The Kidneys and the Urinary System

Chapter 15 The Kidneys and the Urinary System



Ivan Damjanov, MD, PhD




1 List the most important kidney diseases



image Developmental disorders

image Glomerular diseases

image Tubulointerstitial diseases (One percent of all people in the United States will develop renal stones during their life span.)

image Vascular and circulatory disorders

image Tumors


2 Name the main clinical renal syndromes



image Acute nephritic syndrome

image Nephrotic syndrome

image Asymptomatic hematuria, proteinuria, or both

image Acute renal failure

image Chronic renal failure

image Renal tubular defects

image Urinary infections

image Obstructive uropathy

image Urinary stones

image Tumors


3 What are the principal laboratory findings in uremia?


Uremia is a set of clinical and laboratory findings encountered in patients with end-stage kidney disease. Key laboratory features reflect inadequate excretion of degradation products and minerals and include:


image Azotemia (increased blood urea nitrogen [BUN] and creatinine [Cr] due to decreased renal excretion)

image Electrolyte abnormalities (retention of sodium, potassium, and phosphate, with secondary changes in the concentration of calcium, which is initially low but also may be high)

image Acidosis

image Anemia (normocytic anemia resulting from a deficiency of erythropoietin)

image Prolonged bleeding time (because of functional defects of platelets)



Key Points: Types of Renal Diseases



1. The main types of renal disease are developmental, immunologic, metabolic, infectious, circulatory, and neoplastic.

2. Autosomal dominant polycystic kidney disease is the most common clinically significant developmental renal disease.


4 What are the common clinical features of uremia?


Clinical features of uremia may be found in essentially all major organs and include:


image Cardiopulmonary disorders
image Hypertension

image Congestive heart failure

image Uremic pericarditis

image Gastrointestinal disturbances
image Nausea and loss of appetite

image Chronic esophagitis, gastritis, and enteritis

image Neuromuscular disorders
image Muscle weakness

image Functional peripheral nerve disease

image Encephalopathy

image Skin
image “Uremic frost”

image Chronic dermatitis and pruritus

image Sallow color (urochrome)

image Bones
image Renal osteodystrophy

image Osteomalacia or osteoporosis


5 What are the features of acute nephritic syndrome?


Acute nephritic syndrome classically presents 1 or 2 weeks after an upper respiratory tract infection caused by streptococci. Clinically, it is characterized by:


image Oliguria: It is a consequence of a reduced glomerular filtration rate (GFR).

image Hematuria: It results from rupture or increased porosity of damaged glomerular basement membrane (GBM). Glomerular hematuria presents with brownish-red urine (“bouillon soup–like”). Red blood cells (RBCs) may be found in the urine sediment examined by microscopy. The sediment also contains fragmented and distorted RBCs and RBC casts.

image Proteinuria: It reflects the increased permeability of the GBM. The amount of protein found in urine varies from mild to severe.

image Generalized edema: It is a complication of hypoalbuminemia. Typically it is most prominent on the face (“puffy eyes”) because of periorbital edema but may involve body cavities and internal organs. Somnolence of affected children is in part related to brain edema.

image Hypertension: It results from the reduced GFR and a consequent release of renin.

image Low complement levels in blood: This laboratory findings reflect the consumption of complement, which is bound to immune complexes deposited in the glomeruli.

image Azotemia: Elevated BUN and Cr in blood and electrolyte disturbances (e.g., hypernatremia) result from the reduced excretion of these substances in urine.


6 List the features of nephrotic syndrome



image Proteinuria: It is massive and typically in the “nephrotic range” (i.e., >3.5g/day).

image There is hypoalbuminemia (<3g/dL).

image Generalized edema: It results from hypoalbuminemia and reduced plasm oncotic pressure.

image Hyperlipidemia: It is mostly due to an increased amount of low density lipoproteins (LDLs) and lipiduria (lipid casts in urine).

image Affected patients are prone to infection and thrombotic events because of increased urinary loss of serum proteins involved in immunity and coagulation.


7 What are the features of acute renal failure?


Acute renal failure has a rapid onset and develops over a period of several days or weeks. Most often it is characterized by a reversible deterioration of renal function, oliguria (or anuria), azotemia, and electrolyte disturbances. Most patients recover, but in some patients, the injury is irreversible. Such patients may die or require dialysis (“artificial kidneys”) to survive.



8 What are the causes of acute renal failure?


Three types of renal failure are recognized: prerenal, renal, and postrenal. See Table 15-1.


TABLE 15-1 Cause of Acute Renal Failure















































Type of Renal Failure Pathogenesis Clinical Condition
Prerenal Decreased renal perfusion Congestive heart failure
Loss of blood Massive bleeding  
Renal Glomerular disease Acute glomerulonephritis
Tubulointerstitial nephritis Drug reaction  
Vasculitis Wegener granulomatosis  
Toxic tubular necrosis Mercury poisoning  
Postrenal Intratubular obstruction Acute urate nephropathy
Renal–pelvic obstruction Nephrolithiasis  
Ureteric obstruction Urinary stones  
Bladder/urethral obstruction Prostatic hyperplasia  


9 How does chronic renal failure develop?


Chronic renal failure develops insidiously. It results from a gradual but progressive loss of normal renal function. In most instances, it occurs in four sequential steps:


image Diminished renal reserve: These patients do not have clinical or laboratory signs of renal disease (BUN and Cr are normal). Additional testing will reveal that GFR is significantly reduced, and azotemia may develop during intercurrent diseases.

image Renal insufficiency: These patients have reduced GFR (20%–50% of normal) and show signs of reduced tubular function. Laboratory findings include azotemia, anemia, and polyuria.

image Renal failure: These patients have markedly reduced GFR (<20% of normal), edema, metabolic acidosis, hypocalcemia, and multisystemic signs of uremia.

image End-stage renal failure: These patients have almost no measurable GFR (<5% of normal) and show clinical signs of uremia.


10 Define derangements of urine volume



image Anuria: It is characterized by reduced urine output (<100mL urine per day), reflecting renal injury.

image Oliguria: It is defined as reduced urine output below 400mL/day. Such urinary volume is insufficient to excrete the daily osmolar load. It occurs often in the clinical setting and may be caused by prerenal, renal, or postrenal renal failure.

image Polyuria: It is defined as increased volume of urine (>3 L of urine per day). It may result from excessive fluid intake (e.g., beer), osmotic diuresis (e.g., diabetes mellitus), inappropriate fluid loss (e.g., diabetes insipidus), or impaired tubular concentration (e.g., tubular necrosis). Polyuria is typically found during the recovery phase of renal tubular necrosis. (Note: Regenerating renal tubules cannot concentrate urine.)


11 What are the features of urinary tract infection (UTI)?


UTI is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). Bacteriuria is defined for clinical purposes as the presence of more than 100,000 bacteria per milliliter of cultured urine. Leukocytes are counted in the urinary sediment examined microscopically. The diagnosis of urinary bacterial infection affecting either the kidneys or the lower urinary tract is made if the patient has signs of urinary irritation, urgency, or pain and the urinalysis shows more than 100,000 colonies per milliliter. If the urine contains more than 100,000 bacterial colonies per milliliter but the patient has no clinical symptoms, the diagnosis of asymptomatic bacteriuria is made.



DEVELOPMENTAL DISORDERS



12 Describe the most common congenital kidney disease


Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disease. It has an incidence of 1 in 800 and accounts for approximately 10% of patients on maintenance renal dialysis. ADPKD, also known as adult polycystic renal disease, is usually asymptomatic in childhood. Although it is congenital, it is diagnosed only during adult life. Renal dysplasia is the most common renal congenital anomaly diagnosed during infancy and childhood.



13 What are the pathologic features of cystic renal dysplasia?


This developmental abnormality may be unilateral or bilateral. It results from irregular differentiation and morphogenesis of the metanephros, the primordium of the fetal kidneys. Histologically, the parenchyma of these abnormal kidneys consists of immature nephrons, often showing signs of cystic dilatation. The tubules and glomeruli are surrounded by immature mesenchyma and heterologous cells (e.g., cartilage or striated muscle). On gross examination, the abnormal kidneys appear enlarged and cystic. It may be associated with ureteropelvic obstruction and other anomalies of the lower urinary tract.



14 Describe how cystic renal dysplasia presents clinically


Unilateral cystic dysplasia, which is more common than bilateral dysplasia, usually is discovered on abdominal palpation as an abnormal mass. With nephroblastoma (Wilms tumor) and neuroblastoma of the adrenal, it is one of the three most common abdominal masses diagnosed in infants and young children.


Bilateral cystic dysplasia, which is often associated with other urinary tract abnormalities, presents with early onset of renal failure in the neonatal period or early childhood.



15 What are the differences between autosomal dominant and autosomal recessive kidney disease?


Comparisons of autosomal dominant and autosomal recessive polycystic kidney disease are illustrated in Fig. 15-1 and listed in Table 15-2.


image

Figure 15-1 Polycystic kidney disease (PCKD). A, Autosomal recessive PCKD. Small, uniform cysts visible on cross-section account for the spongy texture of the moderately enlarged kidney. Both kidneys are symmetrically involved. B, Autosomal dominant PCKD. Large cysts filled with fluid distort the kidney. Both kidneys are affected and may become extremely large.


TABLE 15-2 Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease (PCKD)







































Feature Autosomal Dominant PCKD Autosomal Recessive PCKD
Incidence Common (1:800) Rare (1:15,000)
Inheritance Autosomal dominant Autosomal recessive
Gene Polycystin genes (PKD1 = 85%) Fibrocystin, PKHD1
Bilateral Yes Yes
Gross appearance Large cystic kidneys (>1000g) Spongelike symmetrically enlarged (100–200g)
Cysts Large (from any tubule) Small (collecting duct derived)
Symptoms Infancy, childhood Adulthood (>35 years)
Associated anomalies Polycystic liver disease (20%)
Berry aneurysms of cerebral arteries		 Small bile duct cysts, liver fibrosis


GLOMERULAR DISEASES



16 What is the difference between primary and secondary glomerular diseases?


The traditional distinction of glomerular diseases into primary and secondary glomerulopathies is arbitrary and not always convincing. Those diseases that selectively affect glomeruli or most prominently damage glomeruli are called primary.


Primary glomerular diseases are, for example:


image Minimal change glomerulopathy (lipoid nephrosis)

image Primary membranous nephropathy

image Acute poststreptococcal glomerulonephritis

Secondary glomerular diseases occur in the course of systemic diseases such as:


image Immunologic diseases (e.g., systemic lupus erythematosus)

image Metabolic disorders (e.g., diabetes mellitus)

image Hereditary diseases (e.g., Fabry’s disease)

image Acquired immune deficiency syndrome (AIDS)


17 List the five main glomerular syndromes



image Acute nephritic syndrome

image Rapidly progressive glomerulonephritis

image Nephrotic syndrome

image Chronic renal failure

image Asymptomatic hematuria/proteinuria


18 Which cells contribute to glomerular hypercellularity in glomerulonephritis?


Glomerular hypercellularity can be caused by proliferation of endogenous cells or exudation of inflammatory cells carried by blood. Morphologically, such hypercellularity can be intracapillary (i.e., the cells are found inside the capillaries and the mesangial areas) or extracapillary (i.e., the cells are found in the urinary space enclosed by the Bowman capsule). Such extracapillary cell aggregates are called crescents. From the pathogenetic standpoint, glomerular hypercellularity can be due to:


image Cellular proliferation: Mesangial, endothelial, and sometimes parietal epithelial cells

image Exudation: Neutrophils, monocytes (macrophages), and sometimes lymphocytes

image Crescent formation: Accumulation of proliferating epithelial cells lining the Bowman capsule and exudates composed of macrophages (Fibroblasts can grow into the urinary spaces from outside through the ruptured Bowman capsule.)



Key Points: Glomerular Diseases



1. Glomerular diseases can cause nephritic or nephrotic syndrome, chronic renal failure, or only minor biochemical abnormalities.

2. Primary glomerulonephritis is most often an immunologic disease.

3. Glomerular diseases often occur in the course of systemic diseases such as diabetes and hypertension or amyloidosis.


19 What is the difference between global and segmental, diffuse and focal glomerulopathy?


Because many of the primary glomerulonephritides are of unknown cause, they are often classified by their histology. Histologic changes can be subdivided into:


image Global: Involving the entire glomerulus

image Segmental: Affecting a part of a glomerulus

image Diffuse: Involving all glomeruli

image Focal: Involving only a certain proportion of the glomeruli

According to this nomenclature, mild nephritis of systemic lupus erythematosus (SLE) is classified as focal and segmental. This means that some and not all glomeruli are affected. In the affected glomeruli, only some loops show pathologic changes, whereas others are normal.



20 Describe two forms of antibody-associated forms of glomerular injury



image Antibodies to endogenous antigens of the GBM: This mechanism accounts for the renal injury in Goodpasture syndrome, a disease caused by antibodies to collagen type IV.

image Antibodies to nonglomerular antigens: Antigen–antibody complexes found in the glomeruli may result from two pathogenetic mechanisms: in situ formation or intraglomerular deposition of circulating immune complexes.
image In situ immune complex formation results from the binding of circulating antibodies and the “implanted” antigen fixed to the basement membrane of the glomerulus. This mechanism accounts for the formation of glomerular lesions in poststreptococcal glomerulonephritis. It is assumed that the streptococcal antigens are implanted into the GBM during the infection, and when the antibodies are formed, they reach the implanted antigens in the glomeruli, thus forming immune complexes.

image Circulating immune complexes are antigen–antibody complexes formed from soluble antigens and corresponding antibodies in the circulating blood. The bloodstream carries these immune complexes to the glomeruli, where the blood is normally filtered. Because the preformed immune complexes represent large protein aggregates that cannot pass through the GBM, they are “caught” on the subepithelial, subendothelial side of the GBM or the lamina rara or densa of the GBM. This type of immune complex deposition typically occurs in SLE.


21 What pattern of staining of glomeruli is seen by immunofluorescence microscopy in anti-GBM nephritis?


Immunofluorescence microscopy tests are performed with fluoresceinated rabbit or mouse antibodies that recognize human antigens. Using these antibodies to human immunoglobulin (Ig) G, one can demonstrate where the immunoglobulins are deposited. In typical anti-GBM glomerulonephritis, such as Goodpasture syndrome, IgG is bound diffusely to all collagen type IV molecules in the GBM. Staining with antihuman IgG will produce a linear pattern (i.e., the fluoresceinated antibodies outline the GBMs).



22 What pattern of staining of glomeruli is seen by immunofluorescence microscopy in circulating immune complex nephritis?


Circulating immune complexes form granular deposits along the basement membrane. Typically this is seen in SLE. Depending on the size, solubility, and electric charge of the immune complexes, they may get “stuck” on the endothelial, intramembranous, or subepithelial region of the GBM or in the mesangial areas.



23 Describe where immune complexes found in the glomeruli are affected by membranous nephropathy


Membranous glomerulopathy is an immunologic disease in which immune complexes appear on the GBM in a uniform granular manner (usually referred to as “lumpy-bumpy”). The subepithelial (epimembranous) location of these antigens indicates that they may be formed locally through the action of antibodies and a local foot-process antigen (megalin or gp-330) or by the implantation of preformed circulating immune complexes.



24 In which parts of the glomeruli may the antigen–antibody complexes be seen by electron microscopy in various forms of glomerulonephritis?


Depending on their location, immune complexes are classified as follows:


image Subepithelial “humps” (e.g., acute glomerulonephritis)

image Epimembranous granular deposits (e.g., membranous nephropathy or the membranous form of SLE nephritis)

image Subendothelial (e.g., SLE and membranoproliferative glomerulonephritis)

image Intramembranous (e.g., SLE)

image Mesangial (e.g., IgA nephropathy and SLE)

See Fig. 15-2.


image

Figure 15-2 Immunologic diseases of the kidneys. Typical location of immune complexes, as seen using electron microscopy. A diagram of a normal capillary is included for comparison. Left, Normal glomerulus. The basement membrane (BM) is lined from the capillary side by a fenestrated endothelial cell (En). On the urinary side, the BM is covered with the foot processes (FP) of the epithelial cell (Ep). The mesangial cell (Mes) is surrounded by matrix and does not extend to the capillary BM. Right, Immune complex deposits in the glomerulus. A, Large subepithelial “humps” typical of poststreptococcal or other forms of acute postinfectious glomerulonephritis. B, Subepithelial “lumpy-bumpy” deposits typical of membranous nephropathy. C, Subendothelial deposits typical of systemic lupus erythematosus (SLE). D, Intramembranous deposits seen in many immunologic diseases, most notably SLE and membranoproliferative glomerulonephritis. E, Mesangial deposits seen in immunoglobulin A nephropathy (Berger disease) and SLE.



25 Why does the immunologic injury of the GBM cause proteinuria?


Proteinuria results from:


image Increased permeability of the GBM without interruption of the filtration barrier: It results from complex physicochemical changes caused by the action of activated complement, enzymes, and cytokines. These changes involve the biochemical composition and electric charges of the GBM and the size of internal pores that serve as normal channels for the passage of proteins.

image Rupture of the GBM: It is usually associated with a passage of large plasma proteins (e.g., fibrinogen) and red blood cells into the urinary space. Clinically, such proteinuria is associated with hematuria. Polymerization of fibrinogen into fibrin inside the urinary space of the glomeruli can be recognized as fibrinoid necrosis of capillary loops or the early formation of crescents for which this fibrin forms the scaffold.


26 Which cells participate in the antibody-induced glomerular injury?


Polymorphonuclear neutrophils, lymphocytes (including T cells and natural killer cells), platelets, and resident glomerular cells (especially the mesangial cells).



27 List the soluble mediators of inflammation that contribute to the antibody-mediated glomerular injury


Most mediators of inflammation mentioned in the chapter on inflammation have been identified in the inflamed glomeruli:


image Activated complement components act as chemotactic fragments and mediate the influx of neutrophils and macrophages. Complement may also increase the permeability of the GBM and cause mechanical lesions through the action of membrane attack (C5–C9 terminal complex).

image Cytokines (especially interleukin-1 and tumor necrosis factor) and chemokines participate in the recruitment of inflammatory cells and their activation and also directly contribute to the injury of the GBM. Transforming growth factor-beta promotes extracellular matrix synthesis and contributes to glomerulosclerosis in later stages of the disease.

image Growth factors, such as platelet-derived growth factor, promote mesangial cell proliferation.

image In the coagulation system, fibrin and thrombin may activate platelets and other blood cells and local glomerular cells, as well as damage the GBM.

image Prostaglandins, nitrous oxide, and endothelin act on endothelial, mesangial, and epithelial cells and may have an important role in regulating the blood flow through the inflamed glomerulus.


28 What are the histologic signs of chronic progression of glomerular disease?



image Focal segmental glomerulosclerosis: This is a secondary change that occurs in the relatively unaffected glomeruli of a diseased kidney that has lost many nephrons. Normal glomeruli receive increased amounts of blood and undergo hypertrophy. The hemodynamic changes in the overburdened and enlarged glomeruli lead to segmental hyalinization of capillary loops and progressive narrowing of their lumen by sclerosis.

image Tubulointerstitial damage: Tubular damage results in hyalinization of tubular basement membranes and atrophy of tubular cells associated with a loss of their specific functions. The peritubular interstitial spaces increase in size and change their biochemical composition. Chronic inflammatory cells, predominantly lymphocytes, appear in the interstitial spaces. The factors leading to tubulointerstitial injury include ischemia distal to sclerotic glomeruli, concomitant immune reactions to shared antigens, and biochemical injury by retention of metabolites or minerals (e.g., phosphate, calcium, or ammonia).


29 Discuss the histologic features of acute glomerulonephritis


Acute glomerulonephritis is an endocapillary exudative and proliferative glomerulonephritis. By light microscopy, one may see:


image Hypercellularity of glomeruli, which is in part due to exudation of inflammatory cells (neutrophils and macrophages) and in part due to proliferation of endogenous glomerular cells

image Widening of mesangial areas by an increased number of mesangial cells

image Narrowing of capillary spaces and reduced blood flow through the glomeruli (few RBCs in the glomerular capillaries)

image RBCs in the urinary space and the lumen of tubules (a definitive sign of glomerular hematuria)

image Proteinaceous and RBC casts in the lumen of tubules (result from combined effects of glomerular proteinuria and hematuria)

image Interstitial edema and inflammation may be present (indicates that the entire kidney is reacting to the immunologic injury of the glomeruli)


30 Describe the most common cause of postinfectious glomerulonephritis


Group A beta-hemolytic streptococci (Streptococcus pyogenes) account for 90% of all glomerulonephritis cases. Glomerulonephritis typically occurs 1 to 4 weeks after a strep throat or skin infection (impetigo) caused by one of the nephritogenic strains of this microbe. Occasionally the same clinical and pathologic findings may follow staphylococcal infection and even some viral diseases, such as hepatitis B or C or hepatitis caused by human immunodeficiency virus (HIV). See Fig. 15-3.


image

Figure 15-3 Poststreptococcal glomerulonephritis. Left, Normal glomerulus. Right, Poststreptococcal glomerulonephritis. The glomerulus is hypercellular and contains neutrophils (N) and increased numbers of mesangial cells (Mes). Large immune complex deposits form spikes on the subepithelial side of the basement membrane in the form of humps (H).



31 What are “subepithelial humps” in acute glomerulonephritis, and how can they be seen?


Subepithelial humps represent epimembranous deposits of immune complexes on the GBM in postinfectious glomerulonephritis. They can be seen using electron microscopy. These humps represent only the “tip of the iceberg”—that is, they are the only ultrastructurally visible immune complexes. Immunofluorescence microscopy shows that the glomeruli contain many other immune complexes, which probably are not dense enough to be seen by electron microscopy. These smaller immune complexes are found in the mesangial areas and in the basement membrane and are distributed without any regularity.



32 What are the symptoms and signs of acute poststreptococcal glomerulonephritis?


Classic acute glomerulonephritis is a childhood disease. It usually presents with fever, nausea, oliguria, hematuria, RBC casts in urine, mild proteinuria (usually <1g/day), periorbital edema, and mild to moderate hypertension.


Atypical glomerulonephritis is the term used for the disease occurring in adults. The onset may be insidious, or the disease may present with a sudden appearance of hypertension or edema and biochemical signs of azotemia.



33 Why is the concentration of serum complement C3 low in acute poststreptococcal glomerulonephritis?


As immune complex deposits are formed in the glomeruli, they activate complement through the classical pathway, leading to a depletion of serum complement. C3 is the complement protein consumed in both the classical and the alternate complement pathways and is therefore used for monitoring the serum concentration of the entire complement system. Other complement proteins are also depleted, but there is no need to measure all of them at the same time. When the disease wanes, C3 levels return to normal.



34 What is the typical outcome and what are the possible long-term consequences of acute poststreptococcal glomerulonephritis?


The disease has a better prognosis in children than in adults:


image Children
image Ninety percent recover within 2 or 3 months with conservative therapy aimed at maintaining sodium and water balance.

image Five to eight percent have persistent glomerulonephritis, in much milder form, with abnormal urinary findings for 6 to 8 months.

image Less than 1% of cases develop rapidly progressive glomerulonephritis.

image One or two percent slowly progress to chronic glomerulonephritis.
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Jul 23, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on The Kidneys and the Urinary System

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