Docstoc

Renal-handout

Document Sample
Renal-handout Powered By Docstoc
					University of Colorado at Denver and HSC Department of Pathology Child Health Associate Program

May 13, 2005

PATHOLOGY OF THE KIDNEY AND ITS COLLECTING SYSTEM
Francisco G. La Rosa, M.D. ASSISTANT PROFESSOR Department of Pathology, UCHSC Francisco.LaRosa@UCHSC.edu

LEARNING OBJECTIVES
This chapter intends to provide the basic knowledge on the pathology of the kidney and its collecting system at the organ, cellular and molecular levels. A basic review of the embryology, anatomy and histology of the kidney will be provided to better understand the basic principles of renal pathology. Special emphasis will be given to the study of most common congenital and genetic anomalies, inflammatory processes, metabolic diseases, and benign and malignant tumors. The present outline does not necessarily match the outline of the lecture and it is given to the students as an aid for their study in reviewing the most important topics of renal pathology. However, this handout does not intend to replace the basic reading in textbooks and other academic literature. We recommend the reading of the corresponding sections of the books Pathology by Stevens and Lowe; Essential Pathology by E Rubin and JL Farber; Basic Pathology by Kumar, Cotran, Robbins; Atlases/books available in Denison library and suggested in this course. If possible, it is recommended that the students review other bibliographic references for a more complete understanding of pancreas pathology.

Introduction to Renal Disease:
1. Understand the structural relationship between the glomeruli, tubules and vessels in the kidney and the significance of this relationship in terms of function and dysfunction. 2. List the normal renal functions and the clinical result of disturbance of these functions. 3. Understand the relationship between creatinine clearance, glomerular filtration rate, and serum creatinine. 4. Compare and contrast acute and chronic renal failure in terms of time course, clinical presentation, distribution of nephron injury, causes, reversibility, kidney size and endocrine functions. 5. Define the classification and causes of acute renal failure. 6. Define the causes of chronic renal failure. 7. Understand the causes of progression in chronic renal disease. 8. Define uremia and its manifestations and complications.

Glomerular Diseases:
1. Define the clinical syndromes associated with glomerular diseases.

Pathology of the Kidney and its Collecting System

1

2. Explain the most common pathogenetic factors involved in glomerular disease. 3. List the glomerular diseases caused by immune-complex deposition. 4. Define and recognize the 4 morphologic glomerular changes that accompany glomerular injury. 5. Explain the relationship of morphologic patterns of injury with clinical presentation. 6. Understand the role of immunofluorescence, serology and electron microscopy in the evaluation and diagnosis of glomerular disease. 7. Describe the pathophysiology, clinical manifestations and complications of nephrotic syndrome. 8. Be able to describe the typical clinical manifestations, morphology, pathogenesis and prognosis of the common glomerular diseases summarized in the handout.

Tubulointerstitial Diseases of the Kidney:
1. Describe the pathogenesis of urinary tract infection in terms of routes of infection, organism virulence factors, host defense mechanisms, predisposing factors, clinical manifestations, and complications. 2. Compare and contrast the features and pathogenesis of the two major causes of chronic pyelonephritis (urinary tract obstruction and vesicoureteral reflux).

Congenital Malformations, Nephrolithiasis, Cysts and Tumors of the Kidney:
1. Describe the most important congenital malformations. 2. Describe the characteristics of the renal stones and their pathophysiology. 3. Describe the most important cystic diseases. 4. Describe the most common benign and malignant tumors of the kidney and urinary system.

Pathology of the Kidney and its Collecting System

2

INTRODUCTION TO RENAL DISEASE Normal Kidney
Weight: 150 gram each Structure: The cut surface is made of Cortex, Medulla, Renal Pyramids (papillae), Major/Minor Calyces, and Pelvis that empties into the Ureter. The kidney is divided into 12 lobes, each consisting of a pyramid, of Medullary and Cortical Tissue. The Basic Unit of Kidney Structure is the NEPHRON made up of Glomerulus surrounded by Bowman’s Capsule, and the renal tubules. Functions: 1. Regulation of the Osmotic pressure of the Plasma and Extracellular Fluid 2. Regulation of excretion of ions (Sodium, Potassium…etc) and Water and the volume of the Extracellular fluid 3. Regulation of hydrogen ion concentration 4. Elimination of metabolic waste products like urea 5. Production of Hormones (e.g. erythropoeitin)

Laboratory Values: URINE ANALYSIS
           Specific gravity: 1.001 – 1.035 pH : 4.6 – 8.0 Creatinine: 0.6 – 1.3 mg/dl Normal Creatinine clearance is 75 – 125 ml/min, decreases with age. Negative for bilirubin, blood, acetone, glucose, protein, nitrite (bacteria), and Leukocyte esterase. RBCs count 0-5/HPF WBCs count 0-4/HPF. Epithelial Cells: Occasional Hyaline Casts: Occasional. Crystals: Disease, Medications. BUN: 7- 18 mg/dl. When elevated called AZOTEMIA

The normal kidney is a complex organ, both structurally and functionally. Thus, it is not surprising that renal disease is a complex subject. Most medical students find it difficult. In these lectures we will attempt to give you a pathophysiologic approach to renal disease to provide a frame of reference for the specific diseases discussed in your text.

I.
A.

General Considerations: The spectrum of manifestations of renal disease has 2 aspects:
Those aspects related to the specific disease in the kidney. For example: swelling in the kidney can cause flank pain; or proteinuria can lead to edema. 1. Some kidney diseases have a characteristic (although very rarely pathognomonic) constellation of clinical features and laboratory abnormalities, e.g. acute pyelonephritis; nephrotic syndrome. Other diseases have only very nonspecific signs and symptoms, e.g. hematuria in IgA disease or Alport’s; nocturia; oliguria. Some kidney diseases are asymptomatic until very late in their course, e.g SLE.

2. 3.

Pathology of the Kidney and its Collecting System

3

B.

Those aspects related to impairment of renal function and to the possible progression of the disease towards irreversible renal failure. To what extent is glomerular filtration rate (GFR) maintained or decreased? 1. 2. 3. 4. Some diseases do not cause a reduction in GFR. Some diseases heal with no permanent loss of GFR even though GFR may have been decreased during the acute illness. Some diseases resolve with some permanent loss of GFR but this loss is not sufficiently significant to threaten life or health. In some diseases the irreversible loss of GFR progresses at a slow or rapid rate until the patient dies or is treated with the artificial kidney or a kidney transplant.

C. The above two aspects are not necessarily related to each other. Diseases which present with characteristic symptoms can resolve. Diseases which can progress to chronic renal failure may have no symptoms for years.

II.
A.

Structure of the Kidney and Urinary System
Gross - outer cortex – glomeruli and convoluted tubules - inner medulla – collecting ducts, Henle’s loops, osmotic gradient - collecting system: calices, pelvis, ureter - bladder and urethra Microscopic - Nephron: glomerulus and its tubule. Each nephron is an independent unit of function. Approx. 1 million nephrons in each kidney. - Glomerulus: compact tuft of capillary loops surrounded by Bowman’s capsule. Ultrafiltration apparatus: cells and protein are held within blood while small solutes and water pass into tubules - Tubule: divided into segments – proximal, distal, Loop of Henle. Absorption (water, sodium, glucose, etc), secretion (K+,H+), formation of osmotic gradient (Loop of Henle, distal tubule). - Collecting ducts: concentration of urine under control of ADH Blood supply - renal artery: 25% of cardiac output to glomerulus: interlobar arteries  arcuate arteries  interlobular arteries  afferent arterioles  glomerulus - from glomerulus: glomerulus  efferent artery  peritubular plexus (superficial and middle cortex) vasa recta (juxtamedullary cortex) - thus, decreased glomerular flow leads to decreased flow to tubules as well

B.

C.

III.
A.

Normal renal functions
Regulation of water and electrolyte (Na+, K+, PO4-, H+ etc) balance - other factors in regulation include dietary intake, pulmonary excretion of C02, hormonal regulation, metabolic activity, etc. - renal dysfunction  metabolic acidosis, fluid overload (hypertension, dyspnea, etc), hyper or hypokalemia, etc. Excretion

B.

Pathology of the Kidney and its Collecting System

4

- metabolic waste products (urea and creatinine from protein, uric acid from nucleic acids, bilirubin from hemoglobin, etc.) - some drugs and toxins (others are metabolized in the liver) - renal dysfunction  azotemia, uremia (see below), drug toxicity, gout C. Hormonal functions - regulation of blood pressure (renin-angiotensin-aldosterone) - regulation of erythrocyte production in the bone marrow (erythropoietin) - regulation of calcium and phosphorus metabolism (activation of vitamin D) - renal dysfunction, hypertension, anemia, secondary hyperparathyroidism and metabolic bone disease

IV.
A.

Renal Functional Reserve and Renal Failure
Function reserve. As in many organs, the kidneys have considerable "redundancy." This permits unilateral nephrectomy (for carcinoma of the kidney or for transplant donation, for example) with no apparent ill effect. In fact, signs and symptoms from loss of renal function do not occur until over 85% of nephron function is lost. Glomerular filtration rate (GFR). The rate at which fluid crosses the glomerular filter, that is, crosses the glomerular capillary wall from capillary lumen to Bowman's space, is the standard measure of nephron function. - GFR = single nephron GFR x total # of nephrons - thus, disease which alters SNGFR of majority of nephrons  renal failure, or: if enough nephrons are destroyed  renal failure Azotemia. Creatinine and urea are nitrogenous products of protein catabolism, and are normally excreted in the urine. When nephron function is sufficiently depressed, they are retained in the blood. The relationship between blood urea nitrogen (BUN) or serum creatinine and GFR is:

B.

C.

Figure 2. Approximation of the Steady-State Relation between Serum Creatinine, BUN and GFR. D. Creatinine Clearance: GFR is difficult to measure directly in a clinical setting. A reasonable approximation can be obtained by calculating the clearance of creatinine, i.e., the rate at which the kidneys remove or "clear" creatinine from the blood. Since creatinine crosses the glomerular capillary wall freely, and is neither secreted nor

Pathology of the Kidney and its Collecting System

5

reabsorbed by the tubules, its clearance provides a good estimate of the GFR. When GFR is seriously impaired, BUN and serum creatinine serve as good indicators of the degree of renal failure. When GFR is less seriously impaired, BUN and serum creatinine are within normal limits, and the degree of impairment is determined by creatinine clearance

V.

Classification of renal disease

Renal diseases are classified by the part of the nephron which is initially or primarily injured. Thus, the broad classification is: A. B. C. Glomerular disease Vascular disease Tubulointerstitial disease

Since the tubules and the interstitial (i.e., the tissue surrounding the tubules) usually react to injury together, diseases initially affecting the tubules and those affecting the interstitium are usually lumped together.

VI.
A.

Acute and Chronic Renal Failure
From the above, it is apparent that not all renal disease will cause renal failure; to do this a process must involve 75% or more of the nephrons. For those that do, there are two main pathways: Acute and Chronic Renal Failure. Comparison of acute and chronic renal failure: Time course ACUTE GFR decrease to near 0 values over hours to days. CHRONIC GFR decreases slowly or in steps over months to years.

B.

Clinical

Oliguria, fluid overload, Uremia, hypertension hypertension, hyperkalemia, acidosis. All nephrons affected severely and at one time. Reduced SNGFR. Toxins, severe ischemia, acute inflammation, etc. Often reversible Often low Usually normal Preserved until late Nephrons destroyed a few at a time. Reduced total GFR. Chronic inflammation, vascular disease, hereditary disease, etc Seldom reversible Usually normal Often small Anemia, bone disease

Distribution

Causes

Reversibility Urine volume Kidney size Endocrine function

Pathology of the Kidney and its Collecting System

6

VII. Causes of a Sudden Decrease in GFR: “Acute Renal Failure”
A. Pre-renal: The hemoperfusion of the kidney is good enough to provide 0 2 for the metabolic needs of the kidney but not enough to form an adequate glomerular filtrate. This is usually easy to reverse. Tubule function is preserved until late: urea absorbed more easily than creatinine  BUN: creatinine ratio 1. 2. 3. B. Hypotension (due to shock, hemorrhage, dehydration, fluid loss from burns, etc). Heart failure. Vasoconstrictor drugs (-adrenergic agents, etc)

Post-renal: Bilateral obstruction of the urinary tract. (Unilateral obstruction does not cause renal failure since other kidney will increase function). 1. 2. 3. Intraluminal masses (stones, blood clots, tumors, etc). Extrinsic compression (hemorrhage, tumors, scar). Perforation of the bladder or urethra with back leak of urine.

C.

Renal 1. Parenchymal renal disease when very severe (relatively uncommon) e.g., interstitial nephritis (drugs), glomerulonephritis, infection (pyelonephritis), vascular disease (thrombosis, emboli, vasculitis, malignant hypertension), etc. Intratubule precipitation of organic compounds (e.g., uric acid (chemotherapy, gout), myeloma proteins, oxalates (ethylene glycol intoxication), etc.) Renal ischemia (when 02 delivery to the kidney is insufficient for metabolic requirements of the kidney for same reasons as pre-renal except more severe). Nephrotoxic substances. a. Drugs, especially certain antibiotics, non-steroidal anti-inflammatory agents. b. Heavy metals (mercury salts, chromium compounds). c. Organic solvents (ethylene glycol, carbon tetrachloride). Destruction of cells containing hemoglobin or myoglobin with circulating heme pigments and other tissue breakdown products.

2. 3. 4.

5.

(NOTE: Items 3-5 are usually grouped under the term "acute tubular necrosis”).

VIII. Chronic Renal Failure: Permanent loss of renal function.
A. 3 stages: 1. Renal Insufficiency -  GFR - azotemia mild - nocturia - anemia mild

Pathology of the Kidney and its Collecting System

7

2.

Renal Failure -  GFR -  azotemia - hypertension - hypocalcemia - hyperphosphatemia - acidosis - dilute urine - anemia Uremia -  GFR -  azotemia -  K+  P04-, Ca++ - acidosis - anemia - bone disease - hypertension - pruritus - CNS, PNS disturbance - N/V - intercurrent problems of infection, drug toxicity, hyponatremia, etc.

3.

B.

Causes of Chronic Renal Failure 1. Causes: Patients Entering Transplantation, Chronic Dialysis in the U.S., 1997 Diabetes Hypertension Glomerulonephritis Interstitial nephritis Polycystic kidney disease Unknown/other 40% 27% 11% 4% 3% 15%

In 1997, about 300,000 patients were being maintained on either transplantation or chronic dialysis. 2. C. Costs: In the United States, Medicare pays about 95% of the costs for renal transplantation and chronic dialysis. In 1997, this amounted to $10.8 billion.

The End-Stage Kidney Disease Regardless of the primary site of injury in chronic renal disease (i.e., glomerular, vascular or tubulointerstitial), when one element of a nephron is destroyed, the remainder undergoes atrophy. This is accompanied by varying degrees of interstitial fibrosis and chronic inflammation. For instance, if a glomerulus is destroyed by chronic glomerulonephritis, its arterioles collapse and become sclerotic, its tubule atrophies, and fibrous tissue is laid down in the adjacent interstitium. With atrophy, the kidney becomes smaller. Thus, late in the course of chronic renal disease the kidney is shrunken and there is vascular and glomerular sclerosis, tubular atrophy, and interstitial fibrosis. At that time, it may be difficult or impossible to tell what the original disease was. Such kidneys are called "end-stage kidneys". The large number of "unknown" causes in the above table reflects this problem.

Pathology of the Kidney and its Collecting System

8

D.

Progression in Chronic Renal Disease In many cases of chronic renal disease there appears to be continuing deterioration of renal function, although the initial injurious process is over or has been controlled. The possible control of progression has major clinical (and economic) implications. Causes of progression: 1. 2. Persistence/recurrence of original disease process. Hypertension: This is a consequence of most chronic renal disease. The increased blood pressure injures renal arterioles and small arteries, which in turn causes further renal injury. Infection: Some forms of chronic renal disease predispose to urinary tract infection. "Hyperfiltration": When some nephrons are destroyed, blood flow to the remaining ones increases. While the total GFR falls, the GFR of each remaining nephron increases. These appear to be "normal" compensatory mechanisms. However, the resulting increase in glomerular capillary flow and pressure can damage glomeruli, and accelerate the rate of loss of nephrons. The importance of this process in chronic renal failure, and the possible control of it by medication and by dietary protein and/or phosphate restriction, is a subject of current investigation. 5. Other mechanisms have been proposed and are under active investigation.

3. 4.

IX.
A.

Uremia
Uremia: A group of clinical abnormalities which occur when there is severe loss of renal function. (Note that this is not a synonym of azotemia). 1. These manifestations are seen only after the GFR has decreased by more than 75%. They become more severe as GFR declines further. They cause death when GFR has declined by 97-100% unless the artificial kidney or transplantation are used. Some manifestations of uremia can be related to failure of basic renal functions. a. Excretory and regulatory renal functions. i. Failure to regulate body fluid volume. Causes edema. ii. Failure to regulate body fluid solute concentrations and pH. Causes acidosis, K+, PO4, Ca++. iii. Failure to excrete potentially toxic, nitrogenous metabolites. Causes azotemia. iv. Failure to excrete drugs normally handled by the kidney. Non-excretory renal functions. i. Abnormal production of renin and possibly other substances related to BP control. Causes hypertension. ii. Decreased production of erythropoietin. Causes anemia. ii. Impaired metabolic function. (e.g. decreased activation of vitamin D). Causes bone disease.

2.

b.

Pathology of the Kidney and its Collecting System

9

3.

Other manifestations are not clearly related to failure of renal function. For the most part, these are relieved by dialysis, suggesting that they are caused by a filterable, circulating toxin. However, no specific toxin or toxins have been identified with certainty. Some of these manifestations are: a. Cardiovascular: Pericarditis Hypertension Arrhythmias Heart failure Paraesthesias Tremors, tics Weakness Lethargy Seizures Coma Nausea Vomiting Loss of appetite Ulcers Secondary hyperparathyroidism, abnormal vitamin D metabolism and metabolic bone disease. Amenorrhea, infertility. Hyperlipidemia and accelerated atherosclerosis. Carbohydrate intolerance. Fluid, electrolyte, acid-base imbalance. Anemia Bleeding disorders Decreased resistance to infection. Insomnia

b. Neuromuscular:

c. Gastrointestinal:

d. Endocrine and metabolic:

e. Hematologic: f. General:

GLOMERULAR DISEASES
The glomerular diseases are the most complex and potentially confusing of the diseases of the kidney. This is because they are numerous, their manifestations are protean, and in many instances their etiologies are obscure. The approach taken in this course will be to characterize glomerular disease the way a nephrologist and renal pathologist approach an individual patient. This is feasible because there are a limited number of clinical syndromes in glomerular disease, a limited number of pathogenetic mechanisms involved, and a limited number of morphologic patterns of glomerular reaction to injury. These data establish the clinicopathologic diagnosis and provide the basis for prognosis and therapy. This approach will be taken in the lectures, and you will use it to analyze the case exercises in the laboratory. Use your text as a reference source for the factual data needed in your analysis.

I.
A.

Clinical Syndromes.
Asymptomatic proteinuria and/or hematuria 1. 2. Normal urinary protein  150 mg/24 hr (anything greater = “proteinuria”). Normal glomerulus filters  500 mg protein/24 hrs, most of which is resorbed by tubules. Therefore, total tubular dysfunction only could result in  500 mg/24

Pathology of the Kidney and its Collecting System

10

hrs proteinuria. Most clinically significant proteinuria is a result of glomerular disease (leakage of protein through the GBM). 3. GBM both size and charge selective. - loss of electrostatic barrier results in “selective proteinuria” (albumin). - loss of size barrier (GBM disruption) results in nonselective proteinuria (albumin, globulin, etc.). 4. 5. Massive proteinuria (> 3.5 gm/24 hrs) can lead to nephrotic syndrome (see below). Hematuria is a nonspecific sign of disease since RBC’s can enter the urine at any level from glomerulus to urethra. - nonglomerular causes include tumors, infections, stones, instrumentation. - gross hematuria = urine discolored (smoky or dark, clots). - microhematuria = grossly nl urine but RBC’s on microscopic exam. Red cell casts are specific for glomerular bleeding. - casts are proteinaceous molds of the lower nephron tubule which traps RBC’s, WBC’s or epithelial cells originating from the higher portions of the nephron. Hematuria and proteinuria may occur together when due to glomerular disease.

6.

7. B.

Acute nephritic syndrome. 1. 2. If an acute glomerular injury is severe enough, it will cause some degree of impairment of the GFR in addition to hematuria and proteinuria. This loss of renal function results in symptoms attributable to azotemia, hypertension, Na+ & H20 retention and fluid overload (edema, dyspnea, orthopnea, pulmonary edema, etc). RBC casts and leukocyte casts may be seen. Due to inflammatory diseases of glomeruli. Usually can remit.

3. 4. 5. C.

Rapidly progressive glomerulonephritis (RPGN). 1. 2. More severe form of acute nephritis that progresses rapidly to renal failure, sometimes accompanied by oliguria. Acute renal failure can also be caused by nonglomerular disease such as acute interstitial nephritis and acute tubular necrosis (not RPGN).

D.

Chronic renal failure. 1. Renal function is lost as a result of nephron loss rather than a decrease in single-nephron GFR.

Pathology of the Kidney and its Collecting System

11

2.

A low grade, persistent, destructive glomerular disease can remain asymptomatic until enough nephrons are lost to result in renal failure, often terminating in uremia (months to years). Many conditions, in addition to glomerular disease, can lead to CRF such as vascular disease, hypertension, infections, drugs/toxins, urinary tract obstruction, etc.

3.

E.

Nephrotic syndrome. 1. 2. Massive proteinuria (>3.5 gm/day) which cannot be compensated by hepatic albumin synthesis. Decreased plasma oncotic pressure leads to a syndrome to massive edema, hypercholesterolemia, and lipiduria (discussed in greater detail later in these notes).

F.

Mixed syndromes. 1. 2. CRF can occur with asymptomatic hematuria/proteinuria or nephritic syndrome, etc. Occasionally, nephritic-nephrotic syndromes can occur.

II.

Pathogenesis of Glomerular Injury

Modified from Couser, W.G., Mediation of Immune Glomerular Injury, J. Am. Soc. Nephrol, 1:13-29 (1990).

A.

Non-inflammatory mechanisms 1. Circulating factors and/or immunoglobulins bind to membranes of glomerular epithelial cells (GEC) without fixing complement causing: a. increased glomerular permeability (?mechanism). b. GEC detachment from GBM. c. Examples: minimal change disease/focal sclerosis.

Pathology of the Kidney and its Collecting System

12

2.

Complement-fixing anti-GEC antibodies (extracapillary-epithelial cell surface). a. Activate complement (alternative pathway). b. Membrane attach complex (C5b-9) causes increased permeability of GBM. - Mechanism may involve release of oxidants/proteases by GEC. c. Example: membranous nephropathy.

B.

Inflammatory mechanisms (examples: post-infections GN, RPGN, lupus nephritis, MPGN). 1. Neutrophil and platelet activation. a. Deposition of Ig and complement activation occurs within capillaries or in areas accessible to circulating inflammatory cells (subendothelium and mesangium). Ag-Ab complexes may be endogeneous (DNA and nucleoprotein in SLE, components of the GBM itself in Goodpasture’s syndrome) or exogeneous (Streptococcus or hepatitis B antigens, etc). In many cases, the Ag is unknown. b. C5a  infiltration by PMN’s. c. PMN’s undergo “respiratory burst”  release of toxic 02 metabolites which directly damage GBM and GEC. d. Fibrin deposition in Bowman’s space  crescents. e. Platelets augment injury (? release of cytokines). Macrophages. a. May be activated by humoral and cell mediated (cytokines) immune reactions. b. Release oxidants/proteases  direct damage to GBM. c. Release of cytokines which stimulate production of extracellular matrix (sclerosis) Mesangial cells a. Activated by immune-complexes, complement, cytokines from cell-mediated immune reactions. b. Release oxidants/proteases, growth factors and extracellular matrix components. c. May be dominant in IgA, mesangial proliferative GN and lupus. Cell-mediated immunity. a. Sensitized T-cells interact with and activate macrophages and mesangial cells. b. Mechanisms of sensitization unclear.

2.

3.

4.

C. D.

Loss of Glomerular Polyanion. (See nephrotic syndrome below). Hyperfiltration. In addition to being a mechanism of progression in chronic renal disease, hyperfiltration is a possible mechanism in diabetic glomerulosclerosis and focal, segmental glomerulosclerosis. Coagulation 1. The coagulation cascade is often triggered in complement-mediated inflammation, and probably plays a role in the pathogenesis of some forms of glomerulonephritis. There is good evidence that it is the major stimulus to the formation of epithelial-cell crescents. Glomerular injury manifested primarily by endothelial injury and glomerular thrombosis is seen in some renal vascular diseases.

E.

2.

Pathology of the Kidney and its Collecting System

13

3.

Platelet activation and subsequent release of cytokines from platelets probably plays a role in the pathogenesis of immunologic glomerular injury

III.

Morphologic Patterns of Glomerular Disease.

A process that involves all or almost all glomeruli is termed diffuse; one that involves only some glomeruli is termed focal. For any individual glomerulus, a process that involves the entire tuft is termed global; one that involves only a portion of the tuft is termed segmental. A. Normal – Some glomerular diseases show no significant glomerular abnormalities by light microscopy. 1. Bundle of capillaries (glomerular tuft) suspended within a urinary receptacle (Bowman’s space) and bounded by Bowman’s capsule; the entire structure composed of these three elements is termed the renal corpuscle. At the tubular pole, Bowman’s space is continuous with proximal tubule. Opposite the tubular pole, the vascular pole represents the hilum in which the afferent arteriole enters and the efferent arteriole leaves the glomerulus. a. Capillary branches therefore lie between two arterioles which results in high hydrostatic pressure ( 50 mmHg). b. Efferent arteriole then gives rise to capillaries which supply blood to the tubules in the cortex and medulla. 4. The mesangium occupies the axial region of the glomerular tuft and supports the capillaries. a. Composed of mesangial cells and matrix. b. Mesangial cells are very specialized and can secrete a variety of vasoactive substances, are contractile (may regulate capillary flow), and are phagocytic and moderate immune functions via cytokine secretion. 5. Glomerular capillary wall components: – the site of ultrafiltration; has three major

2. 3.

a. Fenestrated endothelium. b. Glomerular basement membrane (GBM) – forms a continuous sheet over the capillary tuft with concave reflections over the mesangium; reflects to become continuous with Bowman’s capsule. i. composed of Type IV collagen and variety of other components including laminin, heparan sulfate, fibronectin, etc. ii. these components confer an overall negative charge to the GBM. c. Visceral epithelial cells. i. give rise to numerous cell processes (foot processes) which insert into the outer aspect of the GBM. ii. complex interdigitations between the foot processes of multiple epithelial cells from filtration slits along the outer aspect of the glomerular capillaries.

Pathology of the Kidney and its Collecting System

14

d. Thus, the glomerular capillary wall form both a size-selective and selective filter. B. Cell proliferation (proliferative glomerulonephritis). 1. 2.

charge-

Hypercellularity of the glomerulus resulting from proliferation of mesangial, endothelial and/or epithelial cells. In acutely active glomerulonephritis, there is often an increase in both mesangial and endothelial cells which results in narrowing or occlusion of the glomerular capillaries (examples: postinfectious GN, membrano-proliferative GN). In less active or resolving glomerulonephritis, proliferation may be restricted to mesangial cells (mesangial proliferation), with relatively normal capillary loops surrounding hypercellular and expanded mesangial regions (example: IgA nephropathy). Crescents – clusters of proliferated epithelial cells, often admixed with blood monocytes, which form crescent-shaped aggregates in Bowman’s space surrounding the glomerular tuft. a. Crescents are a non-specific reaction to severe glomerular injury that results in necrosis or disruption of the capillary walls and leakage of blood and fibrinogen into Bowman’s space. b. Most crescents heal within growth of fibroblasts and resultant scarring, which collapses capillaries and destroys the glomerulus. Thus, glomerulonephritis with large numbers of crescents carries a poor prognosis.

3.

4.

C.

Leukocytic infiltration – Neutrophils, monocytes and occasionally eosinophils infiltrate the glomeruli in many instances of active glomerulonephritis. Release of lysosomal enzymes and release of toxic oxygen radicals from cell membranes contribute to glomerular injury. Basement membrane thickening – can occur in a variety of glomerular diseases, particularly some of the chronic diseases; often results in pertubations of filtration (proteinuria, example: membranous GN, MPGN). Abnormally thin GBM’s can also occur in some hereditary glomerular diseases. Sclerosis 1. Some forms of chronic glomerular diseases are characterized by progressive deposition of extracellular matrix material (example: diabetes). Can lead to obliteration of capillary lumens and collapse of the glomerular tuft eventually resulting in nephron loss.

D.

E.

2.

IV.
A.

Pathogenetic Data: Characterization of Immunopathogenesis.
Immunoflourescence. The deposition of immunoglobulins (IgG, IgA, IgM) and complement components (C3, C1q) may be identified in the glomeruli by immunoflourescence microscopy. The distribution (mesangial, along capillary loops) and pattern (granular, linear) as well as the specific proteins identified, help to characterize the disease.

Pathology of the Kidney and its Collecting System

15

B.

Electron microscopy. Antigen-antibody complexes may be seen as electron- dense, extracellular “deposits” by electron microscopy. Their location (mesangial, inner or outer aspects of the basement membrane) as well as any changes to the GBM, helps to characterize the disease. Depressed serum levels of complement components are often seen in active glomerulonephritis, presumably indicating “consumption” of the components in the glomeruli, and can be generally used as indices of the activity of the process. Serologic tests can suggest the possible antigen involved (antinuclear antigen in lupus, antistreptolysin in post-streptococcal GN, antineutrophil cytoplasmic antibodies in vasculitis, etc.).

C.

D.

V.

Nephrotic Syndrome.

Chronic and/or sclerosing diseases of the glomerulus often lead to nephrotic syndrome. This is a complex situation and will be considered in some detail. A. Pathophysiology. 1. The basic lesion leading to a cascade of complications is increased permeability of the glomerular capillary wall to plasma proteins. a. albumin, the major oncotic protein of the plasma, is lost in urine. b. causes a drop in serum albumin which initially is compensated by increased hepatic albumin synthesis. 2. As process progresses, eventually hepatic albumin synthesis fails to keep pace with urine losses (?synthesis may be blunted in some cases). a. The resultant hypoalbuminemia leads to decreased plasma oncotic pressure and a shift of fluid to extravascular spaces, causing edema. b. Associated with increased albumin synthesis is increased hepatic synthesis of low density lipoprotein and (in some cases) hyper-lipidemia and lipiduria. 3. 4. B. Decreased effective intravascular volume leads to Na+ and H20 retention (?glomerular disease may cause primary Na+ retention in some cases). The retained fluid results in more edema.

Pathogenesis of glomerular capillary wall defect which leads to protein loss. 1. Small solutes freely pass through small pores ( 42Å) that are located in the slit diaphragms separating epithelial cell foot processes. Albumin (radius 36 Å) would be filtered except for its negative charge and the anionic charge barrier in the endothelial cells and GBM. 2. There are a negligible number of larger pores that allow for filtration of macromolecules. 3. As previously mentioned the GBM is both size and charge selective.

Pathology of the Kidney and its Collecting System

16

4.

Therefore, increased permeability of the glomerular capillary wall could be caused by structured damage (size selectivity) or loss of negative charge (charge selectivity). Experimental examples of both situations exist.

C.

Complications of nephrotic syndrome. These conditions comprise a great threat to the health of the nephrotic patient, and are not corrected by diuretics. 1. Protein deficiency: a. Antithrombin III, etc.: b. High density lipoprotein: c. Immunoglobin, complement: d. Albumin: e. General: 2. 3. Hypercholesterolemia: Thromboembolic tendency Renal vein thrombosis Accelerated atherogenesis Susceptibility to infection proteins Edema, hypotension, toxicity of albumin-bound drugs Protein malnutrition, growth retardation

-Accelerated atherogenesis

Hyponatremia and hypokalemia: - Tiredness, cramps

D.

The nephrotic syndrome is seen in many different glomerular diseases. In many cases, the glomerular process is a manifestation of a systemic disease (diabetes, amyloidosis, lupus, etc.). In other cases, it is associated with some other condition (neoplasm, drug abuse, some medicinal drugs, etc.). In still other cases, no such underlying disease or association is found. In all three situations different morphologic patterns in the glomeruli may be seen. Since treatment and prognosis varies greatly depending on the morphologic and immunopathologic findings, renal biopsy is often done. It is particularly important to identify associated conditions, since correction of the condition may alleviate the nephrotic syndrome.

VI.

Specific Glomerular Diseases.

The most important ones will be summarized here using the characterization scheme described above. It is important to remember that these summaries give only the most common clinical presentations, morphologic patterns, etc. for each disease. These may vary in any given case, depending on the severity of the process. For instance, while IgA nephropathy usually presents clinically as asymptomatic hematuria and morphologically as focal

Pathology of the Kidney and its Collecting System

17

mesangioproliferative glomerulonephritis, in severe cases it may present as an acute nephritic syndrome and the renal biopsy may show diffuse proliferative or even crescentic disease. A. IgA Nephropathy 1. 2. 3. Clinical: usually asymptomatic hematuria. Morphologic usually focal, mesangioproliferative. Pathogenesis: probably immune complex - IF – Mesangial IgA, C3 - EM – Mesangial deposits Therapy: acute disease often treated with steroids. Prognosis: some progress to end-stage renal disease.

4. 5. B.

Post-infectious glomerulonephritis. 1. 2. 3. Clinical: usually poststreptococcal; acute nephritic syndrome. Morphologic: diffuse proliferative glomerulonephritis. Pathogenesis: Exogenous immune complex. - IF – Granular GBM pattern for IgG, C3 - EM – Subepithelial deposits Therapy: supportive Prognosis: good

4. 5. C.

Crescentic glomerulonephritis. This is not a specific clinicopathologic entity, but a group of conditions with a common clinical and morphologic presentation. 1. 2. 3. Clinical: rapidly progressive glomerulonephritis. Morphologic: crescents predominate, glomerular necrosis Pathogenesis: variable - immune complex (postinfectious) - anti-GBM (if associated with pulmonary hemorrhage, Goodpasture’s syndrome) - systemic vasculitis (pauci-immune) - other, idiopathic - IF, EM depend on the above Therapy: depends on pathogenesis; steroids, cytotoxic agents, plasmapheresis. Prognosis: often poor; many progress to end-stage renal disease.

4. 5. D.

Lipid Nephrosis (nil disease, minimal change disease). 1. Clinical: Nephrotic syndrome, usually in children.

Pathology of the Kidney and its Collecting System

18

2.

Morphologic: Normal or minimal change by light microscopy; loss of epithelial cell foot processes by EM (Note: loss of foot processes is not specific for lipoid nephrosis; it is seen in most instances of heavy proteinuria). Pathogenesis: Possibly caused by a circulating, T-cell produced factor which affects the glomerular epithelial cell and produces increased permeability. Therapy: steroids. Prognosis: good.

3. 4. 5. E.

Focal Segmental Glomerulosclerosis (Focal Sclerosis, FSGS). 1. 2. 3. 4. 5. Clinical: nephrotic syndrome. Morphologic: focal glomerulosclerosis. Pathogenesis: Some cases probably caused by a circulating factor which injures glomerular epithelial cells. Hyperfiltration injury. Therapy: none of proven value. Prognosis: some progress to end-stage renal disease.

F.

Membranous nephropathy (membranous glomerulonephritis). 1. 2. 3. Clinical: nephrotic syndrome. Morphologic: glomerular basement membrane thickening. Pathogenetic: chronic immune complex; C5b-9 injury to/activation of glomerular epithelial cells increases permeability. - IF – granular GBM pattern for IgG, C3 - EM – sub-epithelial deposits Therapy: steroids. Prognosis: some progress to end-stage renal disease.

4. 5. G.

Diabetic glomerulosclerosis. 1. 2. 3. 4. 5. Clinical: proteinuria, occasionally nephrotic syndrome, chronic renal failure. Morphologic: glomerulosclerosis, often nodular. Pathogenesis: probably multifactorial; see notes on Diabetes lecture. Therapy: Tight control of blood glucose may prevent the disease. Tight control of blood pressure slows progression. Prognosis: poor.

Pathology of the Kidney and its Collecting System

19

Remember that diabetes also causes renal vascular disease and is associated with pyelonephritis and papillary necrosis. H. Lupus Erythematosus 1. Clinical: variable. Most patients with lupus have no clinical evidence of renal disease. Those who do, may have any of the clinical syndromes of glomerular disease. Morphologic: variable. WHO classification: I – Normal by light microscopy II – Mesangial proliferative III – Focal, segmental GN IV – Diffuse proliferative GN V – Membranous GN Pathogenesis: endogenous immune complex - IF – Granular GBM and/or mesangial patterns for IgG, IgA, IgM, C3, Clq, etc., (full-house pattern). - EM – Subendothelial, subepithelial, mesangial deposits Therapy: Steroids, cytotoxic agents for active WHO class III & IV disease. Prognosis: good, with therapy.

2.

3.

4. 5. I.

Membranoproliferative Glomerulonephritis (MPGN Type I).

Note: MPGN II is a different disease, with some clinical and morphologic similarities to MPGN I. It is very rare, and will not be discussed here. 1. 2. 3. Clinical: mixed nephritic/nephrotic. Morphologic: proliferation, complex GBM thickening. Pathogenesis: chronic immune complex. - IF – granular GBM pattern for IgG, C3 - EM – subendothelial deposits Therapy: steroids. Prognosis: some progress to end-stage renal disease.

4. 5.

TUBULOINTERSTITIAL DISEASE I. Acute tubular necrosis (ATN)

The major causes of acute renal failure (<400 mlurine/24 hr) are initially reversible. A. Types: 1. Ischemic (shock kidney): Caused by hypotension following bactermia, burns, hemorrhage. Can also be seen following massive hemolysis or rhabdomyolysis.

Pathology of the Kidney and its Collecting System

20

2. Proximal tubules and the thick portion of the ascending limb are the most vulnerable part to Ischemic injury 3. Focal tubular necrosis, casts in the tubules, rupture of BM, interstitial edema, and inflammatory infiltrate. B. Nephrotoxic: 1. Usually involves the proximal convoluted tubules. 2. Secondary to drugs ( antibiotics e.g. aminoglycosides, anaesthetic e.g. methoxyflurane), contrast media, heavy metals ( ethylene glycol,CCL4) and poisons (insecticides, herbicides, and poisonous mushrooms)

II.

Acute interstitial nephritis

Interstitial inflammation almost always involves the tubules because of the intimate relationship between the two. A. Acute pyelonephritis: 1. 2. 3. 4. B. C. Fever, flank pain, dysuria, pyuria. Most common organisms are gram negative bacilli (E.Coli, Proteus, Klebsiella) Spread through hematogenous, ascending infection or vesicoureteral reflux. May complicate obstruction or tumor masses. Suppurative inflammation with areas of necrosis and abscess formation, predominantly cortical.

Pyonephrosis: Caused by obstruction with formation of pus, this is unable to drain. Acute hypersensitivity nephritis: 1. Drug induced; e.g. aminoglycosides, NSAIDs, diuretics etc 2. Non-drug induced; e.g. Viral ( HIV,HSV,CMV,EBV etc), Autoimmune disease ( e.g. SLE)

III. Renal papillary necrosis: Common in obstructed patients with diabetes, alcoholism, sickle cell disease, analgesic abusers.

CONGENITAL ANOMALIES
Congenital renal disease can be hereditary but is most often due to acquired developmental defect during gestation B. C. D. E. Renal Agenesis Hypoplasia Ectopic kidney Horseshoe kidney: fusion of upper or lower poles (90% at lower poles), across the midline anterior to the great vessels. Common found in 1/500-1000 autopsies.

Pathology of the Kidney and its Collecting System

21

CYSTIC DISEASE OF THE KIDNEY
Not all cysts in the kidney are congenital. Here we review cysts congenital and acquired. A. Cystic Renal Dysplasia: Abnormality in metanephric differentiation and persistence of abnormal structures (cartilage, cysts, undifferentiated mesenchyme, immature glomeruli). Often associated with urine outflow obstruction. When unilateral has excellent prognosis. When bilateral it is often fatal. Polycystic Kidney Disease (Adult): Autosomal dominant, bilateral, common in 1-1000 live births, Initially only involve portion of the nephrons, with patients Asymptomatic, with progressive involvement the patients present in the 4 th or 5th decades with chronic renal failure and hypertension. 40% of patients have liver cysts, 10-30% have berry aneurysms in the circle of Willis, 20-25% have mitral valve prolapse Genetics; caused by mutation of three separate genes PKD1 gene located on chromosome 16p13.3 (85% of cases), PKD2 gene located on chromosome 4q13-23 (10% of cases), PKD3 gene (in minority of cases) Morphology; kidneys are bilaterally enlarged, may reach enormous size, mass of cysts 3-4cm in diameter containing clear serous fluid, with little intervening parenchyma. The cysts arise from any part of the tubules, hence different lining of cysts. Polycystic kidney disease (childhood): Autosomal recessive, bilateral, rare. Perinatal, neonatal, infantile, and juvenile subcategories. In almost all cases liver cysts are also present with development of congenital hepatic fibrosis. Morphology; kidneys are enlarged with a smooth external surface. On cut section the kidney has a sponge like appearance with numerous small cysts lined with cuboidal epithelium. All arise from the collecting tubules and replace the medulla and cortex. Medullary sponge kidney Occurs in adults, incidental finding, usually asymptomatic. Multiple cysts in the medulla of collecting duct origin and lined by cuboidal epithelium. Nephronphthisis (uremic medullary cystic disease) Progressive renal disorders with onset in childhood. Children present with polyuria and polydypsia and progress into terminal renal failure in 5-10 years. There are cysts in the medulla, lined by cuboidal epithelium, in association with cortical tubular atrophy and interstitial fibrosis. Acquired (dialysis-associated) cystic disease Numerous cortical and medullary cysts, often contain calcium oxalate crystals. Patients are asymptomatic. Simple cysts Single or several simple cysts, from 1-5 cm, containing clear translucent fluid usually in the cortical area more than the medulla. No clinical significance.

B.

C.

D.

E.

F.

G.

Pathology of the Kidney and its Collecting System

22

NEPHROLITHIASIS (KIDNEY STONES)
1% of all US population Can occur primary without the presence of renal disease or secondary to renal disease. Four type of stones:  65-75 % are Calcium oxalate and calcium phosphate (sarcoidosis, hyperparathyroidism, multiple myeloma etc)  5-20 % are uric acid stones (e.g. gout)  15% are magnesium ammonium phosphate (sturvite or triple stones) associated with urea splitting bacteria (Proteus)  1-2% are cystein.

TUMORS
There are a considerable number of kidney tumors. Here we discuss some of the most commonly encountered.

A.
-

WILMS’ TUMOR
peak age 2-4 years, 5-10% are bilateral Patients present with a large abdominal mass, hematuria and pain. Histologically three components; epithelial tissue, mesenchymal undifferantiated blastema. Overall cure rate is ~ 90% with chemotherapy +/- radiotherapy tissue, and

B.
-

RENAL CELL CARCINOMA
peak age 55-60 years, M:F is 3:1, 85% of all renal malignancies Triad presentation: hematuria, flank pain, abdominal mass arise from the tubular epithelium, consists of large optically clear cells or granular cells with a vascular stroma has metastatic potential particularly to lung, bone and regional lymph nodes treatment: Nephrectomy and chemotherapy

C.
-

TRANSITIONAL CELL CARCINOMA
10-15% of adult kidney tumors patient presents with gross hematuria, hydronephrosis, flank pain arise from the transitional lining in the renal pelvis and ureter and can be multicentric 5-year survival rate is 10-70% depending on tumor stage and grade. treatment: nephroureterectomy TCC can also be originated in the mucosa of all the collecting system (ureters and bladder). **************

This handout was prepared based on material provided by Drs. Scott Lucia and Said Sherif.

Pathology of the Kidney and its Collecting System

23


				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:189
posted:7/3/2009
language:English
pages:23