AGN by Dr Getachew-1 (1).............pptx

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1. Glomerulonephritis Getachew Wondafrash ( MD, Internist, Nephrologist 2-4-14 EC 1

2. A 20-year-old athletic man with no significant past medical history is found to have isolated asymptomatic microscopic hematuria on routine phys exam. He is not on any medications, and does not use illicit drugs. Which one of the following observations suggests hematuria of glomerular origin? A. Presence of many isomorphic red blood cells (RBCs) in urine sediment B. Presence of many isomorphic RBCs and white blood cells (WBCs) in urine sediment C. Presence of many dysmorphic RBCs or acanthocytes in urine sediment D. Presence of many “decoy cells” in urine sediment E. All of the above 13-Aug-24 2

3. A 19-year-old man presents with malaise, nausea , and decreased urine output. He was previously well, and his physical examinations is normal except for an elevated jugular venous pressure (JVP ) and a pericardial rub . His electrolytes reveal acute renal failure (ARF). Which of the following findings on the urinalysis is most likely in keeping with acute glomerulonephritis (GN) ? (A) Proteinuria (B) White blood cell casts (C) Granular casts (D) Erythrocyte ( RBC)casts (E) Hyaline casts (F) Dysmorphic RBC 3

4. Which of the following cause of ascites is associated with SAAG of > 1.1 g/dl -except 1-Cirrhosis 2 - Nephrotic syndrome 3- CHF 4-Budd chiari syndrome 5-Protein losing enteropathy 6- All of the above are associated

5. Lipid cast is seen in which of the following A-ATN B- Nephrotic syndrome C-Nephritic syndrome D- Prerenal azotemia E - All 5

6. Massive proteinuria is associated with mostly with which of the following except- A- Amyloidosis B- Renal vein thrombosis C - Membraneus glomerulonephritis D-RPGN ( rapidly progressive glomerulonephritis ) E- Renal artery thrombosis F-None 6

7. IF you find crescent shaped in the glomeruli biopsy of patient with renal problem Most likely the renal problem is A- PSGN B- RPGN C- FSGN D- Membranoproliferative GN E- Membranous GN

8. Sub epithelial humps are characteristic of A- Minimal change GN B- Membranous GN C- Membrano proliferative GN D-PSGN E-None 8

9. The most common cause of nephrotic syndrome in Adult is A- Membroproliferetive GN B- Membranous GN C-Focal Segmental GN D- Minimal change disease E- Multiple myeloma 9

10. The most common cause of nephrotic syndrome in children is A- Membroproliferetive GN B- Membranous GN C-Focal Segmental GN D- Minimal change disease( Nil disease ) E- Reflux uropathy 10

11. A 28-year-old woman presents with a recent episode of coughing up some blood , frequent nose bleeds , and now decreased urine out put . A nasal mucosa ulcer was seen on inspection. Her urinalysis is positive for protein and red cells consistent with a GN. The CXR shows two cavitary lesions and her serology is positive for antineutrophil cytoplasmic antibodies (ANCA). Which of the following is the most likely diagnosis? (A) Wegener’s granulomatosis (granulomatous with polyangitis) (B) Bacterial endocarditis Good pasture’s syndrome (D) Lupus erythematosus (SLE ) (E) Poststreptococcal disease 11

12. A 28-year-old woman presents with a recent episode of coughing up some blood,, and now decreased urine out put.. Her urinalysis is positive for protein and red cells consistent with a GN. Her serology is positive for antiglomerular basement antibody (anti - GBM.antibody positive) Which of the following is the most likely diagnosis? (A) Wegener’s granulomatosis (B) Bacterial endocarditis (C ) Good pasture’s syndrome (D) Lupus erythematosus (SLE ) (E) Poststreptococcal disease 12

13. Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent a spectrum of thrombotic microangiopathies idiopathic thrombocytopenic purpura, hemolytic anemia, fever, renal failure, and neurologic disturbances 13

14. GLOMERULUS 14 Normal histological structure of a glomerulus. On the right, is a 3-D illustration of a glomerulus. Left one shows AA = affrent arteriole, EA= Efferent arteriole, BC= Bowman’s capsule, US= Urinary space

15. GLOMERULONEPHRITIS GN is defined as a disease X-zed by intraglomerular inflammation and cellular proliferation which causes the kidneys to malfunction. It is also called Acute Nephritis . Glomerulonephritis is a subset of glomerulopathies. It is a relatively uncommon cause of AKI, accounting for about 5% of cases and 10-15% of ESRD . 15

16. Glomerular disease pattern Naming: Segmental Vs. Global (part/most of the glomerulus) Focal Vs. Diffuse ( </> 50% of nephrons) Proliferative Vs. Non-proliferative Primary – confined to the kidney Secondary – Due to a systemic disease 16

17. 17

18. PATHOGENESIS OF GN Pathogenic mechanisms responsible for the development of glomerular injury are:- Immunologic mechanisms Most of the cases of GN encountered in clinical practice are secondary to immunologic attack . Metabolic abnormalities Hyper filtration injury Hereditary abnormalities 18

19. CAUSES OF GN GN is caused by a number of disorders that are all characterized by glomerular injury accompanied by inflammation . IgA nephropathy GN (Berger's disease) is the most common glomerulonephritis worldwide.

20. Patterns of Clinical Glomerulonephritis Glomerular Syndromes Proteinuria Hematuria 1. Acute Nephritic Syndromes Poststreptococcal GN +/++ ++/+++ Subacute bacterial endocarditis +/++ ++ Lupus nephritis +/++ ++/+++ Anti-GBM disease ++ ++/+++ IgA nephropathy +/++ ++/+++

21. 1. Acute Nephritic Syndromes … Glomerular Syndromes Proteinuria Hematuria Vascular Injury Granulomatosis with polyangiitis (Wegener's) +/++ ++/+++ ++++ Microscopic polyangiitis +/++ ++/+++ ++++ Churg -Strauss syndrome +/++ ++/+++ ++++ Henoch-Schönlein purpura +/++ ++/+++ ++++ Cryoglobulinemia +/++ ++/+++ ++++ Membranoproliferative glomerulonephritis ++ ++/+++ – Mesangioproliferative glomerulonephritis + +/++ – ANCA Small Vessel Vasculitis

22. 2. Pulmonary-Renal Syndromes Proteinuria Hematuria Vascular Injury Goodpasture's syndrome ++ ++/+++ – ANCA small-vessel vasculitis Granulomatosis with polyangiitis (Wegener's) +/++ ++/+++ ++++ Microscopic polyangiitis +/++ ++/+++ ++++ Churg-Strauss syndrome +/++ ++/+++ ++++ HSP +/++ ++/+++ ++++ Cryoglobulinemia +/++ ++/+++ ++++

23. 3. Nephrotic Syndromes Glomerular Syndromes Proteinuria Hematuria Vascular Injury Nephrotic Syndromes Minimal change disease ++++ – – Focal segmental glomerulosclerosis +++/++++ + – Membranous glomerulonephritis ++++ + – Diabetic nephropathy ++/++++ –/+ – AL and AA amyloidosis +++/++++ + +/++ Light-chain deposition disease +++ + – Fabry's disease + + –

24. 4. Basement Membrane Syndromes Proteinuria Hematuria Vascular Injury Anti-GBM disease ++ ++/+++ – Alport's syndrome ++ ++ – Thin basement membrane disease + ++ – Nail-patella syndrome ++/+++ ++ –

25. 5. Glomerular Vascular Syndromes Glomerular Syndromes Proteinuria Hematuria Vascular Injury Sickle cell disease +/++ ++ +++ Thrombotic microangiopathies ++ ++ +++ Antiphospholipid syndrome ++ ++ +++ ANCA small-vessel vasculitis Henoch-Schönlein purpura +/++ ++/+++ ++++ Cryoglobulinemia +/++ ++/+++ ++++ AL and AA amyloidosis +++/++++ + +/++

26. 6. Infectious Disease–Associated Syndromes Glomerular Syndromes Proteinuria Hematuria Vascular Injury PSGN +/++ ++/+++ – SBE +/++ ++ – HIV +++ +/++ – Hepatitis B and C +++ +/++ – Syphilis +++ + – Leprosy +++ + – Malaria +++ +/++ – Schistosomiasis +++ +/++ –

27. ACUTE GLOMERULONEPHRITIS 27

28. CLASSIFICATION OF GN Glomerulonephritis can be classified on the basis of:- The Etiologic cause Primary (idiopathic) - when the glomerular disease is not part of systemic disease and the cause is unknown . Minimal Change Disease Membranous GN Focal Segmental GS Membranous Proliferative GN Diffuse Proliferative GN Rapidly Progressive GN Chronic GN IgA Nephropathy Anti GBM GN ANCA associated GN

29. B. Secondary - when glomerular disease is part of a systemic disease or due to a known cause. Diabetes Mellitus SLE Lymphoma Solid tumors Amyloidosis Malaria Endocarditis 29 CLASSIFICATION…

30. Classification… The Histopathologic findings on examination of kidney biopsy Minimal change (Nil-change) disease Focal and segmental glomerulosclerosis Membranous glomerulonephritis Proliferative glomerulonephritis 30

31. Classification… The clinical presentation Patients with glomerulonephritis generally present with one of five clinical syndromes : Asymptomatic hematuria Acute glomerulonephritis Nephrotic syndrome Rapidly progressive glomerulonephritis Chronic glomerulonephritis

32. Acute glomerulonephritis(AGN) AGN refers to a specific set of renal diseases in which an immunologic mechanism triggers inflammation and proliferation of glomerular tissue that can result in damage to the BM, mesangium, or capillary endothelium. Acute glomerulonephritis is often called the “ nephritic syndrome .”

33. AGN Cont…. It is a syndrome characterized by : Hematuria Oliguria ARF, manifested by a sudden decrease in the GFR Fluid retention manifested by: Edema HTN. 13-Aug-24 33

34. AGN Causes 1 . Postinfectious etiologies Group A beta hemolytic streptococci - t he most common type of postinfectious AGN. Infective endocarditis Abdominal abscesses Syphilis and other STD Typhoid fever Viral diseases such as mononucleosis, measles, mumps 34

35. AGN Causes… 2. Systemic causes Wegener granulomatosis Polyarteritis Nodosa Collagen vascular diseases e.g., SLE Henoch-Schönlein purpura Goodpasture syndrome Drug-induced (i.e. Gold, Penicillamine) 3. Renal diseases Membranoproliferative glomerulonephritis Berger disease (IgA nephropathy) Idiopathic rapidly progressive glomerulonephritis 35

36. AGN Pathogenesis Glomerular lesions in AGN are the result of glomerular deposition or in situ formation of immune complexes . Most forms of AGN are mediated by Humoral immune mechanisms. With the exception of  PSGN , the exact triggers for the formation of the immune complexes are unclear. 36

37. AGN… clinical manifestation Hematuria Oliguria Hypertension - 80% of  patients Oedema – periorbital and scrotal regions. Flank pain 2 to stretching of the renal capsule. Headache – due to HTN Confusion 2 to malignant HTN may be seen in 5% of patients. SOB on exertion 2 to CHF or pulmonary Oedema. 37

38. Diagnosis Urinalysis for RBCs and Protein Red blood cells . RBC casts and Dysmorphic RBCS on urinalysis confirm Dx. Proteinuria is usually <3 g/d ( non nephrotic range or non massive). Sometimes pyuria Renal function test BUN (  ) Creatinine(  ) Serum electrolyte esp. Potassium Renal Ultrasound 38

39. Workup 39 A kidney biopsy reveals inflammation of the glomeruli, which may indicate the cause. Tests to determine the cause of the acute nephritic syndrome may include: ANA titer (lupus) ANCA ( for vasculitis) Anti-GMB antibody Serum complement (C3 and C4) ASO Titer Blood culture Culture of the throat or skin

40. Perio Peri -orbital edema In an 8 yr boy with headaches, dark urine and BP=150/90 10 days following a severe pharyngitis

41. AGN….Treatment The goal of treatment is to reduce the inflammation . Admission is recommended for patients with: Anuria Nephrotic syndrome Significant hypertension Pulmonary symptoms 13-Aug-24 41

42. Cont…. Corticosteroids or other anti-inflammatory medications may be used to reduce inflammation. Supportive care: Bed rest Fluid and salt restriction The cause must be identified and treated. Management of complications 42

43. Possible Complications of AGN ARF CRF ESRD HTN CHF Pulmonary edema Chronic GN Nephrotic syndrome 43

44. Acute poststreptococcal glomerulonephritis APSGN protypical GN affects children between the ages of 2 and 14 years , but 10% of cases are patients older than 40yrs. The incidence of Poststreptococcal glomerulonephritis is decreasing in Western countries, but common in some rural areas, poor hygiene places, and tropical countries. Males are more often affected. The preceding infection is usually in the URTI(pharyngitis), but can be in the skin( pyoderma ) or at other sites . 44

45. PSGN…pathogenesis PSGN is an acute immune complex disease characterized by the formation of antibodies against streptococcal antigens (SPEB and NAPlr ) and localization of immune complexes with complement in the kidney. Repeat infections are not common as immunity is type specific and not usually transient . Poststreptococcal glomerulonephritis is prototypical for acute endocapillary proliferative GN . 45

46. Cont…. Two types have been described M types 1, 2, 4, 3, 25, 49, and 12 with , PSGN following pharyngitis usually observed in winter. M types 47, 49, 55, 2, 60, and 57 PSGN is seen following impetigo usually observed in the summer and fall. PSGN develops 2–6 weeks after skin infection and 1–3 weeks after streptococcal pharyngitis. 46

47. Clinical features The classic presentation is that of acute nephritic picture . Note: 5% of children and 20% of adults have nephrotic range proteinuria. Systemic symptoms of headache, malaise, anorexia, and flank pain are reported in as many as 50% of cases. 47

48. Diagnosis Common suggestive laboratory findings for PSGN include: Depressed complement (C3) levels . Positive rheumatoid factor (30–40%) Circulating immune complexes (60–70%) ANCA against myeloperoxidase (10 %). Positive cultures for streptococcal infection are inconsistently present ( 10–70% ) 48

49. Cont…. Presence of any of the following may help to confirm the diagnosis ASO titer (30%) anti-DNAase (70%) Antihyaluronidase antibodies (40%) The diagnosis of Poststreptococcal glomerulonephritis rarely requires a renal biopsy. 49

50. wgc 0454 Acute crescentic glomerulonephritis Suspect this lesion in patients who have anuria over 24 hrs or oliguria without recovery over 7 days

51. Treatment Treatment is supportive , with control of hypertension, edema, and dialysis as needed. Antibiotic treatment for streptococcal infection should be given to all patients and their cohabitants. Penicillin is the drug of choice in treating acute PSGN. Antibiotics do not change the course of illness once established but should be given to reduce infectivity . 51

52. Treatment (PSGN)… There is no role for immunosuppressive therapy, even in the setting of crescents. Recurrent Poststreptococcal glomerulonephritis is rare despite repeated streptococcal infections. 52

53. PSGN (prognosis) Early death is rare in children but does occur in the elderly. Overall, the prognosis is good, with permanent renal failure being very uncommon (1–3%), and even less so in children. Complete resolution of the haematuria and proteinuria in children occurs within 3–6 weeks of the onset of nephritis. 53

54. Summary GN generally presents as a constellation of findings that includes haematuria, edema, and hypertension . GN is caused by a number of disorders that are all characterized by glomerular injury accompanied by inflammation . Presence of RBC casts dysmorphic RBC in the urine is diagnostic for GN. PSGN is caused by prior infection with specific nephritogenic strains of group A β -haemolytic streptococcus. 13-Aug-24 54

55. Which of the following is true A-GN occurs in acute infective endocarditis but not in SBE B- GN occurs in SBE but rare in ABE C –Treatment is with steroid for GN which is associated IE D- Treatment is with Antibiotics for GN which is associated IE E-None of the above 55

56. SBE related GN( subacute bacterial endocarditis) Complicates SBE, particularly in patients who remain untreated for a long time GN is unusual in acute bacterial endocarditis because it takes 10–14 days to develop immune complex–mediated injury Patients who present with a clinical picture of RPGN have crescents Embolic infarcts or septic abscesses may also present The pathogenesis hinges on the renal deposition of circulating immune complexes in the kidney with complement activation 13-Aug-24 56

57. Cont … Patients present with gross or microscopic hematuria , pyuria, and mild proteinuria or, less commonly, RPGN with rapid loss of renal function A normocytic anemia, elevated ESR , hypocomplementemia , and circulating immune complexes are often present Levels of serum creatinine may be elevated at diagnosis Primary treatment is eradication of the infection with 4–6 weeks of antibiotics, and If accomplished expeditiously, the prognosis for renal recovery is good. 13-Aug-24 57

58. Lupus Nephritis Lupus nephritis is a common and serious complication of SLE Most severe in African-American female adolescents 30-50% of pts will have clinical features of renal disease at Dx Lupus nephritis results from the deposition of circulating immune complexes, which activate the complement cascade leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of various cytokines

59. Lupus nephritis – C/F & Dx The c/fs, course of disease, and Rx of lupus nephritis are closely linked to renal pathology The most common clinical sign of renal disease is proteinuria, but hematuria, HTN, varying degrees of renal failure, and active urine sediment with RBC casts can all be present The extrarenal manifestations of lupus are important in establishing Dx of SLE b/c, while serologic abnormalities are common in lupus nephritis , they are not diagnostic.

60. Lupus nephritis – C/F & Dx… Hypocomplementemia is common (70–90%) and declining complement levels may herald a flare Renal biopsy is the only reliable method of identifying the morphologic variants of lupus nephritis.

61. Membranoproliferative Glomerulonephritis MPGN is sometimes called mesangiocapillary glomerulonephritis or lobar glomerulonephritis . It is an immune-mediated glomerulonephritis characterized by thickening of the GBM with mesangioproliferative changes; 70% of patients have Hypocomplementemia. MPGN is rare in African Americans, and idiopathic disease usually presents in childhood or young adulthood. MPGN is subdivided pathologically into type I, type II, and type III disease .

62. Mesangioproliferative Glomerulonephritis Mesangioproliferative glomerulonephritis is characterized by expansion of the mesangium, sometimes associated with mesangial hypercellularity; t hin, single contoured capillary walls; and mesangial immune deposits . Clinically, it can present with varying degrees of proteinuria and, commonly, hematuria. Mesangioproliferative disease may be seen in IgA nephropathy , Plasmodium falciparum malaria , resolving post infectious glomerulonephritis , and class II nephritis from lupus, all of which can have a similar histologic appearance.

63. NEPHROTIC SYNDROME 65

64. NEPHROTIC SYNDROME Definition The nephrotic syndrome is defined by: Proteinuria >3.5 g/1.73m 2 /day (in practice > 3 to 3.5 g/day ) Hypoalbuminemia Edema Hyperlipidemia lipiduria Hypercoagulability The cardinal sign of nephrotic syndrome is “ nephrotic-range” proteinuria ; the other manifestations are consequences of the proteinuria.

65. PATHOPHYSIOLOGY Nephrotic syndrome results from a marked increase in glomerular permeability to protein and other macromolecules . Hypoalbuminemi a is in part a consequence of -urinary protein loss. It is also due to the -catabolism of filtered albumin by the proximal tubule, - as well as redistribution of albumin within the body. 67

66. Pathophysiology… Edema is the most common presenting symptom of patients with the nephrotic syndrome. The pathophysiology of edema formation in nephrotic syndrome is poorly understood. It may occur through at least two different major mechanisms. Arterial underfilling as the low plasma oncotic pressure leads to plasma volume depletion ( The underfilling hypothesis ) Sodium retention directly induced by the renal disease ( primary renal salt and water retention ) 68

67. Under filling hypothesis of edema An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia . In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure , causing greater transcapillary filtration of water throughout the body and thus the development of edema. Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure determine the movement of fluid from the vascular compartment to the interstitium. The oncotic pressure is mainly determined by the protein content. The flux of water across the capillary wall can be expressed by the following formula: Qw = K ([P c  -­ pp] ­- [P i  ­- pi] In this formula, Q w  is net flux of water, K is the capillary filtration coefficient, P c  is capillary hydrostatic pressure, and pp is the plasma oncotic pressure, while P i  is the interstitial fluid hydrostatic pressure and pi is the interstitial fluid oncotic pressure, shown schematically below. 13-Aug-24 69

68. Cont … . With a high enough capillary hydrostatic pressure or a low enough intravascular oncotic pressure, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. In patients with nephrotic syndrome, this causes a reduction in plasma volume, with a secondary increase of sodium and water retention by the kidneys. In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier. In health, urine albumin is less than 50 mg/day, because most of the filtered albumin is re-absorbed by the tubules. Amounts above 500 mg/day point to glomerular disease The three structures the fenestrated endothelium, glomerular basement membrane, and glomerular epithelium—are the glomerular filtration barrier .  13-Aug-24 70

69. Cont … 13-Aug-24 71

70. Cont … 13-Aug-24 72

71. Over filling hypothesis An alternative hypothesis is an intrinsic defect in the renal tubules which cause a decrease in sodium excretion . This could occur if the filtered intraluminal protein directly stimulated renal epithelial sodium reabsorption. Two facts support this hypothesis: (1) sodium retention is observed even before the serum albumin level starts falling (2) intravascular volume is normal or even increased in most patients with nephrotic syndrome. A third possible mechanism is an enhanced peripheral capillary permeability to albumin, as shown by radioisotopic technique in human studies of 60 patients with nephrotic syndrome. This would then lead to increased tissue oncotic pressure and fluid retention in the peripheral tissues.   13-Aug-24 73

72. Metabolic consequences of proteinuria Metabolic consequences of the nephrotic syndrome include the following: Infection Hyperlipidemia and atherosclerosis Hypocalcemia and bone abnormalities Hypercoagulability Hypovolemia Acute kidney injury may indicate an underlying glomerulonephritis but is more often precipitated by hypovolemia or sepsis. Edema of the kidneys that causes a pressure-­mediated reduction in the GFR has also been proposed. Additional consequences include the following: Hypertension related to fluid retention and reduced kidney function may occur Edema of the gut may cause defective absorption, leading to malnutrition Ascites and pleural effusions may develop 13-Aug-24 74

73. Infection Is a major concern in nephrotic syndrome Both gram positive and gram negative bacterial infect. Varicella infection is also common. The most common infectious complications are bacterial sepsis, cellulitis, pneumonia, and peritonitis. Proposed explanations for the increased infection risk include the following: Urinary immunoglobulin losses Edema fluid acting as a culture medium Protein deficiency Decreased bactericidal activity of the leukocytes Immunosuppressive therapy Decreased perfusion of the spleen caused by hypovolemia Urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria 13-Aug-24 75

74. Hyperlipidemia and atherosclerosis Hyperlipidemia is a classic feature of the nephrotic syndrome, rather than a mere complication. It is related to the hypoproteinemia and low serum oncotic pressure of nephrotic syndrome, which then leads to reactive hepatic protein synthesis, including of lipoproteins .   In addition, reduced plasma levels of lipoprotein lipase results in diminution of lipid catabolism. Some of the elevated serum lipoproteins are filtered at the glomeruli, leading to lipiduria and the classic findings of oval fat bodies and fatty casts in the urine sediment. Atherosclerotic vascular disease appears to occur in greater frequency in persons with nephrotic syndrome than in healthy persons of the same age. frequency and extent of coronary artery stenosis were greater in patients with nephrotic syndrome than in non-nephrotic control subjects.   13-Aug-24 76

75. Hypocalcemia Hypocalcemia is common in the nephrotic syndrome, but rather than being a true hypocalcemia , it is usually caused by a low serum albumin level . Nonetheless, low bone density and abnormal bone histology are reported in association with nephrotic syndrome. This could be caused by urinary losses of vitamin D–binding proteins, with consequent hypovitaminosis D and, as a result, reduced intestinal calcium absorption.   13-Aug-24 77

76. Hypercoagulability Venous thrombosis and pulmonary embolism are well-known complications of the nephrotic syndrome. Hypercoagulability in these cases appears to derive from urinary loss of anticoagulant proteins, such as antithrombin III and plasminogen , along with the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X. 13-Aug-24 78

77. Hypovolemia Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure , resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume. Hypovolemia is generally observed only when the patient's serum albumin level is less than 1.5 g/dL. Symptoms include vomiting, abdominal pain, and diarrhea. The signs include cold hands and feet, delayed capillary filling, oliguria, and tachycardia. Hypotension is a late fe ature. 13-Aug-24 79

78. Proteinuria Hypoalbuminemia  Plasma oncotic pressure Transcapillary fluid shift Intravascular volume depletion Underperfussion of the kidneys Activation of RAAS Activation of SNS Release of AVP Suppression of ANP release  Renal Na & volume retention The underfilling hypothesis EDEMA NEPHROTIC SYNDROME 80

79. Pathophysiology… Hyperlipidemia is believed to be due to: Increased hepatic lipoprotein synthesis that is triggered by reduced oncotic pressure. Increased urinary loss of proteins that regulate lipid homeostasis Defective lipid catabolism . 81

80. Cont…. LDL and cholesterol are increased in the majority of patients, whereas VLDL and TGs tend to rise in patients with severe disease. Hyperlipidemia may accelerate atherosclerosis and progression of renal disease . it is associated with lipiduria then lipid casts in the urine 82

81. Pathophysiology… Hypercoagulability is due to: Increased urinary loss of antithrombin III Altered levels and/or activity of proteins C and S Hyperfibrinogenemia due to increased hepatic synthesis Impaired fibrinolysis Increased platelet aggregability . 83

82. Pathophysiology… Consequence of these impairments are : Spontaneous peripheral arterial or venous thrombosis like DVT Renal vein thrombosis Pulmonary embolism 84

83. Pathophysiology… Other metabolic complications of nephrotic syndrome include : Protein malnutrition Iron-resistant microcytic hypochromic anemia due to transferrin loss . Hypocalcaemia and secondary hyperparathyroidism can occur as a consequence of vitamin D deficiency due to enhanced urinary excretion of cholecalciferol-binding protein. 85

84. Pathophysiology… Loss of thyroxine-binding globulin can result in depressed thyroxine levels or hypothyroidism An increased susceptibility to infection due to low IgG levels as a result of urinary loss and increased catabolism. Unpredictable changes in the pharmacokinetics of therapeutic agents that are normally bound to plasma proteins 86

85. Cont…. Clinical condition against or not suggestive of NS: Decrease in renal function is unusual early in the course of disease. A rise in the serum creatinine level is usually a feature of more advanced disease . The urinary sediment is typically devoid of red and white cells or casts and is termed an inactive urinary sediment . Pulmonary edema is uncommon in nephrotic syndrome. 87

86. Etiologies of nephrotic syndrome The aetiology of nephrotic syndrome is separated into primary and secondary causes. Primary glomerular diseases make up to 75% of cases of nephrotic syndrome. About ¼ - 1/3 of adult patients with NS have a systemic renal disease such as DM, amyloidosis, or SLE . Congenital and hereditary focal glomerulosclerosis may result from mutations of genes that code for podocyte proteins , including nephrin, podocin, or the cation channel 6 protein.   Nephrotic syndrome can result from drugs of abuse, such as heroin. 88

87. Primary (idiopathic) NS The most common primary ( idiopathic ) glomerular diseases that cause nephrotic syndrome in adults are: Membranous nephropathy [ 20%] Focal segmental glomerulosclerosis [ 1/3] Minimal change disease [ 10–15% ] Membranoproliferative glomerulonephritis [ 5 % ] Other proliferative and sclerosing glomerulonephritides [ 15–30 % ] Although these disease entities are usually primary (and idiopathic), each can also be secondary to an underlying systemic disease. However, the glomerular histology is indistinguishable in primary and secondary forms. 89

88. Which of the following is associated with leukemia and lymphoma A- minimal change disease B- membranous nephropathy C- Focal Segmental Glomerulosclerosis (FSGS D- Diabetic Nephropathy E- None 90

89. Cont. Which of the following is associated with solid tumors like breast and lung ca A- minimal change disease B- membranous nephropathy C- Focal Segmental Glomerulosclerosis (FSGS D- Diabetic Nephropathy E- None 13-Aug-24 91

90. NEPHROTIC SYNDROME ASSOCIATED WITH SPECIFIC CAUSES (“SECONDARY” NS) SYSTEMIC DISEASES Diabetes mellitus Amyloidosis T he leading causes of 2 nephrotic syndrome. SLE & other collagen diseases Vasculitic-immunologic disease INFECTIONS Bacterial (Poststreptococcal, congenital and 2 syphilis, SBE) Viral (HBV, HCV, HIV infection, infectious mononucleosis, CMV infection) Parasitic (malaria, toxoplasmosis, Schistosomiasis, filariasis) MEDICATION RELATED Gold, mercury, and the heavy metals Penicillamine NSAID Lithium NEOPLASMS Hodgkin's lymphoma and leukemia-lymphomas (with minimal change lesion ) Solid tumors (with membranous nephropathy ) 92

91. “ SECONDARY ” NEPHROTIC SYNDROME … HEREDITARY AND METABOLIC DISEASE Alport's syndrome Sickle cell disease F amilial nephrotic syndrome OTHER Pregnancy related (includes preeclampsia) Transplant rejection Serum sickness Accelerated hypertensive nephrosclerosis Unilateral renal artery stenosis Massive obesity–sleep apnea syndrome Reflux nephropathy 93

92. Diagnosis Initial evaluation of a nephrotic patient includes laboratory tests to define whether the patient has 1 NS or a 2 cause related to a systemic disease, toxin, or medication. Common screening tests include: FBS and Hgb A1c - tests for diabetes ANA - test for collagen vascular disease Serum complement - to screen for many immune complex–mediated diseases. In selected patients, Hepatitis B and C serology, ANCA, anti-GBM antibodies, and other tests may be useful. 94

93. Cont…. 24-h urine for protein; creatinine clearance Urine dipstick is easy and can easily pick nephrotic range proteinuria ( 3+ or 4+) Serum albumin, cholesterol, complement Urine protein electrophoresis Review drug exposure Renal biopsy Consider malignancy (in elderly pt. with membranous GN or minimal change disease ) Consider renal vein thrombosis (if membranous GN or symptoms of pulmonary embolism are present) 95

94. Treatment Once secondary causes have been excluded , treatment of an adult nephrotic patient often requires a renal biopsy which is the best guide to treatment and prognosis. If renal biopsy is impossible, infectious disease (HBV, HCV, HIV, syphilis) should be effectively ruled out before thinking of any immune-suppressive therapy. Minimal change disease, the commonest type of NS in young age, is highly responsive to steroid therapy. 96

95. Therapeutic Principles in NS Four principles guide the management of the nephrotic syndrome. Treat any complications : Reduce fluid overload with diuretics & salt restriction Provide anticoagulation therapy for patients at high risk for venous thrombosis (e.g., those with a serum albumin level < 2.0 g) Aggressively treat hypertension ( BP goal < 130/80 mm Hg) Decrease hyperlipidaemia with statins . Lower proteinuria to less than 1 g/24 hr. Use disease-specific therapy when possible. Treat the underlying secondary cause if one is present. 97

96. Cont…. Nonspecific measures that may reduce proteinuria include ACE inhibitors, ARBs , ACE inhibitors and ARBs reduce proteinuria and slow the rate of progression of renal failure by lowering intraglomerular pressure and preventing the development of hemodynamically mediated FSGS. ACE inhibitors are renoprotective in human diabetic nephropathy and many other proteinuric glomerulopathies. 98

97. Cont…. Anticoagulation is indicated for patients with DVT , arterial thrombosis, and pulmonary embolism . Patients may be relatively resistant to heparin as a consequence of antithrombin III deficiency. The potential value of dietary protein restriction for reducing proteinuria must be balanced against the risk of contributing to malnutrition . Vitamin D supplementation is advisable in patients with clinical or biochemical evidence of vitamin D deficiency. 99

98. Summary NS is classically characterized by four clinical features : Nephrotic range proteinuria, Hypoalbuminemia, Edema, & Hyperlipidaemia. Primary (idiopathic) glomerular diseases make for the majority of cases of NS. FSGS is the commonest of NS in adults as is minimal change disease in children . Urinalysis is the single most important screening tool for nephrotic syndrome. Treatment of adult NS should be based on renal biopsy finding and ruling out secondary causes. 100

99. Which of the following nephropathy is associated with lymphoma and leukemia ? A- Rapidily progressive glomerulonephritis ( RPGN) B- Focal segmental glomerulonephritis C-Membranous GN D- Minimal change disease E –ALL 101

100. Minimal Change Disease MCD or nil lesion/lipoid nephrosis causes 70–90% of nephrotic syndrome in childhood but only 10–15% in adults Characterized by intense proteinuria leading to edema and intravascular volume depletion. MCD usually presents as a primary renal disease but can be associated with Hodgkin's disease, allergies, or use of NSAIDs On renal biopsy shows no obvious lesion by light microscopy and is negative for deposits by immunofluorescent microscopy Electron microscopy, however, consistently demonstrates an effacement of the foot process with weakening of slit-pore membranes. On laboratory testing, profound proteinuria and oval fat bodies may be observed. In children, the critical level for diagnosis is proteinuria of more than 40 mg/h/m 2 . In adults, the threshold is more than 3.5 g/d/1.73 m 2

101. Pathophysiology of MCD MCD is a disorder of T cells , which release a cytokine that injures the glomerular epithelial foot processes . This leads to a decreased synthesis of polyanion s. The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4). IL-13 overexpression can cause podocyte foot process fusion and  proteinuria 13-Aug-24 103

102. MCD - C/F & Dx Presents with the abrupt onset of dependent edema and nephrotic syndrome accompanied by acellular urinary sediment Average urine protein excretion in 24 hours is 10 grams with severe hypoalbuminemia Less common c/fs are HTN, microscopic hematuria, and decreased renal function (<5% in children, 30% in adults) Although up to 30% of children have a spontaneous remission, all children today are treated with steroids; only children who are non responders are biopsied in this setting Facial edema is noted first. Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee sting, the use of certain drugs, or malignancies. Malaise and easy fatigability can occur. Weight gain often is an additional feature. The patient also may present with one or more of the following: Hypovolemia, Hypertension Thromboembolism, Infection

103. Cont … . Physical Examination The blood pressure usually is normal in children   but may be elevated in adults. the plasma creatinine in adults is often slightly elevated at presentation Dependent edema is the most prominent sign . The retina has a wet appearance . Subungual edema with horizontal lines (called Muehrcke lines) also may occur. Hernias may be found, and the elasticity of the ears may be decreased. Heavy proteinuria over an extended period of time leads to a state of protein depletion with muscle wasting, thinning of the skin, and growth failure. Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be the first indication of an underlying nephrotic syndrome. Children may have growth failure. 13-Aug-24 105

104. Cont … Causes Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause. Secondary cases may be due to any of the following : Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon, ampicillin/penicillin, trimethadione, mercury-containing cosmetic skin cream Toxins - Mercury,   lithium, bee stings, fire coral exposure. Infection - Infectious mononucleosis, HIV, immunization Tumor - Hodgkin lymphoma  [14]  (most commonly), carcinoma, other lymphoproliferative diseases Hematopoietic stem cell transplantation. 13-Aug-24 106

105. Focal Segmental Glomerulosclerosis (FSGS)– C/F FSGS can present with hematuria, HTN , any level of proteinuria or renal insufficiency. Nephrotic-range proteinuria, African-American race, and renal insufficiency are associated with a poor outcome 50% of these patients reach renal failure in 6–8 years. FSGS rarely remits spontaneously FSGS causes asymptomatic proteinuria or nephrotic syndrome with or without renal insufficiency. Generally, FSGS results in progressive kidney injury; it accounts for 2.3% of all cases of end-stage renal disease (ESRD), and is the leading glomerular cause of ESRD.

106. Signs and symptoms The most common clinical presenting feature of FSGS (> 70% of patients) is nephrotic syndrome, characterized by generalized or dependent edema, along with fatigue and loss of appetite. Examination of patients with FSGS may include the following findings: Leg edema Ascites Pleural effusion Abdominal pain: Common in children; may be a symptom of peritonitis Ulcerations and infections in dependent regions Hypertension (may be severe, with diastolic blood pressure ≥120 mm Hg; this is common in Black patients, especially those with kidney insufficiency  13-Aug-24 108

107. Laboratory testing Urinalysis: Large amounts of protein; hyaline and broad waxy casts, generally no RBC casts Serum creatinine ( Scr ) concentration or creatinine clearance ( Ccr ): Usually within reference range; in later stages, varying degrees of elevated Scr or decreased Ccr Albumin levels: Generally low Lipid studies: Hyperlipidemia Imaging studies On ultrasonography, kidney findings in FSGS include the following: Early stages : Normal or large kidneys with increased echogenicity, suggesting diffuse intrinsic medical renal disease Advanced renal failure : Small and shrunken kidneys, indicating severe glomerular scarring and interstitial fibrosis HIV-associated disease: Generally, large echogenic kidney 13-Aug-24 109

108. Expected kidney biopsy result Kidney biopsy is the most definitive way to confirm the diagnosis. Findings are as follows : Segmental solidification of the glomerular tuft: Characteristic lesion Segmental obliteration of glomerular capillaries by accumulation of acellular matrix and hyaline deposits , along with adhesion to the Bowman capsule Fusion of diffuse foot process, predominantly in the sclerotic segments; morphologic subsets may occur HIV-associated FSGS: Collapsing glomerular lesions with microcystic dilatation of renal tubules and tubuloreticular inclusions in endothelial and mesangial cells 13-Aug-24 110

109. Management Therapy for FSGS includes nonspecific measures (eg, nutrition) and symptomatic treatment. In patients with persistent nephrosis, the general consensus is to use aggressive measures to induce remission (eg, use of corticosteroids and immunosuppressive agents such as cyclophosphamide, calcineurin inhibitors ). Nonspecific, general management Control hypertension, including pharmacotherapy (eg, diuretics, antihypertensive) Reduce lipid levels Reduce daily salt and protein intake Nephrotic syndrome: Maintain adequate nutrition, minimize/eliminate proteinuria, prevent complications from edema 13-Aug-24 111

110. Cont … . Specific management Idiopathic FSGS is difficult to treat due to its highly variable clinical course. The following medications are used in the management of FSGS: Immunosuppressant's (eg, prednisone, ACTH, cyclophosphamide, cyclosporine ) Loop diuretics (eg, furosemide) Potassium-sparing diuretics (eg, spironolactone, triamterene) Other diuretics (eg, metolazone) Volume expanders (eg, albumin) Osmotic agents (eg, mannitol) Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers 13-Aug-24 112

111. FSGS – C/F FSGS can present with hematuria, HTN , any level of proteinuria or renal insufficiency. Nephrotic-range proteinuria, African-American race, and renal insufficiency are associated with a poor outcome 50% of these patients reach renal failure in 6–8 years. FSGS rarely remits spontaneously

112. Which of the following nephropathy is associated with solid tumours ? A- Rapidily progressive glomerulonephritis ( RPGN) B- Focal segmental glomerulonephritis C-Membranous GN D- Minimal change disease E –ALL 114

113. Membranous Glomerulonephritis Membranous glomerulonephritis (MGN), or membranous nephropathy as it is sometimes called, accounts for approximately 20% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30 and 50 years and a male to female ratio of 2:1. It is rare in childhood and the most common cause of nephrotic syndrome in the elderly. In 25–30% of cases, MGN is associated with a malignancy (solid tumors of the breast, lung, colon), infection (hepatitis B, malaria, schistosomiasis), or rheumatologic disorders like lupus or rarely rheumatoid arthritis

114. Membranous Glomerulonephritis Membranous glomerulonephritis (MGN) , or membranous nephropathy as it is sometimes called, accounts for approximately 30% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30 and 50 years and a male to female ratio of 2:1. It is rare in childhood and the most common cause of nephrotic syndrome in the elderly. In 25–30% of cases, MGN is associated with a malignancy (solid tumors of the breast, lung, colon), infection (hepatitis B, malaria, schistosomiasis ), or rheumatologic disorders like lupus or rarely rheumatoid arthritis

115. Diabetic Nephropathy Is the single most common cause of CKD ~ 40% of pts with types 1 or 2 diabetes develop nephropathy Within 1–2 yrs after the onset of clinical diabetes, morphologic changes appear in the kidney Thickening of the GBM The composition of the GBM is altered notably with a loss of the negatively charged filtration barrier This change results in ↑ ed filtration of serum proteins into the urine, predominately negatively charged albumin

116. Diabetic Nephropathy… Risk factors for the dev’t of nephropathy: Hyperglycemia, HTN, Dyslipidemia, smoking & a family history of diabetic nephropathy Expansion in mesangial matrix is associated with the dev’t of mesangial sclerosis Some pts also develop eosinophilic, PAS+ nodules called nodular glomerulosclerosis or Kimmelstiel -Wilson nodules Renal biopsies from patients with types 1 and 2 diabetes are largely indistinguishable

117. Diabetic Nephropathy - Dx Proteinuria ranges from 500 mg to 25 g/24 h, and is often associated with nephrotic syndrome > 90% of pts with T1DM and nephropathy have diabetic retinopathy So the absence of retinopathy in T1DM patient with proteinuria should prompt consideration of a dx other than diabetic nephropathy Only 60% of pts with T2DM with nephropathy have diabetic retinopathy Pts with advanced diabetic nephropathy have normal to enlarged kidneys

118. Diabetic Nephropathy - Rx BP control inhibition of the RAAS are beneficial in retarding the progression of diabetic nephropathy In T1 diabetes, intensive control of blood sugar clearly prevents the dev’t or progression of diabetic nephropathy The evidence for benefit of intensive blood glucose control in T2 diabetes is less certain

119. 40 years old known RVI patient develops renal failure and you consider HIV associated nephropathy (HIVAN ) as a cause of renal failure for this patient and which is not true about HIVAN A-The lesion in HIVAN is Focal segmental glomerulosclerosis( FSGS) B- It is collapsing glomerulopathy C-Typically present with nephrotic-range proteinuria and hypoalbuminemia D- They commonly have hypertension, edema, or hyperlipidemia E-None 121

120. HIV related kidney disease The risk of ESRD is much higher in HIV-infected African Americans About 50% of HIV pts with kidney disease have HIVAN on biopsy The lesion in HIVAN is FSGS , characteristically revealing a collapsing glomerulopathy Renal epithelial cells express replicating HIV virus, but host immune responses also play a role in the pathogenesis Other renal lesions include MPGN,DPGN, IgA nephropathy, and MCD

121. HIV associated glomerular disease – C/F & Rx Pts typically present with nephrotic-range proteinuria & hypoalbuminemia They do not commonly have HTN, edema, or hyperlipidemia Renal ultrasound also reveals large, echogenic kidneys Rx with ACEIs or ARBs decreases the proteinuria Effective ART benefits both the patient and the kidney Improves survival even with CKD or ESRD HIVAN is an indication to initiate therapy irrespective of CD4 count

122. Other Infections associated with Glomerular disease Hepatitis B and C MALARIA Other Viruses: CMV, Influenza, measles, mumps, EBV Syphilis Schistosomiasis

123. Thank you 125