Glomerulonephritis and nephrotic syndrome (1).pptx

Lecturer

1. Glomerulonephritis Nephrotic syndrome ARF mulualem N(MD,Pediatrician)

2. Introduction The kidneys lie in the retroperitoneal space slightly above the level of the umbilicus. They range in length and weight, respectively, from approximately 6 cm and 24 g in a full-term newborn to 12 cm or more and 150 g in an adult .

3. Anatomy & physiology The kidney has two layers Outer layer what we call the cortex, Containg the glomeruli, proximal and distal convoluted tubules, and collecting ducts Inner layer, the medulla, contains the straight portions of the tubules, the loops of Henle , the vasa recta, and the terminal collecting ducts .

4. CONT.. The blood supply to each kidney usually consists of a main renal artery that arises from the aorta. The main artery divides into segmental branches within the medulla and these into interlobar arteries that pass through the medulla to the junction of the cortex and medulla. At this point, the interlobar arteries branch to form the arcuate arteries, which run parallel to the surface of the kidney. Interlobular arteries originate from the arcuate arteries and give rise to the afferent arterioles of the glomeruli .

5. CONT The afferent arteriole divides into the glomerular capillary network, which then merges into the efferent arteriole. Each kidney contains approximately 1 million nephrons (glomeruli and associated tubules)

6. CONT The glomerular network of specialized capillaries serves as the filtering mechanism of the kidney. The glomerular capillaries are lined by endothelial cells and have very thin cytoplasm that contains many holes (fenestrations). The glomerular basement membrane (GBM) forms a continuous layer between the endothelial and mesangial cells on one side and the epithelial cells on the other .

7. GBM has 3 layers : 1) a central electron-dense lamina densa 2) the lamina rara interna ; which lies between the lamina densa and the endothelial cells . 3) the lamina rara externa ; which lies between the lamina densa and the epithelial cells. The visceral epithelial cells cover the capillary and project cytoplasmic “foot processes,” which attach to the lamina rara externa . Between the foot processes are spaces or filtration slits.

8. CONT The mesangium lies between the glomerular capillaries on the endothelial cell side of the GBM and forms the medial part of the capillary wall. The mesangium may serve as : - A supporting structure for the glomerular capillaries - H as a role in the regulation of glomerular blood flow -F iltration and in the removal of macromolecules

9. Bowman's capsule; which surrounds the glomerulus, is composed of :- 1) a basement membrane, which is continuous with the basement membranes of the glomerular capillaries and the proximal tubules 2) the parietal epithelial cells, which are continuous with the visceral epithelial cells .

10. Renal structure and function The glomerular capillaries filter 120–180 L/d of plasma water containing various solutes for reclamation or discharge by downstream tubules Most large proteins and all cells are excluded from filtration by a physicochemical barrier governed by pore size and negative electrostatic charge. The kidney has 3 basic function Excrete waste products of food metabolism Regulate mineral and H2O balance. Synthesis(EPO,Renin)

11. Renal Pathology A renal biopsy in the setting of glomerulonephritis can quickly identify the type of glomerular injury and often suggests a course of treatment. based on the histologic discription there are different types of glomerular injuries. Focal lesions: If <50 % of the glomeruli are involved is considered focal. Diffuse lesions: > 50 % of the glomeruli are involved. S egmental: Injury in each glomerular tuft involving a portion of the tuft. G lobal: involving most of the glomerulus .

12. T ype of glomerular injury Crescents: Develop when fibrocellular /fibrin collections fill all or part of Bowman's space Sclerotic glomeruli:- Show acellular , amorphous accumulations of proteinaceous material throughout the tuft with loss of functional capillaries and normal mesangium Mesangial : - I mmune deposits in the mesangial matrix Membranous : reduplication or splitting of the basement membrane.

13. Glomerulonephritis Glomerulonephritis is a term reserved for a variety of renal diseases which is characterized by inflammation of the glomerulus(proliferation of cellular elements) mostly secondary to an immunologic mechanism. When there is Glomerular injury: Impairment of selective filtering properties of the kidney leading to a decreased GFR Molecules normally not filtered such as constituents of the blood, pass into the urine and are excreted. 15

14. Classification Glomerulonephritis is amixture of clinical and pathological descriptions and classified based on defferent criteria. Based on Etiology 1. Primary - When major problem starts in the Glomerulus (minimal change disease, idiopathic membranous GN). 2. Secondary - when involvement is part of systemic disease, Metabolic Diseases, Hereditary Nephropathies , Neoplasms, Infections Based on mode 1. Inherited (alport syndrome,thin basment membrane disease) 2. Acquired ( Proliferative ,n on proliferative )

15. Based on mechanism(pathogenesis) Immune mediated( PSGN, Lupus nephritis,HSP,Mixed connective tissue disease,anti-GBM Anti Body Mediated glomerulonephritis} Pauciimmune or non immune mediated( Wegner’s granulomatosis,Polyarteritis Nodosa,Shurg Straus Syndrome) Based on Morphology(various histologic pattern) Based on clinical features( hematuria,protenuria,renal syndroms,acute renal failure,ESRD )

16. Acute nephritic syndrome Clinical correlate of acute glomerular inflammation characterized by s udden onset of hematuria, proteinuria and red blood cell casts in the urine, edema, and hypertension with or without oliguria. Acute Post Infectious GN - a prototype of acute nephritic syndrome with proliferative GN. 18

17. Acute poststreptococcal glomerulonephritis is one of the most common glomerular causes of gross hematuria in children, surpassed only by IgA nephropathy. A link between hemolytic streptococci and acute glomerulonephritis was recognized in the 20th century .

18. Pathophysiology Poststreptococcal glomerulonephritis follows infection with only certain strains of streptococci designated as nephritogenic . Acute poststreptococcal glomerulonephritis (APSGN) follows pyodermatitis with streptococci M types 47, 49, 55, 2, 60, and 57 and throat infection with streptococci M types 1, 2, 4, 3, 25, 49, and 12. ASPGN is believed to be an immune-mediated disease, in which an immune complex containing a streptococcal antigen is deposited in the affected glomeruli .

19. Pathology The kidneys appear symmetrically enlarged. All glomeruli appear enlarged and relatively bloodless and show diffuse mesangial cell proliferation with an increase in mesangial matrix . Polymorphonuclear leukocytes are common in glomeruli during the early stage of the disease.

20. Pathology Crescents and interstitial inflammation may be seen in severe cases. Immunofluorescence microscopy reveals lumpy-bumpy deposits of immunoglobulin and complement on the glomerular basement membrane (GBM) and in the mesangium . On electron microscopy, electron-dense deposits, or “humps,” are observed on the epithelial side of the GBM .

21. Clinical manifestations APSGN is most common in children aged 5–12 yr and is uncommon before the age of 3 yr. Recent history of pharyngitis, tonsillitis, or pyoderma . Latent period In general, the latent period is 1-2 weeks after a throat infection and 3-6 weeks after a skin infection. Clinically May be asymptomatic Might have sever symptoms Gross hematuria and/or edema represents the most common clinical presentation

22. Clinical manifestations Oliguria This is present in 10-50% of cases . Oliguria is indicative of the severe crescentic form of the disease. It is often transient, with diuresis occurring within 1-2 weeks. Hematuria caused by hemolysis of red blood cells that have penetrated the glomerular basement membrane and have passed into the tubular system is present universally, gross hematuria In 30% of cases

23. Clinical manifestations Hypertension occurs in 60-80% of cases and is more common among elderly individuals Hypertensive encephalopathy occurs in no more than 5-10% of patients Edema Edema is present in 80-90% of cases, and it is the presenting complaint in 60% of cases. Compromised intraglomerular blood flow due to glomerular hypercellularity results in progressive encroachment on the cross-sectional area of the glomerular capillaries.

24. Diagnosis A rising antibody titer to streptococcal antigen(s) confirms a recent streptococcal infection. (ASO) titer is commonly elevated after a pharyngeal infection. The best single antibody titer to document cutaneous streptococcal infection is the anti- deoxyribonuclease ( DNase ) B level. The Streptozyme test detects antibodies to streptolysin O, DNase B, hyaluronidase , streptokinase, and nicotinamide -adenine dinucleotidase using a slide agglutination test

25. Diagnosis S Urinalysis shows red blood cells (RBCs), RBC casts, proteinuria, and polymorphonuclear leukocytes. A mild normochromic anemia caused by hemodilution and low-grade hemolysis. The serum C3 level is usually reduced in the acute phase and returns to normal 6–8 wk after onset.

26. Diagnosis Renal biopsy should be considered only in the presence of acute renal failure, nephrotic syndrome, absence of evidence of streptococcal infection, or normal complement levels. In addition, renal biopsy is considered when hematuria and proteinuria, diminished renal function, and/or a low C3 level persist more than 2 mo after onset .

27. Diagnosis The clinical diagnosis of poststreptococcal glomerulonephritis is quite likely in a child presenting with acute nephritic syndrome, evidence of recent streptococcal infection, and a low C3 level.

28. Differential diagnosis IGA nephropathy Good pasture syndrome HSP Idiopathic rapidly progressive glomerulonephritis

29. Complications Acute complications result from hypertension and acute renal dysfunction. Hypertension is seen in 60% of patients and may be associated with hypertensive encephalopathy in 10% of cases. Other potential complications include heart failure, hyperkalemia, hyperphosphatemia , hypocalcemia , acidosis, seizures, and uremia.

30. TREATMENT Management is directed at treating the acute effects of renal insufficiency and hypertension . Although a 10-day course of systemic antibiotic therapy with penicillin is recommended to limit the spread of the nephritogenic organisms, antibiotic therapy does not affect the natural history of glomerulonephritis .

31. TREATMENT Treatment of hypertension Sodium restriction, diuresis with intravenous Lasix pharmacotherapy with calcium channel antagonists, vasodilators, or angiotensin-converting enzyme inhibitors.

32. PROGNOSIS. Complete recovery occurs in more than 95% of children with acute poststreptococcal glomerulonephritis. Hypertension Chronic Renal Disease (CRD) Recurrences are extremely rare(b/c of long-term persistence of antibodies to nephritis-associated streptococcal antigen )

33. Nephrotic Syndrome 35

34. introduction Nephrotic syndrome is primarily a pediatric disorder and is 15 times more common in children than adults. The incidence is 2-3/100,000 children per year; and the majority of affected children will have steroid-sensitive minimal change disease. The characteristic features of nephrotic syndrome are heavy protinuria (>3.5 g/24 hr in adults or 40 mg/m 2 /hr in children), hypoalbuminemia (<2.5 g/dL), edema, and hyperlipidemia 36

35. Classification Primary nephrotic syndrome   nephrotic syndrome in the absence of systemic disease . Secondary nephrotic syndrome   nephrotic syndrome associated with systemic diseases or secondary to another process that cause glomerular injury. 3 . Congental nephrotic syndrome 37

36. Etiology Most children (90%) with nephrotic syndrome have a form of the idiopathic nephrotic syndrome . Causes of idiopathic nephrotic syndrome include : minimal change disease (85 %), mesangial proliferation (5 %), focal segmental glomerulosclerosis (10 %). The remaining 10% of children with nephrotic syndrome have secondary nephrotic syndrome related to systemic or glomerular diseases such as membranous nephropathy or membranoproliferative glomerulonephritis. 38

37. Mechanism of protinuria Glomerular capillary wall consists of three components : the fenestrated endothelial cell; the glomerular basement membrane (GBM); and the epithelial cell foot processes. The pores between the foot processes are closed by a thin membrane called the slit diaphragm . 39

38. Mechanism of protinuria The filtration of macromolecules across the glomerular capillary wall is normally restricted by two mechanisms : charge-selectivity The endothelial cells and the GBM have a net negative charge due to polyanions such as heparan sulfate proteoglycans. This creates a charge barrier to the filtration of large anions such as albumin Size-selectivity at the GBM and at the slit diaphragms between the adjacent epithelial cell foot processes. 40

39. CONTD In minimal change disease, there is a loss of anionic charge that is not accompanied by any structural damage or change to the glomerular filtration unit observed by light microscopy, that results in protinuria. In non minimal nephrotic syndrome structural damage allows movement of normally restricted proteins of varying sizes (including large neutral proteins, such as IgG) across the filtration barrier . 41

40. Pathogenesis High glomerular permeability  hyperalbuminuria  hypoalbuminemia  low plasma colloid osmotic pressure  transcapillary filtration of water  edema. Urinary immunoglobulin losses lower the patient's resistance to infections and increase the risk of serious sepsis and peritonitis. The loss of antithrombin III and plasminogen via urine and the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X, increases the risk for arterial thrombosis, venous thrombosis, and pulmonary embolism, which occurs in 5% of children with nephrotic syndrome. 42

41. CONTD In the nephrotic state, levels of almost all serum lipids are elevated. Two pathogenic processes are operative : H ypoproteinemia stimulating generalized protein synthesis in the liver , including the lipoproteins . D iminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase 43

42. Idiopathic Nephrotic Syndrome Approximately 90% of children with nephrotic syndrome have idiopathic nephrotic syndrome. H istologic types : minimal change disease, mesangial proliferation, and focal segmental glomerulosclerosis. These 3 disorders may represent 3 separate diseases with a similar clinical presentation; alternately, these disorders may represent a spectrum of a single disease 44

43. Minimal change nephrotic syndrome 85% of total cases of nephrotic syndrome in children the glomeruli appear normal or show a minimal increase in mesangial cells and matrix. Electron microscopy simply reveals effacement of the epithelial cell foot processes. More than 95% of children with minimal change disease respond to corticosteroid therapy . 45

44. Mesangial proliferation 5% of total cases characterized by a diffuse increase in mesangial cells and matrix on light microscopy. Immunofluorescence microscopy may reveal trace to 1+ mesangial IgM and/or IgA staining. Electron microscopy reveals increased numbers of mesangial cells and matrix as well as effacement of the epithelial cell foot processes. Approximately 50% of patients with this histologic lesion respond to corticosteroid therapy. 46

45. Focal segmental glomerulosclerosis 10% of total cases, light microscopy -----mesangial proliferation and segmental scarring . Immunofluorescence microscopy shows IgM and C3 staining in the areas of segmental sclerosis. Electron microscopy shows segmental scarring of the glomerular tuft with obliteration of the glomerular capillary lumen. Only 20% of patients with FSGS respond to prednisone. progressive, ultimately involving all glomeruli , and leads to end-stage renal disease in most patients. 47

46. MCD FSGS Mesangial prolififeration Membraneus nephropathy MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS Prevalence(children) 85% 10% 5% 5% 10% Prevalence(adults) 15% 15% 50% 10% Light microscopy Normal Segmental scaring&mesangial prolifer Mesangial cells&matrix Thickened GBM, spikes Thickened GBM, proliferation immunoflouresence negetive IGM&c3 Trace- +1IGM%IGA Fine granular IgG, C3 Granular IgG, C3 Electron microscopy Effaced foot process Segmental scaring Mesangial cell,matrix,effaced foot process Subepithelial deposits Mesangial and subendothelial deposits Steroid responsivity 95% 20 50% May be slow progression Not established 48

47. Clinical features more common in males than in females (2:1) Common between the ages of 2 and 6 yr. reported as early as 6 mo of age and throughout adulthood. MCNS is present in 85–90% of patients <6 yr of age; FSGS develops in older children. Twenty to 30% of adolescents have MCNS. Preceded by minor infections and, occasionally, reactions to insect bites, bee stings, or poison ivy. 49

48. Clinical features mild edema, which is initially noted around the eyes and in the lower extremities. With time, the edema becomes generalized, with the development of ascites, pleural effusions, and genital edema. Anorexia , irritability, abdominal pain, and diarrhea are common hypertension and gross hematuria are uncommon . 50

49. differential diagnosis protein-losing enteropathy, hepatic failure, congestive heart failure, acute or chronic glomerulonephritis, protein malnutrition. 51

50. DIAGNOSIS. urinalysis reveals 3+ or 4+ protinuria; microscopic hematuria may be present in 20% of children. urinary protein excretion exceeds 3.5 g/24 hr in adults and 40 mg/m 2 /hr in children. The serum creatinine value is usually normal The serum albumin level is generally <2.5 g/dL, and serum cholesterol and triglyceride levels are elevated. C3 and C4 levels are normal. Renal biopsy is not required for diagnosis in most children. 04/11/2024 52

51. Secondary nephrotic syndrome Secondary nephrotic syndrome should be suspected in patients with age >8 yr, hypertension, hematuria, renal dysfunction, extrarenal symptomatology (rash, arthralgias, fever), or depressed serum complement levels. Poor response to steroid 04/11/2024 53

52. Secondary nephrotic syndrome Nephrotic syndrome also occurs as a secondary feature of many forms of glomerular disease: Membranous nephropathy, membranoproliferative glomerulonephritis, postinfectious glomerulonephritis(malaria ,schistosomiasis , hepatitis B virus, hepatitis C virus, filaria, leprosy, and HIV) lupus nephritis, and Henoch-Schönlein purpura nephritis 54

53. Secondary nephrotic syndrome malignancy, particularly in the adult population solid tumors, such as carcinomas of the lung and gastrointestinal tract lymphomas produce a lymphokine that increases glomerular capillary wall permeability. Immune complexes composed of tumor antigens and tumor-specific antibodies presumably mediate the renal involvement. Nephrotic syndrome develop before or after the malignancy is detected, resolve as the tumor regresses, and return if the tumor recurs. 04/11/2024 55

54. Congenital Nephrotic Syndrome Infants who develop nephrotic syndrome within the first 3 mo of life Finnish-type congenital nephrotic syndrome, an autosomal recessive disorder , is most common in populations of Scandinavian descent (1:8,000 ). Congenital nephrotic syndrome may be caused by mutations in 1 of 2 genes, NPHS1 and NPHS2, which encode the proteins nephrin and podocin, respectively. 56

55. Congenital Nephrotic Syndrome Infants with the Finnish type of congenital nephrotic syndrome present with massive proteinuria (detectable in utero by increased α-fetoprotein), a large placenta, and marked edema. Additional clinical features include prematurity, respiratory distress, and separation of the cranial sutures. The natural history of the disease is one of persistent edema, recurrent infections, and progressive renal failure with death by the age of 5 yr. Corticosteroids and immunosuppressive agents are of no value. 04/11/2024 57

56. Congenital infections congenital infections such as syphilis, toxoplasmosis, rubella, and cytomegalovirus. HIV and hepatitis B have also been reported to cause nephrotic syndrome in the neonatal period The nephrotic state in congenital infections is generally less severe than the Finnish type of congenital nephrotic syndrome, may improve or resolve with treatment of the underlying infection . 58

57. Treatment Prednisone (after negative PPD test) 60 mg/m 2 /day for 4-6 consecutive weeks. 80% to 90% achieve remission (urine trace or negative for protein for 3 consecutive days), by 2 wks. After the initial 6-wk course, taper prednisone to 40 mg/m 2 /day given every other day as a single morning dose. The alternate-day dose is then slowly tapered and discontinued over the next 2–3 mo. 59

58. Complications of NS Infection Enbcapsulated bacterial pathogens Spontaneous bacterial (pneumococcal) peritonitis In MCNS relapse: Soluble Imm. Resp. suppressor (SIRS)  Circulating IgG & IgA  Thromboembolic tendency Renal Vein Thrombosis More in MGN & FSGS than in MCNS d/t nonspecific Vs. specific protein losses? Acute renal failure Effective blood volume - uncertain Fanconi Syndrome Pan-Proximal tubular damage 60

59. Steroid response classification steroid dependent relapse while on alternate-day steroid therapy or within 28 days of stopping prednisone therapy. frequent relapsers Patients who respond well to prednisone therapy but relapse ≥4 times in a 12-mo period steroid resistant Children who fail to respond to prednisone therapy within 8 wk. Steroid-resistant nephrotic syndrome is usually FSGS (80%), MCNS (20%), and rarely mesangial proliferative. 61

60. Treatment Steroid-dependent patients, frequent relapsers, and steroid-resistant patients may be candidates for alternative agents like Cyclophosphamide high-dose pulse methylprednisolone Cyclosporine 62

61. Prognosis Most children with steroid-responsive nephrotic syndrome have repeated relapses, which generally decrease in frequency as the child grows older. in those children with MCD 1/3rd have just one episode 1/3rd have infrequent relapses 1/3rd have frequent relapses which abate during adulthood Children with steroid-resistant nephrotic syndrome, most often caused by FSGS, generally have a much poorer prognosis.

62. 64 Thank you !!