Renal Final Exam PDF

**Renal Final** **[PRINCIPLES OF GLOMERULAR DISEASES AND NEPHRITIC SYNDROME ]** **Distinguishing Nephrotic Syndrome from Nephritic Syndrome.** 1. **Describe the characteristic clinical manifestations of nephrotic syndrome, including edema, proteinuria, hypoalbuminemia, and hyperlipidemia...

**Renal Final** **[PRINCIPLES OF GLOMERULAR DISEASES AND NEPHRITIC SYNDROME ]** **Distinguishing Nephrotic Syndrome from Nephritic Syndrome.** 1. **Describe the characteristic clinical manifestations of nephrotic syndrome, including edema, proteinuria, hypoalbuminemia, and hyperlipidemia.** **Nephrotic Syndrome:** - Clinical manifestations: - Edema: typically begins with periorbital edema, peripheral edema (pitting) - Hypoalbuminemia: decreased serum albumin - Hyperlipidemia: increased triglycerides and cholesterol AND lower HDL (increased hepatic lipogenesis) - Massive proteinuria: \>3.5 g/24 hrs - Frothy urine with fatty casts - Associated with hypercoagulable state due to antithrombin III loss in urine and increased risk of infection (loss os IgGs in urine and soft tissue compromise by edema) - Etiology: podocyte damage impaired charge barrier proteinuria - Examples: 1^st^ or 2^nd^ degree damage; Focal segmental glomerulosclerosis, Minimal change disease, Membranous nephropathy, Amyloidosis, Diabetic glomerulonephropathy **Nephritic Syndrome:** - Clinical manifestations: - Hematuria: presence of RBC in urine; can also have acanthocytes - Hypertension: systolic bp \> 140mmHg and/or diastolic of \>90 mmHg - Rapidly progressive glomerulonephritis: rapid decline in renal function in days to weeks; caused by anti-glomerular basement membrane antibodies (Goodpasture syndrome), immune complex deposition (lupus nephritis), and vasculitis (granulomatosis with polyangiitis) - Oliguria: production of an abnormally small amount of urine - **Etiology:** glomerular inflammation GBM damage loss of RBCs into urine dysmorphic RBCs, hematuria - **General pathophysiology:** inflammation cytokine release glomerular capillary damage - **Porous** glomerular basement membrane leakage of proteins and RBCs nephritic sediment (all blood components are detectable on urinalysis) - **Examples:** Infection-associated glomerulonephritis; Goodpasture syndrome; IgA nephropathy (Berger disease); Alport Syndrome; Membranoproliferative glomerulonephritis **Nephritic syndromes** - **Infection-related glomerulonephritis:** - Mechanism: Type 3 HS reaction with consumptive hypocomplementemia; Children: seen every 2-4 weeks after group A streptococcal pharyngitis or skin infection; Adults: staphylococcus is additional causative agent - Light Microscopy: enlarged and hypercellular glomeruli - Immunofluorescence: granular (starry sky appearance); "lumpy-bumpy" due to IgG, IgM, and C3 deposition along GBM and mesangium - **IgA Nephropathy (Berger Disease):** - **Mechanism:** occurs concurrently with respiratory or GI tract infections (IgA is secreted by mucosal linings); renal pathology of IgA vasculitis; most common cause of primary glomerulonephritis; most frequently affects male individuals in the second to third decades of life. Clinical manifestations include gross hematuria, flank pain, and sometimes proteinuria, are often triggered by upper respiratory tract or gastrointestinal infections and may be episodic. - **Light microscopy:** mesangial proliferation - **Immunofluorescence:** IgA-based IC deposits in mesangium - **Electron Microscopy:** Mesangial IC deposition - **Diffuse Proliferative Glomerulopnephritis:** - **Mechanism:** often due to SLE (think "wire lupus"); DPGN and MPGN often present as nephritic and nephrotic syndromes concurrently - **Light microscopy:** "wire looping" of capillaries - **Immunofluorescence:** Granular - **Electron Microscopy:** subendothelial, sometimes subepithelial or intramembranous IgG-based ICs often with C3 deposition - **Alport syndrome:** - Mechanism: Type IV collagen mutation glomerular basement membrane alterations; X-linked dominant; - Clinical manifestations: eye problems (retinopathy, anterior lenticonus); glomerulonephritis, SNHL (cant see, cant pee, cant hear a bee) - Light microscopy: irregular thinning and thickening and splitting of glomerular basement membrane - Immunofluorescence: Initially negative; irregular deposits of IgG, IgM, and/or C3 may be observed later - Electron Microscopy: "basket-weave" appearance due to irregular thickening and longitudinal splitting of GBM - **Membrano-proliferative glomerulonephritis:** - **Mechanism:** Type 1 may be 2^nd^ degree to HBV or HCV infection; Type 2 associated with C3 nephritic factor (IgG autoantibody that stabilizes C3 convertase persistent complement activation decrease C3 - **Light Microscopy:** mesangial ingrowth GBM splitting "tram tracking" on H&E and PAS stains - **Immunofluorescence:** granular - **Electron microscopy:** Type 1 subendothelial IC deposits; Type 2 intramembranous deposits, dense deposit disease - **Rapidly progressive (crescentic) glomerulonephritis:** - **Mechanism:** poor prognosis; multiple causes: Type II HSR in Goodpasture syndrome - **Light microscopy:** Crescent moon shape; crescents consist of fibrin and plasma proteins (eg, C3b) with glomerular parietal cells, monocytes, macrophages - **Immunofluorescence:** Linear IF due to antibodies to GBM and alveolar basement membrane: Goodpasture syndrome hematuria/hemoptysis; Type II hypersensitivity reaction; Negative IF/Pauci0iimune (no IgC3 deposition): granulomatosis with polyangiitis-PR3-ANCA/c-ANCA, eosinophilic granulomatosis with polyangiitis, or Microscopic polyangiitis -MPO-ANCA/p-ANCA; Granular IF-PSGN or DPGN - **Electron Microscopy:** [Goodpasture syndrome:] breaks in GMB, necrosis and crescent formation with no deposits; [Pauci-immune:] usually no deposits, if IC deposits are present more severe presentation; [PSGN]: dome-shaped subendothelial and subepithelial electron-dense deposits (humps) **[TUBULOINTERSTITIAL DISORDERS LECTURE ]** **Acute Interstitial Nephritis (tubulointerstitial nephritis):** acute inflammation of the renal interstitium and tubules that causes a decline in renal function over a period of days to weeks (NO CHANGES IN GLOMERULUS) - **Etiology:** medications (antibiotics, NSAIDs, proton pump inhibitors, loop diuretics); Infection (mycoplasma); autoimmune (Sjogren syndrome, sarcoidosis, SLE); nonsteroidal anti-inflammatory drugs; penicillins; Sulfa drugs; Antineoplastic agents; Lithium; antiviral agents - **Pathogenesis:** immune-mediated tubulointerstitial damage is the most widely accepted theory drugs act as haptens which type 4 HS - **Acute obstruction:** crystals (from medications, uric acid) or proteins (light chains) obstruct tubules - immune mediated infiltration of the interstitium; lethal/sublethal injury to the ducts; expression of new local antigens; tubular dysfunction w/without acute kidney injury - Is **reversible,** reflecting the regenerative capacity of tubules with preserved basement membrane - **Clinical features:** morbilliform rash, fever, arthralgias, flank pain **Acute Kidney Injury:** sudden loss of renal function with a subsequent rise in creatinine and blood urea nitrogen (BUN) - **Etiology:** prerenal causes include any condition that leads to decreased renal perfusion (hypovolemia, hypotension, decreased circulating volume (CHF, cirrhosis, acute pancreatitis), renal artery stenosis, drugs) **Postrenal Acute Kidney Injury:** postrenal causes include any condition that results in bilateral obstruction of urinary flow from the renal pelvis to the urethra - **Acquired obstructions:** Benign prostatic hyperplasia (BPH), Iatrogenic (catheter-associated injuries), Tumors, Stones, Bleeding - **Neurogenic bladder:** due to multiple sclerosis, spinal cord lesions, or peripheral neuropathy - **Congenital malformations** **Diagnosis:** - **Blood tests:** BMP (increased BUN and creatinine); CBC (increased eosinophils) - **Urine studies:** urinalysis (sterile pyuria, subnephrotic-range proteinuria, microscopic hematuria); Urine microscopy: WBC casts, urine eosinophils - **Renal ultrasound:** findings are often normal, may demonstrate enlarged kidneys with increased echogenicity, reflecting interstitial edema - **Renal Biopsy:** diffuse or patchy peritubular inflammatory cell infiltrates: T-cell lymphocytes and monocytes (macrophages, eosinophils, and plasma cells) - **Angiogram:** renal artery stenosis (plaque builds up on the inner lining of the renal arteries) **Chronic Tubulointerstitial Nephritis:** condition of chronic inflammation of the renal tubules and interstitium and can progress to end-stage renal disease (ESRD) after months or years; insidious onset - **Pathophysiology:** - **Analgesic neuropathy:** NSAID use (prostacyclin synthesis vasoconstriction of the medullary blood vessels papillary ischemia and papillary necrosis); Associated with an increased risk of urothelial carcinoma (can progress into ESRD - **Precipitation of light chains in renal tubules** tubular obstruction; interstitial scarring, fibrosis, and tubule atrophy - **Etiology:** - **Medications:** analgesic nephropathy, NSAIDs, acetaminophen; cyclosporine, tacrolimus, cisplatin, ifosfamide, cidofovir, tenofovir, lithium - **Toxins:** lead; cadmium - **Systemic disease:** multiple myeloma, Sjogren syndrome, SLE, sickle-cell disease - **Metabolic disease:** hyperuricemia, hypercalcemia, hyperoxaluria, hypokalemia **Treatment:** - Address underlying cause, manage electrolyte imbalances - **Nutritional Management** - **Corticosteroids:** mainstay of therapy but mycophenolate mofetil may also have a role - **Prednisone:** @ high doses! For allergic interstitial nephritis, acute events - **Hydration:** (in hospital) for ischemic injuries and as supportive measure for interstitial disease **Lead Nephropathy for chronic TN:** half-life of several decades; if untreated can cause intermittent acute poisoning and low-level environmental exposure result in chronic cumulative lead poisoning causing kidney disease usually in the 3^rd^ -4^th^ decades (linked to chronic kidney disease) - **Medical history:** myalgia, fatigue, weight loss, anorexia, and headache - Fever, rash, eosinophilia, elevated IgE - Children with severe poisoning encephalopathy and acute renal failure - Can be accompanied by **Fanconi Syndrome**: renal tubular disorder characterized by a generalized defect in reabsorption in the proximal renal tubules; increased excretion of glucose, phosphate, amino acids, bicarbonate, uric acid, sodium, potassium, and water; can be hereditary - Stroke, pre-existing atherosclerosis in relation to ischemic interstitial injury - **Diagnosis:** kidney biopsy is seldom necessary to make a definitive diagnosis **Histopathology:** - **Hallmark** interstitial inflammatory cell infiltration and edema; cells are most commonly lymphocytes, neutrophils, and plasma cells, but drug-induced nephritis involves eosinophil infiltration; Tubulitis will show irregular luminal contours, cytoplasmic simplification, loss of brush border, and tubular atrophy - **Immunofluorescence:** negative in patients with drug-induced TIN; usually only methicillin-induced nephritis **Acute Tubular Necrosis (ATN):** causes 85% of intrinsic AKIs; high metabolic demand and relatively less blood supply - **Location:** straight segment of the proximal tubule and the straight segment of the distal tubule (thick ascending limb) are susceptible to ischemic damage; convoluted segment of the proximal tubule is particularly susceptible to damage from toxins - **Etiology:** acute ischemic; toxic event or sepsis; hypovolemic states; diarrhea; vomiting, bleeding, dehydration, burns, renal losses via diuretics or osmotic diuresis; 3^rd^ fluid sequestration; **Edematous states** such as heart failure and cirrhosis cause reduced kidney perfusion; sepsis or anaphylaxis leads to systemic vasodilation, Coagulopathy, such as disseminated intravascular coagulation, can also cause acute tubular necrosis; **Heme-pigment protein (**direct proximal tubular injury, tubular obstruction, or renal vasoconstriction); **Crystal-induced Nephropathy** due to high cell turnover**; Radiocontrast media** - **Histopathology: Ischemic** - Early: swelling of cell epithelial necrosis and apoptosis desquamation of cells into the tubular lumen dilated proximal tubules loss or thinning of brush border casts especially in distal and collecting ducts white blood cells in dilated vasa recta Eosinophilic hyaline casts of Tamm-Horsfall protein - Later: regeneration of epithelia (dilated tubular lumina, flattened epithelium, large nuclei with prominent nucleoli and mitotic activity **Rare Inherited Kidney Diseases** - **Bartter Syndrome:** autosomal recessive; affect chloride reabsorption in the thick ascending limb of the loop of Henle - **Prevalence:** rare - **Age of onset:** infancy or early childhood - **Mutations:** NKCC2, ROMK, CLCNKB - **Pathophysiology:** defects in sodium chloride reabsorption in the thick ascending limb of the loop of henle (Na-2K-CL transporter \*\*like loop diuretics), resulting in increased sodium and chloride excretion; in the thick ascending loop of Henle; activates RAAS increases aldosterone levels; decreased paracellular reabsorption of calcium - **Manifestations:** hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism; NaCl wasting and Hypercalciuria; - **Clinical features:** preterm birth, polyhydramnios, severe polyuria, polydipsia, hypotension, muscle atrophy, weakness, cramps, dysmorphic facies - **Gitelman Syndrome:** autosomal recessive; impaired function of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule impaired Na+ and Cl- reabsorption - **Prevalence:** relatively rare - **Age of onset:** late childhood or early adulthood - **Mutations:** SLC12A3 - **Pathophysiology:** defects in sodium chloride reabsorption in the distal convoluted tubule (Na-Cl co-transporter like thiazide diuretics), leading to increased sodium excretion and potassium and magnesium wasting - **Manifestations:** Hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria; NaCl wasting **Renal Tubular Acidosis:** distal renal tubular disorders within a group of diseases considered rare or minority; dRTA can be inherited or acquired, with a reported estimated prevalence of 0.46/10,000 inhabitants 1. **Distal RTA:** Type 1 - **Cause:** failure of H+ excretion - **Location:** distal tubular (cortical collecting duct) - **Presentation:** osteomalacia, renal stones, nephrocalcinosis - **Potassium status:** hypokalemia 2. **Proximal RTA:** Type 2 - **Cause:** bicarbonate wasting - **Location:** proximal tubular - **Presentation:** osteomalacia, uric acid stones - **Potassium status:** hypokalemia 3. **Hyperkalemic RTA:** Type 4 - **Cause:** Hypoaldosteronism - **Location:** distal tubular - **Presentation:** reduced aldosterone production or aldosterone resistance - **Potassium status:** Hyperkalemia 4. **MIXED:** Type 3: rare form of disease with features of both distal and proximal RTA; MIXED - **Cause:** inherited carbonic anhydrase II deficiency or early juvenile distal RTA with proximal features and high-salt diet - **Location:** combined proximal and distal - **Presentation:** cerebral calcification, mental retardation, osteopetrosis **[ACID/BASE DISORDERS LECTURE]** **Importance relies on** medical history and physical examination; Interpretation of Arterial Blood Gas (ABG) labs is crucial. 3 major Approach methods: Physiological Approach, Base-Excess Approach, and Physiochemical Approach (Stewart method) Acidosis vs alkalosis: normal range is 7.35-7.45; **Acidosis** is below; **Alkalosis is above** **Respiratory Disturbances:** - **Metabolic Acidosis:** decreased pH and decreased HCO3-(bicarbonate) 22mmol; secondary (respiratory) response within 12-24 hrs - **PaCO2 =** 1.5 x (HCO3) + 10 - **ABG values:** - pH: 7.30, HCO3-: 18 - PaCO2= 1.5 x (18) + 10 37 - Calculate serum anion gap (difference between the serum concentrations of the major cation (Na+) and the major anions (Cl-, HCO3-) \[Na+\] -- \[(Cl-) + (HCO3-)\] normal value is 12+/- 2 - **Metabolic Alkalosis:** increased pH and increased HCO3- 26 mmol; secondary (respiratory) response within 24-36 hrs - **PaCO2 =** 0.7 x \[(HCO3) -24\] + 42 - **ABG values:** - pH: 7.47, HCO3-: 30 - PaCO2: 0.7 x \[(30) - 24\] +42 46.2 - Kidney is efficient in excreting large amounts of bicarbonate; either an increase in alkali or impairment of renal excretion of bicarbonate is needed; or BOTH - Cause: loss of gastric fluid and the use of diuretics; measure Chloride in urine for non-renal vs renal - Mechanism: if circulating volume is reduced, the kidneys avidly reabsorb filtered sodium, bicarbonate, and chloride thru RAAS reducing the concentration of urinary chloride; conc. Of \40 mEq/L):** severe magnesium deficiency, extreme hypercalcemia/hypokalemia, high alkali load, loop or thiazide diuretics, Genetic syndromes, HTN: Hyperaldosteronism, Cushing syndrome, Liddle syndrome, Licorice ingestion - **Respiratory Acidosis:** decreased pH and increased PaCO2 \> 42mmol; secondary (metabolic) response within hrs - **Acute:** HCO3- is increased by 1 mmol for each PaCO2 10 mg above 42 - **ABG values:** - pH: 7.30, PaCO2: 62 - HCO3- = (24) + \[(62-42)/10\] = 26 - **Causes for acute:** acute lung disease (pneumonia, pulmonary edema), acute exacerbation of COPD/asthma, CNS depression (head trauma, postictal state, drug toxicity, central sleep apnea) - **Cause for chronic:** airway obstruction (COPD, asthma), Respiratory muscle weakness due to myasthenia gravis, ALS, Guillain-Barre syndrome, Poliomyelitis, Multiple sclerosis, severe hypokalemia - **Respiratory Alkalosis:** increased pH and decreased PaCO2 \< 38; secondary (metabolic) response within 2-5 days - **Acute:** HCO3- is decreased by 2 mmol for each PaCO2 10 mg below 42 - **ABG values:** - pH: 7.47, PaCO2: 16 - HCO3-: (24) -- {\[(42-16)/10\] x 2} = 18.8 - **Causes for acute:** pulmonary disease, pain, anxiety, panic attacks, fever, drug toxicity, CNS infections, stroke, severe anemia, CHF, sepsis, hypoxemia, hyperventilation while on mechanical ventilation - **Causes for chronic**: pulmonary embolism during pregnancy, liver failure, hyperthyroidism, brainstem tumor (may cause central neurogenic hyperventilation **Basic Facts to Remember:** - Acid-base physiology always involves an acid, a base, and a hydrogen ion (proton); changes in one affects the others - Buffer systems DO NOT ELIMINATE added acid or base equivalents, but only limit the effect of the equivalents on blood pH - The buffer is gradually reduced in concentration - CO2 is a [respiratory component] = respiratory acid; moves opposite to the direction of pH, as PaCO2 in blood increases, pH decreases respiratory acidosis and vice versa - Bicarbonate (HCO3-) is a metabolic component and is considered a base; moves in the same direction as pH **Arterial Blood Gas Interpretations:** - **Arterial Blood:** pH (7.35-7.45), paO2 (80-100 mmHg), O2 saturation (95%), PaCO2 (35-45 mmHg), HCO3- (22-26 mEql-1), BE (-2 to +2) - **Mixed Venous:** pH (7.31-7.41), paO2 (35-40 mmHg), O2 saturation (70-75%), PaCO2 (41-51 mmHg), HCO3- (22-26 mEql-1), BE (-2 to +2) **Workup: PATIENT**, CBC, Blood chemistry (glucose, kidney panel creatinine, BUN, urea), Electrolytes (Na, Cl, K, Ca, Mg, Po), Urine (urine electrolytes: Na, Cl, K), Osmolality (measured/calculated), Arterial/Venous blood gases **Anion Gap:** cations must equal the total number of anions - Decrease in the serum HCO3- conc. must be offset by an increase in the concentration of other anions - If the anion accompanying excess H+ is Cl- - The decrease in serum \[HCO3-\] is matched by and equal increase in serum \[Cl-\] referred to as a "normal anion gap" or a "non-anion gap" or a hyperchloremic metabolic acidosis - **By contrast,** if excess H= is accompanied by an anion other than Cl-, the decreased \[HCO3-\] is balanced by an increase in the concentration of the unmeasured anion (gap), \[Cl-\] remains the same acidosis in this setting is said to be "high anion gap" or "anion gap" metabolic acidosis **Corrected Anion Gap:** because many of the unmeasured anions consist of albumin, the normal anion gap is increased by approx. 2.5 mmol/L for each 1g/dL decrease in the serum albumin concentration below normal - Formula (albumin 2.1): \[(4-level) x 2.5 + Agap\] \[(4-2.1) x 2.5 +12\] 16.75 - Example: pH: 7.30, pO2: 70 mmHg, pCO2: 34 mmHg, HCO3-: 16 mEq/L; - Na+: 132, Cl-:102, BUN:25, K+:3.6, HCO3-: 16, Cr:1.01; Glucose: 90, Alb: 2.1 - Anion gap: \[Na+\] -- \[(Cl-) + (HCO3-)\] 132 -- (102+16) anion gap = 14 Corrected AGap: \[(4-level) x 2.5 + AGap\] \[(4-2.1) x 2.5 + 14\] 18.75 **High anion gap: GOLDMARK**; G: Glycols (osmolal gap), O: Oxoproline (chronic acetaminophen use), L: Lactate (lactic A acidosis, hypoxic; lactic B, non-hypoxic), D: D-lactate (exogenous lactic acid, short bowel, carbohydrates, bacteria), M: Methanol (and other alcohols, osmolal gap), A: Aspirin (late effects), R: Renal failure, K: Ketones (diabetic, alcoholic, starvation) **Normal/NON-AGap Metabolic Acidosis:** - **Renal:** when renal bicarbonate generation, which results from net acid excretion, does not balance the loss of bicarbonate and other alkali buffers consumed in the buffering of normal endogenous acid production failure of net acid excretion is termed **renal tubular acidosis (RTA)** - **Extrarenal:** causes occur when exogenous acid loads, endogenous acid production, or endogenous bicarbonate losses are elevated and exceed renal net acid excretion most common cause is chronic diarrhea (GI loses) - **HARDASS:** H: Hyperchloremia/Hyperalimentation (NaCl solutions, Parenteral nutrition), A: Addison Disease (H+/ATPase pump, lack off), R: Renal tubular acidosis, D: Diarrhea (loss of bicarbonate, pancreatic, etc), A: Acetazolamide (carbonic anhydrase inhibitors, impaired reabsorption), S: Spironolactone (Na/H+ waste, sodium in urine, increase H+, S: Saline infusion (NaCl) **Urinary Anion Gap (UAG):** (\[Na+\] + \[K+\] -- \[Cl-\]); normally a positive value of 30 to 50 mmol/L; negative value increased renal excretion of an unmeasured cation (other than Na+ or K+, such as NH4+) - Will become positive when excretion of urinary ammonium (NH4+) is dimished, as in renal failure, distal renal tubular acidosis, or hypoaldosteronism - It helps us to determine if the causes are renal losses or extrarenal loses or alkali - Negative UAG: diarrhea, NaCl infusion (non-renal) - Positive UAG: renal tubular acidosis (renal) **[DIURETIC AGENTS LECTURE]** **Thiazide and related drug:** - **Hydrochlorothiazide:** most commonly prescribed; in HTN management combined with ACEi or ARB; edema from CHF, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, costicosteroid and estrogen therapy - **Site of action:** early segment of distal convoluted tubule; targets: SLC12A3 or NCC, Calcium-activated potassium channel subunit alpha-1 - **MoA:** inhibition of Na+-Cl- cotransporters (NCC) in the early distal convoluted tubule increased excretion of Na+ and Cl- decreased diluting capacity of nephron and increased excretion of potassium; decreased excretion of calcium; Increased reabsorption of Ca2+ - **AE:** Hypotension, Hypokalemic metabolic alkalosis, hyponatremia, hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia, can induce Sulda allergy (Hypergluc mnemonic) - **Interactions:** with calcitrol or any calcium supplementation increase risk of hypercalcemia; with combo with cephalosporin increase the risk of nephrotoxicity (3^rd^ and 4^th^ gen) - **Indapamide:** long-acting thiazide-like diuretic that acts on the proximal segment of the distal tubule of the nephron; commonly used to treat HTN and edema due to congestive heart failure - **Site of Action:** distal tubule of the nephron - **MoA:** acts on the nephron, @ the proximal segement of the DCT where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption reduced plasma volume and venous return, lower cardiac output, and decreased blood pressure - **AE:** arrythmia, severe stomach pain, diarrhea, etc **Loop diuretics:** - **Ethacrynic acid:** - **Site of action:** nephron; proximal and distal tubules, as well as in the thick ascending loop of Henle; (SLC12A1 or NKCC2), Carbonic anhydrase 2 inhibitor, G-protein coupled receptor 35 agonist - **MoA:** blockage of Na+-K+-2Cl- cotransporter; in thick ascending loop of Henle diminishing concentration gradient between the (usually hypertonic) renal medulla and the cortex concentration of urine is no longer possible increased diuresis; **also increased PGE release:** dilation of renal afferent arterioles (can be inhibited by NSAIDs) - **AE: OHH DAANG!** Ototoxicity, Hypokalemia, Hypomagnesemia, Dehydration, Allergy (sulfa), metabolic Alkalosis, Nephritis, Gout - **Interactions: ACEi or ARA hypotension and renal failure** - **Furosemide:** fast onset and short duration; **indications** are edema associated with CHF, cirrhosis of the liver, renal disease (nephrotic syndrome) - **Site of action:** nephron; proximal and distal tubules, as well as in the thick ascending loop of Henle; (SLC12A1 or NKCC2), Carbonic anhydrase 2 inhibitor, G-protein coupled receptor 35 agonist - **MoA:** blockage of Na+-K+-2Cl- cotransporter; in thick ascending loop of Henle diminishing concentration gradient between the (usually hypertonic) renal medulla and the cortex concentration of urine is no longer possible increased diuresis; **also increased PGE release:** dilation of renal afferent arterioles (can be inhibited by NSAIDs) - **AE: OHH DAANG!** Ototoxicity, Hypokalemia, Hypomagnesemia, Dehydration, Allergy (sulfa), metabolic Alkalosis, Nephritis, Gout - **Interactions: ACEi or ARA hypotension and renal failure** **Potassium-sparring diuretics:** - **Amiloride & Triamterene:** epithelial sodium channel blockers; indications are steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism; for patients who develop hypokalemia - **Site of action:** nephron; act on the late distal tubule to the collecting duct; **Molecular targets:** antagonist of amiloride-sensitive sodium channel subunit alpha, beta, gamma, and delta; Antagonist of the Amiloride-sensitive amine oxidase (copper-containing); Antagonist of the Acid-sensing ion channel 1 and 2; Antagonist of the sodium/hydrogen exchanger , antagonist of the Urokinase-type plasminogen activator - **MoA:** direct inhibition of the epithelial sodium channels (ENaC) in the distal convoluted tubule and the collecting duct reduced Na+ reabsorption and reduced K+ secretion diuresis - **AE:** hyperkalemia (can lead to arrythmias), metabolic acidosis - **Interactions:** ACEis and ARA, some beta-blockers can decrease their concentration secondary to the effects of spironolactone - **Spironolactone & Eplerenone:** are **aldosterone receptor antagonists;** indications are heart failure, hyperaldosteronism, adrenal hyperplasia, HTN, female pattern fair loss, adult acne vulgaris; used in medical gender transition - **Site of Action:** in the nephron, competitively inhibits mineralocorticoid receptors in the distal convoluted tubule to promote sodium and water excretion and potassium retention - **MoA:** inhibition of the mineralocorticoid receptor prevents the expression of ENaC, Na+/K+ ATPase in the basolateral membrane, and activation of Sgk1 and CAP1 decreasing the transport of sodium ions from the luminal side into the basolateral side for reabsorption but inducing the potassium and hydrogen ions reabsorption **MoA part 2:** Competitively bind to aldosterone receptors in the late distal convoluted tubule and the collecting duct  inhibition of the effects of aldosterone decreased Na+ reabsorption and K+ excretion;;; decreased H+ excretion acidosis;;; evolving hyperkalemia induces H+/K+-ATPases in all cells; K+ enters cells in exchange for H+ amplifies acidosis;;; Spironolactone also acts on sex hormone receptors endocrine side effects - **AE:** endocrine disturbances; men: antiandrogenic effects (gynecomastia, ED); women: amenorrhea (lack of menses) general: hyperkalemia; metabolic acidosis, can lead to cardiac arrythmias **Osmotic Diuretics:** - **Glycerol:** - **Mannitol:** occurs naturally as a sugar/sugar alcohol in fruits and vegetables; used to test for asthma, reduce intracranial and intraocular pressure, measure GFR, manage pulmonary symptoms associated with cystic fibrosis - **Site of action:** nephron, glomerulus, proximal convoluted tubule, descending limb in loop of Henle; NO molecular targets - **MoA:** elevates blood plasma osmolality, resulting in an enhanced flow of water from tissues into interstitial fluid and plasma; in the kidneys induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating the excretion of water and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes - **AE:** dehydration, hypo/hypernatremia, pulmonary edema; CI: anuria and HF - **Interactions:** induce the renal elimination of several drugs, which may need correction if used in continuous infusion **Carbonic anhydrase inhibitor:** - **Acetazolamide & Dorzolamide:** treats edema from HF or medications, certain types of epilepsy, and glaucoma; can be effective against absence seizures, adjuct in Tx of tonic-clonic, myoclonic, and atonic seizures especially in women whose seizures are worse during menstrual cycle - **Site of Action:** nephron, proximal tubule, thick ascending limb of the loop of Henle, late distal convoluted tube; **Molecular targets:** antagonist of carbonic anhydrase 1, 2, 3, 4, 7, 12, & 14; Aquaporin 1 antagonist - **MoA:** According to the classical view the only acid-base transporters at the apical membrane in the proximal tube are the Na-H exchanger NHE3 and the vacuolar-type H+ pump. The CA-IV catalyzes the slow dehydration of H2CO3 into H2O and CO2 then they present inward flux through the AQ1 channel to the epithelial cell. In the cytosol the CA-II catalyzes the H2O and CO2 into H2CO3 and then is dissociated into HCO3- and H+. The H+ is pumped to the lumen and the HCO3- is pumped to the interstitial space and the blood. - The diuretic effect depends on the inhibition of carbonic anhydrase, causing a reduction in the availability of hydrogen ions for active transport in the renal tubule lumen. This leads to alkaline urine and an increase in the excretion of bicarbonate, sodium, potassium, and water. - MoA per AMBOSS: - **AE:** proximal renal tubular acidosis (Type 2 RTA), paresthesia's, NH3 toxicity, sulfa allergy, hypokalemia; promotes calcium phosphate stone formation (insoluble at high pH); - **Mnemonic:** ACID acetazolamide causes acidosis - **Interactions:** increase risk of AE when combined with GABA agonists and benzodiazepines - **Urine NaCl:** increase with all diuretics - **Urine K+:** increase with loop and thiazide diuretics; decrease with K+ sparing diuretics - **Blood pH:** decrease (acidemia) with Carbonic Anhydrase inhibitors and K+ sparing diuretics; Increase (alkalemia) with loop diuretics and Thiazides - **Urine Ca+:** increase with loop diuretics; decrease with thiazides **[NEPHROTIC SYNDROME LECTURE]** **Glomerular disease** has a clinical presentation that vary from the asymptomatic individual who is found to have HTN, edema, hematuria or proteinuria at a routine medical assessment to a patient who has fulminant illness with AKI **Nephrotic syndrome:** clinical syndrome defined by massive proteinuria responsible for hypoalbuminemia; caused by increased permeability through the damage basement membrane in the renal glomerulus; results from an abnormality of glomerular permeability that may be primarily due to intrinsic renal disease in the kidneys or secondary due to congenital infections, diabetes, systemic lupus erythematosus, Neoplasia, Certain drug use - **Characteristic PENTAD**: Proteinuria, Hypoalbuminemia, Edema, Hypercholesterolemia, Lipiduria - **Etiology:** in **child \3.5 g/24hrs; Hypoalbuminemia \ - hepatic synthesis of LDL and VLDL secondary to the hypoalbuminemia = Urinary losses of HDL - **Xanthelasmas:** clinical stigmata of hyperlipidemia, harmless yellow bump on or near your eyelid skin, can have rapid onset - **Edema:** 2 major mechanisms are involved - Underfill: edema appears from the low serum albumin decrease in plasma oncotic pressure increased transudation of fluid from capillary beds into the extracellular space - Overfill: consequent decrease in circulating blood volume results in secondary stimulation of the renin-angiotensin system this merely aggravates edema because the low oncotic pressure alters the balance of capillary wall in favor of hydrostatic pressure this forces more fluid into the interstitial space rather than retaining it within the vascular compartment - **Minimal change disease:** most common in childhood; usually idiopathic; despite massive proteinuria, renal function remains good, and there is commonly no HTN or hematuria; most protein of the proteinuria is **albumin** - Dramatic response to corticosteroid therapy - **Focal segmental glomerulosclerosis:** 10-15% of cases; light microscopy of renal biopsy sample shows scarring, or sclerosis, of portions of selected glomeruli which can progress into global glomerular sclerosis and tubular atrophy negative immunofluorescence - **Membranoproliferative glomerulonephritis:** more commonly presents as nephrotic syndrome; involves immune complex deposition; immunofluorescence staining shows a granular pattern; on light microscopy thickened basement membrane - **Membranous glomerulonephritis:** most common type in adults; thickened basement membrane and granular pattern on immunofluorescence; "**spike and dome"** appearance on electron microscopy, with membrane deposition growing around subepithelial immune complex deposition - Light microscopy: glomeruli appear normal in early stages of the disease or exhibit uniform, diffuse thickening of the glomerular capillary wall **Evaluation:** urine tests with proteinuria being 3+ or 4+; urine samples over 24 hrs and proteinuria (3g protein) is DIAGNOSTIC - Urine may demonstrate casts (hyaline, granular, fatty, waxy, or epithelial cell). Lipiduria, the presence of free lipid or lipid within tubular cells, within casts, or as free globules, suggests a glomerular disorder - Blood tests: low albumin level in serum; creatinine levels vary by degree of renal impairment; total cholesterol and triglyceride levels are typically increased **Prognosis:** - Excellent with pts with minimal change pathology; most pts go into remission after corticosteroid treatment; **however,** 85-90% of pts are steroid-responsive and may relapse, placing them at risk for steroid toxicity, systemic infections, and other complications **Complications of proteinuria:** metabolic consequences include infection, Hypocalcemia and bone abnormalities, Hyperlipidemia and atherosclerosis, Hypercoagulability, Hypovolemia - AKI may suggest underlying glomerulonephritis but is more commonly precipitated by hypovolemia or sepsis **[NEOPLASMS OF THE KIDNEY]** **BENIGN NEOPLASMS** - **Angiomyolipoma:** - **Epidemiology:** most common benign renal tumor - **Etiology:** sporadic; associated with Tuberous Sclerosis (TSC) & Sporadic lymphangioleiomyomatosis syndromes - **Clinical features:** mostly asymp if \4cm in diameter - **Tuberous Sclerosis:** genetic condition that causes growths; autosomal dominant neurocutaneous syndrome cause by **TSC1 and TSC2 gene mutations;** presents with intellectual disability, seizures, and skin manifestations such as adenoma sebaceum, ash-leaf spots, Shagreen patch, and small benign tumors (e.g. brain hamartomas, cardiac rhabdomyomas, and renal angiomyolipomas) - **Oncocytoma:** - **Epidemiology:** accounts for 5-15% of renal neoplasms; epithelial tumor arising from the intercalated tubular cells in the collecting duct - **Etiology:** no known cause - **Clinical features:** painless hematuria, abdominal mass, flank pain - **Diagnostics:** - **Pathology:** Macroscopy smooth, clearly defined brown tumor with central radial scar (can increase up to 12cm in diameter); Microscopy large acidophilic cells, excessive amount of mitochondria acidophilic, granular cytoplasm without perinuclear clearing - **Tx:** resection to exclude RCC; **nephrectomy** for surveillance for tumor size - **Prognosis:** oncocytomas are NOT invasive, but may transform into a malignant oncocytic RCC **MALIGNANT NEOPLASMS** - **Renal Cell Carcinoma:** - **Epidemiology:** most common malignancy of the renal parenchyma; greater in males than females; peak incidence between 55-74 yrs - **Etiology:** sporadically with risk factors including SMOKING, obesity, sickle cell disease, substance exposure - **Clinical features:** asymp in early stages; symptoms begin with tumor \>10cm and or metastases are present; RCC diagnosed after incidental finding or imaging; TRIAD hematuria, flank pain, and a palpable flank mass; hematuria can be initial presentation of RCC - **\>25%** of pts present with paraneoplastic syndrome: Polycythemia, Renin (HTN), Hypercalcemia (PTHrP) and Hypercortisolism - **Diagnostics:** imaging for another indication, abdominal US, CT, or MRI with contrast pursue workup based on findings (CBC, CMP, urinalysis) - **Pathology:** adenocarcinomas that usually arise from the epithelial cells of the PCT - **Tx:** nephrectomy (partial or radical) for local or locoregional disease - targeted immunotherapy, or surgery in certain pts for metastatic disease - Conventional chemo: many RCC tumors are resistant due to expression of **multidrug resistance protein 1 (MDR-1)** by tumor cells - Surgery: for pts with solid renal masses or renal cysts with **Bosniak classification III or IV** - **Partial nephrectomy:** T1a renal mass, solitary kidney, bilateral masses, familial RCC, preexisting CKD or proteinuria - **Relative nephrectomy:** removal of entire kidney along with adrenal gland and surrounding perinephric fat, with or without lymph node dissection pts with increased oncological risk and/or high surgical risk - **Embolization:** of primary tumor and/or metastases for Sx control in pts with nonresectable disease - **Prognosis:** early-stage RCC with growth limited to kidney; 5 yr survival rate with RCC is about 70%; 100% in the absence of distant metastases - **Most common locations:** lungs, bones, regional lymph nodes, aorta, inferior vena cava, liver, adrenal glands, and brain - **If renal vein** is invaded or extension into the perinephric fat survival rate down to 60% **Hereditary Renal Cell Carcinoma:** - **Birt-Hogg-Dube Syndrome:** autosomal dominant by mutations in **BHD gene, folliculin gene (FLCN)** on chromosome 17 - **Characteristics:** Fibrofolliculomas (benign on hair follicles); lung cysts; RCC (usually chromophobic RCC or oncocytic RCC) - **Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome (HLRCC):** autosomal dominant caused by mutation on **FH gene** (fumurate hydratase) on **chromosome 1** - **Characteristics:** cutaneous and uterine leiomyomas, looks like raised rash - Uterine fibroids or leiomyomata are the most common benign tumors affecting women; fibroids originate from uterine smooth muscle cells (myometrium) whose growth is primarily dependent on the levels of circulating estrogen - **Von Hippel-Lindau Syndrome (VHL):** autosomal dominant; 40% develop renal cysts and renal cell carcinomas (clear cell RCC); **VHL gene** involved in both familial and sporadic clear-cell carcinomas; **tumor development** - **Hereditary papillary renal cell carcinoma (HPRCC):** autosomal dominant condition with a high penetrance; mutation of the **MET proto-oncogene** located on the long arm of **chromosome 7;** usually associated with type 1 papillary RCC - **Clear Cell Carcinoma:** most common subtype of RCC; 70-80% of cases - Cells with clear or granular cytoplasm and are nonpapillary; most cases are sporadic - Familial cases are related to VHL syndrome - 98% of tumors loss of sequences on chromosome 3p25.3, where the VHL gene gene resides - VHL functions as tumor suppressor, its inactivation leads to **high levels of hypoxia-inducible factor-1 (HIF-1),** even in normal oxygen conditions innapropriate activation of genes that promote angiogenesis (**VEGF)** and cell growth (**IGF-1)** - HIF + MYC oncogene tumor growth - Mutations in genes that regulate histone modifications suggest epigenetic dysregulation plays a role in the development of clear cell carcinoma - Cytogenetics: deletions on chromosome 3 sporadic clear cell - Genetics: loss of VHL, inactivated/mutated VHL, or Hypermethylation of VHL hereditary clear cell - **Pathology:** arise from proximal tubular epithelium and typically present as solitary, unilateral, spherical masses that distort the renal outline; these tumors are bright yellow-gray-white due to lipid accumulation in the cells and contain areas of necrosis and hemorrhage - **They extend into the renal calyces and pelvis** invade walls of the collecting system potentially reaching ureter - **Tend to invade RENAL VEIN;** can reach heart - **Papillary Carcinoma:** 10-15% of renal cancers; papillary growth pattern - Cytogenic abnormalities are **trisomies 7 and 17** and **loss of the Y chromosome in sporadic cases familial involve trisomy 7 (MET gene)** - **MET gene** proto-oncogene that encodes a tyrosine kinase receptor for hepatocyte growth factor (HGF) promotes growth, cell mobility, and invasion - Papillary carcinomas are often **multifocal**, unlike clear cell carcinomas - **Pathology:** arise from DCT, can be multifocal and bilateral; hemorrhagic and cystic when large - Composed of cuboidal or low columnar cells arranged in papillary formations - Interstitial foam cells in papillary cores - Psammoma bodies may be present - Stroma is usually scanty but highly vascularized - **Chromophobe Carcinoma:** 5% of renal cell cancers and consists of cells with prominent membranes, **pale eosinophilic cytoplasm,** and a **nuclear halo** - **Exhibit multiple chromosome losses and extreme hypoploidy** - They are believed to **originate from intercalated cells of the collecting ducts**, *similar to benign oncocytomas*, and have a much better prognosis compared to clear cell and papillary cancers - **Collecting Duct (Bellini Duct Carcinoma)** - Rare variant, less than 1% or less of cases - Originates from collecting duct cells in the renal medulla - Various chromosomal losses and deletions; **no distinct pattern has been identified** - Feature malignant cells forming glands within a prominent fibrotic stroma, typically located in the medulla - Irregular channels lined by highly atypical epithelium with a **hobnail pattern** - Sarcomatoid changes arise infrequently in all types of renal cell carcinoma and are a decidedly ominous feature - **Nephroblastoma:** Wilm's Tumor most common primary tumor in children, affecting about 1 in 10,000 in the US and is the **4^th^** most common pediatric malignancy; **ages 2-5,** with 95% of cases before 10 yo - **5-**10% of cases involve both kidneys; bilateral cases appearing earlier due to presumed germline mutations in Wilm's tumor predisposing genes - **Loss of function mutations of tumor suppressor genes WT1 or WT2 on chromosome 11** - **Clinical features:** children large palpable unilateral flank abdominal mass; if extra large can extend across midline and into the pelvis; hematuria, abdominal pain (after trauma), intestinal obstruction, and hypertension - **Many patients have pulmonary metastases at the time of diagnosis** - **Pathology:** soft and homogeneous with occasional hemorrhage, cyst formation, and necrosis; exhibit triphasic composition of **blastemal, stromal, and epithelial cell types** mimicking stages of kidney development - **Anaplasia** in 5% of cases large, abnormal nuclei and correlates with **TP53 mutations chemotherapy resistance** - Nephrogenic rests and precursor lesions in 25-40% of unilateral and almost all bilateral cases signals increased risk of future tumors in the contralateral kidney - Prognosis: generally favorable; but anaplastic histology is a significant adverse prognostic factor, increasing the risk of recurrence and mortality, even without extrarenal spread - Poor prognosis comes from loss of heterozygosity on chromosome 1p and 16q and gain of chromosome 1q - Survival rate have increases increased risk of developing second primary tumors such as soft tissue sarcomas, leukemias, lymphomas, and breast cancers - Some can arise from treatment such as **radiation** - Wilm's Tumor Syndromes: - WAGR complex syndrome: Wilms tumor, Aniridia (no iris), Genitourinary malformations, Range of developmental delays; **WT1 deletion** - Denys-Drash Syndrome: Wilms tumor, Diffuse mesangial sclerosis (early onset nephrotic syndrome), Dysgenesis of gonads (male pseudohermaphroditism); **WT1 Mutation** - Beckwith-Wiedemann Syndrome: Wims tumor, Macroglossia, Organomegaly, Omphalocele, Hemihyperplasia; **WT2 Mutation** **[VASCULAR DISEASE OF THE KIDNEY LECTURE ]** **Fibromuscular dysplasia:** most common cause of Renal Vascular Hypertension in children and young adults - 90% women with usual onset at 44yo most common adult clinical presentation is early onset RVH in young middle-aged women - \#1 Renal arteries 66%; \#2 Extracranial cerebral arteries pathognomonic arteriographic abnormalities focal or multifocal stenoses in a **string of beads** appearance histologically, FMD is associated with distortion of the architecture of the arterial wall involving one or more layers - Pathophysiology: idiopathic, non-inflammatory, non-atherosclerotic, developmental condition that primarily affects small and medium-sized muscular arteries results in ischemia by stenosis, saccular aneurysms, arterial dissection - Clinical features: secondary HTN, abdominal bruit, CKD symptoms, flank or abdominal pain - Diagnosis: first is doppler ultrasound of renal arteries renal angiography - Treatment: **Atherosclerotic renal artery stenosis:** can also be considered renal hypertension; due to atherosclerosis, fibromuscular dysplasia, polyarteritis nodosa, aortic arch syndrome - Epidemiology: most common cause over 50 yo; among pts with chronic CHF, RA stenosis has been reported in 50-68% - Tx: screening recommended in pts presenting with resistant or accelerated hypertension and those presenting with heart failure - RA stenosis = \>60% - Bilateral = 40% - ARA patients with: past medical history of atherosclerosis; 14% hypertension and 20% diabetes; 68% chronic heart failure - Pathophysiology: narrowing of one or both renal arteries obstruction of renal blood flow ischemia renin release and activation of RAAS hyperreninemic hyperaldosteronism increased sodium retention and PVR renovascular hypertension - Hyperplasia of the juxtaglomerular apparatus - No improvement in renal bloodflow ischemic renal injury renal insufficiency and progressive renal atrophy - Clinical features: HTN severe and/or early onset; abdominal bruit heard over the flank or epigastrium (during both systole and diastole); flash pulmonary edema; features of atherosclerosis in other parts of the body (peripheral artery disease, coronary artery disease, carotid stenosis) - Diagnosis: BMP, urinalysis; US, MRangiography **Ischemic renal disease** **Kidney infarction:** acute loss of blood supply to the renal parenchyma resulting in necrosis and loss of kidney function - **Etiology:** usually caused by embolism or in situ thrombosis with idiopathic cause, Cardiovascular disease, renal artery disease, or hypercoagulable states - **CF:** stones, pyelonephritis and muscle strains; fever, acute onset flank or abdominal pain, nausea and vomit, increased BP, oliguria - **Dx:** CBC, serum **(increased creatinine and lactate dehydrogenase)** urinalysis; abdominal CT, doppler US - **Tx:** antihypertensive therapy, anticoagulation; percutaneous endovascular therapy - **Notes:** most common arrythmia associated with renal infarction Atrial fibrillation **[URILITHIASIS & CYSTIC DISEASES OF THE KIDNEY ]** - **Autosomal Dominant PolyCystic Kidney Disease (ADPKD):** most common inherited cause of CKD - Multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma (renal failure); renal function maintained until 4-5^th^ decades of life - Mutation: - **PKD1 (chromosome 16; 85%)**; tubular epithelial cells; exact function is unknown; involved in cell-cell and cell-matrix interactions - **PKD2 (chromosome 4; 15%);** membrane protein in all segments of the renal tubules; Ca2+ permeable cation channel (less severe disease) - **Pathophysiology:** two-hit hypothesis; 1^st^ is inherited mutation; 2^nd^ is additional second somatic acquired mutation in tubule epithelial cells abnormal cilia-mediated signaling pathways activation of the RAAS, ischemia, and destruction of the kidney parenchyma - **Pathogenesis:** tubular epithelial cells contain a single nonmotile primary cilium, projects into the tubular lumen, attached to a basal body derived from the centriole function in the lumen and intracellular are: mechanosensory (fluid flow and shear stress) and intracellular monitor (forces between cells and attachments) respectively in turn, regulate ion flux (cilia can induce Ca2+ flux in cultured kidney epithelial cells) and cellular behavior, including cell polarity and proliferation Polycystin-1 and polycystin-2 appear to form a protein complex that regulates intracellular Ca2+ in response to fluid flow - **Clinical features:** asymptomatic, masses at palpation, hematuria, renal failure onset, HTN, UTI, **renal stones** - **Tx:** ACE inhibitor/ARBs HTN or proteinuria - **Dx: USG , CT if prior unclear, MR angiography** - **Autosomal Recessive (childhood) Polycystic Kidney Disease (ARPKD);** neonatal (most common), perinatal, infantile and juvenile - Manifestations at birth and succumbs rapidly to renal failure - **Mutation PKHD1 gene on chromosome 6** - **PKHD1:** fibrocystin (adult/fetal kidney, liver, pancreas; fibrocystin part of cilium of tubular cells as a receptor for differentiation of collecting duct cystic dilation of collecting ducts - **Morphology:** enlarged kidneys with smooth external appearance; small cysts in cortex and medulla spongelike - Patients who survive infantile forms develop hepatic injury (periportal fibrosis and proliferation of well-differentiated biliary ducts) - **Clinical features:** detectable on prenatal USG associated to congenital **hepatic fibrosis** hepatic disease, oliguric renal failure in utero Potter Sequence - **Postnatal:** systemic hypertension, HTN, progressive renal insufficiency, portal HTN, splenomegaly - **Perinatal & neonatal presentations are the most common & serious variants** - **Dx:** USG, CT, MR angiography - **Autosomal Dominant Tubulointerstitial Kidney Disease/Medullary Kidney Disease** - Medullary cysts not visualized externally, papillary ducts in medulla are dilated and small cyst may be present, smaller kidneys - Sponge kidney; RF preserved; mutations in **NPHP1-11** (nephrocystins) - Tx: prophylactic tx, extracorporeal shock wave lithotripsy, dialysis may be needed - Dx: USG, contrast CT, IVP - **Simple Renal Cysts:** single or multiple cysts involving cortex, translucent, lined by a gray, glistening, smooth membrane and clear fluid filled - **Clinical:** common, most renal masses, majorly asymp, complex require removal - **Multicystic Renal Dysplasia:** unilateral or bilateral; enlarged irregular multicystic kidneys; presence of islands of undifferentiated mesenchyme, often w/ cartilage and immature collecting ductules; uretopelvic obstruction, ureteral agenesis,; gross appearance; filated tubules w/primitive stroma and an island of cartilage - **Acquired cystic disease:** in patients who have undergone prolonged dialysis; cortical & medullary renal cysts; mostly asymptomatic, can bleed \> hematuria increased risk to renal cell carcinoma at 100-fold **[UROLITHIASIS:]** obstructive lesions increase susceptibility to infection and tone formation; unrelieved obstruction renal atrophy (hydronephrosis or obstructive uropathy); obstructions may be sudden or insidious, partial or complete - Location: at any level of the urinary tract from the urethra to the renal pelvis; caused by intrinsic lesions or extrinsic lesions that compress the ureter - Affects 5-10% of people in US, with most stones arising in the kidney - 4 main types: - Calcium stone (70%) calcium oxalate or mixed with calcium phosphate - Triple stones or struvite stones (15%) magnesium ammonium phosphate, urease, infections associated - Uric Acid stones: 5-10% (less common?) - Cystine: 1-2% - **Pathogenesis:** increased concentration of stone constituents (exceeds their solubility supersaturation), changes in urinary pH, decreased urine volume, and the presence of bacteria influence the formation of calculi, many calculi occur in absence of these factors - Stone formation is enhanced by deficiency of inhibitors of crystal formation in urine such as: pyrophosphate, diphosphate, citrate, glycosaminoglycans, osteopontin, glycoprotein (nephrocalcin) - **Clinical features:** asymptomatic, produce severe renal colic and abdominal pain (radiating anteriorly to the groin), Giordano +, nausea, vomiting, or may cause significant renal damage, UTI (recurrent, chronic infection), hematuria, calculus anuria, Interruption of urinary system - **DX:** clinical assessment, ab USG, x-ray, IVP - **Tx:** non-medical, oral chemolitholysis, extracorporeal shock wave lithotripsy; surgical removal - **Under a microscope:** - Calcium: oxalate crystals, a pseudocast of calcium oxalate crystals accompanied by crystals of calcium oxalate dihydrate - Rhomboid: uric acid crystals, complex crystals suggestive of acute uric acid nephropathy - Hexagonal: a typical hexagonal cystine crystal, a single crystal provides a definitive diagnosis of cystinuria - Struvite: coffin lid crystals of magnesium ammonium phosphate - Imaging: plain abdominal radiograph with views of kidneys, ureters, and bladder (KUB) reveals opacifications as result of calcium, cystine or struvite stones - Uric acid and xanthine calculi are radiotranslucent - Unenhanced helical computed tomography (CT) - Kidney ultrasound **[ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE LECTURE ]** **[Acute Kidney Injury]:** sudden loss of renal function with a subsequent rise in creatinine and blood urea nitrogen (BUN) - Etiology/Risk factors: - Pre-renal: most frequent is decreased renal perfusion; non-specific (ischemia, toxic injury); 30-60% of AKI - Hypovolemia, Hypotension, decreased circulating volume, renal artery stenosis, drugs - Renal: including specific kidney diseases; intrarenal or intrinsic 40% of AKI - Acute tubular necrosis, acute interstitial nephritis, vascular diseases, glomerulonephritis - Post-renal: obstructive nephropathy; inadequate urine drainage; 10% of AKI - Acquired obstructions, neurogenic bladder, congenital malformations - **Classification:** - R: - I: - F: - L: - E: - A: - K: - I: - N: - **Phases:** - **Initiating event:** injury, symptoms of the underlying illness causing AKI may be present (hours to days) - **Oliguric and anuric phase:** maintenance phase; progressive deterioration of kidney function (reduced urine production, increased retention of urea and creatinine), complications fluid retention, hyperkalemia, metabolic acidosis, uremia, lethargy, asterixis; about 1-3 weeks - **Polyuric/diuretic phase:** glomerular filtration returns to normal, which increases urine production (polyuria), while tubular reabsorption remains disturbed; complications loss of electrolytes and water (dehydration, hyponatremia, and hypokalemia); about 2 weeks - **Recovery phase:** kidney function and urine production normalize; months to years - **Nephrotoxic medications:** - Antimicrobials (aminoglycosides, vancomycin, cephalosporins, colistin, sulfonamides, streptomycin; acyclovir, foscarnet, cidofovir, tenofovir; amphotericin B) - Antimetabolites: methotrexate, Cladribine - Chemotherapeutic agents (platinum based): cisplatin, Carboplatin - Anti-inflammatories and immunosuppressants: NSAIDs, Cyclosporine, calcineurin inhibitors - Others: inhalational anesthetics, lithium, herbal remedies, phosphate-containing bowel preparations - **Pathophysiology's:** - **Pre-renal:** decreased blood supply to kidney decreased GFR activation of renin-angiotensin system inceased aldosterone release increased reabsorption of Na+, H2O increased urine osmolality secretion of antidiuretic hormone increased reabsorption of H2O and urea - **Blood BUN:creatinine ratio increases** **(ratio \>20:1)** - **Renal/Intrinsic:** necrosis or apoptosis of tubular cells decreased reabsorption capacity of electrolytes (Na+), water, and/or urea; increased Na+ and H2O in the urine decreased urine osmolality **(ration \0.3 mg/dL within 48 hrs - Increase in serum creatinine to \> 1.5 times baseline level within 7 days - Decrease in urine output to \< 0.5 mL/kg/hour for \> 6 hrs - **Treatment:** - focus on underlying cause - Prerenal: correct adverse hemodynamic factors and replace the depleted volume - Consider indications for acute dialysis - Provide supportive care to all patients hold potentially nephrotoxic substances, manage volume status, identify and manage complications (electrolyte disturbances, acidosis, fluid overload) **[Acute Kidney Disease (AKD):]** symptoms for less than 3 months - Functional criteria: AKI or GFR \35% over baseline or increase in sCr by \>50% over baseline OR - Structural criteria: elevated marker of kidney damage (albuminuria, haematuria or pyuria are most common) - AKI stage 2 and 3 - Risk factors: kidney disease, liver disease, diabetes, especially if its not well controlled, HTN, HF, morbid obesity **[Chronic Kidney Disease (CKD):]** abnormalities of kidney structure or function present for \> 3 months, with implications of health; be able to differentiate it from AKDs - Criteria: either one OR both for at least 3 months - 1 GFR \< 60 mL/min per 1.73m2 (G3a-5) - Markers of kidney damage (1 or more) - Albuminuria - Urinary sediment abnormality electrolyte or other abnormality due to tubular disorder - Abnormalities on histology - Structural abnormalities detected by imaging - History of a kidney transplantation - Etiology/risk factors: lead to CKD and eventually ESRD - Type 2 DM, Type 1 DM, HTN, Primary glomerulonephritis, Chronic Tubulointerstitial nephritis, Hereditary or cystic diseases, Secondary Glomerulonephritis or vasculitis, Plasma cell dyscrasias or neoplasm, Sickle Cell Nephropathy - Classification: - G1: - G2: - G3a: - G3b: - G4: - G5: - Pathophysiology: - Diabetic nephropathy: hyperglycemia nonenzymatic glycation of proteins varying degrees of damage to all types of kidney cell Pathological changes: - hypertrophy and proliferation of mesangial cells, GBM thickening, and ECM protein accumulation eosinophilic nodular glomerulosclerosis - thickening and diffuse hyalinization of afferent and efferent arterioles/interlobular arteries - Hypertensive nephropathy: benign nephrosclerosis (sclerosis of afferent arterioles and small arteries) decrease perfusion ischemic damage - Glomerulonephritis: lupus nephritis - **Maladaptive cellular response to injury that leads to persistent activation of proinflammatory and profibrotic signaling** - **Decreased glomerular filtration rate H+ retention decreased pH of interstitial fluid of kidney OR decreased intracellular pH of renal Tubular Cells increased angiotensin 2 and increased aldosterone, increased endothelin, increased pro-inflammatory cytokines and chemokines, increased NH3 with activation of complement interstitial fibrosis progression of CKD** - Signs and symptoms: fatigue, fluid retention (HTN and HF; pulmonary and peripheral edema), electrolyte imbalances, anemia, confusion, taste of metallic food, cramps, dry or itchy skin - Diagnostic approaches: - CBC - Blood levels: Creatinine, BUN, Urea - Urine analysis with microscopy, 24 hr urine collection - Bicarbonate - Iron - Serologic: ANA, ANCA, Anti-GBM, HBV, HCV, HIV - Urinalysis - Ultrasound of kidneys - Treatment: - Lifestyle: healthy diet, physical activity, smoking cessation, weight management - First-line drug therapy: - **SGLT2i** (initiate eGFR \> 20; continue until dialysis or transplant) **+ metformin** (if eGFR \> 30) GLP-1 RA if needed to achieve individualized glycemic target other glucose-lowering drugs if needed to achieve individualized glycemic target - **RAS inhibitor** @ max tolerated dose if HTN is present **non-steroidal MRA** if ACR \> 30 mg/g and normal potassium OR **dihydropyridine CCB and/or diuretic** if needed to achieve individualized BP target **steroidal MRA** if needed for resistant hypertension (if eGFR \> 45) - **Moderate or High-intensity statin Antiplatelet agent** for clinical ASCVD OR **Ezetimibe, PCSK9i, or icosapent based on ASCVD risk and lipids** - Renal replacement therapy: non operative hemodialysis or peritoneal dialysis; Operative: kidney transplant **[URINARY TRACT INFECTIONS LECTURE ]** **Lower UTI:** occurs when bacteria travel as high as the urethra or bladder **Upper UTI:** occurs when bacteria travel beyond this point and into the ureters or kidneys **Etiology:** infection ascends from the urethra to the bladder; can ascend further to the ureters and the renal pelvises - Bacteria that cause UTI: - Escherichia coli (leading cause) - Stephylococcus saprophyticus: 2^nd^ leading cause of UTI in sexually active women - Klebsiella pneumonia: 3^rd^ leading cause of UTI - Proteus mirabilis: produces ammonia, giving urine a pungent or irritating smell associated with **struvite stone formation** - Nosocomial bacteria: Serratia marcescens, Enterococci spp, and Pseudomonas aeruginosa are associated with increased drug resistance - Predisposing factors: - Structural or functional abnormalities of the urinary tract - Sex - Pregnancy - Prior conditions - Sexual intercourse - Catheter-associated urinary tract infection (CAUTI) UTI risk factors: occur most commonly in women, except in infants and older adults (that's male) - After 50 yo, obstruction from prostatic hypertrophy becomes common in men, and the incidence of UTI is almost as high among men as among women - Risk factors: in healthy **postmenopausal women**, sexual activity, diabetes mellitus, and incontinence are risk factors for UTI many factors predisposing women to cystitis also increase the risk of pyelonephritis - Risk factors: in young healthy women, for pyelonephritis include frequent sexual intercourse, a new sexual partner, a UTI in the previous 12 months, a maternal history of UTI, diabetes, and incontinence - In men: lack of circumcision is associated with an increased risk of UTI because E.coli is more likely to colonize the glans and prepuce and subsequently migrate into the urinary tract **Pathogenesis:** bacteria can gain access to the urinary tract through the bloodstream; hematogenous spread accounts for \< 2% of documented UTIs and usually results from bacteremia caused by relatively virulent organisms, such as salmonella and S. aureus **Clinical syndromes:** - **Asymptomatic Bacteriuria:** no local or systemic symptoms; usually detected when a patient undergoes a screening urine culture for a reason unrelated to the genitourinary tract - **Cystitis:** dysuria, urinary frequency, and urgency; nocturia, hesitancy, suprapubic discomfort, and gross hematuria; unilateral back or flank pain upper urinary tract is involved; fever invasive infection beyond the bladder, involving kidney, prostate, or bloodstream - **Complicated UTI:** presents as a systemic illness with an infectious focus in the urinary tract; occurs in patients with an anatomic predisposition to infection foreign body in the urinary tract, or with factors predisposing to a delayed response to therapy **Diagnosis:** symptomatic urinalysis (clean-catch midstream) will find Pyuria, Bacteriuria - Leukocyte casts may indicate pyelonephritis - Alkaline urine urease-producing organisms - Urine culture: suspected complicated UTI - Imaging: CT of abdomen and pelvis US of kidneys and bladder **Treatment:** - Uncomplicated cystitis: Nitrofurantoin, TMP-SMX, Fosfomycin, Pivmecillinam, Fluoroquinolones, dose varies by agent; B-lactams - Enterobacteriaceae: antibiotics with guidance by in vitro susceptibility test results and clinical experience; Carbapenems: additionally, used to be used but stopped, as well as B-lactam antibiotics; Antibiotic resistance is more common in hospital-acquired infections than in community-acquired infections - Pregnant women: nitrofurantoin, ampicillin, and the cephalosporins are relatively safe; avoid sulfonamides in first trimester and near term; Avoid Fluoroquinolones because of possible AE on fetal cartilage development - Pregnant women with ASB for 4-7 days in absence of evidence to support single-dose therapy - UTI in men: since the prostate is involved in the majority of cases of febrile UTI in men, the goal in these patients is to eradicate the prostatic infection as well as the bladder infection 7-14 day course of a fluoroquinolone or TMP-SMX is recommended if the uropathogen is susceptible **[PYELONEPHRITIS LECTURE ]** **Usually caused by an ascending bacterial infection of the bladder (cystitis)** **Pathogens:** gram-negative bacteria (E.coli, P.aeruginosa, KP, Proteus mirabilis); gram-positive bacteria Risk factors: more in women due to short urethra; pregnancy, urinary tract obstruction, cystitis, antibiotics, immunosuppression, renal transplant **Classification:** - Uncomplicated pyelonephritis: pyelonephritis in an immunocompetent, nonpregant female with normal genitourinary anatomy and renal function - Complicated: associated with any fo the following RF sepsis, male sex, over 60 yo, UT abnormalities, hospital-acquired infection, nephrolithiasis, pregnancy **Clinical Features:** - **Mild:** low-grade fever with/without lower-back or costovertebral-angle pai - **Severe:** high fever, rigors, nausea, vomiting, and flank pain - **"picket fence" fever, resolving in 72 hrs** **Other:** - **Bilateral papillary necrosis:** rapid rise in the serum creatinine **Differentials:** - **Emphysematous pyelonephritis:** severe form, production of gas in renal and perinephric tissues and occurs almost exclusively in diabetic patients - **Xanthogranulomatous:** from chronic urinary obstruction (staghorn calculi), together with chronic infection, leads to suppurative destruction of renal tissue; on pathologic exam residual renal tissue frequently has a yellow coloration, with infiltration by lipid-laden macrophages - **Pyelonephritis:** can be complicated by intraparenchymal abscess formation suspected when pt has continued fever and/or bacteremia despite antibacterial therapy **Treatment:** Fluoroquinolones for uncomplicated; 7 days of oral ciprofloxacin; oral TMP-SMX (2 daily for 14 days) Exceptions: