USMLE World Step 1 – Nephrology

ContentsAcute Tubular Necrosis..........................................................................................................................1

Membranous Glomerulopathy (MG).....................................................................................................2

Minimal Change Nephropathy...............................................................................................................3

NSAID-associated nephropathy.............................................................................................................4

Anti-GBM Antibodies.............................................................................................................................5

Post-infectious GN.................................................................................................................................5

Renal Cell Carcinoma.............................................................................................................................7

Ischemic Renal Injury.............................................................................................................................7

Myeloma Kidney....................................................................................................................................8

Proteinuria.............................................................................................................................................9

IF Findings in PSGN................................................................................................................................9

Postinfectious GN, Prognosis...............................................................................................................10

Renal vein thrombosis.........................................................................................................................10

Lab findings in postinfectious GN........................................................................................................10

Membranous glomerulonephritis........................................................................................................10

ANCA Associated RPGN.......................................................................................................................11

Acute Tubular Necrosis Decreased renal blood flow triggers a chain of pathophysiologic changes in the nephron that

causes:o Epithelial necrosis o Acute renal failure

Stages of acute tubular necrosis:o The initiating stage of ischemic acute tubular necrosis is usually unnoticed by

clinicians as the symptoms of the main disorder: Haemorrhage, acute MI, sepsis, etc. prevail

o If significant tubular damage occurs, the maintenance stage (oliguric stage) follows in 24-36 hours.

o During this stage of the disease, urine output decreases and metabolic change of acute renal failure are manifest.

o The most significant of these changes are: Increased extracellular fluid can cause weight gain, edema and pulmonary

vascular congestion Hyperkalemia is usually asymptomatic when potassium is less than 6.

Above this level, peaked T waves are apparent on EKG o Potentially fatal ventricular arrhythmias are possible.

Retention of both hydrogen and anions (e.g. sulphate, phosphate and urate) will lead to high anion gap metabolic acidosis.

Other electrolyte changes include a decreased concentration of sodium and calcium – an increased level of phosphate and magnesium.

Urinalysis: Pathognomonic muddy brown casts Low urine osmolarity (less than 350) High urinary sodium (greater than 30) High urinary fractional sodium excretion (FeNa > 1)

In spite of the seemingly profound damage that occurs to nephrons in ATNo Tubular epithelial cells have an excellent regenerative capacity

If the patient survives the maintenance stage (by conservative management or dialysis) the recovery stage will follow in 1-2 weeks.

o It manifests with vigorous diuresis but renal tubules are still not functional Electrolyte balance is altered.

o A high volume, hypotonic urine may lead to decreased serum concentrations of: K Mg PO4 Ca

Stages of acute tubular necrosis

Initiation:

Ischemic injury to renal tubules precipitated by haemorrhage, acute MI, sepsis, surgery, etc. Maintenance stage:

o Decreased urine output o Fluid overload

o Increasing creatinine/BUN, hyperkalemia Recovery phase:

o Gradual increase in urine output Leading to high volume diuresis

o Electrolyte abnormalities may include decreased concentrations of K, Mg, PO4 and Ca due to slowly recovering tubular function.

Membranous Glomerulopathy (MG)

Nephrotic syndrome o Characterised by general edema and marked proteinuria (greater than 3.5g/day) o The presence of nephrotic syndrome and his underlying malignancy suggest

membranous glomerulopathy. o MG is one of the most common causes of nephrotic syndrome in adultso Up to 85% of MG are idiopathic o The remainder occur secondary to:

Systemic diseases: Diabetes mellitus Solid tumour (lung and colon) Immunologic disorders

o SLE Infections:

o Hep. Bo Hep. Co Malariao Syphillis

Biopsy finding:o Uniform, diffuse thickening of the glomerular capillary wall on light microscopy

without an increase in cellularity – consistent with diagnosis of MGo Electron microscopy reveals that this thickening us caused by:

Irregular dense deposits laid between the basement membrane and epithelial cells.

These protrusions resemble ‘’spikes’’ when stained silver. Immunofluorescence microscopy reveals:

Granular deposits contain immunoglobulins (IgG) and C3. Histology:

o During the maintenance phase we see flattening of tubular epithelial cells and tubular epithelial necrosis with denudation of tubular basement membrane.

o During the recovery phase, ATN is characterised by re-epithelization of tubules. Polyuria and gradual normalization of GFR occur

Leading to complete restoration of renal function in the majority of patients.

Minimal Change Nephropathy The presentation includes a child with:

o Nephrotic syndrome that occurs after an episode of upper respiratory nfection

o Characteristic of MCD – most common condition responsible for nephrotic syndrome in children age 2-8 years.

Investigations:o Light microscopy and immunofluorescent studies show completely normal kidneys.

Some features of this disease point to its immunologic mechanism, such as:o Association with previous infections and atopic diseaseo Excellent response to steroid therapy

The proteinuria of MCD is selective:o Largely albumin is lost.

Current hypothesis suggests that MCD is caused by a decrease:o In the normal content of sialic acid (a polyanion) in the basement membrane. o Subsequent loss of negative charge:

may cause a loss in selective permeability of the glomerular basement membrane

Increase in capillary transport of anionically charged particles such as albumin

Glomerular basement membrane disruption may be seen focally in a number of glomerular diseases:

o Most prominent in Alport’s syndrome o Caused by an inherited defect of alpha-5 chain of collage type 4 of the basement

membrane

Crescent formation in the glomeruli:o A sign of profound renal injury with bad prognosiso Rapidly progressive glomerulonephritis (RPGN) can be the outcome of a number of

conditions.

Ovoid or spherical hyaline masses are found in the glomerular mesangium of patients with diabetic nephropathy.

These nodules are:o Eosinophilic o PAS positive

Represent Kimmelstiel-Wilson Disease Diabetic nephropathy may present as nephrotic syndrome.

Nephrotic syndrome:o Clinically characterised by facial edema with massive proteinuria.

MCD – lipoid necrosis The disease may be associated with:

Respiratory infections Immunization

o Light microscopy in MCD shows normal glomeruli:

o Immunofluorescence microscopy doesn’t reveal any immunoglobulin or complement deposits.

o Electron microscopy: Diffuse effacement of the foot processes of the podocytes with a

morphologically normal glomerular basement membrane. The fusion of foot processes is the only pathological finding in MCD:

Renal function and light microscopy remains unchanged.

NSAID-associated nephropathy

Most patients with chronic pain take NSAIDs or less commonly COX-2 inhibitor to manage their pain

These two types of medications can cause renal failure if taken in large amounts for long periods of time.

These effects can be reversible. Pathogenesis:

o Analgesic nephropathy is multifactorialo NSAIDs concentrate in the renal medulla, allowing higher levels in the papillae than

in the renal cortex. o Decreased prostaglandin synthesis also facilitates the constriction of medullary vasa

recta, promoting ischemia. o While previous factors predispose to papillary necrosis

NSAIDs also uncouple the oxidative phosphorylation in renal mitochondria – thus causing direct cell damage.

o With prolonged NSAID use – the major pathophysiologic abnormality is chronic interstitial nephritis.

Patchy interstitial inflammation with subsequent fibrosis, necrosis and scarring of papillae.

Distortion of caliceal architecture Tubular atrophy seen in light microscopy

Clinically:o Modest elevation in serum creatinineo Evidence of tubular dysfunction (polyuria, nocturia) o Fanconi syndrome

Aminoaciduria Glycosuria Hypophosphatemia Hypouricemia

o Proteinuria is mild, less than 1 gm/day. o Papillary necrosis:

Colicky flank plain Gross hematuria Passage of tissue fragments in urine

Anti-GBM Antibodies

Goodpasture syndromeo A condition caused by anti-glomerular basement membrane antibodies

That target the alpha 3-chain of collagen type IV Patients develop rapidly progressive glomerulonephritis (RPGN)

Acute renal failure Crescent formation on light microscopy Crescents will have fibrin deposition Fluorescence microscopy shows linear IgG and C3 deposition.

o Nephritic: Red blood cell casts and mild proteinuria

o Patient may become hypertensive o These anti-GBM antibodies cross-react with other basement membranes, especially

those in the lung alveoli – causing pulmonary haemorrhage (hemoptysis)

Wegner’s o Granulomatosis with polyangiitis (Wegner’s)

Involvement of upper respiratory tract Sinusitis, nasal ulceration

Lower respiratory tract Hemoptysis

Kidneys Develop acute renal failure due to RPGN and hemoptysis due to

pulmonary haemorrhage Associated with anti-neutrophil cytoplasmic antibodies (c-ANCA) Additionally the RPGN in granulomatosis with polyangiitis is considered with

‘’pauci-immune’’: No anti-GBM antibodies or immune complex deposition.

o Combination of malar rash and pleural effusion: SLE

Circulating immune complex nephritis Most SLE patients are ANA positive The ANA test is quite sensitive if not specific. Antibodies to ds-DNA and Smith (Sm) antigen are more specific to

SLE

Post-infectious GN An older child or young adult present with:

o Edemao Hematuriao Proteinuria

Following a skin or pharyngeal infection PSGN is the most likely diagnosis.

o In this condition an inflammatory reaction involves all glomeruli in both kidneys.

o The kidneys are enlarged and swollen with multiple surface punctuate hemorrhages.

o On light microscopy: All glomeruli are engaged with hypercellular due to leukocyte infiltration Proliferation of endothelial and mesangial cells.

o On electron microscope: Electron dense deposits (humps) on the epithelial side of the basement

membrane are seen. o Immunofluorescence reveals:

Coarse granular deposits of IgG and C3 Characteristic lumpy bumpy appearance.

Basement membrane splitting:o Seen in MPGN o Alport syndrome

Uniform diffuse thickening of glomerular capillary walls on light microscopy is characteristic of membranous glomerulopathy

o One of the most common causes nephrotic syndrome in adults. o Clinical manifestations:

Nephrotic syndrome Generalised edema Marked proteinuria ( more than 3.5 g per day) Hypoalbuminemia Hyperlipidemia Lipiduria

Linear IgG and C3 deposits on immunofluorescence microscopy are characteristic of Goodpasture syndrome (anti-GBM disease)

o This is crescent formation on light microscopy. o Renal involvement is accompanied by pulmonary symptoms

Glomerular basement membrane (GBM) disruptions and fibrin deposition on electron microscopy are findings in Goodpasture syndrome.

o GBM breaks are due to fibrinoid necrosis of the glomeruli. o There is typically crescent formation on light microscopy

Crescents not detectable in early disease

Renal Cell Carcinoma

Gross painless hematuria in an older adult should be considered a sign of urothelial cancer unitl proven otherwise.

Renal biopsy:o Round/polygonal cells with an abundant clear cytoplasm o Standard tissue fixation and techniques typically dissolve glycogen and lipids from

pathologic specimens leaving clear spaces which are wide Thus inferring these cells are fully of glycogen and lipids Clear cell carcinoma

Most common form of renal carcinoma o Originate from tubular epithelial cells

Ischemic Renal Injury

ATN can develop secondary to low cardiac output during cardiac arrest. This cardiogenic shock causes ischemic injury to the kidneys, which is represented by

increased BUN , creatinine and oliguria (low urine output) Ischemic injury is not universal

o Some parts of the nephron are most susceptible Proximal tubules and the thick ascending limb of Henle’s loop are located in

the outer medulla of the kidney An area that even under normal conditions has a low blood supply.

In addtition, the proximal tubuules and ascending limb participate in the active (ATP consuming) transport of ions

When oxygen delivery to the kidney is compromised these portions of the nephron will suffer first.

Histologicallyo Over ATN is characterised by:

Flattening of the epithelial cells Loss of the brush border in proximal tubular cells Subsequently:

Cell necrosis Denudation of tubular basement membrane (TBM)

Muddy brown casts are pathognomonic for ATN – a variant of granular pigmented casts.

Papillary necrosis is associated with:o Diabeteso Analgesic nephropathy o Sickle cell disease

Myeloma Kidney

Consider MM when an elderly patient presents with the following combination of findings:o Easy fatigability (due to anemia) o Constipation (due to hypercalcemia o Bone pain, most commonly in the back and ribs

Due to the production of osteoclast activating factor by myeloma cells and subsequent bone lysis)

o Renal failure A number of factors contribute to renal failure in MM:

o Hypercalcemiao Hyperuricemia o Infiltration of the kidney cells by myeloma cells o AL amyloidosiso Frequent infection

Myeloma cast nephropathy (myeloma kidney) due to the excess excretion of free light chains is the most common form of nephropathy diagnosed in MM

o Composed of Bence Jones protein (light chains) Filtered by the glomerulus in small amounts and then reabsorbed in the

tubules. When levels exceed the reabsorptive capacity of tubules

o These light chains precipitate with Tamm Horsfall protein and form eosinophilic casts

The casts compress the tubular epithelium and obstruct tubular lumens

Impeding renal function Also directly toxic to tubular epithelial cells

Ischemic tubular necrosis classically presents with muddy brown granular and epithelial cell casts along with free tubular epithelial cells

Acute pyelonephritis would present with pyuria, possibly with white blood cells casts (indicating renal origin of pyuria)

Hypersensitivity interstitial nephritis can manifest with sterile pyuria and there is often a history of exposure to an offending drug.

o Peripheral eosinophilia and eosionphiliuria while non-specific may help confirm the diagnosis

Aminoglycoside antibiotics accumulate within the renal cortex and cause acute tubular necrosis

Chronic lead intoxication produces chronic tubulointerstitial nephritis that leads to renal failure.

Proteinuria

Albumin loss with minimal loss of the more bulky proteins (such as IgG and macroglobulin) defines selective proteinuria

Filtration barrier to protein molecules is provided by the glomerular capillary wall, which contains three components:

o Fenestrated endothelium o The glomerular basement membrane o Epithelial cells

The barrier is selective to size and charge. Tubular proteinuria

o Associated with the presence of low molecular weight proteins such as b2-microglobulin, immunoglobulin light chains, amino acids and retinol binding protein.

o Normally filtered by the glomerulus and almost completely reabsorbed in the proximal tubule.

Appear in the urine when the proximal tubular function is disrupted for instance in tubulointerstitial nephritis

Overload proteinuria o Proteins of low molecular weight are normally filtered by the glomerulus and

reabsorbed at the proximal tubuleo But when these low molecular weight proteins are produced in a greater amount,

the reabsorptive capacity of the proximal tubules is exceeded – overload proteinuria occurs.

Commonly occurs in multiple myeloma Functional proteinuria

o Caused by a change in blood flow through the glomerulus o Precipitating factors include:

Exercise High fever Stress Cold exposure

Orthostatic:o Occurs in older, tall, thin adolescents and is characterised by increased protein

excretion in the upright position, but normal protein excretion in the supine position.

IF Findings in PSGN IF shows granular deposits of IgG, IgM and C3 in the mesangium and basement membranes

– producing a starry sky appearance.

Postinfectious GN, Prognosis

Age is an important prognostic factor in poststreptococcal glomerulonephritis.o 95% of affected children but only 60% of affected adults recover completely.

Renal vein thrombosis Venous drainage from the left testis travels through the left testicular vein into the left renal

vein and from there enters the IVCo In contrast the right testicular vein empties directly into the IVCo The difference in venous drainage gives diagnostic significance to left sided

varicocele, a condition that often indicates Occlusion of the left renal vein by:

Malignant tumour Thrombus

Membranous glomerulopathy is a common cause of nephrotic syndrome in adults:o Due to the increased permeability of the glomerular capillary wall in nephrotic

syndromeo Many important substances are lost o Loss of anticoagulant factors:

Especially antithrombin III Responsible for the thrombotic and thromboembolic complications

of nephrotic syndrome Renal vein thrombosis can be a manifestation of this

hypercoagulable state o Patients present with sudden onset of abdominal or flank pain

Gross hematuria o When renal thrombosis occurs on the left side in males:

Obstruction impedes venous flow into the left testis Left sided varicocele appears.

Lab findings in postinfectious GN Lab findings include:

o Elevated anti-Streptolysin O (ASO) titerso Elevated anti-DNAse B titers o Decreased C3 and total complement levels o Presence of cryoglobulins o C4 is usually normal

Membranous glomerulonephritis Presentation with serum antibodies to the PLA2R indicative of GN The M-type PLA2R is a transmembrane receptor found in high concentration in glomerular

podocyteso Major antigen in the pathogenesis idiopathic MGN

MCD is possibly due to abnormal T cell production of a glomerular permeability factor that affects the glomerular capillary wall:

o Leading to fusion of foot processes and marked proteinuria Mixed cryoglobulinemia:

o Found in patients with Hepatitis C Renal disease is likely due to IgM deposition in the glomerulus that leads to

basement membrane thickening and cellular proliferation

ANCA Associated RPGN

Crescent formation on light microscopy is diagnosis of RPGN:o This syndrome of severe glomerular injury that rapidly progresses to renal failure

within weeks to months of its onset. o RPGN can be caused by a number of different diseases. o RPGN is divided into 3 types based on immunologic findings:

Type 1: Characterised by anti-GBM antibodies Linear GBM deposits of IgG and C3 are found on IF Anti-GBM antibodies cross-react with pulmonary alveolar basement

membranes, producing pulmonary hemorrhages (hemoptysis) Goodpasture Syndrome

Type 2: Immune complex mediated Lumpy bumpy granular pattern of staining on IF microscopy Can be a complication of PSGN SLE IgA Nephropathy HSP

Type 3: Pauci immune

o No immunoglobulin or complement deposits on the basement membrane

o Have ANCA (anti-neutrophil cytoplasmic antibodies) in their serum

o Associated with granulomatosis with polyangiitis (Wegner’s) – also idiopathic.

o Patients present with: Renal failure Pulmonary symptoms

Cough Dyspnea Hemoptysis

Upper respiratory tract symptoms Epistaxis Mucosal ulceration Chronic sinusitis

o Crescents found under light microscopy.

Henoch-Schonlein Purpura (HSP)

Most common small vessel vasculitis in children o Disease affects boys aged 2-10o Often preceded by viral or streptococcal upper respiratory infections.

Symptoms generally develop a few weeks after the associated illness resolves. Hypothesized that antigen from the infection stimulates production of IgA antibodies:

o IgA containing immune complexes then deposit on vessel walls Inducing an inflammatory reaction

IgA-mediated leukocytoclastic (hypersensitivity) vasculitis Symptoms

o GIT: Intermittent severe abdominal pain Vasculitis within the GIT may result in upper and lower GI bleeding

(hematemesis and bloody diarrhea) Bowel edema Increased risk of intussusception

o Kidneys Renal involvement in HSP is identifical to that seen in IgA nephropathy

Mesangial proliferation and crescent formation o Skin

Palpable purpura on the buttocks and lower extremitis: These lesions may begin as urticarial papules or plaques and

subsequently evolve into purpura Cutaneous findings in HSP are a result of IgA leukocytoclasis of

cutaneous vessels. o Joint

Self-limited migratory arthralgias and arthritis seen in the large joints of the lower extremities.