kidney transplantation. Noninvasive biomarkers that could serve as predictive tools or surrogate end points for rejection might help clinicians individualize immunosuppression and allow for early intervention, ideally prior to clinically evident organ dysfunction. Although the growing understanding of organ rejection has provided numerous candidate biomarkers, none has been confirmed in robust validation studies as sufficiently useful to guide clinical practice independent of traditional clinical methods. In this Review, the general characteristics of biomarkers and surrogate end points; current biomarkers under active clinical investigation; and the prominent barriers to the translation of biomarkers into clinical practice are discussed.

Concepts: Immune system, Immunology, Organ transplant, Kidney transplantation, Transplant rejection, Immunosuppressive drug, Transplantation medicine, Ciclosporin

21

Intravenous fluid therapy is one of the most common interventions in acutely ill patients. Each day, over 20% of patients in intensive care units (ICUs) receive intravenous fluid resuscitation, and more than 30% receive fluid resuscitation during their first day in the ICU. Virtually all hospitalized patients receive intravenous fluid to maintain hydration and as diluents for drug administration. Until recently, the amount and type of fluids administered were based on a theory described over 100 years ago, much of which is inconsistent with current physiological data and emerging knowledge. Despite their widespread use, various fluids for intravenous administration have entered clinical practice without a robust evaluation of their safety and efficacy. High-quality, investigator-initiated studies have revealed that some of these fluids have unacceptable toxicity; as a result, several have been withdrawn from the market (while others, controversially, are still in use). The belief that dehydration and hypovolaemia can cause or worsen kidney and other vital organ injury has resulted in liberal approaches to fluid therapy and the view that fluid overload and tissue oedema are ‘normal’ during critical illness; this is quite possibly harming patients. Increasing evidence indicates that restrictive fluid strategies might improve outcomes.

9

The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, however, with new studies demonstrating that inhibition of renal glucose reabsorption reduces blood pressure, ameliorates glucotoxicity and induces haemodynamic effects that lead to improved cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. In this Review we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease.

Concepts: Kidney, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Glucose, Urine, Renal physiology, Blood sugar