Jack DeRuiter, PhD Dept of Pharmacal Sciences April, 2000 RENAL DISEASE: Overview of Kidney Structure and Function Pathophysiology of Disease: Chapter 16 (382-404) Jack DeRuiter, PhD Dept of Pharmacal Sciences April, 2000

Introduction (page 382) Renal Disease: General Characteristics: Early Renal Disease: Abnormal urine volume and/or composition (electrolyes, proteins, cells) Advanced: Edema, electrolyte abnormalities, anemia, etc. Rate of Progression: Disease-dependent Disease Course: Transient-fatal: Disease-dependent Pain: Variable, depending on nature of disease Renal Disease prominent in: Diabetes Mellitus Hypertension Autoimmune disorders (SLE)

KIDNEY STRUCTURE AND FUNCTION GROSS ANATOMY OF THE KIDNEY: (Page 382): Location: Retroperitoneal Blood flow: Renal Artery and Renal Vein Flow from cortex to medulla Medulla has relatively low blood flow and high metabolism; thus particularly susceptible to ischemic injury Cardiac Output: 25% Function: Filter wastes from blood Regulate electrolytes and intravascular volume Modulation of other hormones/regulators Anatomic/Functional Unit: Nephron

Anatomical Location and Gross Structure

Kidney: Blood Supply/Ureter

Kidney: Cross-Section

THE NEPHRON (pages 382, 384) Glomerulus Renal Tubule Afferent and Efferent arteriole with intervening capillary tuft Blood filtration site Renal Tubule Proximal Convoluted Tubule Loop of Henle: Consists of descending, thin and thick ascending limbs Distal Convoluted tubule Collecting Ducts

NEPHRON: Overview 1: Interlobular artery 2: Interlobular Vein 3: Glomerulus/Bowman’s Capsule 4. Distal Tubule 5. Proximal Tubule 6: Loop of Henle 7: Collecting Duct

Cortical and Medullary Nephrons Cortical nephrons: 85% -peritubular capillaries encirling all nephron sections Juxtamedullary nephrons: 15% -some peritubular capillaries and vascular loops (vasa recta) which surround loop of Henle which descend into medulla

Glomerulus Structure Summary (pages 382-385) Afferent and Efferent Arterioles Juxtaglomerular apparatus Capillary bed: Endothelial Cells: Fenestrated/negatively charged Epithelial Cells (“Podocytes”) Basement Membrane Mesangium: Intrinsic glomerular cells and macrophages

Glomerulus and Glomerular Capillary

Nephron: The Glomerulus (pages 382-384)

Glomerular Filtration (page 385) Rate (GFR): 120 mL/min (normal) Substances “Filtered”: water, electrolytes (Na, K, etc.), sugars (glucose), nitrogenous waste (urea, creatinine) Substances “Excluded”: Substances of size > 70 kDa Plasma protein bound substances

Tubular Resorption (page 385) Proximal Tubules: GF: 120-125 mL/min Reabsorption of Na (55%), Cl, phosphate, amino acids, glucose and bicarbonate (85%). Secretion of proton (CA) Loop of Henle: (30 mL/min) Na/K/2Cl Cotransporter (25% Na reabsorbed) Water impermeable: Hypertonic medullary inst Ca & Mg paracellular diffusion Distal Tubules: EDT: Na/Cl cotransporter; Ca/Na counter transport LDT: Na Channels, K channels, H pump: Aldosterone reg. Collecting Tubules: 5-10 mL/min Water channels: Vasopressin regulated Ureters: 1-2 mL/min (stored inbladder until voiding)

Summary of Tubular Resorptive Processes

Role of the Kidney: Overview The kidney excretes wastes, maintains fluid and electrolyte homeostasis, and is capable of responding to physiologic needs and variation by generating either a concentrated or dilute urine: Counter-current multiplier in the loop of Henle Hypertonic medulary interstitium Vassopressin and other hormones

Regulation of Renal Function (page 387) Tubuloglomerular feedback Medullary Vasoconstriction Medullary Vasodilation Inhibition of transport in the thick ascending limbs

Regulation of Renal Function (page 387) Tubuloglomerular Feedback: Regulation of GFR in response to solute concentration in the distal tubule: macula densa (PCT): Afferent arteriolar vasoconstriction in response to high tubular Na (Decr GFR) Juxtaglomerular apparatus (Afferent): Renin release and angiotensin II formation with low perfusion pressure (Aldosterone secretion and Na and water retention)

Regulation of Renal Function (page 387) Cortical Flow: Adequate to maintain GFR Medullary Blood Flow and Oxygen demand: Important for nephron cell survival and function (oxygen is required for ATP, used in trnasporters) Too high: Disruption of osmolar gradient of counter-current exchange mechanism Too low: hypoxic injury Modulators: Table 16-2 (page 387)

Regulation of Renal Function (page 387) Adaptive Changes: Glomerular hyperfiltration (increased GFR per nephron) nephron loss. ( may progress to chronic renal failure). Neural and Hormonal regulation: low perfusion results in afferent arteriolar vasodilation and efferent arteriolar vasconstriction Alteration in Na systemic balance Renal nerve (sympathetic)

The Kidney and Physiologic Regulation: Blood Pressure (pages 385-386) Macula Densa and Na concentration Juxtaglomerular Apparatus and Renin release and angiotensin II production Direct vasoconstriction Aldosterone Secretion: na and water rentention Vasopressin and intravascular volume depletion: Enhanced water resorption at the collecting ducts Morphologic: i.e. number of nephrons, etc.

The Kidney and Physiologic Regulation: Calcium Metabolism (page 386-387) Formation of the active form of vitamin D required for Ca absorption from gut, etc. Site of Parathyroid Hormone action: Ca retention and phosphate wasting (see earlier endocrine lectures)

The Kidney and Physiologic Regulation: Erythropoiesis (page 387) Erythropoietin stimulates bone marrow production and maturation of RBCs. Profound anemia in ESRD: hematocrits 20-25% Therapy: Erythropoietin administration