Renal, Urologic, and Reproductive System

**Four basic morphological component**

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* glomeruli (immunologically mediated injure)
* tubules (frequently toxic or infectious injury)
* interstitium
* blood vessels

**Azotemia**

elevation of blood urea nitrogen (BUN) and creatinine levels, largely due to decrease glomerular filtration rate (GFR)

**Prenal azotemia**

occurs with kidney hypoperfusion (reduction of blood flow in the kidney)

**Postrenal azotemia**

occurs when urinary outflow is obstructed after exiting the kidney

**Uremia**

constellation of clinical signs and symptoms associated with azotemia; includes metabolic, hematologic, endocrine, gastrointestinal, neural, and cardiovascular effects (so this happens when the kidney send out urine in the bloodstream)

**Renal disease**

typically manifest as clinically- recognizable syndromes

**Nephritic syndrome**

characterized by hematuria, mild to moderate proteinuria, and hypertension and is due to glomerular injury

Hematuria

* there’s a presence of blood in a person’s urine
* increased levels of protein in the urine

**Rapidly progressive glomerulonephritis**

nephritic syndrome with a rapid decline in GFR

**Nephrotic syndrome**

characterized by more than 3.5g/day proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria, and is also due to glomerular injury (dito naman bumababa yung level albumin and tumataas naman yung lipids sa blood flow)

**Asymptomatic Hematuria or proteinuria**

manifestation of mild glomerular injury

**Renal tubular defects**

due to disorders of tubules and/or interstitium—manifest with polyuria and electrolyte abnormalities

**Urinary tract infections**

can affect the kidney (pyelonephritis) or bladder (cystitis); there is pyuria and bacteriuria, but symptoms are variable

**Nephrolithiasis**

calculi (stones) in the urinary space, manifested by renal colic and hematuria

Glomerular Disease

constitutes some of the major problems in nephrology

**Chronic glomerulonephritis**

one of the most common cause of chronic kidney disease in human

Secondary glomerular disease

kidney is damaged by a systemic disease

* Systemic Immunologic Disease - Systemic Lupus Erythematosus (SLE)
* Vascular Disorders - hypertension
* Metabolic disease – diabetes mellitus
* Hereditary Conditions – Fabry disease
* Primary Glomerulonephritis – Kidney is the only predominant organ involved

**Glomerulus**

consist of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelial cells

Two layers of epithelial cells

**Visceral** – commonly referred as podocyte; intrinsic part of the capillary wall \n **Parietal** – cavity in which plasma filtrate first collects

**Visceral**

commonly referred as podocyte; intrinsic part of the capillary wall

**Parietal**

cavity in which plasma filtrate first collects

Glomerular capillary wall

filtering membrane

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1. thin layer of fenestrated endothelial cells
2. glomerular basement membrane
3. visceral epithelial cells – important for the
maintenance of the glomerular barrier function; slit diaphragm – present a size- selective distal diffusion barrier to the filtration protein; cell type that is largely responsible for synthesis of GBM components.
4. mesangial cells

* highly permeable to water and small solutes, impermeable to proteins of the size of albumin
* permeability characteristics of the glomerular filtration barrier – allow discrimination among various protein molecules, depending on their size (larger, less permeable) and charge (more cationic, more permeable)

**Hypercellularity**

increase in the number of cells in the glomerular tufts

* proliferation (mesangial/endothelial cells)
* infiltration of leukocytes (dito hindi lang leukocytes, it also includes the neutrophils, monocytes, and in some diseases

lymphocytes)
* formation of crescents (pag sinabing

formation of crescents, this is the accumulation of cells, composed of proliferating glomerular epithelial cells)

Pathologic response of the glomerulus to injury

1. **Hypercellularity**
2. **Basement membrane thickening**
3. **Hyalinosis and Sclerosis**

**Hyalinosis**

accumulation of material that is homogenous and eosinophilic by light microscopy

**Sclerosis**

characterized by deposition of extracellular collagenous matrix

Two forms of antibody associated injury

1. Injury by antibodies reacting in situ within glomerulus – either binding to insoluble fixed glomerular antigens or extrinsic molecules planted within the glomerulus
2. Injury resulting from deposition of circulating antigen-antibody complexes in glomerulus

**Heymann model of glomerulonephritis**

induced by immunizing rats with an antigen— megalin, present in epithelial cell foot processes

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Rats develop antibodies to this antigen, and disease develops from the reaction of antibody with the megalin-containing protein complex located on the basal surface of visceral epithelial cells, leading to localized immune complex formation.


1. Antibody binds to megalin
2. complement activation and shedding of the immune complexes to form sub epithelial deposits

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The pattern of immune deposition by immunofluorescence microscopy is granular rather than linear, reflective of the very localized antigen- antibody interaction.

**Goodpasture syndrome**

anti-GBM antibodies cross-react with other basement membranes, especially those in the lung alveoli, resulting in simultaneous lung and kidney lesions.

Glomerular injury

caused by the trapping of circulating antigen-antibody complexes within the glomeruli

Endogenous and exogenous

antigens that trigger the formation of circulating immune complexes

Endogenous

GN is associated with SLE or in IgA nephropathy

Exogenous

GN that follows certain infections

**Neutrophils and monocytes**

* infiltrate the glomerulus in certain types of glomerulonephritis.
* release proteases (causes GBM degradation); oxygen-derived free radicals (cause cell damage); arachidonic acid metabolites (contribute in reduction in GFR)

**Macrophages and T Lymphocytes**

* Infiltrate the glomerulus antibody and cell mediated reactions.
* Release cytokines, cytotoxic cell mediators and growth factors.

**Platelets**

* aggregate in the glomerulus during immune- mediated injury
* release eicosanoids, growth factors and other mediators (contribute to vascular injury and proliferation of glomerular cells)

**Resident glomerular cells (particularly mesangial cells)**

* stimulated to produce several inflammatory mediators including Reactive oxygen species (ROS), cytokines, chemokines, growth factors, eicosanoids, nitric oxide and endothelin.
* can initiate inflammatory responses in the glomerulus even in the absence of leukocytic infiltration.

Soluble Mediators

1. Complement activation
2. Eicosanoids, nitric oxide and endothelin
3. Cytokines (interleukin-1) & Tumor Necrosis Factor (TNF)
4. Platelet-derived growth factor
5. Coagulation proteins (fibrin)

**Complement activation**

* generation of chemotactic products that induce leukocyte influx
* formation of C5b-C9 or the membrane attack complex (causes cell lysis and induces mesangial cell activation

**Eicosanoids, nitric oxide and endothelin**

affect vascular flow

**Cytokines (interleukin-1) & Tumor Necrosis Factor (TNF)**

influence inflammatory cell adhesion and recruitment

**Platelet-derived growth factor**

* influences mesangial cell proliferation;
* transforming growth factor B and fibroblast

growth factor - maintains matrix deposition
* vascular endothelial growth factor - maintains endothelial integrity and regulates capillary

permeability

**Coagulation proteins (fibrin)**

can simulate parietal epithelial cell proliferation (crescent formation)

**Focal Segmental Glomerulosclerosis**

initiated as an adaptive change (on the unaffected glomeruli sa diseases kidney)

**Compensatory Hypertrophy**

* remaining glomeruli putatively preserves renal function > pero mag dedevelop yung proteinuria and segmental glomerulosclerosis > total glomerular scarring and uremia


* Glomerular hypertrophy > hemodynamic changes (it includes inc in glomerular blood flow, filtration, transcapillary pressure (htn))
* Endothelial and epithelial injury leads to protein accumulation, and then magkakaron ng macrophage recruitment, mag-activate yung mesangial cell and mag increase yung matrix synthesis.

**Tubulointerstitial Fibrosis** \n

* **tubulointerstitial injury** – component of many forms of acute and chronic GN \n renal function generally correlates better with the extent of interstitial damage than with the
* severity of glomerular injury \n results from ischemia (diminished perfusion
* downstream of sclerotic glomeruli or damaged capillaries) and inflammation in the surrounding interstitium
* **proteinuria** – causes direct injury to and activation of tubular cells > elaborate proinflammatory cytokines and growth factors that drive interstitial fibrosis

**Nephritic patient**

usually presents hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate htn (oliguria pag bumaba yung urine output less than 400ml per day)

**Acute proliferative Glomerulonephritis (Poststreptococcal, Postinfectious)**

* this cluster of diseases is characterized histologically by diffuse proliferation of glomerular cells associated with influx (exudation) of leukocytes. Lesions are typically caused by immune complexes
* immune complex-mediated disorder caused by the deposition of antigen-antibody complexes containing proteins derived from certain bacterial infections

Rapidly progressive (crescentic) glomerulonephritis

* Syndrome associated with severe glomerular injury, but does not denote a specific etiologic form of glomerulonephritis
* rapid, progressive renal decline
* most common histologic picture is the

presence of crescents in most of the glomeruli
* divided into three broad groups based on

immunologic findings \n

Type 1

characterized by linear IgG and C3 GBM deposits; in some cases, the anti-gbm antibodies cross- react with pulmonary alveolar basement membranes to produce pulmonary hemorrhages; solvent exposures or virus infections – inciting trigger in susceptible hosts. 20% of rpgn \n

Type 2

complication of any of the immune complex nephritides, including yung postinfectious GN. (25% of rpgn \n

Type 3

characterized by the absence of anti-GBM antibodies or immune complexes. More than 50% of rpgn

Nephrotic syndrome

caused by derangement in glomerular capillary walls resulting in increased permeability to plasma proteins.

Manifestation of nephrotic syndrome

* Depending on the lesions, the proteinuria can be highly selective, for example, primarily low-molecular-weight proteins (chiefly albumin)
* Heavy proteinuria leads to hypoalbuminemia, decreased colloid osmotic pressure, and systemic edema.

Membranous neprhropathy

* characterized by diffuse thickening of the glomerular capillary wall due to the accumulation of deposits containing Ig along the subepithelial side of the basement membrane
* common cause of adult nephrotic syndrome \n idiopathic in 85% of patients, while the remainder
* occurs in association with malignancy \n It is a form of chronic immune complex-mediated disease. Antibodies can be against self-antigens or exogenous proteins or haptens; lesions are similar
* to those seen in Heymann nephritis \n Capillary leakiness results from complement
* activation that, in turn, activates epithelial and mesangial cells to liberate damaging proteases and oxidants
* MGN usually manifest by insidious onset of nephrotic syndrome; htn and/or hematuria also occur in 15% to 35% of cases
* proteinuria persist in 60% of patients, but only 10% die or progress to renal failure in 10 years; 40% eventually progress to renal insufficiency

Minimal change disease

* relatively benign disorder characterized by diffuse effacement of foot processes of visceral epithelial cells, detectable only by electron microscopy, in glomeruli that appear virtually normal by light microscopy.
* major cause of nephrotic syndrome in children. \n usually it follows a respiratory infection or routine
* immunization \n response of corticosteroid and/or other
* immunosuppressive therapy \n also associated with atopic disorders and Hodgkin
* lymphoma

Pathogenesis of minimal change disease

* result from immune dysfunction and elaboration of one or more circulating cytokines that affect visceral epithelial cells
* most characteristic feature – dramatic response to corticosteroid therapy

Focal segmental glomerulosclerosis

* most common cause of nephrotic syndrome in adults in the US.
* primary disorder of podocytes

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Occurs as:


1. primary idiopathic disorder
2. secondary to other known disorders
3. after glomerular necrosis due to other causes
4. adaptive response to loss of renal tissue
5. secondary to mutations of protein that maintain the glomerular filtration barrier

Pathogenesis of focal segmental glomerulosclerosis

primary glomerular lesion in all FSGS is visceral epithelial damage in affected glomerular segment, (could be effacement or detachment)

**HIV-associated nephropathy**

manifest as a severe collapsing glomerulopathy variant of FSGS (retraction and/or collapse of the entire glomerular tuft and striking cystic dilation of tubular segments with associated inflammation and fibrosis)

Membranoproliferative glomerulonephritis (MPGN)

* best considered a pattern of immune- mediated injury rather than a specific disease.
* accounts for 10-20% of nephrotic syndrome
* can be idiopathic or secondary to another

disorder or agent

Pathogenesis of membranoproliferative glomerulonephritis (MPGN)

* categorized into two forms but in most cases of type I MPGN, there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways
* antigens in the complexes can originate from infection, SLE or malignancy but in most cases the source is unknown.
* type II – dense-deposit disease – due to activation of the alternate complement pathways, mostly ng patients na may ganito may C3 nephritic factor sa serum and an autoantibody against C3 convertase na nagstabilize nung proteolytic activity.
* most patient present in adolescence or young adulthood with nephrotic syndrome, occasionally with hematuria. (napapabagal ng steroids yung progression, about 50% of patients develop chronic renal failure within 10 years)
* mas mataas recurrence rate ng transplantmrecipients sa mga may type 2 disease.

Isolated urinary abnormalities IgA nephropathy (Berger disease)

* characterized by the presence of prominent IgA deposits in the mesangial regions and recurrent hematuria.
* most common type of glomerulonephritis worldwide

Pathogenesis of isolated urinary abnormalities IgA nephropathy (Berger disease)

* genetic or acquired defects in immune regulation
* result in increased mucosal IgA secretion in response to ingested or inhaled antigens
* patients typically present with gross hematuria following a respiratory, gastrointestinal, or urinary infection

Hereditary nephritis

group of heterogenous familial renal disease associated with mutations in collagen genes that manifest primarily with glomerular injury

Alport syndrome

* because the lesions and genetic defects have been well studied and THIN BASEMENT MEMBRANE LESIONS > because it is the most common cause of benign familial hematuria
* manifest by hematuria with progression to chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts and corneal dystrophy

Pathogenesis of alport syndrome

manifestations are due to defective assembly of type IV collagen in the GBM, normally composed of trimeric complex of a3, a4, and a5 subunits

Thin basement membrane lesion

* fairly common hereditary entity manifested clinically by familiar asymptomatic hematuria – usually uncovered on routine urinalysis and morphologically by diffuse thinning of the GBM to widths between **150 – 225 nm**
* result of mutations in genes coding for GBM type IV collagen kaya kinoconsider siya as part of a spectrum of diseases that includes hereditary nephritis

Chronic glomerulonephritis

end-stage glomerular disease that result from specific types of glomerulonephritis or may develop without antecedent history of any of the well-recognized forms of acute glomerulonephritis

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**Poststreptococcal gn** – 1-2% **RPGN** – 90% \n **Membranous gn** – 30-50% **FSGS** – 50-80%

**MPGN** – 50% \n **IgA Nephropathy** – 30-50%

Lupus nephritis

* sle gives rise to a wide variety of renal lesions and clinical presentations
* can include recurrent microscopic or gross hematuria

Henoch-schonlein purpura

* childhood syndrome consist of purpuric skin lesions, abdominal pain and intestinal bleeding, and arthralgias along with renal abnormalities inflammation of the small blood vessels of the skin, joints, bowels and kidneys. When blood vessels get inflamed, they can bleed into the skin, causing a reddish-purple rash
* occur at any age but typically present in children between ages of 3 and 8 years

**Glomerulonephritis Associated with Bacterial Endocarditis and Other Systemic Infections**

* represent a type of immune complex nephritis initiated by complexes of bacterial antigen and antibody.
* presentations typically involve hematuria, although nephritic syndrome and even RPGN can occur.

**Diabetic Nephropathy**

* dm is major cause of renal morbidity and mortality
* leading cause of chronic kidney failute in US.
* occurs in 40% of type 1 and type 2 diabetics.
* most commonly marked by glomerular dse

leading to proteinuria with or without nephrotic

syndrome.
* also cause hyalinizing arteriolar sclerosis,

increases the susceptibility to pyelonephritis and papillary necrosis, and causes a host of tubular lesions

**Fibrillary Glomerulonephritis**

morphological variant of glomerulonephritis associated with characteristic fibrillar deposits in the mesangium and glomerular capillary walls that resemble amyloid fibrils superficially but differ ultrastructurally and do not stain with Congo red

Tubulointerstitial diseases

Most forms of tubular diseases involve the

interstitium too

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TYPES:


1. Ischemic/Toxic injury → acute tubular injury/ necrosis
2. Inflammation → tubulointerstitial nephritis


1. Infection


1. pyelonephritis
2. toxins/ metabolic disease


1. drugs, heavy metals, neuropathy, etc.
3. Physical


1. obstruction and neoplasm
4. Immunologic


1. sarcoidosis
2. transplant
3. rejections
5. Miscellaneous


1. idiopathic

Acute tubular injury / necrosis

* a clinicopathologic entity that can be characterized by acute renal failure; (+/-) morphologic evidence of injury to tubules (necrosis)
* Rapid reduction of renal function and urine output → acute renal failure
* Mc cause of acute renal failure (accounts for 50% of hospitalized patients)

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Renal tubules a prone to injury d/t:

* Tubules requiring more oxygen for normal

functioning → sensitive to ischemia and

vulnerable to toxins
* Proximal convoluted tubules
* Inc surface area for reabsorption
* Very active transport systems for ions and organic acids

Cause of acute tubular injury / necrosis

1. Ischemia d/t decreased or interrupted blood flow
2. Direct toxic injury to the tubules
3. Acute tubulointerstitial nephritis
4. Urinary obstruction

Reversible

redistribution of membrane protein → loss of cell polarity → abnormal ion transport inc Na+ delivery to distal tubules → VASOCONSTRICTION via tubuloglomerular feedback; or detachment of cells → tubular obstruction → inc intratubular pressure → reduced GFR

Irreversible

Death of cells → tubular backleak → dec tubular flow → reduced GFR; or (starting from) tubular backleak → interstitial edema → inc interstitial pressure → further tubular damage → reduced GFR

Ischemia

Sublethal endothelial injury → vasoconstrictor endothelin → VASOCONSTRICTION → reduced GFR → Oliguria

* Ruptures of tubular basement membrane (tubulorrhexis)
* Lumen filled with casts
* Interstitium
* Evidence of regeneration can also be seen (recovery)

Focal tubular epithelial necrosis at multiple points along the nephron with large skip areas in between, often accompanied by \n

Initiation

dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATI

* 36hrs
* Due to dec urine output; inc BUN
* Oliguria could be explained on the

basis of a transient dec in blood flow and dec GFR

Maintenance

is characterized by sustained dec in urine output between 40 & 400 mL/day

* X2 inc BUN
* Salt and water overload
* hyperkalemia\*
* Metabolic acidosis\*

Recovery

* Steady ince in urine output (3L/day)
* Large amounts of Na+, K+ are lost d/t tubules still damages
* Hypokalemia \*
* Susceptibility to infection (prone)

Tubulointerstitial nephritis

group of renal disease involves inflammatory injuries of the tubules and interstitium that are often insidious in onset and are principally manifest by azotemia

Acute tubulointerstitial nephritis

* Rapid clinical onset
* Interstitial edema accompanied by \n infiltration of interstitium and tubules and tubular injury

Chronic tubulointerstitial nephritis

* Insidious
* Infiltration with predominantly mononuclear leukocytes, prominent interstitial fibrosis, and widespread tubular atrophy

Advanced stages tubulointerstitial nephritis

both have glomerular and vascular damage that can occur

Pyelonephritis

* Inflammation affecting the interstitium, and renal pelvis
* One of the mc diseases of the kidney tubules

Acute pyelonephritis

* Caused by bacterial infection
* Associated with urinary tract infection

Chronic pyelonephritis

* Complex disorder
* Bacterial infection plays a dominant role
* Vesicoureteral reflux, obstruction
* Repeat episodes of acute pyelonephritis

**Routes by which bacteria can reach the kidneys**

1. Through the bloodstream (Hematogenous)

* Less common


* Septicemia, emboli from IE

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2. From the lower urinary tract (Ascending infection)

* Mc
* Urethra to bladder: colonization of distal uretha → catheterization → infection to bladder

**Vesicoureteral reflux**

The normal ureteral insertion into the bladder is a one-way valve that prevents retrograde flow of urine when the intravesical pressure rises, as in micturition. An incompetent vesicoureteral orifice allows the reflux of bladder urine into the ureters

**Intrarenal reflux**

* Vesicoureteral reflux also affords a ready mechanism by which the infected bladder urine can be propelled up to the renal pelvis and deep into the renal parenchyma through open ducts at the tips of the papillae
* most common in the upper and lower poles of the kidney, where papillae tend to have flattened or concave tips rather than the convex pointed type present in the midzones of the kidney

Acute pyelonephritis

Suppurative inflammation of the kidneys caused by bacterial/ viral infection (e.g. polyomavirus)

Complications of acute pyelonephritis

3Ps: **Papillary necrosis, Pyonephrosis, Perinephric abscess**

**Papillary necrosis**

* Death of the renal papillae
* Mainly seen in: diabetics, sickle cell disease,
urinary tract obstruction


* Usually bilat or may be unilat
* Tips of the distal 2⁄3 of the pyramids have
areas of gray-white to yellow necrosis

Pyonephrosis

* When there is total or almost complete obstruction
* Renal pelvis, calyces, and ureter are filled with pus

**Perinephric abscess**

Extension of suppurative inflammation through the renal capsule into the epinephrine tissue

Chronic pyelonephritis and reflux neuropathy

* A d/o in which there is chronic tubulointerstitial inflammation and scarring → involves the calyces and pelvis
* Pelvocalyceal damage an important diagnostic clue
* \*\*an important cause of kidney destruction in children with severe lower urinary tract abnormalities