URINARY SYSTEM PATHOLOGY Glomerulonephritis DR: NAWAL ALMOHAMMADI CLINICAL PHARMA STUDENTS 2015

Normal structure of the glomerulus

Low-power electron micrograph of rat glomerulus

The renal biopsy Glomeruli – Glomerulonephritis Renal tubules and Interstitium – Acute tubular necrosis – Acute interstitial nephritis – Chronic tubulointerstitial nephritis Vasculature – Nephrosclerosis – Renal artery sclerosis

The renal biopsy

Terms… Azotemia: is an elevation of blood urea nitrogen and creatinine levels and usually reflects a decreased glomerular filtration rate (GFR). - Prerenal azotemia - Postrenal azotemia Uremia: is azotemia associated with clinical manifestations and systemic biochemical abnormalities Hematuria: red blood cells and red cell casts in urine Proteinuria: albumin in the urine Lipiduria: lipid in the urine

The clinical manifestations of renal disease Nephritic syndrome: - acute onset grossly visible hematuria - mild proteinuria -azotemia -Edema -Hypertension Nephrotic syndrome -heavy proteinuria (excretion of greater than 3.5 g of protein/day in adults) -Hypoalbuminemia -severe edema - hyperlipidemia, and lipiduria

The clinical manifestations of renal disease Asymptomatic hematuria or non-nephrotic proteinuria -is usually a manifestation of subtle or mild glomerular abnormalities. Rapidly progressive glomerulonephritis - associated with severe glomerular injury and results in loss of renal function in a few days or weeks. -microscopic hematuria, dysmorphic RBC,red cell casts in the urine sediment, proteinuria. Acute kidney injury is dominated by oliguria or anuria (no urine flow), and recent onset of azotemia. Chronic kidney disease, characterized by prolonged symptoms and signs of uremia.

The clinical manifestations of renal disease Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). -The infection may be symptomatic or asymptomatic, and it may affect the kidney (pyelonephritis) or the bladder (cystitis) only. Nephrolithiasis (renal stones) is manifested by renal colic, hematuria (without red cell casts), and recurrent stone formation.

Mechanisms of Glomerular Injury and Disease

Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy Granular, characteristic of circulating and in situ immune complex deposition Linear, characteristic of classic anti-glomerular basement membrane (anti-GBM) antibody glomerulonephritis.

Glomerular response to injury Increased cells (Hypercellularity) – Seen in “inflammatory diseases” – Proliferation of mesangial and endothelial cells – Inflammatory cells – Proliferation of epithelial cells +/- crescent formation Increased matrix / connective tissue (Hyalinization / Fibrosis) – Hyalinization = accumulation of pink homogenous material – Plasma protein/BM/Mesangial matrix – Eventually leads to Fibrosis Increased basement membrane – Thickened capillary loops – Increased BM / immune deposits

GLOMERULAR DISEASES Primary glomerulonephritis (GN). the kidney is the principal organ involved. Secondary glomerular disease the kidney is one of many organ systems damaged by a systemic disease.

Nephritic syndrome:  It is characterised by hematuria with red cell cast, decreased GFR, azotemia, oliguria and hypertension. proliferative inflammatory responses  It is provoked by group of diseases that produce proliferative inflammatory responses ( i.e. increase the cellular component of the glomeruli e.g. endothelium, podocytes and mesengial cells).  This inflammation leading to escape of RBCS and protein in urine.  There are two types : 1.Acute proliferative GN 2.Rapidly progressive GN

Acute proliferative GN Acute post-infectious glomerulonephritis Onset 1 – 4 weeks after upper respiratory / cutaneous infection with Group A  -haemolytic streptococci It is diffused proliferative injury caused by trapping of immuncomplex after infection with group A B-hemolytic streptococcai, staph. Infection, mumps, measles, or chicken box, HBV, HCV. The reaction leading to proliferation in the endothelial cells of the glomeruli with leukocyte infilteration and escaping of RBCs and protein. It occurs in children and young adult.

Post infectious / Diffuse proliferative GN Clinical manifestation: by hematuria with red cell cast (cola- like urine), decreased GFR (due to loss of protein), azotemia, oliguria, edema in face and hand due to Na and water retention (aldosterone secretion)and hypertension (renin release). Diagnosis: elevated anti-streptolysin O titer. The condition may resolved spontaneously especially in children.

Post infectious / Diffuse proliferative GN

Light microscopy (LM) Diffuse glomerular proliferation

Electron microscopy (EM) Sub epithelial deposits

Rapidly progressive (Crescentic) GN subacute GN It is subacute severe focal proliferative inflammation in the glomeruli with formation of crescent shaped structure that obliterating the Bawman’s capsule (These are produced in part by proliferation of the parietal epithelial cells of Bowman's capsule in response to injury and in part by infiltration of monocytes and macrophages). It is provoked by number of immunologic diseases e.g. SLE and Goodpasture’s syndrome (antibodies (IgG) formed against the basement membrane of the glomeruli and alveoli). it is characterized by rapid and progressive loss of renal function with features of the nephritic syndrome, often with severe oliguria and (if untreated) death from renal failure within weeks to months. Treatment: immunosuppresive drugs after plasma electrophoresis (to remove antibodies).

Light microscopy (LM) Cellular crescents of epithelium and inflammatory cells

Chronic Glomerulonephritis Slowly progressive diffused glomerular destruction (oblitration) from long standing GN. chronic GN develops insidiously and is discovered only late in its course, after the onset of renal insufficiency. It is characterized by polyuria or oliguria, proteinuria, hypertension, progressive azotemia and death from uremia. The kidneys become contracted with progressive destruction in all structures inside “end-stage kidney” Within 2-40 ys. Hemodialysis or renal transplantation may delay the rate of disease progression.

Nephrotic syndrome  It is the disease which affect the integrity of the glomerular capillary membrane that increased its permeability leading to massive loss of only protein in urine (>3.5 gm/day), hypoalbuminemia, generalized edema (termed anasarca) and hyperlipidemia (reflex increase in the lipoprotein synthesis by the liver) and lipiduria. N.B. At the onset there is little or no azotemia, hematuria, or hypertension. Etiology: 1.Primary (i.e. changes in the kidney): usually occur in children focal and segmental glomerulosclerosis (FSGS minimal-change disease (MCD). membranous nephropathy membranoproliferative GN 2. Secondary (i.e. Caused by systemic diseases) e.g. diabetes, amyloidosis, and SLE. It occur mainly in adults.

Minimal-Change Disease (Lipoid Nephrosis) Also called foot-process disease. (most common nephrotic syndrome in children). flattened podocyte foot processes is characterized by glomeruli that have a normal appearance by light microscopy but show diffuse flattened podocyte foot processes when viewed with the electron microscope without any evidence of immunologic reaction. Immunofluorescence (IF) – Normal (no immune deposits) Respond well to corticosteroides Respond well to corticosteroides Prognosis well.

Light microscopy (LM) – Normal

Electron microscopy (EM) – Fusion of podocyte foot processes

Focal and Segmental Glomerulosclerosis (FSGS) Idiopathic or secondary to: – Other glomerular disease (IgA) – Other renal disease (chronic reflux / pyelonephritis / interstitial nephritis) – Systemic disorder (HIV) – Drugs (Heroin) Characterised by: – Sclerosis of portions of some, not all glomeruli – Often progresses to chronic renal failure (CRF) – Recurs in 25-50% renal transplants

Light microscopy (LM) Focal segmental sclerosis

Membranous GN Commonest cause of nephrotic syndrome in adults Idiopathic (85%) or secondary (15%) to: – Neoplasms (lung, colon, melanoma) – Autoimmune disease (SLE, thyroiditis) – Infections (Hep B, syphilis, malaria) – Drugs (Penicillamine, gold) 40% progress to chronic renal failure (CRF) Pathogenesis – Sub epithelial immune deposits – Thickening of BM between deposits – eventually envelopes and covers the deposits

Membranous GN

Light microscopy (LM) Thickened capillary BM

Light microscopy (LM) BM spikes on silver stain

Immunofluorescence (IF) – diffuse granular GBM staining

Electron microscopy (EM) – subepithelial deposits

Membranoproliferative Glomerulonephritis It is characterized by both deposition of immune complex under the basement membrane with hyperproleferation of glomerular cells either primarily or secondary to other disease. The prognosis is bad “50% developed End-stage renal failure”. High recurrence rate in renal transplants

Light microscopy (LM) Mesangial proliferation Thickened capillary BM