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Nephrotic Syndrome

proteinuria (>3.5 g/day)
injury to podocytes
change in glomerual architecture - scarring

podocyte disruption → charge barrier impaired. Massive proteinuria (> 3.5 g/day) with hypoalbuminemia, hyperlipidemia, edema. May be 1° (eg, direct podocyte damage) or 2° (podocyte damage from systemic process [eg, diabetes]).

• Focal segmental glomerulosclerosis (1° or 2°)
• Minimal change disease (1° or 2°)
• Membranous nephropathy (1° or 2°)
• Amyloidosis (2°)
• Diabetic glomerulonephropathy (2°)


Nephritic syndrome

hematuria - also dysmorphic RBCs and RBC casts
inflammation and prolifferation of immune cells
breaks in GBM
some protein, but <3.5g/day
high BP
decreased GFR

due to GBM disruption. Hypertension, ↑ BUN and creatinine, oliguria, hematuria, RBC casts in urine. Proteinuria often in the subnephrotic range (< 3.5 g/day) but in severe cases may be in nephrotic range.

• Acute poststreptococcal glomerulonephritis
• Rapidly progressive glomerulonephritis
• IgA nephropathy (Berger disease)
• Alport syndrome
• Membranoproliferative glomerulonephritis


Fanconi Syndrome

Generalized reabsorption defect in PCT --> INCREASED excretion of amino acids, glucose, HCO3–, and PO43–, and all substances reabsorbed by the PCT

Effects:May lead to metabolic acidosis (proximal RTA), hypophosphatemia, osteopenia

Causes: Hereditary defects (eg, Wilson disease, tyrosinemia, glycogen storage disease), ischemia, multiple myeloma, nephrotoxins/drugs (eg, ifosfamide, cisplatin, expired tetracyclines), lead poisoning


Barter Syndrome

Resorptive defect in thick ascending loop of Henle (affects Na+/K+/2Cl– cotransporter)

Effects:Metabolic alkalosis, hypokalemia, hypercalciuria

Causes: Autosomal recessive Presents similarly to chronic loop diuretic use


Liddle Syndrome

Gain of function mutation --> INCREASED activity of Na+ channel --> INCREASED Na+ reabsorption in collecting tubules

Effects: Metabolic alkalosis, hypokalemia, hypertension, DECREASED aldosterone

Causes: Autosomal dominant Presents similarly to hyperaldosteronism, but aldosterone is nearly undetectable Treat with amiloride


Syndrome of Apparent Mineralcoricoid Excess

In cells containing mineralocorticoid receptors, 11β-hydroxysteroid dehydrogenase converts cortisol (can activate these receptors) to cortisone (inactive on these receptors) Hereditary deficiency of 11β-hydroxysteroid dehydrogenase -->  excess cortisol --> INCREASED mineralo corticoid receptor activity

Effects: Metabolic alkalosis, hypokalemia, hypertension DECREASED serum aldosterone level; cortisol tries to be the SAME as aldosterone

Causes: Autosomal recessive Can acquire disorder from glycyrrhetinic acid (present in licorice), which blocks activity of 11β-hydroxysteroid dehydrogenase
Treat with K+-sparing diuretics (DECREASED mineralocorticoid effects) or corticosteroids (exogenous corticosteroid-->  endogenous cortisol production ---> DECREASED mineralocorticoid receptor activation


Potassium Shifts into cell

beta agonist


Potassium shifts out of cell

high blood sugar (low insulin)
beta blockers
digitalis (blocks ATPase)
cell injury - lysis


metabolic acidosis

elevated anion gap:
Methanol (formic acid) Uremia Diabetic ketoacidosis Propylene glycol Iron tablets or INH Lactic acidosis Ethylene glycol (oxalic acid) Salicylates (late)

normal anion gap:
Hyperalimentation Addison disease Renal tubular acidosis Diarrhea Acetazolamide Spironolactone Saline infusion


Renal Tubular Acidosis Type 1

Inability of α-intercalated cells to secrete H+ -->  no new HCO3– is generated -->  metabolic acidosis

urine pH> 5.5

decreased serum K

Causes: Amphotericin B toxicity, analgesic nephropathy, congenital anomalies (obstruction) of urinary tract, autoimmune diseases (eg, SLE)
INCREASED risk for calcium phosphate kidney stones (due to INCREASED urine pH and INCREASED bone turnover)


Renal Tubular Acidosis Type 2


Defect in PCT HCO3– reabsorption --> INCREASED excretion of HCO3– in urine -->  metabolic acidosis Urine can be acidified by α-intercalated cells in collecting duct, but not enough to overcome the increased excretion of HCO3– -->  metabolic acidosis

urine pH< 5.5
decreased serum K

Causes: Fanconi syndrome, multiple myeloma, carbonic anhydrase inhibitors
ICREASED risk for hypophosphatemic rickets (in Fanconi syndrome)


Renal Tubular Acidosis Type 4

Hypoaldosteronism or aldosterone resistance; hyperkalemia --> DECREASED NH3 synthesis in PCT --> DECREASED NH4+ excretion

urine pH< 5.5 (or variable)

High Serum K
causes: DECREASED aldosterone production (eg, diabetic hyporeninism, ACE inhibitors, ARBs, NSAIDs, heparin, cyclosporine, adrenal insufficiency) or aldosterone resistance (eg, K+-sparing diuretics, nephropathy due to obstruction, TMP-SMX)


minimal change disease


Most common cause of nephrotic syndrome in children. Often 1° (idiopathic) and may be triggered by recent infection, immunization, immune stimulus. Rarely, may be 2° to lymphoma (eg, cytokine-mediated damage). 1° disease has excellent response to corticosteroids.
ƒ LM—Normal glomeruli (lipid may be seen in PCT cells) ƒ IF—⊝
ƒ EM—effacement of podocyte foot processes


Focal segmental glomerulosclerosis


Most common cause of nephrotic syndrome in African-Americans and Hispanics. Can be 1° (idiopathic) or 2° to other conditions (eg, HIV infection, sickle cell disease, heroin abuse, massive obesity, interferon treatment, or congenital malformations). 1° disease has inconsistent response to steroids. May progress to CKD. ƒ LM—segmental sclerosis and hyalinosis B ƒ IF—often ⊝ but may be ⊕ for nonspecific focal deposits of IgM, C3, C1 ƒ EM—effacement of foot processes similar to minimal change disease


Membranous Nephropathy


Also known as membranous glomerulonephritis. Can be 1° (eg, antibodies to phospholipase A2 receptor) or 2° to drugs (eg, NSAIDs, penicillamine, gold), infections (eg, HBV, HCV, syphilis), SLE, or solid tumors. 1° disease has poor response to steroids. May progress to CKD. ƒ LM—diffuse capillary and GBM thickening C ƒ IF—granular due to IC deposition ƒ EM—“Spike and dome” appearance of subepithelial deposits




Kidney is the most commonly involved organ (systemic amyloidosis). Associated with chronic conditions that predispose to amyloid deposition (eg, AL amyloid, AA amyloid). ƒ LM—Congo red stain shows apple-green birefringence under polarized light due to amyloid deposition in the mesangium


diabetic glomerulonephropathy


Most common cause of ESRD in the United States. Hyperglycemia --> nonenzymatic glycation of tissue proteins -->  mesangial expansion; GBM thickening and INCREASED permeability. Hyperfiltration (glomerular HTN and INCREASED GFR) --> glomerular hypertrophy and glomerular scarring (glomerulosclerosis) leading to further progression of nephropathy.
ƒ LM—Mesangial expansion, GBM thickening, eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson lesions, arrows in D)


Acute poststreptococcal glomerulonephritis


Most frequently seen in children. ~ 2–4 weeks after group A streptococcal infection of pharynx or skin. Resolves spontaneously in most children; may progress to renal insufficiency in adults. Type III hypersensitivity reaction. Presents with peripheral and periorbital edema, cola-colored urine, HTN. ⊕ strep titers/serologies, DECREASED complement levels (C3) due to consumption. ƒ LM—glomeruli enlarged and hypercellular A ƒ IF—(“starry sky”) granular appearance (“lumpy-bumpy”) B due to IgG, IgM, and C3 deposition along GBM and mesangium ƒ EM—subepithelial immune complex (IC) humps


Rapidly progressive (crescentic) glomerulonephritis


Poor prognosis, rapidly deteriorating renal function (days to weeks). ƒ LM—crescent moon shape C. Crescents consist of fibrin and plasma proteins (eg, C3b) with glomerular parietal cells, monocytes, macrophages Several disease processes may result in this pattern which may be delineated via IF pattern.
ƒ Linear IF due to antibodies to GBM and alveolar basement membrane: Goodpasture syndrome—hematuria/hemoptysis; type II hypersensitivity reaction; Treatment: plasmapheresis
ƒ Negative IF/Pauci-immune (no Ig/C3 deposition): Granulomatosis with polyangiitis (Wegener)—PR3-ANCA/c-ANCA or Microscopic polyangiitis—MPO-ANCA/p-ANCA
ƒ Granular IF—PSGN or DPGN


Diffuse proliferative glomerulonephritis


Often due to SLE (think “wire lupus”). DPGN and MPGN often present as nephrotic syndrome and nephritic syndrome concurrently.
ƒ LM—“wire looping” of capillaries
ƒ IF—granular; EM—subendothelial and sometimes intramembranous IgG-based ICs often with C3 deposition


IgA nephropathy (Berger disease)


Episodic hematuria that occurs concurrently with respiratory or GI tract infections (IgA is secreted by mucosal linings). Renal pathology of IgA vasculitis (HSP). ƒ LM—mesangial proliferation
ƒ IF—IgA-based IC deposits in mesangium; EM—mesangial IC deposition


Alport Syndrome


Mutation in type IV collagen -->  thinning and splitting of glomerular basement membrane. Most commonly X-linked dominant. Eye problems (eg, retinopathy, lens dislocation), glomerulonephritis, sensorineural deafness; “can’t see, can’t pee, can’t hear a bee.” ƒ EM—“Basket-weave”


Membranoproliferative glomerulonephritis


MPGN is a nephritic syndrome that often co-presents with nephrotic syndrome. Type I may be 2° to hepatitis B or C infection. May also be idiopathic. ƒ Subendothelial IC deposits with granular IF Type II is associated with C3 nephritic factor (IgG antibody that stabilizes C3 convertase Ž persistent complement activation --> DECRESED C3 levels). ƒ Intramembranous deposits, also called dense deposit disease In both types, mesangial ingrowth Ž GBM splitting Ž “tram-track” appearance on H&E D and PAS E stains.


Kidney Stones - Calcium

Calcium oxalate: hypocitraturia
Shaped like envelope A or dumbbell

Calcium stones most common (80%); calcium oxalate more common than calcium phosphate stones. Hypocitraturia often associated with LOW urine pH.

Can result from ethylene glycol (antifreeze) ingestion, vitamin C abuse, hypocitraturia, malabsorption (eg, Crohn disease).

Treatment: thiazides, citrate, low-sodium diet.

Calcium phosphate: HIGH pH
Wedgeshaped prism
Treatment: low-sodium diet, thiazides.


ammonium magnesium phosphate stones

aka struvite

increased pH
look like Coffin lid

Also known as struvite; account for 15% of stones.

Caused by infection with urease ⊕ bugs (eg, Proteus mirabilis, Staphylococcus saprophyticus, Klebsiella) that hydrolyze urea to ammonia -->  urine alkalinization. Commonly form staghorn calculi C.

Treatment: eradication of underlying infection, surgical removal of stone. NOT lithotripsy - will release bugs


uric acid stones

low pH
RadiolUcent Minimally visible
Rhomboid D or rosettes
About 5% of all stones.

Risk factors: LOW urine volume, arid climates, acidic pH.

Strong association with hyperuricemia (eg, gout). Often seen in diseases with INCREASED cell turnover (eg, leukemia). Treatment: alkalinization of urine, allopurinol.


cysteine stones

Moderately radiopaque

Hexagonal E Hereditary (autosomal recessive) condition in which Cystine-reabsorbing PCT transporter loses function, causing cystinuria. Transporter defect also results in poor reabsorption of Ornithine, Lysine, Arginine (COLA). Cystine is poorly soluble, thus stones form in urine. Usually begins in childhood.
Can form staghorn calculi. Sodium cyanide nitroprusside test ⊕. “SIXtine” stones have SIX sides.

Treatment: low sodium diet, alkalinization of urine, chelating agents if refractory.



Distention/dilation of renal pelvis and calyces. Usually caused by urinary tract obstruction (eg, renal stones, severe BPH, congenital obstructions, cervical cancer, injury to ureter); other causes include retroperitoneal fibrosis, vesicoureteral reflux. Dilation occurs proximal to site of pathology.

Serum creatinine becomes elevated if obstruction is bilateral or if patient has an obstructed solitary kidney. Leads to compression and possible atrophy of renal cortex and medulla.


Renal Cell Carcinoma

Polygonal clear cells filled with accumulated lipids and carbohydrate. Often golden-yellow B due to HIGH lipid content. Originates from PCT--> invades renal vein (may develop varicocele if left sided)--> IVC -->  hematogenous spread --> metastasis to lung and bone.

Manifests with hematuria, palpable masses, 2° polycythemia, flank pain, fever, weight loss.

Treatment: surgery/ablation for localized disease. Immunotherapy (eg, aldesleukin) or targeted therapy for metastatic disease, rarely curative. Resistant to chemotherapy and radiation therapy.

Most common 1° renal malignancy C. Most common in men 50–70 years old, INCREAED incidence with smoking and obesity. Associated with paraneoplastic syndromes (“PEAR”-aneoplastic), eg, PTHrP, Ectopic EPO, ACTH, Renin). Associated with gene deletion on chromosome 3 (sporadic, or inherited as von Hippel-Lindau syndrome). RCC = 3 letters = chromosome 3.


renal oncocytoma

Benign epithelial cell tumor arising from collecting ducts Large eosinophilic cells with abundant mitochondria without perinuclear clearing (vs chromophobe renal cell carcinoma).

Presents with painless hematuria, flank pain, abdominal mass. Often resected to exclude malignancy (eg, renal cell carcinoma)


Nephroblastoma (Wilms tumor)

Most common renal malignancy of early childhood (ages 2–4). Contains embryonic glomerular structures. Presents with large, palpable, unilateral flank mass A and/or hematuria.
“Loss of function” mutations of tumor suppressor genes WT1 or WT2 on chromosome 11. May be a part of several syndromes:
ƒ WAGR complex: Wilms tumor, Aniridia (absence of iris), Genitourinary malformations, mental Retardation/intellectual disability (WT1 deletion)
ƒ Denys-Drash syndrome—Wilms tumor, Diffuse mesangial sclerosis (early-onset nephrotic syndrome), Dysgenesis of gonads (male pseudohermaphroditism), WT1 mutation
ƒ Beckwith-Wiedemann syndrome—Wilms tumor, macroglossia, organomegaly, hemihyperplasia (WT2 mutation)


Transitional cell carcinoma

Also known as urothelial carcinoma. Most common tumor of urinary tract system (can occur in renal calyces, renal pelvis, ureters, and bladder). Can be suggested by painless hematuria (no casts). Associated with problems in your Pee SAC: Phenacetin, Smoking, Aniline dyes, and Cyclophosphamide.


squamous cell carcinoma of the bladder

hronic irritation of urinary bladder --> squamous metaplasia --> dysplasia and squamous cell carcinoma. Risk factors include Schistosoma haematobium infection (Middle East), chronic cystitis, smoking, chronic nephrolithiasis. Presents with painless hematuria.


Acute Kidney Injury

Formerly known as acute renal failure.

Acute kidney injury is defined as an abrupt decline in renal function as measured by INCREASED creatinine and INCREASED BUN or by oliguria/anuria.

Prerenal azotemia: Due to DECREASED RBF (eg, hypotension) --> DECREASED GFR. Na+/H2O and urea retained by kidney in an attempt to conserve volume --> INCREASED BUN/creatinine ratio (urea is reabsorbed, creatinine is not) and DECREASED FENa.

Intrinsic renal failure: Most commonly due to acute tubular necrosis (from ischemia or toxins); less commonly due to acute glomerulonephritis (eg, RPGN, hemolytic uremic syndrome) or acute interstitial nephritis. In ATN, patchy necrosis --> debris obstructing tubule and fluid backflow across necrotic tubule --> DECREASED GFR. Urine has epithelial/granular casts. Urea reabsorption is impaired --> DECREASED BUN/creatinine ratio and INCREASED FENa.

Postrenal azotemia Due to outflow obstruction (stones, BPH, neoplasia, congenital anomalies). Develops only with bilateral obstruction or in a solitary kidney.


renal osteodystrophy

Hypocalcemia, hyperphosphatemia, and failure of vitamin D hydroxylation associated with chronic renal disease --> 2° hyperparathyroidism. High serum phosphate can bind with Ca2+ --> tissue deposits --> DECREASED serum Ca2+. DECREASED 1,25-(OH)2D3 --> DECREASED intestinal Ca2+ absorption. Causes subperiosteal thinning of bones.


Loop Diuretics

Furosemide, bumetanide, torsemide

Sulfonamide loop diuretics. Inhibit cotransport system (Na+/K+/2Cl−) of thick ascending limb of loop of Henle. Abolish hypertonicity of medulla, preventing concentration of urine. Stimulate PGE release (vasodilatory effect on afferent arteriole); inhibited by NSAIDs. INCREASED Ca2+ excretion. Loops Lose Ca2+.

Edematous states (HF, cirrhosis, nephrotic syndrome, pulmonary edema), hypertension, hypercalcemia.

ADVERsE EFFECts Ototoxicity, Hypokalemia, Hypomagnesemia, Dehydration, Allergy (sulfa), metabolic Alkalosis, Nephritis (interstitial), Gout.


thiazide diuretics

Hydrochlorothiazide, chlorthalidone, metolazone. mEChANism
Inhibit NaCl reabsorption in early DCT --> DECREASED diluting capacity of nephron. DECREASED Ca2+ excretion.

Hypertension, HF, idiopathic hypercalciuria, nephrogenic diabetes insipidus, osteoporosis.

ADVERsE EFFECts Hypokalemic metabolic alkalosis, hyponatremia, hyperGlycemia, hyperLipidemia, hyperUricemia, hyperCalcemia. Sulfa allergy.


K sparing diuretics

Spironolactone, Eplerenone, Amiloride, Triamterene.
TaKe a SEAT.
Spironolactone and eplerenone are competitive aldosterone receptor antagonists in cortical collecting tubule. Triamterene and amiloride act at the same part of the tubule by blocking Na+ channels in the cortical collecting tubule.

CLiNiCAL UsE Hyperaldosteronism, K+ depletion, HF, hepatic ascites (spironolactone), nephrogenic DI (amiloride), antiandrogen.

ADVERsE EFFECts Hyperkalemia (can lead to arrhythmias), endocrine effects with spironolactone (eg, gynecomastia, antiandrogen effects).


types of hypertension

PRA >.65
treat with ARB, ACEinhibitor, beta blocker



Primary Hyperaldosteronism

Low  Renin  (<  .6  ng/ml/hr),  High  Aldo

Hypertension  always  present,  hypokalemia,  metabolic  alkalosis,   low  plasma  renin  activity  (PRA)

• Hypokalemia:Renal  loss  of  potassium  
• Metabolic  alkalosis:  increase  renal  H+  secretion

Conn’s:  APA-­aldosterone  producing  adenoma               (unilateral,  surgically  curable)  –65% -­Bilateral  adrenal  hyperplasia-­34% -­Glucocorticoid  remediable  hyperaldosteronism<  1


Secondary Hyperaldosteronism

High  Renin(>6  ng/ml/hr),  High  Aldo

BP  may  be  high,  or  low

High  Blood  Pressure  caused  by HIGH PRA,  HIGH Aldo
• Malignant  hypertension  
• Renal  artery  stenosis  –renovascularhypertension • Renin  secreting  tumors
Low  Blood  Pressure  (volume  depletion)  causes  HIGH PRA,  HIGH Aldo
• Diuretics:  volume  depletion,  stimulation  of  renin
• Bartters/Gitelman’s (low  BP):  genetic  “diuretic  like”  syndromes


Nephropathy deposits

MN --> sub-epithelial (nephrotic)
PSGN --> sub-epithelial (nephritic)
DPGN--> sub-endothelial (nephritic)
MPGN --> sub-endothelial (either?)