2Learning Objectives (1 of 2) Describe normal structure and functions of the kidneysExplain pathogenesis and clinical manifestations of glomerulonephritis, nephrosis, nephrosclerosis, and glomerulosclerosisDescribe clinical manifestations and complications of urinary tract infectionsDescribe causes of renal tubular injury, manifestations, treatment
3Learning Objectives (2 of 2) Explain mechanism of urinary tract calculi formation, complications, manifestations of urinary tract obstructionDifferentiate major forms of cystic disease of the kidney and prognoses; common tumors affecting urinary tractDescribe causes, clinical manifestations, treatment of renal failureDescribe principles and techniques of hemodialysis
4Urinary System Kidneys: produce urine Excretory duct system Ureter: conveys urine into bladder by peristalsisRenal pelvis: expanded upper portion of ureterMajor calyces: subdivisions of renal pelvisMinor calyces: subdivisions of major calyces into which renal papillae dischargeBladder: stores urineDischarges urine into urethra during voidingAnatomic configuration of bladder and ureters normally prevents reflux of urine into uretersUrethra: conveys urine from the bladder for excretion
9Kidneys (1 of 2)Paired, bean-shaped organs below diaphragm adjacent to vertebral columnDivided into outer cortex and inner medulla (renal pyramids and columns)Excretory organs, functions along with lungs in excreting waste products of food metabolismThree basic functions1. Excrete waste products of food metabolismCO2 and H2O: end-products of carbohydrate and fat metabolismUrea and other acids: end-products of protein metabolism that only the kidneys can excrete
10Kidneys (2 of 2) 2. Regulate mineral and H2O balance Excretes excess minerals and H20 ingested and conserving them as requiredBody’s internal environment is determined not by what a person ingests but by what the kidneys retain3. Produces erythropoietin and renin: specialized cells in the kidneysErythropoietin: regulates RBC production in marrowRenin: helps regulate blood pressure
11Nephron (1 of 2) Basic structural and functional unit of the kidney About 1 million nephrons in each kidneyConsists of glomerulus and renal tubuleGlomerulusTuft of capillaries supplied by an afferent glomerular arteriole that recombine into an efferent glomerularMaterial is filtered by a 3-layered glomerular filterInner: fenestrated capillary endotheliumMiddle: basement membraneOuter: capillary endothelial cells (with foot processes and filtration slits)Mesangial cells: contractile phagocytic cells that hold the capillary tuft together; regulate caliber of capillaries affecting filtration rate
12Nephron (2 of 2)Renal tubule: reabsorbs most of filtrate; secretes unwanted components into tubular fluid; regulates H2O balanceProximal end: Bowman’s capsuleDistal end: empties into collecting tubulesRequirements for normal renal functionFree flow of blood through the glomerular capillariesNormally functioning glomerular filter that restricts passage of blood cells and proteinNormal outflow of urine
13A representation of fine structure of glomerular filter as visualized by electron microscopy. Segment of glomerular capillaries
14A representation of fine structure of glomerular filter as visualized by electron microscopy. Cross-section through the center of the glomerulus.
15The structure of the renal tubule, illustrating its relationship to the glomerulus and the collecting tubule.
17Renal Regulation of Blood Pressure Renin: released in response to decreased blood volume, low blood pressure, low sodiumAngiotensin I → angiotensin II by angiotensin converting enzyme (ACE) as blood flows through the lungsAngiotensin II:Powerful vasoconstrictor: raises blood pressure by causing peripheral arterioles to constrictStimulates aldosterone secretion from adrenal cortex: increases reabsorption of NaCl and H2O by kidneysNet effect: higher blood pressure, increased fluid in vascular systemSystem is self-regulating
18The role of the kidneys in regulation of blood pressure and blood volume.
19Developmental Abnormalities Developmental process is disturbedNormal developmentKidneys arise from mesoderm, develop in pelvis, ascend to final positionBladder derived from lower end of intestinal tractExcretory ducts (ureters, calyces, pelves) develop from ureteric buds that extend from bladder into the developing kidneys
22Three congenital abnormalities results Renal agenesis: failure of one or both kidneys to developBilateral: rare, associated with other congenital anomalies, incompatible with lifeUnilateral: common, asymptomatic; other kidney enlarges to compensateDuplications of urinary tractComplete duplication: formation of extra ureter and renal pelvisIncomplete duplication: only upper part of excretory system is duplicatedMalposition: one or both kidneys, associated with fusion of kidneys; horseshoe kidney; fusion of upper pole
23Common congenital abnormalities of kidneys and urinary tract
24GlomerulonephritisInflammation of the glomeruli caused by antigen-antibody reaction within the glomeruliImmune-complex glomerulonephritisUsually follows a beta-streptococcal infectionCirculating antigen and antibody complexes are filtered by glomeruli and incite inflammationLeukocytes release lysosomal enzymes that cause injury to the glomeruliOccurs in SLE; immune complexes trapped in glomeruliOccurs in IgA nephropathyAnti-glomerular basement membrane (anti-GBM) glomerulonephritis: autoantibodies attack glomerular basement membrane
25Glomerulonephritis, also known as glomerular nephritis, is a renal disease (usually of both kidneys) characterized by inflammation of the glomeruli, or small blood vessels in the kidneysThey are categorized into several different pathological patterns, which are broadly grouped into non-proliferative or proliferative types. Diagnosing the pattern of GN is important because the outcome and treatment differs in different types. Primary causes are ones which are intrinsic to the kidney, whilst secondary causes are associated with certain infections (bacterial, viral or parasitic pathogens), drugs, systemic disorders (SLE, vasculitis) or diabetes.
26Non ProliferativeThis is characterized by the numbers of cells (lack of hypercellularity) in the glomeruli. They usually cause nephrotic syndrome. This includes the following types:Minimal change GN (also known as Minimal Change Disease) causes 80% of nephrotic syndrome in children, but only 20% in adults. As the name indicates, there are no changes visible on simple light microscopy, but on electron microscopy there is fusion of podocytes (supportive cells in the glomerulus).Membranous glomerulonephritis a relatively common type of glomerulonephritis in adults, frequently produces a mixed nephrotic and nephritic picture. It's cause is usually unknown, but may be associated with cancers of the lung and bowel, infection such as hepatitis and malaria, drugs including penicillamine, and connective tissue diseases such as systemic lupus erythematosus.
27ProliferativeThis type is characterized by increased number of cells in the glomerulus. Usually present as a nephritic syndrome and usually progress to end-stage renal failure (ESRF) over weeks to years (depending on type).IgA nephropathy (Berger's disease)IgA nephropathy is the most common type of glomerulonephritis in adults worldwide. It usually presents as macroscopic hematuria (visibly bloody urine). It occasionally presents as a nephrotic syndrome. It often affects young males within days (24-48hrs) after an upper respiratory tract or gastrointestinal infection. Microscopic examination of biopsy specimens shows increased number of mesangial cells with increased matrix (the 'cement' which holds everything together).
32Nephrotic versus Nephritic Syndrome Nephritic syndrome is a collection of signs (syndrome) associated with disorders affecting the kidneys, more specifically glomerular disorders. It's characterized by having small pores in the podocytes of the glomerulus, large enough to permit proteins (proteinuria) and red blood cells (hematuria) to pass into the urine. By contrast, nephrotic syndrome is characterized by only proteins (proteinuria) moving into the urine. Both nephritic syndrome and nephrotic syndrome result in hypoalbuminemia due to protein albumin moving from the blood to the urine.
36Nephrotic Syndrome (1 of 2) Marked loss of protein in the urineUrinary excretion of protein > protein productionProtein level in blood fallsCauses edema due to low plasma osmotic pressureClinical manifestationsMarked leg edemaAscites
37Nephrotic Syndrome (2 of 2) PrognosisIn children: minimal glomerular change, complete recoveryIn adults: a manifestation of severe progressive renal diseaseMay result fromGlomerulonephritisDiabetes (causing glomerular changes)Systemic lupus erythematosus, SLEOther kidney diseases
38Arteriolar Nephrosclerosis Complication of severe hypertensionRenal arterioles undergo thickening from carrying blood at a much higher pressure than normalGlomeruli and tubules undergo secondary degenerative changes causing narrowing of lumen and reduction in blood flowReduced glomerular filtrationKidneys shrinkMay die of renal insufficiency
40Diabetic Nephropathy Kimmelstiel-Wilson syndrome Complication of long-standing diabetesNodular and diffuse thickening of glomerular basement membranes (glomerulosclerosis), usually with coexisting nephrosclerosisManifestationsProgressive impairment of renal functionProtein loss may lead to nephrotic syndromeNo specific treatment can arrest progression of diseaseProgressive impairment of renal function may lead to renal failure
44Gout Nephropathy Pathogenesis Manifestations Elevated blood uric acid levels lead to ↑uric acid in tubular filtrateUrate may precipitate in Henle’s loops and collecting tubulesTubular obstruction causes damageManifestationsImpaired renal functionMay lead to renal failureCommon in poorly-controlled gout
46Section of kidney revealing white urate deposits within renal pyramid and large urate deposit near tip of pyramid
47Urinary Tract Infections (1 of 2) Very common; maybe acute or chronicMost infections are caused by gram-negative bacteriaOrganisms contaminate perianal and genital areas and ascend urethraConditions protective against infectionFree urine flowLarge urine volumeComplete bladder emptyingAcid urine: most bacteria grow poorly in an acidic environment
48Urinary Tract Infections (2 of 2) Predisposing factorsAny condition that impairs free drainage of urineStagnation of urine favors bacterial growthInjury to mucosa by kidney stone disrupts protective epithelium allowing bacteria to invade deeper tissueIntroduction of catheter or instruments into bladder may carry bacteria
49Cystitis Affects only the bladder Clinical manifestations More common in women than men; shorter female urethra, and, in young sexually active women, sexual intercourse promotes transfer of bacteria from urethra to bladderCommon in older men, because enlarged prostate interferes with complete bladder emptyingClinical manifestationsBurning pain on urinationDesire to urinate frequentlyUrine contains many bacteria and leukocytesResponds well to antibioticsMay spread upward into renal pelvis and kidneys
51Pyelonephritis Involvement of upper urinary tract from Ascending infection from the bladder (ascending pyelonephritis)Carried to the kidneys from the bloodstream (hematogenous pyelonephritis)Clinical manifestations: similar with an acute infectionLocalized pain and tenderness over affected kidneyResponds well to antibioticsCystitis and pyelonephritis are frequently associatedSome cases become chronic and lead to kidney failure
52Vesicoureteral Reflux Urine normally prevented from flowing back into the ureters during urinationFailure of mechanisms allows bladder urine to reflux into ureter during voidingPredisposes to urinary tract infectionPredisposes to pyelonephritis
55Urinary Calculi (1 of 3) Stones may form anywhere in the urinary tract Predisposing factorsHigh concentration of salts in urine saturates urine causing salts to precipitate and form calculiUric acid in goutCalcium salts in hyperparathyroidismUrinary tract infections reduce solubility of salts in urine; clusters of bacteria are sites where urinary salts may crystallize to form stoneUrinary tract obstruction causes urine stagnation, promotes stasis and infection, further increasing stone formation
56Urinary Calculi (2 of 3)Staghorn calculus: urinary stones that increase in size to form large branching structures that adopt to the contour of the pelvis and calycesSmall stones may pass through ureters causing renal colicSome become impacted in the ureter and need to be removedManifestationsRenal colic associated with passage of stoneObstruction of urinary tract causes hydronephrosis-hydroureter proximal to obstruction
57Urinary Calculi (3 of 3) Treatment Cystoscopy: snares and removes stones lodged in distal ureterShock wave lithotripsy: stones lodged in proximal ureter are broken into fragments that are readily excreted
63Stress Urinary Incontinence Involuntary loss of urine due to increases in intra-abdominal pressure
64HypospadiasAn epispadias is a rare type of malformation of the penis in which the urethra ends in an opening on the upper aspect (the dorsum) of the penis. It can also develop in females when the urethra develops too far anteriorly. It occurs in around 1 in 120,000 male and 1 in 500,000 female births
65Urinary ObstructionBlockage of urine outflow leads to progressive dilatation of urinary tract proximal to obstruction, eventually causes compression atrophy of kidneysManifestationsHydroureter: dilatation of ureterHydronephrosis: dilatation of pelvis and calycesCausesBilateral: obstruction of bladder neck by enlarged prostate or urethral strictureUnilateral: ureteral stricture, calculus, tumorComplications: stone formation; infectionsDiagnosis and treatment: pyelogram, CT scan
66Posterior urethral valves is a congenital defect in males that results in obstruction of the bladder due to extra tissue that projects into the urethra. This excess tissue blocks urine from flowing freely from the bladder to the outside of the body. This blockage, if not corrected, can cause problems in all the organs in the urinary system including the kidneys, ureters, urethra and bladder.
67Possible locations and results of urinary tract obstruction
71Foreign Bodies in Urinary Tract Usually inserted by patientMay injure bladderPredispose to infectionTreatmentUsually removed by cystoscopyOccasionally necessary to open bladder surgically
72X-ray film illustrating foreign body in bladder.
73Renal Tubular Injury Pathogenesis Clinical manifestation Impaired renal blood flowTubular necrosis caused by toxic drugs or chemicalsClinical manifestationAcute renal failure: oliguria, anuriaTubular function gradually recoversTreated by dialysis until function returns
74Renal CystsSolitary cysts common; not associated with impairment of renal functionMultiple cystsCongenital polycystic kidney diseaseMost common cause of multiple cystsMendelian dominant transmissionCysts enlarge and destroy renal tissue and functionOnset of renal failure by late middle ageSuspected by physical examination that reveals greatly enlarged kidneysSome form cysts in liver or cerebral aneurysm
76Renal Tumors Cortical tumors: arise from epithelium of renal tubules Adenomas: usually small and asymptomaticCarcinomas more commonHematuria often first manifestationInvades renal vein and metastasizes into bloodstreamTreated by nephrectomyTransitional cell tumor: Arise from transitional epithelium lining urinary tractMost arise from bladder epitheliumHematuria: common first manifestationLow grade malignancy; good prognosis
77Renal cell carcinoma (Clear Cell) is a kidney cancer that originates in the lining of the proximal convoluted tubule. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases. It is also known to be the most lethal of all the genitourinary tumors. Initial treatment is most commonly a radical or partial nephrectomy and remains the mainstay of curative treatment. Where the tumour is confined to the renal parenchyma, the 5-year survival rate is 60-70%, but this is lowered considerably where metastases have spread. It is resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy.
79Wilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults. Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon (1867–1918) who first described this kind of tumor.Approximately 500 cases are diagnosed in the U.S. annually. The majority (75%) occurs in otherwise normal children; a minority (25%) is associated with other developmental abnormalities. It is highly responsive to treatment, with about 90% of patients surviving at least five years.
82Renal Failure (Uremia) (1 of 2) Retention of excessive byproducts of protein metabolism in the bloodAcute renal failureCauses: tubular necrosis from impaired blood flow to kidneys or effects of toxic drugsRenal function usually returnsChronic renal failureFrom progressive, chronic kidney disease; > 50% from chronic glomerulonephritisOthers include congenital polycystic kidney disease, nephrosclerosis, diabetic nephropathy
83Renal Failure (Uremia) (2 of 2) Clinical manifestationsWeakness, loss of appetite, nausea, vomitingAnemiaToxic manifestations from retained waste productsEdema: retention of salt and waterHypertensionTreatmentHemodialysis
84HemodialysisSubstitutes for the functions of the kidneys by removing waste products from patient’s bloodWaste products in patient’s blood diffuse across a semipermeable membrane into a solution (dialysate) into the other side of the membraneTwo typesExtracorporeal dialysis (more common): patient’s circulation connected to an artificial kidney machinePeritoneal dialysis (less common): patient’s own peritoneum is used as the dialyzing membrane
85Hemodialysis removes wastes and water by circulating blood outside the body through an external filter, called a dialyzer, that contains a semipermeable membrane. The blood flows in one direction and the dialysate flows in the opposite. The counter-current flow of the blood and dialysate maximizes the concentration gradient of solutes between the blood and dialysate, which helps to remove more urea and creatinine from the blood.The concentrations of solutes (for example potassium, phosphorus, and urea) are undesirably high in the blood, but low or absent in the dialysis solution and constant replacement of the dialysate ensures that the concentration of undesired solutes is kept low on this side of the membrane.
86The dialysis solution has levels of minerals like potassium and calcium that are similar to their natural concentration in healthy blood. For another solute, bicarbonate, dialysis solution level is set at a slightly higher level than in normal blood, to encourage diffusion of bicarbonate into the blood, to act as a pH buffer to neutralize the metabolic acidosis that is often present in these patients
88In peritoneal dialysis, wastes and water are removed from the blood inside the body using the peritoneal membrane of the peritoneum as a natural semipermeable membrane. Wastes and excess water move from the blood, across the peritoneal membrane, and into a special dialysis solution, called dialysate, in the abdominal cavity which has a composition similar to the fluid portion of blood.
90Organ Transplants Four varieties Autografts: from one body site to another in the same personIsografts: between identical twinsAllografts: between individuals who are not identical twinsXenografts: from another animal species
91Renal Transplantation (1 of 2) Attempted when kidneys failKidney is from a close relative donor or cadaverSurvival of transplant depends on similarity of HLA antigens between donor and recipientOnly identical twins have identical HLA antigens in their tissues; others invariably contain foreign HLA antigensConsequently, patient’s immunologic defenses will respond to the foreign antigens and attempt to destroy (reject) foreign kidney
92Renal Transplantation (2 of 3) Patient’s immune system must be suppressed by drugs
93Immunosuppressive drugs Immunosuppressive drugs can be classified into five groups:Glucocorticoids – inhibit genes that code for the interleukins s- thus they mainly inhibit cell mediated immunity but also humoralCytostatics – inhibit cell division such as the alkylating agents – like cyclophosphamide, platinum and othersAntibodies – targeted monoclonal antibodiesDrugs acting on immunophilins – inhibit calcineurin – inducer of IL- 2 productionOther drugs (Interferons, TNF binding proteins)
94Kidney is placed in the iliac area, outside the peritoneal cavity Prognosis>90% of transplanted kidneys survive for 5 years when donor’s HLA antigens resemble the patient’sSurvival rate of cadaver transplants has improved in recent years
96Discussion6-year-old boy complained of abdominal discomfort. His mother noted that his face, abdomen, scrotum, and legs were edematous. His urine has large amounts of protein and a few casts. His serum albumin and serum protein were much lower than normal.What is the boy most likely suffering from?Explain the generalized edema in this boy.
97DiscussionHow does diabetes affect the kidneys? What are the clinical manifestations in such case?What is the difference between acute and chronic renal failure in terms of causes, clinical manifestations, and treatment?What is the relationship between glomerulonephritis and beta-streptococcal infection?