Nephrology Lecture 2: Glomerular Syndromes PDF

FACULTY of MEDICINE in ENGLISH LECTURE 2 GLOMERULAR SYNDROMES. GLOMERULOPATHIES Discipline: Internal medicine 2 - Nephrology Year of study: V Teacher: CIPRIAN STOICA, MD, PhD Date: 27th of November 2024...

FACULTY of MEDICINE in ENGLISH LECTURE 2 GLOMERULAR SYNDROMES. GLOMERULOPATHIES Discipline: Internal medicine 2 - Nephrology Year of study: V Teacher: CIPRIAN STOICA, MD, PhD Date: 27th of November 2024 Pentru uz intern Este interzisă copierea și distribuirea neautorizată a acestui material.  At the end of this lecture, participants will be able to: - To recognize the main syndromes underlying glomerular diseases; - To identify the main glomerular diseases; - To understand what are the main investigations in the identification of glomerular diseases and what are the specific treatment. Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy GLOMERULUS Acute or chronic glomerulonephritis The Netter Collection of Medical Ilustrations: Urinary System, Volume 5, Anatomy of the Urinary Tract Elsevier, Second Edition, 2012. HRON Long-looped nephron Short-looped nephron Fibrous capsule 0,000 to 1,400,000 Superficial glomerulus which contain a lar zone Subcapsu ents that alter the. The major seg- Proximal convoluted tubule s the glomerulus, ule, and collecting Distal Distal convoluted tubule Renal cortex are both divided convoluted ile the thin limb is Diabetes mellitus tubule Proximal straight tubule g parts. Juxtamedullary glomerulus ent nephron seg- sible zones in the Henle’s loop ulla. The medulla Proximal convoluted is further subdi- tubule nd an inner zone. Thick ascending limb ons are marked by (distal straight tubule) nt nephron seg- Proximal straight Outer stripe tubule Outer zone Thick Descending thin limb s at the interface ascending stripe Inner hich are arranged limb Henle’s of the nephron, loop owman’s capsule. man’s capsule are Collecting duct renal corpuscle). Renal medulla (pyramid) asses through the on–protein bound Descending ded by Bowman’s thin limb Systemic lupus to form primitive d away from the Ascending Rheumatoid Glomerular capillaries and Bowman’s capsule rteriole. erythematosus itive urine to the wn as the proximal thin limb arthritis Afferent and efferent glomerular arterioles Inner zone y tortuous course The proximal con- Proximal convoluted tubule proximal straight Proximal straight tubule op of Henle. Henle’s loop Thin limb le, each nephron Increased permeability hairpin turn, and arent glomerulus. Opening of papillary Thick ascending limb (distal straight tubule) of glomerular capillaries wn as the loop of raight tubule, thin duct Distal convoluted tubule Macula densa to plasma proteins commonly known ibed above, origi- Collecting ducts sis Multiple e border between outer zone of the Sickle cell Cribriform area of renal papilla Solid and myeloma st part of the thin imb. this point it transitions to the thick ascending limb, which courses back toward the cortex. anemia liquid tumors where it transitions to the distal convoluted tubule. Near this transition point is a specialized group of cells p of Henle differs Thus, based on the above descriptions, two different known as the macula densa, which make direct contact s parent glomeru- populations of nephrons can be distinguished: short- with the nephron’s parent glomerulus. omeruli in more looped nephrons, which are associated with superficial The distal convoluted tubule, like the proximal con- x, the descending e border between and midcortical glomeruli, and long-looped nephrons, which are associated with juxtamedullary glomeruli. NSAIDs voluted tubule, takes a very tortuous course within a small area of the cortex. It transitions to a short con-  The Netter Collection of Medical Ilustrations: Urinary System, Volume 5, Elsevier, Second Edition, 2012. A glomerulus consists of a cluster of capillaries seated within umatoid Bowman’s capsula in the urinary ritis space. Blood flows in, via the afferent arteriole and exits via the efferent arteriole. Filtrate leaves Increased permeability Bowman’s space and moves into of glomerular capillaries the proximal tubule. to plasma proteins d and d tumors 4  The Netter Collection of Medical Ilustrations: Urinary System, Volume 5, Elsevier, Second Edition, 2012. Bowman's capsule has two types of epithelia. Between the parietal epithelium and the visceral umatoid epithelium is the urinary space, ritis where the glomerular ultrafiltrate (primitive urine) is collected. Increased permeability of glomerular capillaries to plasma proteins d and d tumors 5  Anatomy of the Urinary Tract The Netter Collection of Medical Ilustrations: Urinary System, Volume 5, Elsevier, Second Edition, 2012. ELECTRON MICROSCOPY OF THE GLOMERULUS Parietal epithelial cell Bowman’s space The mesangium is the Capillary lumen central structure Podocyte (visceral epithelial cell) between the capillary Endothelial cell loops that ensures the Mesangial cells and matrix mechanical support of Podocyte (visceral epithelial cell) the capillary loops. It Endothelial cell consists of the mesangial Mesangial cell matrix (collagen fibers Afferent arteriole and glycosaminoglycans) Efferent arteriole and cells. Granular cell Macula densa ! 1100 cells are embed- ontains collagen, Mitochondria Podocyte ecules. In histo- e or two mesan- Bowman’s space 6 rix area, with a ogic states.  Anatomy of the Urinary Tract STRUCTURE AND HISTOLOGY OF THE GLOMERULUS Afferent arteriole Basement membrane Endothelium Glomerular basement membrane Parietal epithelial cell Bowman’s capsule The glomerular filtration Basement membrane Endothelium Visceral epithelial cell (podocyte) barrier consists of the Smooth Granular cells Bowman’s fenestrated endothelium muscle space (lamina fenestrata), the Endothelial fenestrations GBM (lamina densa) and podocytes (lamina rara). The glomerular filtration barrier has high permeability to water Proximal and solvents. It is one of Thick ascending tubule the most permeable limb membranes in the body. Macula densa Extra- glomerular The Netter Collection of Medical Ilustrations: At the same time, it is mesangium Urinary System, Volume 5, Elsevier, selective. onsists of the Efferent Second Edition, 2012. Mesangial matrix and cell -lined sac that arteriole as Bowman’s rom the affer- rteriole. They Parietal epithelial cell ameter, which ngial cells and Lumen of capillary loop llaries contain ts of endothe- Bowman’s space Afferent arteriole 6 SECTION I Essential Renal Anatomy and Physiology Glomerular Filtration Barrier R.J.Johnson, J.Floege,M.Tone Cl− Podocytes attach to the GBM lli. Actin Comprehensive NSCC clinical by foot processes via N M Ca2+ nephrology, AT1 Elsevier S PC adhesion molecules, such as publishing Ang II house, 7th TRPC6 Ez Podocin edition, 2023. Ca2+ Z U Cas FAK α3β1 integrines and α&β ILK dystroglycans. CD Cat TPV TPV α-Actinin 4 Nephrin NEPH 1-3 β α β1 α3 WARNING!!! (Anchoring to Laminin 11 P-Cadherin FAT1 Dystroglycan Integrin the GBM is important for the Agrin COLLAGEN IV (α3, α4, α5) selectivity of the glomerular Capillary Capillary filtration barrier. endothelium endothelium Fig. 1.9 Glomerular Filtration Barrier. Two podocyte foot processes bridged by the slit membrane, the glomerular basement membrane (GBM), and the porous capillary endothelium are shown. The surfaces of podocytes and of the endothelium are covered by a negatively charged glycocalyx containing the sialoprotein podocalyxin (PC). The GBM is mainly composed of type IV collagen (α3, α4, and α5), laminin 11 (α5, β2, and γ1 chains), and the heparan sulfate proteoglycan agrin. The slit membrane represents a porous proteinaceous membrane composed of (as far as is known) nephrin, NEPH 1-3, P-cadherin, and FAT1. The actin-based cytoskeleton of the foot processes connects to both the GBM and the slit membrane. Regarding the connec- tions to the GBM, β1α3 integrin dimers specically interconnect the TPV complex (talin, paxillin, vinculin) to laminin 11; the β- and α-dystroglycans interconnect utrophin to agrin. The slit membrane proteins are joined to the cytoskeleton by various adapter proteins, including podocin, zonula occludens protein 1 (ZO-1; Z), CD2-associated protein (CD), and catenins (Cat). Among the nonselective cation channels (NSCC), TRPC6 associates with podocin (and nephrin, not shown) at the slit membrane. Only the angiotensin II (Ang II) type 1 receptor (AT1) is shown as an example of the many surface receptors. Cas, p130Cas; Ez, ezrin; FAK, focal adhesion kinase; ILK, integrin-linked kinase; M, myosin; N, Na+-H+ exchanger regulatory factor (NHERF2); S, synaptopodin. (Modied from Endlich KH, Kriz W, Witzgall R. Update in podocyte biology. Curr Opin Nephrol  Urinary System: VOLUME 5 PATHOPHYSIOLOGY OF NThere areSseveral EPHROTIC YNDROME morphological types of podocyte response to injury. First of all, the deletion of the pediculated processes is an active adaptive modification of the Glomerular protein cell shape, which has as substrate permeability the reorganization of the actin increased skeleton. Second, apoptosis, Increased tubula necrosis, and detachment of sodium and wate podocytes denude the basement reabsorption membrane and initiate (”overfilling The Netter Collection of Medical Ilustrations: Urinary System, Volume 5, Elsevier, Second glomerolosclerosis. Proteinuriahypothesis”) is Edition, 2012. the consequence of podocyte lesions. Proteinuria Increased proximal tubule protein catabolism  Glomerular diseases Some glomerulopathies can have proliferative lesions (inflammatory infiltrate or Terminology increase in the number of cells and are called glomerulonephritis) The lesions mainly affect the renal glomerulus, hence the term glomerulopathies. others have non- proliferative lesions and are called glomerular nephropathies. 10  Glomerular diseases Podocytes are principally involved in glomerular diseases (glomerular nephropathies) that present as the nephrotic syndrome, where Depending on the proteinuria is often heavy predominantly affected compartment, in glomerular diseases, the clinical evolution can be different. Endothelial and mesangial cells are principally involved in glomerular diseases presenting as nephritis (glomerulonephritis), where haematuria, proteinuria and hypertension are present. 11 Clinical classification of glomerular disease Nephrotic syndrome Podocyte malfunction or injury is often causative. Nephritic syndrome Acute glomerulonephritis Rapidly progressive glomerulonephritis Mixed nephritic/nephrotic syndrome 12  Investigations Positive findings Urine microscopy Red blood cells, red blood cell casts Urinary protein Nephrotic or sub-nephrotic-range proteinuria Serum urea May be elevated Serum creatinine May be elevated Culture (throat swab, discharge from Nephritogenic organism Investigation of ear, swab from inflamed skin) Antistreptolysin-O titre glomerular Elevated in post-streptococcal diseases nephritis C3 and C4 levels May be reduced Antinuclear antibody (ANA) Present in significant titre in systemic lupus erythematosus Antineutrophil cytoplasmic Positive in vasculitis antibody (ANCA) Anti-glomerular basement Positive in Goodpasture’s syndrome membrane (anti-GBM) Cryoglobulins Increased in cryoglobulinaemia Chest X-ray Cardiomegaly, pulmonary oedema Renal imaging Usually normal Kidney biopsy Any glomerulopathy !!! KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases  a percutaneous biopsy, bedside; however, select e approaches, including nsjugular biopsies. The 4. The site is sterilized and anesthetized. 5. The biopsy needle is cocked. The first twist retracts techniques include an For larger gauge needles, a scalpel may the cannula. The second twist retracts the stylet. sis, morbid obesity, soli- be used to make a small incision at the kin over the kidneys, and site of planned needle entry. most patients should be low under the abdomen. ngle of needle insertion. KIDNEY BIOPSY visualize the kidney and The Netter Collection d be targeted so that only of Medical Hydronephrosis, multiple Ilustrations neys may be seen, which : Urinary d should be considered System, Volume 5, is complete, the site is Absolute Elsevier, sterile fashion. The site Second tic, and a scalpel may be Edition, Contraindications: a of planned needle inser- ch consists of a spring- 2012. r stylet, is then cocked as edle is passed through the a, often using ultrasound 6. The biopsy needle is inserted. When the tip is in 7. Once proper positioning is confirmed, the tient is instructed to hold the renal parenchyma, the needle will be deflected actuator is depressed, causing the stylet and the actuator button is by the movement of the kidney during respiration. cannula to rapidly advance into the paren- cement of both the inner Proper positioning may also be confirmed using chyma. The needle is then withdrawn. e device’s predetermined ultrasound guidance. core is acquired as the he stylet. Two or three Uncooperative patient; sure an adequate sample. e cores can be assessed silver methenamine, and trichrome. Solitary hematoxylin and eosin, periodic acid–Schiff, Jones’ native kidney; system, perinephric space, or subcapsular space. Patients should thus be monitored for approximately 4 to 6 xamination. An adequate mum of 8 to 10 glomeruli. Uncontrolled severe hypertension; hours after the procedure, with vital signs, hemoglobin levels, and urine color noted. Some centers perform a COMPLICATIONS ed in normal saline to the in fixatives if the labora- Uncontrolled The main complications of a renal biopsy include sound a fewbleeding hours after diathesis. follow-up computed tomography (CT) scan or ultra- the biopsy. In the event of a athologist then examines bleeding, pain, damage/puncture of surrounding struc- major bleed, transfusions or therapeutic procedures opy, electron microscopy, tures (liver, spleen, bowel), and arteriovenous fistula (e.g., angioembolization or laparotomy) should be per- immunohistochemistry. formation. Bleeding is by far the most common com- formed as needed. In very rare cases, a renal biopsy ght microscopy include plication, and it can occur into the urine collecting results in kidney loss or death. EDICAL ILLUSTRATIONS 223 15  a percutaneous biopsy, bedside; however, select e approaches, including nsjugular biopsies. The 4. The site is sterilized and anesthetized. 5. The biopsy needle is cocked. The first twist retracts techniques include an For larger gauge needles, a scalpel may the cannula. The second twist retracts the stylet. sis, morbid obesity, soli- be used to make a small incision at the kin over the kidneys, and site of planned needle entry. most patients should be low under the abdomen. ngle of needle insertion. KIDNEY BIOPSY visualize the kidney and The Netter Collection d be targeted so that only of Medical Hydronephrosis, multiple Ilustrations neys may be seen, which : Urinary d should be considered System, Volume 5, is complete, the site is Relative Elsevier, sterile fashion. The site Second tic, and a scalpel may be Edition, Contraindications: a of planned needle inser- ch consists of a spring- 2012. r stylet, is then cocked as edle is passed through the a, often using ultrasound 6. The biopsy needle is inserted. When the tip is in 7. Once proper positioning is confirmed, the tient is instructed to hold the renal parenchyma, the needle will be deflected actuator is depressed, causing the stylet and the actuator button is by the movement of the kidney during respiration. cannula to rapidly advance into the paren- cement of both the inner Acute pyelonephritis; Proper positioning may also be confirmed using chyma. The needle is then withdrawn. e device’s predetermined ultrasound guidance. core is acquired as the he stylet. Two or three Perinephritic abscess; sure an adequate sample. hematoxylin and eosin, periodic acid–Schiff, Skin infection Jones’ over space, system, perinephric the biopsy site;space. Patients or subcapsular e cores can be assessed silver methenamine, and trichrome. should thus be monitored for approximately 4 to 6 xamination. An adequate mum of 8 to 10 glomeruli. Hydronephrosis; hours after the procedure, with vital signs, hemoglobin levels, and urine color noted. Some centers perform a COMPLICATIONS ed in normal saline to the in fixatives if the labora- The main complications of a renal biopsy include Multiple soundcysts; follow-up computed tomography (CT) scan or ultra- a few hours after the biopsy. In the event of a athologist then examines bleeding, pain, damage/puncture of surrounding struc- major bleed, transfusions or therapeutic procedures opy, electron microscopy, tures (liver, spleen, bowel), and arteriovenous Kidney fistula tumor; (e.g., angioembolization or laparotomy) should be per- immunohistochemistry. formation. Bleeding is by far the most common com- formed as needed. In very rare cases, a renal biopsy ght microscopy include Smallresults plication, and it can occur into the urine collecting hyperechoic kidneys; in kidney loss or death. EDICAL ILLUSTRATIONS Hypotension. 223 16 PSY: PROCEDURE Plate 10-8Plate 10-8 Therapeutics Ther RENAL BIOPSY: PROCEDURE RENAL BIOPSY: PROCEDURE low KIDNEY BIOPSY 3. Ultrasound is used to locate kidney and determine optimal site and dney angle of needle insertion. The needle tip should aim toward the Before biopsy pole so only cortical tissue is biopsied. Perform a coagulation screen; Give the patient a full RENAL B Rexplanation ENAL BIOPSY of IOPSY (Continued) what is1. Patient positioned (Continued) 1. Patient positioned prone in bed, with folded prone in bed, with folded pillow under abdomen. 2. Approximate location of and pillow 3. Ultrasound kidney 3. Ultrasound is used to loc is used to locateandkidney determine optimal s determine optimal siteangleand of needle insertion involved and obtain rejection, drug toxicity (especially from is under abdomen. 2.is Approximate determined location During determined by palpation calcineurin of kidney biopsy by palpation of bone structures. of bone structures. angle of needle insertion. needle The tip should aim to needle tip should aim toward polethe so only cortical tissu rejection, drug consent. toxicity and (especially 5. The biopsy needle is cocked. The first twist retracts inhibitors), BK virus the cannula. The second twist retracts the stylet. inhibitors), and BK virus routinely infection. take biopsies frominfection. Some calcineurin centers from Some centers also also transplanted kidneys at Ask the patient to biopsied. lie prone with a pole so only cortical tissue is biopsied. routinely take biopsies from transplanted kidneys at predetermined time points, even in the absence of overt predetermined time points,because dysfunction even in some the absence renalof overt may initially be disease hard pillow under the abdomen dysfunction clinically because some renal silent. disease may initially be clinically silent. Localize the kidney by ultrasound PROCEDURE PROCEDURE Inject local anaesthetic along the Before a patient undergoes a renal biopsy, anticoagula- tionundergoes Before a patient medications a renal The Netter Collection of Medical Ilustrations: should biopsy,beanticoagula- stopped, and bleeding risk Urinary System, Volume 5, Elsevier, Second biopsy track should be evaluated by obtaining tion medications should be stopped, and bleeding risk a prothrombin time, partial thromboplastin should be evaluated Edition, 2012. time, andtime, by obtaining a prothrombin platelet count. Any Instruct the patient to hold a breath bleeding diathesis partial thromboplastin time, and should be corrected, platelet count. Any if possible, before should bleeding diathesis the procedure. be corrected, if possible, when the biopsy is performed. Most patients can undergo a percutaneous biopsy, before the procedure. n Mostproper 7. Once which patients canisundergo performed positioning at thethe a percutaneous is confirmed, bedside; biopsy, however, select cted actuator which is patients depressed, is performed may require causing the alternate stylet at the bedside; however, andapproaches, select including on. cannula to open, rapidlylaparoscopic, advance into the and paren- transjugular biopsies. The 4. The site is sterilized and anesthetized. 5. The biopsy needle is cocked. The first twis patients chyma. may require isalternate approaches, including For larger gauge needles, a scalpel may the cannula. The first The twist second retracts twist retracts the g The needle then withdrawn. major indications open, laparoscopic, and transjugularfor these techniques biopsies. The 4. include The site isansterilized and anesthetized. 5. The biopsy needle is cocked. be used to make a small incision at the uncorrectable major indications for thesebleeding techniquesdiathesis, includemorbid an For larger obesity, be used to gauge needles, a scalpel may soli- make asite of small planned incision atneedle the entry. 17 the cannula. The second twist retracts the stylet. s’ perinephrictary system,uncorrectable kidney, bleeding space, infectionspace. diathesis, or subcapsular of the morbid skin over the kidneys, and obesity, Patients soli- tary kidney, failed percutaneous should thus be monitored infection of the skin attempts. for approximately over the 4 to 6 kidneys, and site of planned needle entry. hours after the procedure, For awith vital signs, hemoglobin percutaneous biopsy, most patients should be  a percutaneous biopsy, bedside; however, select e approaches, including nsjugular biopsies. The 4. The site is sterilized and anesthetized. 5. The biopsy needle is cocked. The first twist retracts techniques include an For larger gauge needles, a scalpel may the cannula. The second twist retracts the stylet. sis, morbid obesity, soli- be used to make a small incision at the kin over the kidneys, and site of planned needle entry. most patients should be low under the abdomen. ngle of needle insertion. KIDNEY BIOPSY visualize the kidney and The Netter Collection d be targeted so that only of Medical Hydronephrosis, multiple After biopsy Ilustrations neys may be seen, which : Urinary d should be considered Apply pressure dressing to the System, Volume 5, is complete, the site is sterile fashion. The biopsy site tic, and a scalpel may be site and ask the patient to Elsevier, Second rest in bed for 24 h. a of planned needle inser- ch consists of a spring- Edition, 2012. Maximize r stylet, is then cocked edle is passed through the as fluid intake to prevent a, often using ultrasound clot colic tient is instructed to hold 6. The biopsy needle is inserted. When the tip is in 7. Once proper positioning is confirmed, the the renal parenchyma, the needle will be deflected Macroscopic haematuria actuator is depressed, – up causing to 10% the stylet and Check the the actuator button is cement of both the inner pulse and blood pressure by the movement of the kidney during respiration. cannula to rapidly advance into the paren- Proper positioning may also be confirmed using Pain chyma. in theThe flank needle is then withdrawn. core is acquired as regularly e device’s predetermined ultrasound guidance. the Perirenal haematoma Advise he stylet. Two or three sure an adequate sample. the patient hematoxylin to avoid and eosin, heavy periodic acid–Schiff, Jones’ Arteriovenous aneurysm formation system, perinephric space, or subcapsular space. Patients e cores can be assessed silver methenamine, and trichrome. should thus be monitored for approximately 4 to 6 lifting or gardening for 2 weeks. xamination. An adequate Profuse haematuria demanding blood hours after the procedure, with vital signs, hemoglobin mum of 8 to 10 glomeruli. levels, and urine color noted. Some centers perform a COMPLICATIONS ed in normal saline to the in fixatives if the labora- The main complications of a renal biopsy include transfusion or occlusion of the bleeding follow-up computed tomography (CT) scan or ultra- sound a few hours after the biopsy. In the event of a bleeding, pain, damage/puncture of surrounding struc- major bleed, transfusions or therapeutic procedures athologist then examines opy, electron microscopy, tures (liver, spleen, bowel), and arteriovenous fistula vessel at angiography or nephrectomy (e.g., angioembolization or laparotomy) should be per- formation. Bleeding is by far the most common com- formed as needed. In very rare cases, a renal biopsy immunohistochemistry. ght microscopy include Complications plication, and it can occur into the urine collecting (approximately 1 in 400) results in kidney loss or death. EDICAL ILLUSTRATIONS Infection 223 Mortality rate of about 0.1% 18  Proteinuria 150 mg to 3 g per day sis Hematuria >2 red blood cells itis Hematuria >2fieldredinblood per high-power spuncells urine per high-power field 6 in spun urine or >10 × 10 6cells/liter NEPHROTIC SYNDROME or >10 ×of10the The substrate cells/liter nephrotic syndrome is (red (redblood theblood cells usually cells usually increase dysmorphic) in thedysmorphic) permeability of the The Netter Collection of glomerular filtration membrane, Rheumatoid Medical Ilustrations: determined by podocyte injury - arthritis Urinary System, Volume 5, effacement of podocyte processes, Increased permeability Elsevier, Second apoptosis, necrosis, detachment. Macroscopic Macroscopichematuria hematuria Nephrotic Nephrotic syndrome Edition, 2012. of glomerular capillaries to plasma proteins olid and Brown/redpainless painlesshematuria hematuria Proteinuria:adult >3.5 g/day; adult >3.5 g/day; quid tumors Brown/red Proteinuria: 2 eroin abuse (no(noclots); clots);typically typicallycoincides coincides with with Positive >40mg/h child>40 child mg/h per per mm 2 diagnosis intercurrent infection intercurrent infection Hypoalbuminemia