The proximal convoluted tubule.

[image]

Water yes, sodium no: thin descending loop of Henle.

Water no, sodium yes: thin ascending loop of Henle.

Diuretic, inhibiting the Na/K/2Cl cotransporter in the TAL apical membrane. Reduces osmolality of interstitium, which decreases fluid reabsorption and increases urination.

Disorder of fluid retention, leading to frequent urination and hypokalemia. Results from defective NA/K/2Cl cotransporter in the apical membrane of the TAL of the renal tubule.

Diuretic, working in the DCT. Inhibits apical Na/Cl cotransporter, reducing subsequent water reabsorption in the collecting duct.

Diuretic, inhibiting sodium transporter in the apical membrane of the collecting duct. Enhances fluid retention in the collecting duct, increasing urine output.

High: lots of water, so ~600 mOsm/L.

Low: not a lot of water, so ~1200 mOsm/L.

Pathological diuresis caused by defect in NaCl cotransporter in DCT.

Diabetes insipidus caused by defect in passive sodium transporter in the collecting duct cells' apical membranes.

The DCT is the site of the macula densa where filtrate composition is reported back to the glomerulus to facilitate tubuloglomerular feedback.  High Na and Cl concentration at the macula densa are interpreted as volume overload and lead to constriction of the afferent arteriole.  Low Na and Cl concentrations are interpreted as volume depletion and trigger renin release (with subsequent Na retention, systemic vasoconstriction, and GFR preservation through efferent>afferent arteriolar vasoconstriction).

In the DCT, Na reabsorption is increased by aldosterone (increasing systemic BP and fluid retention) and blocked by atrial natriuretic peptide (ANP - decreasing systemic BP and fluid retention).

ANP: powerful vasodilator and a protein (polypeptide) hormone secreted by heart muscle cells.

Aldosterone: steroid hormone (mineralocorticoid family) produced by the outer section (zona glomerulosa) of the adrenal cortex in the adrenal gland. It acts mainly on the distal tubules and collecting ducts of the nephron, the functional unit of the kidney, to cause the conservation of sodium, secretion of potassium, increased water retention, and increased blood pressure. The overall effect of aldosterone is to increase reabsorption of ions and water in the kidney -- increasing blood volume and, therefore, increasing blood pressure.

FF = GFR/RPF

GFR: glomerular filtration rate

RPF: renal plasma flow

FF: filtration fraction

The FF is the part of renal plasma flow that is filtered/diverted into the tubule. It changes wtih ultrafiltration pressure. With an increased FF, the oncotic pressure of the efferent arteriole increases, facilitating reabsorption of tubular fluid.

At times of hypertension and high renal plasma flow, afferent arteriole constriction lowers glomerular capsule pressure (and FF) to maintain a constant GFR.  

At times of hypotension and low RPF, efferent arteriole constriction increases GCP (and FF) to preserve GFR.

Angiotensin II (a peptide hormone) comes from the following pathway:

low BP --> release of renin --> release of angiotensin I --> conversion by ACE in lungs into angiotensin II --> increase in BP

Angiotensin 2 and the sympathetic nervous system preferentially constrict the EA > AA at times of hypotension, acting directly on smooth-muscle-cell-like mesangial cells. 

Prostaglandins dilate the afferent arteriole at times of volume depletion, acting alongside angiotensin II to maintain GFR during a low BP event.

Clearance is the volume of plasma completely cleared of a substance per unit of time.  It can be calculated with a time urine collection using the formula:

C = U V / P

It is the product of membrane properties and filtration pressures that determines how much blood plasma is filtered through the glomerulus per unit time.

GFR = Lp x S x (Pgc - (Pbs + ngc))

Lp = a constant, S = membrane permeability, Pgc = hydrostatic pressure of the glomerular capsule, Pbs = hydrostatic pressure of Bowman's space, and ngc = osmotic pressure of the glomerular capsule.

Substance: inulin. It is cleared readily from the plasma (electrically neutral), and is not secreted or absorbed in the tubule.

GFR = Cx = Ux(V/Px)

Cx = clearance of substance x, Ux = urine concentration of substance x, V = urine flow rate/unit time, Px = plasma concentration of substance x

The body is compartmentalized into an intracellular space (2/3 of body water) and an extracellular space (1/3 of body water) by the cellular membrane.  Each compartment has a unique chemical composition, with K being the key intracellular cation and Na the key extracellular cation.

The capillary membrane further divides the extracellular space into the interstitium (3/4 of extracellular volume) and the plasma (1/4 of extracellular volume, or 1/12 of total body water).  The plasma is maintained by plasma proteins which produce a higher oncotic pressure.

Volume depletion is sensed in the afferent arteriole, macula densa, and aortic/carotid bodies.  The renin-angiotensin-aldosterone (RAA) system, sympathetic nervous system (SNS), and anti-diuretic hormone (ADH) act to increase systemic vascular resistance (AII, SNS, ADH), increase tubular sodium reabsorption (SNS, AII, aldo), and retain water (ADH).

HF results in volume overload by reducing cardiac output, lowering renal perfusion, and stimulating Na retention.  Cirrhosis results in volume overload by dropping plasma oncotic pressure (through impaired albumin synthesis).  This drops intravascular volume, and stimulates renal Na retention to correct the perceived depletion.  Arteriovenous malformations in cirrhosis also drop SVR and BP, leading to renal underperfusion and Na retention.  In nephrotic syndrome, protein loss in the urine lowers plasma oncotic pressure and intravascular volume, stimulating renal Na retention.

K+-sparing diuretics block the Na+ channel in the CT. This reduces the tendency for fluids to diffuse across the CT epithelium.

ADH is release from the posterior pituitary under circumstances of 1) hyperosmolality sensed by the osmoreceptors of the hypothalamus, or 2) significant ineffective circulating volume sensed by the carotid and aortic bodies.  ADH leads to the incorporation of aquaporins (water channels) in the normally water impermeable membrane of the CT.  This facilitates water reabsorption from the dilute filtrate (50 mOsms/L at the end of the DCT) into the hypertonic renal medulla (1200 mOsms/L).  ADH results in urinary concentration and water retention, whereas the absence of ADH results in urinary dilution and water loss.

Hypoosmolality/hyponatremia is lack of ions or sodium in the body plasma. It is caused by excess water intake or inadequate urinary dilution.  Excess water intake occurs when intake exceeds the water excretory capacity as dictated by the urinary osmolality and the osmolar load.  Inadequate urinary dilution occurs from appropriate (ineffective circulating volume) or inappropriate (SIADH, hypothyroidism, adrenal insufficiency) ADH.

Treatment requires inducing a negative water balance with decreased water intake and increased water excretion.  Increased water excretion can be achieved by suppressing ADH (if possible) or blocking ADH receptors (with drugs called Vaptans).  The serum Na concentration should be raised by no more than 0.5 mEq/L/hr to prevent central pontine myelinolysis.

Hereditary nephropathy (X-linked dominant or recessive) caused by defect in alpha 3, 4 or 5 collagen IV. In the kidney the glomerular basement membranes show thickening with lamellation and splitting. The clinical presentation is initially micro- and later macrohematuria (nephritic presentation).

There are also lens abnormalities (triangular profile shape of cornea when looking down), skin abnormalities, and hearing loss.

An autosomal dominant disease also known as benign familial hematuria. The underlying molecular defect is a mutation in collagen IV alpha 3 or 4 subunit. In the kidney the glomerular basement membranes show normal structure, but are markedly thinned at less than 200 nm (normal 250-350 nm). The clinical presentation is microhematuria detected in most cases as an incidental finding during routine physical.

Loss of 30-50% of nephrons leads to steady and progressive loss of kidney function (measured by decline in GFR) and end stage renal disease (ESRD) with all/nearly all glomeruli irreversibly damaged and non-functional.

Glomeruli damaged beyond the point of recovery show increased mesangial cellularity and matrix, collapse of the capillary tuft and closure of capillary lumina. These changes are referred to as glomerulosclerosis. In ESRD all glomeruli appear sclerosed.
Since the efferent glomerular capillary gives rise to the vasa recta feeding the tubular part of the nephron, there is no blood flow to the tubule, which undergoes atrophy. The tubular atrophy is accompanied by interstitial inflammation and later fibrosis.

Agenesis: Bilateral renal agenesis is very rare. It usually occurs in the setting of other developmental abnormalities and is incompatible with life. Unilateral agenesis is rare. The solitary kidney undergoes compensatory hypertrophy as a result of taking over the increased filtration load.

Hypoplasia: May be unilateral or bilateral. The kidneys are small and have a reduced number of lobes and pyramids. This differentiates these kidneys from small atrophic kidneys resulting from infection or limited blood supply (ischemia). It usually leads to renal failure in childhood.

Horseshoe kidney: The kidneys are fused at the lower (more common) or upper poles. Usually an incidental finding; however, the kidneys may be more prone to medical disease.

Ectopic kidney: Ectopic means outside the normal location. Usually found at a lower anatomic level or even in the pelvis. Because of ureteral tortuosity, ectopic kidneys are more prone to develop infections.

Autosomal recessive metabolic disorder characterized by the inability to absorb nonpolar amino acids (most importantly, tryptophan). Tryptophan deficiency results in a downstream deficiency in serotonin, melatonin, and niacin.

The defective gene is a portion of a sodium-dependent and chloride-independent neutral amino acid transporter that controls amino acid absorption from the intestine and the reabsorption of those amino acids in the kidneys. Consequently, a person with Hartnup disease cannot absorb amino acids properly from the intestine and cannot reabsorb them properly from tubules in the kidneys. Excessive amounts of amino acids, such as tryptophan, are excreted in the urine.

Hartnup disease manifests during infancy with variable clinical presentation: failure to thrive, photosensitivity, intermittent ataxia, nystagmus and tremor.

Symptoms are sporadic, and damage is usually unilateral; may be bilateral.
Results in a maldeveloped kidney, with multiple cysts and abnormal histology with persistence of immature structures and mesenchyme (often cartilage).

Cystic renal dysplasia is a common cause of kidney failure in the childhood.  It can be seen on prenatal ultrasound.

Autosomal Dominant (Adult) Polycystic Kidney Disease.

Genetics: Autosomal dominant with variable penetrance (incidence = 1 in 1000).

Clinical: Usually apparent in adulthood with increasing symptoms with age. Presents with hypertension (most common), mass, hematuria, pain, urinary tract infections, and eventually kidney failure.

Gross Features: Bilateral large, distorted kidneys with bosselated surface and large fluid filled cysts replacing both cortex and medulla.

Microscopic Features: Spherical, thin walled cysts (involving all parts of the nephron) which are lined by flattened epithelial cells.  Secondary glomerular scarring, tubular atrophy and interstitial fibrosis may be

Other Features: Scanning electron microscopy has demonstrated that these are not true cysts but saccular dilatations of nephron.  Micro dissection and cyst fluid analysis show that epithelium retains its functional capacity.

Associated Abnormalities: Hepatic cysts (no functional impairment); cerebrovascular (berry) aneurysms, cysts of pancreas, spleen, lungs.

Autosomal Recessive (Childhood) Polycystic Kidney Disease

Genetics: Autosomal recessive.

Clinical: This is a rare condition presenting in fetal life or infancy with bilateral abdominal masses or with renal insufficiency. Most die within weeks to months due to uremia.

Gross Features: Bilateral renal enlargement with smooth cortical surfaces.

Cut surfaces:  innumerable small cysts in cortex and medulla.

Microscopic Features: Elongated cysts of collecting ducts (tubules) oriented at right angles to the cortical surface.

Associated Abnormalities: Congenital hepatic fibrosis.

Rare condition associated with small cysts in renal medulla.

Renal cortical cysts which are usually asymptomatic.
May mimic renal cell carcinoma. Represent fetal cysts that failed to regress.

Patients with end-stage renal disease on dialysis.
Cortical and medullary cysts often containing calcium oxalate. Tumors (RCC) often present (7%) in the walls of such cysts.

Adult renal adenoma

- Macroscopic appearance

- Microscopic appearance

- Location

- Risk factors

- Treatment and prognosis

- Macro: These are small tumors and need to be <0.5 cm in size to be called benign. Larger tumors have more potential for metastasis and are not included in the benign category.

[image]

- Micro: Morphologically, these tumors are papillary and resemble a papillary variant of renal cell carcinoma.

- Location: Usually renal cortex.

- Risk factors: Male sex.

- Treatment and prognosis: Resection or no action, with excellent prognosis.

Adult renal oncocytoma

- Macroscopic appearance

- Microscopic appearance

- Location

- Risk factors

- Treatment and prognosis

- Macro: A benign tumor which may grow to a large size, and may present as a mass or hematuria, or be an incidental finding on imaging.

[image]

- Micro: The term “oncocytoma” refers to the microscopic appearance of large cells with eosinophilic granular cytoplasm (oncocytes), which can be shown on electron microscopy to contain large numbers of mitochondria.

[image]

- Location: Oncocytomas may also occur at other sites of the body, such as salivary and endocrine glands.

- Risk factors: Male sex.

- Treatment and prognosis: While these tumors can grow to a large size, they have little or no propensity to extend beyond the kidney, to grow into vessels, or to metastasize.  Unfortunately, they cannot always be reliably identified as oncocytomas by radiology or biopsy, and nephrectomy is usually performed, with excellent prognosis.

Renal cell carcinoma

- Macroscopic appearance
- Microscopic appearance
- Location
- Risk factors
- Treatment and prognosis

- Macro: Multiple, large, and malignant bilateral tumors that are historically associated with abdominal mass, flank pain, and hematuria. On dissection, they often show yellow color, with areas of hemorrhage and necrosis.  The yellow color is due to the high lipid content present in the tumor cells.

 [image]

- Micro: There are several histological types, each with their own epidemiology, cell of origin, cytogenetics and prognosis (clear cell, papillary, chromophobe). Clear cell RCC is the most common and comes from PCT. The cytoplasm is clear because these cells contain abundant glycogen and/or lipid, which is lost from the cell during processing of the tissue for microscopy.  Cells are grouped into sheets or nests, with prominent capillaries between groups of cells.  The nuclei are commonly low grade.

[image]

- Location: The tumor usually forms a well defined solid mass, in the renal poles. It frequently invades the renal vein, and may grow along the vein, and even into the vena cava in continuity with the tumor.  Frequent sites of metastasis are including to lung, bone, liver, adrenals, and brain.  Renal cell carcinoma should always be considered as part of the differential diagnosis of a metastatic carcinoma with an undetermined primary site.

- Risk factors: Smoker, renal cysts, male sex (except for chromophobe subtype), advanced age (50-60 years).

- Treatment and prognosis: Patients usually present with systemic symptoms, like fever, weight loss, malaise, anemia, and neuropathy. Clear cell = poor, papillary = better, chromophobe = best. There is no particularly effective chemotherapy, so whole-kidney resection is necessary.

Renal angiomyolipoma

- Macroscopic appearance
- Microscopic appearance
- Location
- Risk factors
- Treatment and prognosis

- Macro: It may be clinically symptomatic because it may form extremely large tumors (20 cm or more), and massive hemorrhage may occur due to prominent vascularity.

[image]

- Micro:

[image]

- Location: Cortex and medulla.

- Risk factors: Female sex.

- Treatment and prognosis: Renal resection. In 25-50% of the tumors, there is associated Tuberous Sclerosis (see box).  Furthermore up to 80% of tuberous sclerosis patients develop angiomyolipoma.  As this tumor is rare (< 2% of all renal tumors), when identified it should prompt investigation for TS. Conversely, in TS patients with a renal mass, angiomyolipoma should be considered high on the list of differential diagnoses.

What are the pathophysiological characteristics of Von Hippel Lindau syndrome?

Autosomal dominant genetic disorder.  33-50% of these patients develop renal cell carcinoma, 30% of VHL patients dying of RCC.  The gene (VHL gene) is on chromosome 3p.

Features:
- Renal cell carcinoma.
- Angiomas of the retina, cerebellum (hemangioblastoma) and brain stem.
- Cysts of pancreas, liver and kidneys.
- Angiomyolipomas (rare, vs tuberous sclerosis).

What are the pathophysiological characteristics of tuberous sclerosis?

Autosomal dominant genetic disorder. Mutation in tuberin and hamartin gene leading to formation of hamartomatous proliferations in different organs.

Clinical triad of angiofibromas, seizures and mental retardation.

CNS:

     - Cortical hamartomas (‘tubers’) – haphazard   neurons/glial cells

     - Subependymal giant cell astrocytomas

     - Retinal hamartomas

Skin:

    - Angiofibromas (face)
    - Subungual fibromas
    - Hypopigmented “ash leaf” patches

Renal:

    - Angiomyolipoma(s), Cysts, renal cell carcinoma

Heart and Lungs:  Myomas

Cysts: Renal, Liver, Pancreas

Transitional cell carcinoma (TCC) - AKA urothelial carcinoma

- Macroscopic appearance
- Microscopic appearance
- Location
- Risk factors
- Treatment and prognosis

- Macro: In papillary tumors, an exophytic polypoid structure is formed.  In flat tumors, the tumor has a relatively smooth surface and does not project much above the level of the adjacent mucosa.

[image]

[image]

- Micro:

[image]

[image]

- Location: Origin is transitional epithelium or urothelium. Therefore this tumor can occur in the pelvocalyceal system in the kidney, the ureters, the urinary bladder and the urethra. Transitional cell carcinoma is much more common in the bladder (95% of urothelial cancers) than in the renal pelvis, calyces, and ureters (5% of urothelial cancers).

- Risk factors: Advanced age (55-70), male sex, long-term travel to Egypt and Asia (schistomiasis), smoking, aniline dyes, radiation, cyclophophamide.

- Treatment and prognosis: Presentation with painless hematuria. Bladder-sloughing medication can be prescribed. Non-invasive or flat tumors = good prognosis upon resection. Invasive tumors = poor prognosis.

Nephroblastoma (Wilms tumor)

- Macroscopic appearance
- Microscopic appearance
- Location
- Risk factors
- Treatment and prognosis

- Macro: Large masses often >500 grams, completely obliterating a kidney. The tumor is soft, tan to gray, with frequent cysts, necrosis and hemorrhage.

[image]

- Micro:
Blastema: Sheets of “small round blue cells”, typical of many childhood tumors (see box).
Epithelium: Forming primitive tubules and glomeruli, resembling in many instances embryonal kidney.
Stroma: Mesenchymal tissue, consisting of fibroblastic (usual), smooth or skeletal muscle, fat, cartilage, bone, neural tissue.

[image]

[image]

- Location: Mesenchyme, tubules, glomeruli (depends on the histology).

- Risk factors: ONLY IN CHILDREN (85% of childhood tumors), nephrogenic nest, family history, certain genetic abnormalities:

Beckwith-Wiedemann syndrome (organomegaly, hemihypertrophy, renal cysts and Wilms tumor) – Associated with WT-2 gene on chromosome 11 (11p15.5)

Denys-Drash Syndrome (gonadal dysgenesis, glomerulopathy and Wilms tumor) has 90% chance of Wilms. It is characterized by mutation on chromosome 11p13.
WAGR syndrome with 33% chance of Wilms. Consists of Wilms tumor, Aniridia, Genital anomalies, Mental Retardation. This syndrome is associated with WT-1 gene deletion on chromosome 11 (11p13).

- Treatment and prognosis: Presents early in life with large abdominal mass, hematuria, pain, hypertension. Anaplasia refers to blastema or epithelial cells showing (1) large hyperchromatic nuclei and (2) multipolar mitotic figures.  Anaplasia correlates with p53 mutations and resistance to chemotherapy. The presence of anaplasia classifies the tumor as being of “unfavorable histology” which indicates poor prognosis and warrants aggressive treatment. However, general prognosis is very good, with chemotherapy and surgery leading to >90% survival rate.

What is type II renal tubular acidosis?

Acidosis caused by failure of carbonic anhydrase in the proximal renal tubule. This reduces the reabsorption of bicarbonate from carbonic acid ( --> water + carbon dioxide) formed in the lumen.

Acidosis caused by defect in H+/ATP-ase protein in the apical walls of the collecting duct.

Injury to glomerular podocytes caused by:

- Circulating/filtered antibodies

- Cytokines

- Drugs (esp. NSAIDs)

- Amyloid deposition

- Collagenous matrix (as in DM)

- Immune complexes in subepithelial space (membranous nephropathy)

- Hereditary nephrotic syndrome (slit diaphragm damage)

- Most accurate test: 24 h timed urine collection

- Most common: dipstick, positive with >30 mg/dL (1+ to 4+, highest is > 2000 mg/dL)

- Proteinuria >500 mg/day --> kidney disease

- Proteinuria >3000 mg/day --> glomerular disease

- Caution: orthostatic proteinuria is normal in adolescents after laying down all night.

- Caution: exercise, illness, hypertensive episodes, inflammatory conditions --> transient proteinuria

Clinical features: normal kidney function and BP, noninflammatory urine sediment

Defining symptoms: Proteinuria >3.5 g/day, hypoalbuminemia (serum <3.5 g/dL), edema, hyperlipidemia/lipiduria

Morbidities:

- Edema/effusion (loss of oncotic pressure)

- Infections (IgG/complement wasting --> decreased immunity --> staph/pneumo sepsis)

- Thrombotic/embolic events, endocrine dysfunction (loss of antithrombin III/plasminogen)

- Endocrine dysfunction (loss of vit. D-binding protein --> calcium aladsorption --> bone disease --> atheromatosis)

1. Minimal Change Disease (MCD)
2. Focal and segmental glomerulosclerosis (FSGS)
3. Mebranous nephropathy (MN)

Clinical features/symptoms: glomerular nephrotic syndrome (proteinuria >3.5 g/day, hypoabluminemia < 3.5 g/dL, hyperlipidemia, edema); normal kidney function and usually no hypertension

Glomeruli are unremarkable except on EM (diffuse, global epithelial cell injury = podocyte foot process flattening/fusion)

[image]

Epidemiology: most common in young children (peak 2-6 yrs.)

Et/path: selective podocyte injury attributed to immune phenomena (assoc. with up. resp. tract inf., vaccines, allergies, Hodgkins)

Treat/Prognosis: steroid-responsive remission and sodium/fluid restriction has good lifetime prognosis; 2/3 relapse when steroids are reduced

Clin/symp: glomerular disorder presenting with nephrotic proteinuria (>3.5 g/day) and nephrotic syndrome (proteinuria, hypoalbuminemia, low oncotic pressure, edema/effusion, hyperlipidemia)

[image]

[image]

Epidemiology: chronic disease; most common cause of NS in adults

Path/eti: minority known etiologic factors includes

- Autoimmune

- Collagen vascular disorder AKA SLE and RA)

- Chronic infection (hep B/C, syphilis, schistosomiasis, malaria)

- Sarcoidosis

- Cancer (10% of MN patients)

- Meds (gold salts, penicillamine)

MOST PATIENTS (80%) ARE IDIOPATHIC. Chronic antigen-antibody mediated disease where circulating IgG reacts with native/planted antigen on subepithelial  glomerular basement membrane --> antigen/antibody complexes --> podocyte injury

Treat/prog: workup for assoc. diseases. No treatment, ~50% patients develop kidney failure

Clinical/symp: glomerular disorder presenting with nephrotic proteinuria (>3.5 g/day), initially normal kidney function, EM glomeruli demonstrate segmental sclerosis

[image]

Epidemiology: most common cause of nephrotic syndrome (NS) in adults; leading cause of chronic kidney disease paralleling obesity incidence; higher prevalence among African Americans and Hispanics; 15% of MCD children w/ steroid resistance develop FSGS; collapsing FSGS in 10% of HIV patients --> kindey failure

Path/eti: ? cytokines, drug/microbe/env toxicity, glom. hyperfiltration --> podocyte injury

Treat/prog: poor, with 50% --> end-stage renal disease in 10 years; no steroid response, recurs in transplant kidneys, may evolve to global glomerulosclerosis

What are the two most common systemic causes of secondary glomerular disease? Give brief clinical features and symptoms, epidemiology, pathogenesis/etiology, treatment/prognosis

Diabetes

Clinical: microalbuminuria --> progressive to nephrotic non-selective proteinuria without GFR loss progression.

[image]

[image]

[image]

Epi: proteinuria in ~50% DM patients after 10 years, with faster GFR loss in type I than II.

Path: nonenzymatic glycosylation of glomerular proteins --> GMB charge and membrane properties change; type IV collagen increase, heparan sulfate decrease

Treat/prog: DM I or II treatment can halt progress.

Amyloidosis

Clinical: positive Congo red glomerular stain, apple green birefringence under polarized light, random non-branching fibrils on EM

[image]

[image]

[image]

[image]

Epi: often found in those with plasma cell neoplasia or familial Mediterranian fever (genetic disease with chronic inflammation and increased serum amyloid A-protein)

Path/eti:

- AL amyloidosis is deposition (immunoglobulin light chain kappa or lambda = amyloid light chain); often with lymphoproliferative disorder or plasma cell neoplasm

- AA amyloidosis is deposition of serum amyloid A-protein synthesized by liver in inflammatory conditions

Clinical features:

- Hematuria

- Azotemia (high serum creatinine, urea, etc.)

- Oliguria (<500 ml/day) or anuria

- Hypertension

- Proteinuria

- Urine inflammatory cells (active)

[image]

Etiology: 

- Glomerular inflammation due to injury to glomerular endothelium --> complement activation (immune phenomena)

- Often caused by systemic infection immune complexes (post-strep glomerulonephritis) depositing in glomerular subendothelial space or mesangium --> complement --> etc.

[image]

- Circulating antibodies against glomerular basement membrane (Goodpasture's or anti-membrane disease)

- IgG antibodies against neutrophils = ANCA; this usually does NOT leads to complex deposition in capillary wall, so known as Pauci-immune glomerulonephritis

Glomerular disease caused by immune complex subendothelial deposition in glomerulus due to systemic infection by strep pharyngitis/staph impetigo, and most frequently group A beta-hemolytic strep. Patient have high ASO (antistreptolysis O) titers and low complement.

[image]

Glomerular disease characterized by basement membrane abnormalities ('double countour' or 'tram tracking'), immune complex deposition, influx of inflammatory cells. Complement levels are chronically low. Most of those affected are adults and young adults.

Glomerular remodeling is due to chronic inflammation and immune complex deposition.

 [image]

[image]

[image]

Two types of MPGN:

- Idiopathic

- Secondary to disorders of chronic circulating antigens, antigen-antibody complexes. Caused by Hep C/B, syphilis, malaria, parasites. Neoplastic lymphocytes/plasma cells create paraproteins.

Prognosis: chronic and progressive, with likely recurrence in transplanted kidneys --> kidney failure.

General: description of rapid loss of kidney function (days) form severe glomerular injury, with presence of glomerular crescents on biopsy. Immunofluorescent studies required to determine cause.

3 presenting diseases:

- Anti-glomerular basement membrane disease

- Immunocomplex deposition diseases

- Pauci-immune crescentic glomerulonephritis (ANCA positive vasculitis)

[image]

Histo: cresents and IgG staining immunofluorescence; linear distribution on capillary walls. No EM deposits.

[image]

Path: anti-GBLM disease triggered by viruses/toxins --> autoimmune disorder (high prevalence of HLA-DR B1). Antibodies may cross-react with pulmonary basement membrane --> pulmonary hemorrhage (Goodpasture's syndrome). Rapid loss of kidney function.

Treat: Plasmapherisis, cytotoxic agents for ab production choking.

Histology: cellular glomerular crescents. Granular IgA immune complexes on immunofluorescence. EM reveals large, electron dense deposits.

[image]

Path: contributory diseases include post-infectious GN, SLE, IgA nephropathy.

Treat: directed at underying disease. Crescents = bad prognosis.

Histo: cellular glomerular crescents, no immune complexes on immunofluorescence. No deposits on EM.

Path: most common form of crescentic GN. Autoimmune response to neutrophil cytpoplasmic antigens (ANCAs) causes binding of autoantibodies to neutrophils in glomerular capillaries and arterioles --> cytokine release --> endothelial cell/basement membrane damage --> necrosis, vasculitis. c-ANCA type = granulomatosis w/ polyangiitis (Wegener's granulomatosis). Vascular disease is systemic.

Treatment: shitty prognosis; requires immunosuppressive treatment with cytotoxic meds.

Histo: IgA deposition; mesangial/subendothelial in IgA nephropathy, systemically vascular in HSP. Cellular crescents upon rupture of endothelium. Immunofluorescence = IgA, EM = electron-dense deposits.

[image]

[image]

[image]

[image]

Path: IgA nephropathy is usually not systemic; HSP is. Associated with liver disease, IBD, celiac, mucosal infections of URT, GI, urinary tract. There is a genetic component --> abnormal IgA response in mucosal linings or defective clearance of IgA molecules by liver (cirrhosis).

Epid: most common cause of glomerular disease in the world (esp. Asia), but not in USA. Male predominance. Usually starts in adolescence --> kidney failure afer 20 years. HSP is usually in young children and is systemic.

Treatment: none.

AKA lupus glomerulonephritis

Histo: damage in any renal compartment and vessel, with morphologic changes in response to immune complex deposition. Immunofluorescence = IgG, IgM, IgA, complement ('full house'). EM = large electron-dense deposits.

[image]