Evaluation of a child with glomerular disease DR :Abdulhadi Altalhi . Department of Pediatrics Nephrology,Children Hospital, King saud Medical City .

GO BACK TO BASICS Gross Anatomy of the Kidney STRUCTURE OF THE KIDNEY

Gross Anatomy of the Kidney

Cortical nephron Juxtamedullary nephron

Electron Micrographs Electron Micrographs Examine the electron Micrographs so that you understand the ultrastructural equivalents of the structures you have seen under the microscope. Vascular Arrangement in Glomeruli (SEM) View larger size Scanning electron micrograph of arterial blood supply to renal glomeruli (*). The afferent arterioles (aa) that supply the glomeruli (asterisk) receive blood from an interlobular artery (ia). Cormack, D.H. Ham's Histology, 9th ed., Lippincott, Philadelphia, 1987

And here we are We are now in Bowman’s space and here are all the capillaries.

Left click anywhere to proceed Now let’s wind up the magnification even further and look at the outside of one single capillary Bowman’s space Tufts of capillaries Left click anywhere to proceed

The next slide will be a scanning electron microscope picture of exactly this - at great magnification Tufts of capillaries

And this is what we would see The out side of all the capillaries are clothed in epithelial cells that have complicated interdigitating patterns that are traditionally called foot processes. Bowman’s space

The glomerular visceral epithelium consists of podocytes that have primary (1) extensions that branch to form secondary (2) processes from which the podocyte feet (pedicels) extend as side branches and contact the glomerular basement membrane. Arrows indicate interdigitating secondary processes of two neighboring podocytes (Inset). Cormack, D.H. Ham's Histology, 9th ed., Lippincott, Philadelphia, 1987, p. 578

And here is the endothelial cell lining of the blood capillary. Here again is the downstream side of the filter with the interlacing foot processes of the epithelial cells. Bowman’s space And here is the endothelial cell lining of the blood capillary. Look at the 3.5nm pores in the endothelial cell lining. These hold back the blood cell but allow plasma access to the basement membrane filter underneath.

Portion of glomerulus with three profiles of capillaries (C ) Portion of glomerulus with three profiles of capillaries (C ). Endothelial lining is highly fenestrated (F). Podocytes (P) extend primary processes (P1) that give rise to numerous foot processes (P2) which lie on the thick basement membrane (BM). Adjacent foot processes( aka pedicels),(separated by filtration slits (FS) are derived from different podocytes. The basement membrane is a product of both the endothelial cells and podocytes. Young, B & Heath, JW, Wheater's Functional Histology, 4th ed., Churchill Livingstone, London, 2000

INTRODUCTION  There are many causes of glomerular diseases in children. Many of these conditions vary in their presentation with mild or no symptoms to serious renal disease with life-threatening complications. As a result, the diagnosis of a specific glomerular disease is challenging in children but important so that therapy, if helpful and needed, can be initiated There are numerous causes of glomerular diseases in children. Many of these conditions vary in their presentation with mild or no symptoms to serious renal disease with life-threatening complications. As a result, the diagnosis of a specific glomerular disease is challenging in children but important so that therapy, if helpful and needed, can be initiated

OVERVIEW —  Glomerular disease either primary (renal disease alone) or secondary (due to systemic autoimmune disorders, vasculitis, or infection) disorders . Dividing childhood glomerular diseases into two clinical patterns is useful because the evaluation can focus on the most likely underlying disease. The identified primary pattern of glomerular disease: nephritic or nephrotic presentation.

Glomerular disease pattern The clinical manifestations, urinalysis,and the rate of protein excretion divide children with glomerular disease into two groups: patients with glomerulonephritis, and those with nephrotic syndrome. In both groups, renal function is assessed by measuring the serum creatinine.

Clinical features   Glomerulonephritis is characterized by edema, hypertension, reddish brown to brown colored urine, and a rising serum creatinine. Nephrotic syndrome usually present only with edema. In severe cases, nephrotic patients may have anasarca with ascites, and respiratory distress caused by pleural effusions. Patients with secondary causes of glomerular disease often have nonrenal symptoms and signs (eg, fever, arthralgias, rash, and pulmonary hemorrhage) that are suggestive of a specific underlying systemic disease.

Urinalysis Children with glomerulonephritis typically urinalysis findings include evidence of glomerular bleeding, such as red blood cells and red cell casts . Patients generally have proteinuria greater than 100 mg/m2 per day, when there is no gross hematuria.  Testing of the urine is the most important noninvasive test in determining whether or not a child has glomerular disease, and if present, distinguishes between the two patterns of glomerular disease. Children who have evidence of glomerular bleeding are likely to have glomerulonephritis, and those with heavy proteinuria are likely to have nephrotic syndrome. The following urinalysis findings, if present, are indicative of glomerular bleeding and glomerulonephritis. However, the absence of these findings does not exclude glomerulonephritis (table 2). Red cell casts (pathognomonic for glomerular bleeding) (picture 1) Red blood cells that are dysmorphic in appearance (picture 2A-B) Protein excretion greater than 100 mg/m2 per day at a time when there is no gross bleeding In contrast, the urinalysis of children with nephrotic syndrome is associated with heavy proteinuria and lipiduria but few cells or cast. Although the urinary dipstick measurement is a qualitative test, a 4+ recording, which corresponds to a concentration of urinary albumin of 1000 mg/dL, is suggestive of nephrotic range proteinuria, defined as a urinary protein excretion greater than 50 mg/kg per day or 40 mg/m2 per hour

Differential diagnosis: other diseases which may present with acute nephritic syndrome.

Presenting clinical features of paedriatric glomerular diseases that may mimic APSGN *Some of these values are estimates, as good epidemiological data are not published. **Incidence depends upon the histological class lupus nephritis. ***A small number of cases presenting early in the clinical course of the disease may have very transiently depressed C4 levels. APSGN, acute post-streptococcal glomerulonephritis; MPGN, membranoproliferative (mesangiocapillary) glomerulonephritis; SLE, Systemic lupus erythematosus; ANCA, anti-neutrophil cytoplasmic antibody; ASOT, antistreptolysin-O titre; ANA, antinuclear antibody; Anti-dsDNA, anti-double-stranded DNA. APSGN Henoch-Schonlein purpura IgA nephropathy MPGN SLE ANCA-positive vasculitis Mean age (years) 5-15 4-14 10-20 8-20 15-20 12-20 Antecedent Infection Yes 35% Concurrent Common Rare Flu-like prodrome Gross Haematuria 30% 20% 50-80% 20-50% <10% Nephrotic Syndrome* 5% 5-10% 30-50% 0-50%** Serum C3 Low Normal Serum C4 Normal*** Normal/low Diagnostic Serology ASOT; streptozyme No ANA,anti- dsDNA ANCA Extra renal disease

PATTERNS OF CHANGE

Biopsy Pathology of Glomerular Disease Patterns of glomerular damage

Pathological features of glomerulonephritis Descriptive Terms Patterns of Damage - 1 One Glomerulus compared with another All glomeruli normal = No glomerulonephritis All glomeruli abnormal = diffuse glomerulonephritis Some glomeruli abnormal = focal glomerulonephritis (often secondary to systemic disease)

Pathological features of glomerulonephritis Within a single glomerulus Descriptive Terms Patterns of Damage - 2 Within a single glomerulus Normal = No glomerulonephritis Damage to part of glomerulus only = segmental glomerulonephritis Damage to all parts = global glomerulonephritis

Pathological features of glomerulonephritis Within a single glomerulus Descriptive Terms Patterns of Damage - 2 Within a single glomerulus There is one further pattern of damage within a single glomerulus that is important because it: 1. Signifies very bad news 2. Picks out a particular group of patients under the collective title of Left click to reveal

Pathological features of glomerulonephritis Descriptive Terms Patterns of Damage - 2 Within a single glomerulus There is one further pattern of damage within a single glomerulus that is important because it: 1. Signifies very bad news 2. Picks out a particular group of patients under the collective title of Rapidly Progressive Glomerulonephritis Rapidly Progressive Glomerulonephritis is uncommon but very serious. Click here to learn more about it

Press here for one slide about Goodpasture’s disease Pathological features of glomerulonephritis Descriptive Terms Rapidly Progressive Glomerulonephritis Causes: 1. Bad end of the spectrum of many mechanism but especially - Anti-basement membrane disease inluding Goodpasture’s disease Press here for one slide about Goodpasture’s disease Otherwise left click in here

Left click to proceed Goodpasture’s Disease Clinical features: 1. Rapidly Progressive Renal Failure 2. Haematuria 3. Haemoptysis Pathological features: 1. (Cresentic Glomerulonephritis) 2. Deposition of linear IgG and IgM along basement membranes. Cause: Specific auto immune immunoglobulin attack on basement membrane’s of 1. Capillaries of the glomeruli in the kidneys and 2. Capillaries in the lung. Left click to proceed

LIGHT MICROSCOPY

Pathology of Glomerular Disease Welcome to a mini-unit on Light microscopy This section describes the central basis for the pathological classification of Glomerulonephritis The way in is to start with the normal components of the Human Glomerulus Left click to proceed Left click to proceed

Normal Components of the Human Glomerulus Stuff = non-cellular material Cells Normally present Normally present Glomerular Basement Membrane Endothelial cells Epithelial cells Mesangial cells

A picture of a normal human glomerulus against which to compare the various diseases. Tufts of capillaries Tufts of capillaries Bowman’s Space Thin basement membranes Afferent arteriole Nuclei of glomerular cells

What can change in disease ? Too many cells = proliferation Stuff (= non-cellular material) Normally present Normally present Endothelial cells Capillary Basement Membrane Epithelial cells Mesangium = stalk Thickening of the basement membrane Too many cells = proliferation Mesangial cells First let’s look at changes the previously normal components. Now click to see changes in normal non-cellular stuff. . Click to see changes in resident normal cells

What can change in disease ? Too many cells = proliferation Stuff (= non-cellular material) Normally present Normally present Endothelial cells Capillary Basement Membrane Epithelial cells Mesangium = stalk Thickening of the basement membrane Too many cells = proliferation Mesangial cells Now we will look at abnormal components that can appear in disease. .

What can change in disease ? Too many cells = proliferation Stuff (= non-cellular material) Normally present Normally present Endothelial cells Capillary Basement Membrane Epithelial cells Mesangium = stalk Thickening of the basement membranes Too many cells = proliferation Mesangial cells Only present when abnormal Amyloid Collagen scars (glomerulosclerosis) Myeloma protein Diabetic deposits Deposits Fibrin Inflammatory cells Too many cells = inflammation. But still called “proliferation” Now left click to see abnormal non-cellular stuff. Left first click to see abnormal cells.

HISTOLOGICAL NAMES USED IN GLOMERULONEPHRITIS What is this called? Proliferative glomerulonephritis Too many cells = Left click anywhere to find out

HISTOLOGICAL NAMES USED IN GLOMERULONEPHRITIS What is this called? Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Left click anywhere to find out

HISTOLOGICAL NAMES USED IN GLOMERULONEPHRITIS What is this called? Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Have a guess. It’s easier than you think Left click anywhere to find out

HISTOLOGICAL NAMES USED IN GLOMERULONEPHRITIS What is this called? Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Nephrotic syndrome but thickening of basement membranes = Minimal Change glomerulonephritis Left click anywhere to find out

HISTOLOGICAL NAMES USED IN GLOMERULONEPHRITIS What is this called? Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Nephrotic syndrome but thickening of basement membranes = Minimal Change glomerulonephritis Collagen scars in some glomeruli = Focal Glomerulosclerosis Left click anywhere to find out

Click in each box in turn to explore each type in turn HISTOLOGICAL NAMES USED IN PRIMARY GLOMERULONEPHRITIS Click in each box in turn to explore each type in turn Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Nephrotic syndrome but thickening of basement membranes = Minimal Change glomerulonephritis Collagen scars in some glomeruli = Focal Glomerulosclerosis . SECONDARY GLOMERULONEPHRITIS

HISTOLOGICAL CLASSIFICATION OF GLOMERULAR DISEASE Proliferative glomerulonephritis (too many cells) Endothelial cells Diffuse Proliferative g/n Inflammatory cells Mesangio-proliferative g/n typical of Berger’s disease Mesangial cells Epithelial cells (as “Cresents” in Bowman’s space) Rapidly Progressive g/n

HISTOLOGICAL CLASSIFICATION OF GLOMERULAR DISEASE Proliferative glomerulonephritis (too many cells) Endothelial cells Diffuse Proliferative g/n Inflammatory cells Left click anywhere to see a picture and to read about the clinical correlations of each Mesangio-proliferative g/n typical of Berger’s disease Mesangial cells Epithelial cells (as “Cresents” in Bowman’s space) Rapidly Progressive g/n

Click in each box in turn to explore each type in turn HISTOLOGICAL NAMES USED IN PRIMARY GLOMERULONEPHRITIS Click in each box in turn to explore each type in turn Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Neohrotic syndrome but thickening of basement membranes = Minimal Change glomerulonephritis Collagen scars in some glomeruli = Focal Glomerulosclerosis left click in here to return to “Pathology” page. SECONDARY GLOMERULONEPHRITIS

Click in each box in turn to explore each type in turn HISTOLOGICAL NAMES USED IN PRIMARY GLOMERULONEPHRITIS Click in each box in turn to explore each type in turn Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Neohrotic syndrome but thickening of basement membranes = Minimal Change glomerulonephritis Collagen scars in some glomeruli = Focal Glomerulosclerosis left click in here to return to “Pathology” page. SECONDARY GLOMERULONEPHRITIS

Click in each box in turn to explore each type in turn HISTOLOGICAL NAMES USED IN PRIMARY GLOMERULONEPHRITIS Click in each box in turn to explore each type in turn Proliferative glomerulonephritis Too many cells = Thickening of basement membranes = Membranous glomerulonephritis Increase number of cells and thickening of basement membranes = Membrano-proliferative glomerulonephritis Neohrotic syndrome but thickening of basement membranes = Minimal Change glomerulonephritis Collagen scars in some glomeruli = Focal Glomerulosclerosis left click in here to return to “Pathology” page. SECONDARY GLOMERULONEPHRITIS

Three types of Membrano-proliferative g/n Type 1 = Mesangiocapillary g/n Immune complex mediated Causes mostly unknown Some associated with infections, drugs, tumours, etc. Many associated with persistent C3 hypocomplementaemia Course = progressive deterioration Type 2 = Dense deposit disease Related to activation of the alternate complement pathway Dense deposits in basement membrane are not immune complexes Type 3 Rare Left click anywhere to return

Click within a box to find out more about each in turn ELECTRON MICROSCOPY Here I have selected for you the three topics that I think are most relevant. Of these the first section is by far the most important. Normal Appearances Changes with Proteinuria Immune Complex Disease Click within a box to find out more about each in turn Otherwise click in here to return to Pathology page