kidney Disease Lecture 4
Introduction • The kidneys play a central role in the homeostatic mechanisms of the human body, and reduced renal function strongly correlates with increasing morbidity and mortality. • Biochemical investigations, both routine and specialized, are an important part of the clinician’s diagnostic tools, and investigations of kidney function constitute a significant element of the workload of most laboratories. • The aim of this chapter is to ensure that the clinical chemist/biochemist understands the perspective of the nephrologist when dealing with laboratory investigations for patients with kidney disease.
ANATOMYNephron • The functional unit of the kidney is the nephron. • Each kidney has been reported to contain between 600,000 and 1.5 million nephrons. • The number of nephrons that an individual isborn with (the “nephron dose”) may determine that individual’s susceptibility to renal injury. • The nephron consists of: • A glomerulus, • Proximal tubule, • Loop of Henle, • Distal tubule, and • Collecting duct
ANATOMY/NephronGlomerulus • Mesangial cells and mesangial matrix provide structural support for the glomerular capillaries. • On the urinary side of the glomerular basement membrane are podocytes, with foot processes that wrap around the glomerular capillaries. • The glomerular filtration barrier is a specialized molecular sieve, with properties that aid filtration of small solutes from the blood to the urine, while limiting the passage of macromolecules such as albumin.
KIDNEY FUNCTION AND PHYSIOLOGY • The kidneys regulate and maintain the constant optimal chemical composition of the blood and the interstitial and intracellular fluids throughout the body through integration of the major renal functions namely: • Filtration, reabsorption, and excretion. • Mechanisms of differential reabsorption and secretion, located in the tubule of a nephron, are the effectors of regulation.
KIDNEY FUNCTION AND PHYSIOLOGY Glomerular Filtration Rate • The GFR is considered to be the most reliable measure of the functional capacity of the kidneys • indicative of the number of functioning nephrons. • As a physiologic measurement, it has proved to be the most sensitive and specific marker of changes in overall renal function. • The rate of formation of glomerular filtrate depends on the balance between hydrostatic and oncotic forces along the afferent arteriole and across the glomerular filter. • The net pressure difference must be sufficient not only to drive filtration across the glomerular filtration barrier but also to drive the ultrafiltrate along the tubules against their inherent resistance to flow.
KIDNEY FUNCTION AND PHYSIOLOGY Glomerular Filtration Rate • In the absence of sufficient pressure, the lumina of the tubules will collapse. • This balance of forces can be expressed as follows: • Where: • Kf = (hydraulic permeability × surface area) • PGCap= glomerular-capillary hydrostatic pressure • ΠBC = oncotic pressure in Bowman’s capsule • PBC = hydrostatic pressure in Bowman’s capsule • ΠGCap= oncotic pressure in the glomerular capillary
KIDNEY FUNCTION AND PHYSIOLOGY/Glomerular Filtration Rate Regulation of GFR • Factors That Influence the Glomerular Filtration Rate
KIDNEY FUNCTION AND PHYSIOLOGY/Glomerular Filtration Rate Regulation of GFR There are other factors that influence renal blood flow. • The afferent and efferent arterioles • Theyare richly supplied with renal sympathetic nerves. • Epinephrineacts via α-adrenergic receptors, leading to constriction of both arterioles and causing a decrease in renal blood flow. • Nitric oxide (NO) • It has been identified as an important vasodilator produced by vascular endothelial cells. • NO is synthesized from L-arginine and oxygen bynitric oxide synthase(NOS), of which three isoenzymes are differentially located and regulated. • Within the kidney are eNOS (endothelial) and iNOS (inducible) isoenzymes.
KIDNEY FUNCTION AND PHYSIOLOGY/Glomerular Filtration Rate Regulation of GFR • Activation of NOS has been shown to occur as a result of shear stress (eg, increased arteriolar tone “constriction”). • A variety of physiologic vasoconstrictors are present, including acetylcholine, bradykinin, endothelin, andserotonin; a rise in intracellular ionized calcium is required for the vasoconstrictors. • NO synthesis is now known to play an important role in the regulation of human vascular tone and has a crucial role in control of blood pressure and kidneyfunction. • NOS has also been found in the macula densaand has been implicated in the regulation of renin release.
KIDNEY FUNCTION AND PHYSIOLOGY/Glomerular Filtration Rate Regulation of GFR
KIDNEY FUNCTION AND PHYSIOLOGY/Glomerular Filtration Rate Regulation of GFR NE, Negligible; N, negative; P, positive; RBF, renal blood flow; GFR, glomerular filtration rate.
PATHOPHYSIOLOGY OF KIDNEY DISEASE • Despite the diverse initial causes of injury to the kidney, progression of kidney disease leading to loss of function and ultimately to kidney failure is a remarkably monotonous process characterized by: • Early inflammation, followed by • Accumulation and deposition of extracellular matrix, • Tubulointerstitial fibrosis, • Tubular atrophy, and • Glomerulosclerosis. • Proteinuria is thought to be one of the most important risk factors for progression of kidney diseases
PATHOPHYSIOLOGY OF KIDNEY DISEASE • Proteinuria is not only a marker of but also contributes directly to progression of kidney disease. • The accumulation of proteins in abnormal amounts in the tubular lumen may trigger an inflammatory reaction, which in turn may contribute to interstitial structural damage and expansion, and progression of kidney disease. • Increasing evidence suggests that megalin maynot just be a scavenger receptor for albumin but that it may have signaling functions that regulate cell survival. • Excessive quantities of albumin in the tubular lumen may downregulate proximal tubular megalin expression, increasing cell sensitivity to apoptosis.
PATHOPHYSIOLOGY OF KIDNEY DISEASE • Nephrons are also lost via toxic, anoxic, or immunologic injury that initially may occur in the glomerulus, the tubule, or both together. • Glomerular damage can involve endothelial, epithelial, or mesangial cells and/or the basement membrane.
PATHOPHYSIOLOGY OF KIDNEY DISEASE • The Renin Angiotensin Aldosterone System (RAAS) plays a pivotal role in many of the pathophysiologic changes that cause kidney injury and is an important therapeutic target. • Renal cells are able to produce Angiotensin II (AII) in a concentration that is much higher than in the systemic circulation, and (AII) generates potentially toxic ROS within renal cells affecting signal transduction. • In addition, many profibrogenic and proinflammatory mediators are induced within the kidney by (AII).
PATHOPHYSIOLOGY OF KIDNEY DISEASE • Aldosterone has been reported to enhance profibrogenic processes also. • Inflammatory mediators released include cytokines, chemokines, and growth factors,and tissue necrosis factor-α (TNF-α); these inflammatory factors activate resident lymphocytes and macrophages and recruit additional cells from the peripheral circulation. • Thus cellular infiltration is a common but not a universal finding in renal biopsy specimens. • These activated cells can cause T cell–mediated cell lysis, activation, and proliferation of interstitial fibroblasts.
PATHOPHYSIOLOGY OF KIDNEY DISEASE • Fibroblast activity results in increased extracellular matrix synthesis and eventually in glomerular and tubular fibrosis. • Extracellular matrix expansion causesdisruption of local blood flow, exaggerating regional ischemia, and a vicious cycle of inflammation, fibrosis, and cell death is propagated.
PATHOPHYSIOLOGY OF KIDNEY DISEASE • The kidneys have considerable ability to increase their functional capacity in response to injury. • Thus a significant reduction in functioning renal mass (50% to 60%) may occur before the onset of any significant symptoms or even before any major biochemical alterations appear. • The most sensitive and specific measure of functional change—the GFR—can be reduced to less than 60 mL/min/1.73 m2 before signs and symptoms of kidney failure will be observed. • This increase in workload per nephron is thought to be an important cause of progressive renal injury.
PATHOPHYSIOLOGY OF KIDNEY DISEASEClinical Manifestations • Most often kidney disease is detected by coincidence by measurement of blood pressure and urine and blood testing in asymptomatic individuals. • Typical findings include isolated hematuria and isolated proteinuria. • Kidney disease may also present with macroscopic hematuria, swollen ankles, headaches and visual disturbances due to severe hypertension. • Symptoms suggestive of advanced kidney disease include fatigue, nausea, vomiting, poor appetite, shortness of breath, fluid retention, poor memory, loss of libido, and itching.
PATHOPHYSIOLOGY OF KIDNEY DISEASEClinical Manifestations • Kidney disease may present with heavy blood and protein detected in a sample of the urine—a so-called “active urinary sediment.” • An acute “nephritic” syndrome may occur as the result of postinfectious glomerulonephritis—for example, following a streptococcal throat or skin infection. • The patient presents with poor urine output, edema, hypertension, and brown-colored urine.
PATHOPHYSIOLOGY OF KIDNEY DISEASEClinical Manifestations • Proteinuria may be the only indicator of kidney disease in many people. Proteinuria, particularly if in excess of 1 g/d, is indicative of glomerular disease. • Kidney disease presenting as nephrotic syndrome is characterized by 3 things: heavy proteinuria (typically defined as exceeding an arbitrary threshold of 3 g/d), hypoalbuminemia, and edema.
DISEASES OF THE KIDNEYHypertensive Nephropathy • Hypertension is second only to diabetes as a primary diagnosis of ESRD for incident patients on dialysis in the United States • Hypertension often develops as a consequenceof CKD because of alterations in salt and water metabolism and activation of the sympathetic nervous and renin-angiotensin systems. • Hypertension can act as an accelerating forcein the development of ESRD. • Treatment of hypertension to predefined target blood pressure values is critical in preventing progression to ESRD.
DISEASES OF THE KIDNEYHypertensive Nephropathy • Large vessel renovascular disease can cause hypertension. • Primary diseases of the renal arteries usually involve the origin of the renal arteries at the aorta. • Secondary diseases with hypertension and CKD with small vessel and intrarenal disease are referred to as ischemic nephropathy. • A complex interplay occurs between renal artery stenosis and ischemic nephropathy. • Atherosclerosis accounts for more than 90% of renal artery stenosis. • The disease is progressive and may cause renal artery occlusion.
DISEASES OF THE KIDNEYGlomerular Disease • Glomerular disease is suggested clinically by the finding of blood and protein in the urine on urine reagent strip testing. • Proteinuria of greater than 1 g/day in the absence of an overflow-type proteinuria, such as myoglobinuria or light chain–related disease, is invariably glomerular in origin.
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease • Glomerulonephritis can be: • Primary (affecting only the kidneys) or • Secondary (in which the kidneys are involvedas part of a systemic process). • Histopathologic classification of glomerulonephritis may appear slightly cumbersome, but it is readily simplified by consideration of: • the glomerular structures and • cells that may be involved and • the presence or absence of immune complexes
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease • In principle, only three cell types are involved—endothelial, epithelial, and mesangial—plus the acellular GBM. • The glomerular cells and the GBM have a limited range of response to injury—namely, proliferation, scarring (sclerosis), and GBM thickening. • The term focalis used if fewer than half of the glomeruli are involved in the disease process as seen on light microscopy, • whereas diffuse glomerulonephritis refers to cases in which all glomeruli are involved.
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease IgA Nephropathy • It is the most common type of glomerulonephritis worldwide where it is commonly reported as an incidental finding in kidney biopsy specimens from potential kidney donors • Up to 50% of patients exhibit increased concentrations of serum IgA, although diagnosis depends on kidney biopsy findings. • Clinical presentation varies considerably from asymptomatic microscopic hematuria to macroscopic hematuria; proteinuria includingnephrotic syndrome; and kidney failure.
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease • Mesangial deposits of immunoglobulin A (IgA). • No treatment is available that specifically modifies mesangial deposition of IgA, and available options are limited to downstream immune and inflammatory events that may lead to scarring Fluoresceinated Anti-IgA Antibody, Immunofluorescence microscopy, original magnification 400x.
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease Nephrotic Syndrome • Nephrotic syndrome is defined as: • heavy proteinuria (>3 g/d), • reduced serum albumin concentration, and • edema. • Nephrotic patients may exhibit a mild urinary sediment with little hematuria. • Nephrotic syndrome can occur at any age from neonate to elderly. • Although the underlying kidney disease tends to vary with age, in all cases the lesion is within the glomerulus and is associated with damage to the specialized visceral epithelial cells, the podocytes.
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease • Proteinuria is a consequence of areduction in the charge-selective properties of the filtration barrier, particularly the GBM, and of alterations in the slit diaphragms of podocytes
DISEASES OF THE KIDNEY/Glomerular Disease Primary Glomerular Disease • The most common causes of nephrotic syndrome are minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy. • Secondary causes include diabetic nephropathy, amyloidosis, and SLE. • A kidney biopsy is generally undertaken in all adult patients who present with nephrotic syndrome. • Nephrotic syndrome is associated with significant morbidity regardless of cause, and patients withthe disease have increased cardiovascular disease as a result of marked hyperlipidemia.
DISEASES OF THE KIDNEY/Glomerular DiseaseAcute Nephritic Syndrome • It is characterized by rapid onset of hematuria, proteinuria, reduced GFR, and sodium and water retention, with resulting hypertension and localized peripheral edema. • Congestive heart failure and oliguria may also develop. • In a number of patients with the acute nephritic syndrome, the pathologic process is related to recent group A β-hemolytic streptococcal infection of the pharynx or, less commonly, the skin. • Only certain strains of streptococci are capable ofinducing acute nephritis. • 2 weeks exists between the time of streptococcal infection and clinical evidence of nephritis. • Evidence of recent infection may be found in increased titers of antibodies to streptococcal extracellular products: antistreptolysin O.
DISEASES OF THE KIDNEY/Glomerular DiseaseAcute Nephritic Syndrome • Abnormal laboratory results are usually present early in the course of acute nephritis. • Hematuria, which may be gross (“cola-colored” urine) or microscopic, and proteinuria, usually less than 3 g/d, are almost always present. • Red blood cell casts are highly suggestive of glomerulonephritis. • Other causes of acute nephritis include: • Reactions to drugs, • Acute infection of the kidneys, • Systemic disease with immune complexes such as SLE, bacterial endocarditis, and • Disease in which the antigen is unknown but is possibly related to precursor viral infection.
DISEASES OF THE KIDNEYProstaglandins and NSAIDs in Kidney Disease • NSAIDs block synthesis of prostaglandins by COX. • Two isoforms of COX synthesize prostaglandins. • COX-1 is a resident or constitutive form, and COX-2 is an inducible form that increases with disorders of inflammation. • NSAIDs are nonspecific inhibitors of both COX isoforms. • Analgesic nephropathy is a common cause of incident kidney failure in many countries. • In Australia, for example, it contributes around 10% of incident ESRD cases, despite awareness of therisk of kidney damage from chronic analgesic ingestion.
DISEASES OF THE KIDNEYProstaglandins and NSAIDs in Kidney Disease • Although most healthy individuals tolerate NSAIDs well, a study of the older people (mean age, 88 years) demonstrated significant reduction of GFR within 1 week of ingestion of NSAIDs. • Renal blood flow, particularly within the medulla, is dependent on systemic and local production of vasodilatory prostaglandins, and analgesic-relatedkidney damage is seen mostly within the medulla, with late changes causing papillary necrosis and interstitial fibrosis. • Hyperkalemia can develop as a consequence of reduced GFR or secondary to hyporeninemic hypoaldosteronism.
DISEASES OF THE KIDNEYPolycystic Kidney Disease • Autosomal dominant polycystic kidney disease (ADPKD) is the second most common inherited monogenic disease (after familial hypercholesterolemia), with an estimated incidence of 1 :1000. • It is by far the most common inherited kidney disease; 12.5 million people worldwide are affected. • In the United Kingdom, ADPKD is responsible for 11% of new ESRD in patients aged younger than 65 years and 4% of incident patients over age 65 years. • The prevalence of the disease ranges from 1 in 200 to 1 in 1000 of the population, but many cases, possibly up to 50%, remain clinically undiagnosedduring life.
DISEASES OF THE KIDNEYPolycystic Kidney Disease • Approximately 50% of ADPKD patients develop kidney failure by age 55 years. • It is therefore important to make the diagnosis in affected families and to monitor kidney function regularly. • The intervals between estimations of GFR will depend on the stage of CKD, as with other progressive kidney diseases. • Hypertension is an early and frequent manifestation, and gross hematuria is a common presenting symptom. • On the basis of effectiveness, cost, and safety, ultrasound is the imaging modality most commonly used to make the diagnosis.
DISEASES OF THE KIDNEYPolycystic Kidney Disease • In polycystic kidney disease, many cysts form in both kidneys. • The cysts gradually enlarge, destroying some or most of the normal tissue in the kidneys.
DISEASES OF THE KIDNEYPolycystic Kidney Disease • ADPKD is caused by mutations in the genes (PKD1 and PKD2) that encode polycystin 1 and 2, which are located in primary cilia. • Mutations affecting PKD1 are more prevalent than those of PKD2 and tend to have a worseprognosis, with larger kidneys and earlier development of kidney failure. • Genetic testing is not used routinely as ascreening tool because current techniques identify only 70% of the hundreds of different PKD1 and PKD2 mutations.
DISEASES OF THE KIDNEYObstructive Uropathy • Benign prostatic hyperplasia (BPH) is one of the most common types of obstructive uropathy and is an almost universal finding in aging men. • For example, for men aged 50 years, the reported prevalence of BPH is 40%, and for men aged over 70 years, it is at least 75%. • Among the most common symptoms are disorders of urination, in particular increased frequency, and in many cases this can progress to bladder outflow obstruction. • Between 10% and 40% of men with bladder outflow obstruction caused by BPH present in acute retention.
DISEASES OF THE KIDNEYObstructive Uropathy • If the obstruction is not removed by surgery, progressive kidney injury can occur as a result of backpressure along the urinary tract. • It is important to identify those patients at risk of developing CKD because failure to remove their enlarged gland can cause kidney failure. • Obstruction can also occur because of kidney stones, which can cause bilateral or unilateral damage. • In children, severe kidney damage can be caused by vesicoureteric reflux. • One of the main complications of reflux, whether caused by obstruction or an inherited defect, is the increased incidence of urinary tract infection.
DISEASES OF THE KIDNEY/Tubular Disease Renal Tubular Acidosis • The RTAs constitute a diverse group of inherited andacquired disorders affecting the proximal or distal tubule. • They are characterized by a hyperchloremic, normal anion gap; metabolic acidosis; and urinary bicarbonate or hydrogen ion excretion inappropriate for the plasma pH. • They may result from failure to retain bicarbonate or from the inability of the renal tubules to secrete hydrogen ion. • Typically, the GFRs in RTAs are normal or slightly reduced, and there is no retention of anions, such as phosphate and sulfate. • The three categories of RTA are: • Distal (dRTA, type I); • Proximal (pRTA, type II); and • Type IV, which occurs secondary to aldosterone deficiencyor resistance.
DISEASES OF THE KIDNEY/Tubular Disease Renal Tubular Acidosis • Distal RTA (Type I) • Type I dRTA occurs most often in infants (sometimes transiently) and young children, but it may also be encountered in adults, in whom it is morecommon than pRTA. • Clinical features generally include metabolic acidosis, muscle weakness, nephrocalcinosis (ie, diffuse, fine, renal parenchymal calcification), and urolithiasis (ie, the formation of calculi in the urinary tract). • Biochemical features typically include hypokalemia, hypocitraturia, and low urinary ammonium ion. • Several subtypes may be seen, and urinary pH greater than 5.5 is a common feature.
DISEASES OF THE KIDNEY/Tubular Disease Renal Tubular Acidosis • Distal RTA (Type I)……. • Classic Hypokalemic dRTA (Proton Secretion Defect) • Both inherited and acquired forms exist. • Inherited forms are associated with mutations in proteins involved in hydrogen ion secretion, including defects of H+, ATPase and anion exchanger 1, or to mutations in carbonic anhydrase. • Acquired impairment of the hydrogen ion secretion mechanism leading to dRTA may occur in association with a wide range of conditions, in particular a range of autoimmune disorders (eg, SLE) • Some medications, such as topiramate and acetazolamide, can also inhibit carbonic anhydrase, leading to dRTA.