W1M1L1 Intro to Kidney

Kidney Function ECF volume maintenance Excretes metabolic wastes Adjusts urinary water excretion Endocrine Renin, angiotensin, prostaglandins, bradykinin Erythropoetin 1, 25 dihydroxy vitamin D

Clinical Presentation of Kidney Disease Pain Midback pain Urinary Abnormalities Protein in urine Blood in urine Hypertension Asymptomatic!

Control of GFR Efferent Arteriole Prostaglandins cause vasodilation of efferent arteriole Decrease GFR Macula Densa Samples contents of arterioles, and produces vasoconstrictive / vasodilatory hormones Low GFR -> High salt load to the distal nephron Afferent Arteriole Angiotensin constricts the afferent arteriole Decreases GFR

Determinants of GFR

Hydrostatic Pressure Outward force pushing blood into glomerulus (filtration) Can be considered what is left of blood pressure

Oncotic pressure Pressure due to protein concentration difference in plasma vs filtrate (acts against filtration)

GFR Calculation
Total GFR = snGFR x nephron mass snGFR = filtration rate of a single nephron = unit permeability capillary wall x net pressure gradient (Starling Force) = LpS x [ (P(gc bs) OP (gc bs) ] - Lp = permeability capillary wall, S = surface area of capillary

OP bs is usually negligible

Renal Failure
GFR is a measure of renal function. Decreased GFR indicates renal failure Causes of renal failure (reduced GFR) Reduced number of glomeruli Surgical removal of kidney tissue Drop out of individual glomeruli, as in aging Reduction in snGFR Reduced renal plasma flow (shock) Increased oncotic pressure

GFR Estimation GFR estimation = The amount of filtration of the ideal filtration marker Ideal filtration marker characteristics Freely filtered Not protein bound in plasma Not secreted or reabsorbed Endogenously produced Easily measured

Filtration Markers Inulin Freely filtered, not protein-bound in plasma, not secreted or reabsorbed. BUT not endogenously produced. So not measured clinically Creatine Freely filtered, not protein-bound, in plasma, not reabsorbed, slightly secreted Produced endogenously from muscle Tends to overestimate GFR Blood Urea Nitrogen (BUN Not produced at a constant rate. Reabsorbed clearance decreases with volume depletion (BUN:creatinine ratio increases)

Glomerular Selectivity Glomerulus Permselectivity The glomerular basement membrane has charge selectivity and size selectivity Water and small molecules pass freely Macromolecules ( > 5nm ) do not pass Albumin (3.6 nm) passes in small amounts Slit Diaphragm Podocytes form slit pores, through which small molecules can pass The slit diaphragm contains nephrin

Slit diaphragm, made of nephrin

Proteinurea Indication of damage to the glomerular filtration barrier Degree < 200 mg / day = Normal 30 300 mg/ day = Microalbuminurea > 300 mg / day = Proteinurea >3 g / day = Heavy proteinurea

Nephrotic Syndrome Definition Syndrome of four conditions Heavy proteinurea Hyperlipidemia The body makes more lipids to compensate for the lost albumin Hypoalbuminemia Edema Common Causes of Nephrotic Syndrome Minimal Change Nephrotic Syndrome Commonest cause of nephrotic syndrome in children (unusual in adults) LM = normal glomeruli (kidney looks normal!) EM = foot process effacement Responds to corticosteroids Focal and Segmental Nephrosclerosis LM = segmental sclerosis and hyalinosis May be primary or secondary HIV patients most common cause of glomerular disease

W1T1L2 Regulation of Salt and Water Fluid compartments 1/3 of bodys water is outside cells!

60% of body mass is water

2/3 of bodys water is inside cells!

Plasma and Body Osmolality Plasma osmolality = Body osmolality = 2 x Na + glucose / 18 + BUN / 2.8 ~ 2 x Na Na, glucose, and urea nitrogen are the most abundant electrolytes. In the body Na and its counter ions are the single most abundant, so osmolality can be estimated with 2 x Na alone Normal 280-290 Effective and Ineffective Solutes

Effective Solute = solutes that cant move across cell membrane (Na, glucose) Ineffective Solute = solutes that can move in and out of cell membranes (urea)

Osmoregulation vs Volume Regulation Osmoregulation Volume Regulation

What is sensed?

Plasma osmolality

Effective circulating volume Carotid sinus Afferent arteriole Atria and ventricles Sympathetic NS ADH RAAS -> Na+ retention ANP -> Na excretion Urinary Na and water excretion Thirst

What are the sensors?

Hypothalamic osmoreceptors

What are the effectors?

ADH -> H2O excretion Thirst -> H2O intake

What is affected?

Urine osmolality Water intake / excretion

Osmoregulation vs Volume Regulation Osmoregulation Volume Regulation Note ADH is used to control osmoregulation and volume regulation. When volume is depleted (drastically), it will sacrifice osmolality balance and cause water retention

What is sensed?

Plasma osmolality

Effective circulating volume Carotid sinus Afferent arteriole Atria and ventricles Sympathetic NS ADH RAAS -> Na+ retention ANP -> Na excretion Urinary Na and water excretion Thirst

What are the sensors?

Hypothalamic osmoreceptors

What are the effectors?

ADH -> H2O excretion Thirst -> H2O intake

What is affected?

Urine osmolality Water intake / excretion

Common Na / Volume Balance Clinical Scenarios Infusion of Normal Saline

Infusion of Normal Saline

Effective circulating volume (ECV) increase

Carotid sinus, afferent arteriole, and atria and ventricles sense ECV

SNS, ADH, RAAS, ANP (Na excretion)

Urinary Na and water excretion Decreased thirst

Common Na / Volume Balance Clinical Scenarios Free water Ingestion

Drinking water

Plasma osmolality

Hypothalamic osmoreceptor firing

ADH

Increases plasma osmolality toward normal

water urine osmolality urinary volume

water permeability at late distal tubule and collecting duct

Common Na / Volume Balance Clinical Scenarios Eating potato chips!

Eat potato chips

Intracellular water shifts to extracellular space (ECV)

Hypothalamic osmoreceptor firing

ADH

Increases plasma osmolality toward normal

water urine osmolality urinary volume

water permeability at late distal tubule and collecting duct

W1T2L3 Sodium Disorders Hepatorenal Syndrome Pathophysiology

W1W1L4 Disorders of K+ Balance Hyperkalemia Pathophysiology Hyperkalemia

Pseudohyperkalemia

True Hyperkalemia

Hyperkalemia Pathophysiology Hyperkalemia

Pseudohyperkalemia

True Hyperkalemia

Leukocytosis WBC > 100,000

Thrombocytosis Plt > 1,000,000

Release of K+ during blood clotting

Hyperkalemia Pathophysiology Hyperkalemia

Pseudohyperkalemia

True Hyperkalemia

Redistribution Tissue Necrosis

Decreased urinary K secretion Voltage-dependent secretory defect

Hypoaldosteronism

Hyperkalemia Pathophysiology True Hyperkalemia

Redistribution

B-adrenergic activity / insulin

Hyperosmolarity

Metabolic Acidosis

Hyperkalemia Pathophysiology True Hyperkalemia

Tissue Necrosis

Tumor lysis

In vivo hemolysis

Rhabdomyolsis

Hyperkalemia Pathophysiology True Hyperkalemia

Hypoaldosteronism
Aldosterone Aldosterone causes Na+ reabsorption and K+ excretion Lack of Aldosterone causes decreased K excretion, causing hyperkalemia Causes of hypoaldosteronism Type IV RTA Adrenal insufficiency NSAIDs, ACEI, ARB, heparin (review)

Hyperkalemia Pathophysiology True Hyperkalemia

Voltage-dependent secretory defect

Tumor lysis

In vivo hemolysis

Rhabdomyolsis

Hyperkalemia Pathophysiology True Hyperkalemia

Decreased urinary K secretion

Tumor lysis

In vivo hemolysis

Rhabdomyolsis

Hyperkalemia Treatment Hyperkalemia

Antagonism of K

Remove K from the body

Drive K into cells

Hyperkalemia Treatment Hyperkalemia

Antagonism of K

Remove K from the body

Calcium Check how this works

Drive K into cells

Hyperkalemia Treatment Hyperkalemia

Antagonism of K

Remove K from the body

Drive K into cells

Insulin and glucose

B2 adrenergic agonist

Sodium bicarbonate

Hyperkalemia Treatment Hyperkalemia

Antagonism of K

Remove K from the body

Drive K into cells

Diuretics

Dialysis

Cation exchange resin Kayexelate

Hypokalemia Pathophysiology True Hypokalemia

Extra-renal causes

Intra-renal causes

K intake Sweat loss

GI Loss Redistribution

W1W2L5 Acute Kidney Injury Acute Kidney Injury Definition / Significance

Acute Kidney Injury (AKI) Sudden impairment in kidney function Increase in serum creatinine, BUN Decrease in urine output Time course Hours or days Contrast with rapidly progressive renal failure (weeks to months) and chronic kidney disease ( > 3 months) Significance

AKI Pathophysiology

Pre-renal

Post-renal

Glomerular filtration falls due to inadequate renal perfusion Causes Hypovolemia Cardiac Causes Liver disease Hepatorenal syndrome Nephrotic syndrome Renovascular

Intrinsic renal

AKI Pathophysiology

Pre-renal

Post-renal

Intrinsic renal

Glomerular Acute glomerulonephritis Tubulointerstitial Acute tubular necrosis MOST IMPORTANT CAUSE Acute tubulointerstitial nephritis Intra-tubular crystal deposition Vascular Vasogenic Microangiopathic hemolyic anemia Cholesterol Emboli

AKI Pathophysiology

Pre-renal

Post-renal

Intrinsic renal Acute tubular necrosis Classification Ischemic ATN Toxic ATN Pathophysiology

AKI Pathophysiology

Pre-renal

Post-renal

Intrinsic renal

Acute tubulointerstitial nephritis Pathophysiology Usually reaction to medications Beta lactams PPIs May be associated with fever, skin rash

AKI Treatment

W1Th1,2L6,7 Glomerular Diseases Normal Renal Anatomy and Histology

Glomerular Histology Glomerulus a network of anastomosing capillaries lined by endothelial cells and covered by epithelial cells

Glomerular Anatomy

Mesangium Basement membrane Covers both

endothelium and mesangium

Endothelium of BV Foot processes

Electron Microscopy of Glomerulus

Mesangial matrix

Mesangial cell Podocytes The presence

of podocytes indicates were in Bowmnas space

Normal Glomerulus

Arteriole lumen

Mesangial matrix

Bowmans space

Electron Microscopy of Glomerular Capillary

Mesangium

Capillary lumen
RBC Endothelial layer Podocytes Bowmans space Parietal epithelial cell

Electron Microscopy of slit diaphragms

Slit diaphragms

Glomerular Disease Terminology Number of glomeruli Focal involving few glomeruli ( < 50%) Diffuse involving most glomeruli ( > 50% ) How much of one glomeruli Segmental involving only a portion of one glomerulus A segment of one glomeruli Global involving most of one glomerulus

Segmental sclerosis only a portion of one glomerulus

Glomerular Histopathology

Glomerular hypercellularity Increased number of inflammatory cells in the capillary loops The lumens are closed from too many cells

Glomerular Injury (and Histopathology ) Types of Injury Nephrotic Syndrome Membranous nephropathy Minimal change nephropathy Focal and segmental glomerulonsclerosis Amyloidosis Diabetes Alports syndrome

Nephritic Syndrome Post streptococcal glomerulonephritis IGA nephropathy (Bergers Disease) Crescentic Glomerulonephritis Alports syndrome
Pauci-immune glomerulonephritis Anti-GBM disease Henoch Schonlein purpura

Nephrotic Syndrome Membranous Nephropathy Overview

Most common cause of nephrotic syndrome in adults Pathophys Subepithelial immune complex deposits Granular IgG and complement by IF Thickened basement membranes Classification Primary Autoimmune disease Secondary Infections Malignancy Rheumatologic

Nephrotic Syndrome Membranous Nephropathy Microscopy

LM Glomeruli enlarged and hypercellular, neutrophils, lumpy bumpy appearance

EM subepithelial immune complex (IC) humps spikes of basement membrane between deposits

IF granular apperance due to IgM, IgG, and C3 deposition

Nephrotic Syndrome Minimal Change Nephropathy Overview

Most common cause of nephrotic syndrome in children Pathophys LM - Normal glomeruli IF - negative Increased lipoproteins in proximal tubular epithelial cells Associated with T cell disorders Frequently follows viral disorders Can be presenting symptom of Hodgkins lymphoma Treatment Treated with steroids Children usually dont need biopsy

Nephrotic Syndrome Minimal Change Nephropathy Microscopy

LM Normal glomeruli

EM podocyte effacement

IF Negative

Nephrotic Syndrome Focal Segmental Glomerulosclerosis Overview

Nomenclature Focal some but not all glomeruli Segmental only a portion of one glomerulus (one segment) Progression Sclerosis progresses to diffuse and global Classification Primary Secondary Part of glomerular ablation nephropathy Due to hyperfilation of remaining glomeruli Congenital Mutation in nephrin, podocin

W1F1L8 Acid / Base

Bicarbonate Carbon Dioxide System Acute Kidney Injur

W1F1L9 Case Presentation, Acute Kidney Disease Acute Kidney Injury Overview Markers Electrolytes Creatinine Men usually less than 1.5 Women less than 1.3 Reflective of amount of muscle BUN Normally 5-25 A waste product Extracellular volume Urinalysis Dipstick FeNa Renal Ultrasound

Acute Kidney Injury

Pre-renal

Post-renal

Intrinsic renal

Glomerular Acute glomerulonephritis Tubulointerstitial Acute tubular necrosis MOST IMPORTANT CAUSE Acute tubulointerstitial nephritis Intra-tubular crystal deposition Vascular Vasogenic Microangiopathic hemolyic anemia Cholesterol Emboli

Mechanism of Acute Kidney Injury Renal Vascular: Stenosis, vasculitis Interstitial damage

Volume Prerenal

Acute Glomerulonephritis Acute tubular damage

Post-renal Obstruction

Mechanism of Acute Kidney Injury Renal Vascular: Stenosis, vasculitis

Urinalysis with urine sediment: RBCs with NO RBC casts

Volume Prerenal Orthostatic hypotension, low BP

Interstitial damage

Acute Glomerulonephritis Urinalysis with urine sediment: Red cell casts are pathognomonic

Acute tubular damage Urinalysis with urine sediment: Renal tubular cell casts are suggestive Post-renal Obstruction

Acute Kidney Injury Overview Case 1 Volume Depletion 50 yo man with low blood pressure, especially upon standing. Creatinine elevated. Negative urinalysis Diagnosed with acute renal failure due to volume depletion Next diagnostic step: Get FeNa it should be less than 1%, because body is trying to hold on to Na+ Treatment: Give patient PO intake and aggressive hydration (restore volume quickly Case 2 Post renal obstruction 60 yo man with increased urgency, frequency, and hesitancy of urination. Has not urinated for more than 24 hours. BUN 140, Cr 6. Diagnosed with post renal obstruction Treatment: Placement of bladder catheter. Send him to ICU and be sure to decompress bladder slowly

Acute Kidney Injury Case 3 Volume Depletion 22 yo with right flank pain, red colored urine, swelling of lower extremities, and sore throat. BP 160/11, some edema. BUN 60, Creatinine 5.2. Diagnosed with acute glomerulonephritis. Next diagnostic step: Urinalysis with urine sediment. The presence of red blood cell casts would be diagnostic for glomerulonephritis Confirm diagnosis: Serum complement levels. They should be low due to consumption. If C3 is low, there are 3 possibilities: post infectious GN, lupus, or MPGN (membranoproliferative GN Case 4 Post renal obstruction 82 yo female with obstructive gall bladder disease. Temp 102. Small woman with no recent weight changes. On Gentamicin, amikacin, for six days. On sixth day, BUN 50, Cr 4.5 Diagnosed with acute tubular necrosis due to drug toxicity. Next diagnositc step: urine sediment. Look for renal tubular cell casts

Acute Kidney Injury Case 4 (continued) Be careful when interpreting elevated Cr. Cr and GFR are normal with advanced age Treatment: Withdraw nephrotoxic agents Case 5 Acute Interstitial Nephritis 35 yo female with dysuria. Given ampicillin for UTI. Has a skin rash and fever. BUN 75, Cr 5. Lots of RBCs in urine but no casts. Diagnosed with acute interstitial nephritis. Presence of RBCs but NO RBC casts indicates the cells did not pass through the glomerulus. They must have entered directly through the glomerulus Next diagnostic step: Eosinophiluria Treatment: Withdrawal of ampicillin and prescribe oral or IV steroids Case 6 Acute tubular necrosis due to rhabdomyolysis Long shoreman with crush injury. BP 90 / 70. Redfish