Nephrotic syndrome

Nephrotic Syndrome

1. Nephrotic Syndrome

2. Learning Outcomes Discuss the pathogenesis of Nephrotic Syndrome and correlate with the clinical presentation Identify the glomerular causes of nephrotic syndrome ; Primary glomerular diseases and systemic causes Discuss pathogenesis of the primary glomerular diseases presenting with nephrotic syndrome C ompare the morphologic changes of these glomerular disorders

3. Structure of Glomerulus

4. Normal Glomerulus W.B. Saunders Company items and derived items Copyright (c) 1999 by W.B. Saunders Company

5. Nephrotic Syndrome (NS) A clinical complex that includes: Massive proteinuria ( 3.5 gm/24hrs or more in adults) Hypoalbuminemia ( decreased plasma albumen) Generalized edema ( anasarca) Hyperlipidemia and lipiduria

6. Types of Proteinuria Selective glomerular proteinuria: Increased excretion of more than 300 mg medium-sized negatively charged proteins such as albumin in a 24-h urine collection, it indicates moderate glomerular damage e.g Minimal-change GN Membranous GN Membranoproliferative GN IgA-nephropathy EPH- gestosis Lupus nephritis with low activity Non-Selective Glomerular Proteinuria: Increased excretion of more than 3000 mg proteins of any size in a 24-h urine collection, it indicates severe glomerular damage e.g Focal segmental glomerulosclerosis Lupus nephritis EPH- gestosis Amyloidosis Microalbuminuria: Microalbuminuria is the presence of more than 30 mg and up 300 mg albumin in a 24-h urine collection . diabetes mellitus hypertension post-streptococcal glomerulonephritis

7. Nephrotic Syndrome Primary (most common)causes of NS Focal segmental glomerulosclerosis ( in adults) Minimal change disease in children ( common in children) Membranous nephropathy ( common in adults) - Membranoproliferative GN - IgA nephropathy Systemic (most frequent) causes of NS (seen in adults) - Diabetes mellitus - Amyloidosis - Systemic Lupus Erythematosus (SLE) Others causes Hypersensitivity reactions; drugs, bee stings, snake bite - Malignancy; carcinoma, myeloma - Pregnancy; toxemia of pregnancy

8. Incidence Most frequent cause of NS in children (1-7yrs) Etiology and p athogenesis Idiopathic majority of the cases Nephrin gene mutation T-cell derived factor, podocyte damage, effaced foot processes Clinical Slow onset of NS Some individuals present only with hematuria or proteinuria in the non-nephrotic range; others combined nephrotic-nephritic picture. Lab Selective proteinuria, normal blood complement levels Pathology LM: Glomeruli normal, epithelial cells of PCT show protein droplets and lipids, secondary to tubular reabsorption of the lipoproteins (Lipoid Nephrosis) EM: Diffuse effacement of foot processes, microvilli, GBM appears normal IFM: No findings Prognosis More than 90% respond to corticosteroid therapy, may r ecur, 5% progress to chronic kidney disease Minimal Change Disease

9. Minimal Change Disease The three hallmarks of MCD

10. Incidence Common c ause of NS in adults (30-50 years) Etiology and p athogenesis Primary (85%) Idiopathic Secondary (15%); Infections (HBV, malaria), Carcinoma (Lung, colon), SLE, heavy metals ( Gold), Drugs ( penicillamine , NSAID’s) Immune deposits and direct action of MAC activate mesangial cells and podocytes to liberate proteases and oxidants, damages capillary walls which become leaky Clinical Nephrotic syndrome Lab Non-selective proteinuria Pathology LM: Subepithelial IgG-containing deposits along GBM, diffuse thickening of capillary wall EM: Subepithelial deposits separated by small spike of GBM matrix "spike and dome” pattern, later spikes close over the deposits to form thick GBM and effacement of foot processes IFM: Granular deposits of IgG and C3 along GBM Prognosis Less response to corticosteroids, 40% progress to glomerular sclerosis and CRF Membranous Glomerulonephritis

11. Membranous GN

12. Incidence Children and young adults (5-25 years) Etiology and pathogenesis Type I; immune complexes deposit and is associated with classical complement pathway . Type II; m ostly associated with dysregulation of alternative complement pathway. Other a ssociations with; chronic infections, SLE, Cancer, cirrhosis, heroin abuse Clinical Nephrotic Syndrome in 50%, acute Nephritic Syndrome in 20% Resent history of URI in 50%, hypertension or renal insufficiency Lab Hypocomplementemia of classic and alternative pathways, C3 nephritic factor (C3NEF), Circulating immune complexes, Non-selective proteinuria Pathology LM: Diffuse proliferative GN, Large Glomeruli with lobular appearance, Thick capillary wall and GBM splitting ( Tram-Track), Mesangial proliferation, leucocyte infiltrate EM: Type I: sub-endothelial deposits, Type II: dense-deposit disease (within GBM) IF: Type I: Granular IgG and C3 deposits along GBM and C1q &C4 often present , Type II: C3 only present in irregular chunky and segmental linear foci in BM, IgG usually absent Prognosis Progressive loss of renal functions, , ESRD within 10 years in 50% of children and 80% of adults Membranoproliferative Glomerulonephritis

13. Membranoproliferative GN MPGN shows intramembranous deposits which leads to "splitting" of the GBM

14. Incidence NS in children and adolescents, leading cause of RF in adults Etiology and p athogenesis Primary; 20-30% of all cases of NS. Idiopathic , may be transformation from MCD, p odocytes injury , entrapment of plasma proteins and lipids, form hyaline masses followed by sclerosis Secondary ; HIV infection or heroin abuse, IgA nephropathy, m utations affecting nephrin , and d iabetic nephropathy Clinical Nephrotic syndrome, RF may be present at the onset Lab Foamy urine due to selective proteinuria, deranged RFTs Pathology LM: Sclerosis affecting some glomeruli (focal) and involves only part of each affected glomerulus (segmental), increased mesangial matrix, obliterated capillary lumens, deposition of hyaline masses and lipid droplets, progress to global sclerosis, tubular atrophy and interstitial fibrosis EM: Effaced foot processes IFM: IgM and C3 in hyalinized areas Prognosis 50% progress to CRF, 20-40% r ecurrence in transplant , Collapsing Variant; may be associated with HIV - worse prognosis Focal Segmental Glomerulosclerosis (FSGS)

15. Focal Segmental Glomerulosclerosis Focal and segmental deposits of IgM and C3

16. Incidence Common, u sually affects children and young adults Etiology and p athogenesis Suggested that increased IgA synthesis in response to respiratory or exposure of GIT to environmental agents (e.g., viruses, bacteria, food proteins) may lead to deposition of IgA and IgA-containing immune complexes in the mesangium , where they activate alternative complement pathway and initiate glomerular injury Clinical Begins as an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper respiratory tract infection Nephrotic syndrome may develop occasionally Lab Blood in urine and mild proteinuria Pathology LM : glomeruli may be normal or may show mesangial widening and segmental inflammation EM : electron-dense deposits in mesangium IFM : mesangial deposition of IgA, often with C3 Prognosis Slow progression to CRF occurs in 25-50% of cases over a period of 20 years IgA Nephropathy

17. IgA nephropathy

18. Self-Assignment Q1. Name the commonest glomerular lesion which can cause nephrotic syndrome in adult and in children.

19. References Basic Pathology, 10 th Edition 2017; Kumar, Abbas, Aster www.web Path.com.