Dr. J. Satish Kumar, MD, Department of Basic & Medical Sciences, AUST

1. Name:_________________________________________ General Medicine Renal System Learning Objectives: Describe the types, aetiology, pathogenesis, clinical manifestations, investigations & treatment of Glomerulonephritis, Acute Pyelonephritis, Nephrotic Syndrome, Chronic renal failure. Dr. J. Satish Kumar, MD, Department of Basic & Medical Sciences, AUST

2. Function of Kidneys • Remove toxic waste products • Remove excess water and salts • Play a part in controlling blood pressure • Produce erythropoetin (epo) which stimulates red cell production • Helps to keep calcium and phosphate in balance for healthy bones • Maintains proper pH for the blood

3. Glomerulonephritis- etiology - “primary” (idiopathic) - pathology is confined to the kidney - any systemic features as direct consequence of glomerular dysfunction “secondary” - kidney abnormality as a part of multi- system disorder

4. glomerulonephritis- location - “focal”: <50% of all glomeruli “diffuse”: ≥50% of all glomeurli “segmental”: part of individual glomerulus “global”: entire glomerulus

5. major determinants of glomerular injury • nature of primary insult and secondary mediator systems • site of injury within glomerulus • nature of injury - speed of onset - extent - intensity

6. 1. primary insult major insult to glomerulus a. immune attack b. metabolic stress c. mechanical stress

8. 2. site of injury • injury to endothelium and subendothelial aspect of GBM (1) recruitment of leukocytes inflammatory glomerulonephritis (2) perturbed hemostasis thrombotic microangiopathy (1) or (2) + intrarenal vasoconstriction mesangial cell contraction renal failure

9. 2. site of injury • injury localized to mesangial area asymptomatic abnormalities of urinary sediment mild renal insufficiency • injury to subendothelial aspect of GBM and visceral endothelial cells proteinuria

10. 2. site of injury • injury to mesangium mildly compromised GFR • injury to parietal epithelial cells crescent formation (acute or subacute renal failure)

11. 3. nature of injury • rapid, extensive, immune complex deposition (poststreptococcal glomerulonephritis) diffuse acute inflammation “acute diffuse proliferative glomerulonephritis” acute renal failure • - complement activation • - leukocyte recruitment • - lysosomal enzyme release • - free radical generation • purturbation of vascular tone & • permeability

12. 3. nature of injury • slow, but sustained IgA-immune complex formation (IgA nephropathy) less active inflammation relatively well maintained GFR or slowly progressive renal insufficiency over decades

13. major mechanisms of injury • immune attack (immunologic glomerular injury) background abnormalities • dysregulation of humoral immunity autoantibody • cellular immune mechanism modulating antibody production antibody-dependent cell cytotoxicity “pauci-immune” glomerulonephritis robust glomerular inflammation without immunoglobulin deposition

14. b. metabolic stress (metabolic injury) hyperglycemia (1) advanced glycosylation end-products (AGEs) (2) reactive oxygen species cell sorbitol accumulation mitogen-activated protein kinase activation (3) high glucose-triggered glomerular hypertension (i) mesangial cell hypertrophy (ii) increased mesangial cell matrix production (iii) reduced matrix catabolism (iv) glomerulosclerosis

15. c. mechanical stress(hemodynamic glomerular injury) • systemic hypertension malignant hypertension massive fibrinoid necrosis of afferent arteriole and glomeruli thrombotic microangiopathy nephritic urinary sediment acute renal failure chronic sustained hypertension arteriolar vasoconstriction and sclerosis secondary glomerular and tubulointerstitial atrophy and sclerosis

16. c. mechanical stress(hemodynamic glomerular injury) • glomerular hypertension glomerular hypertension as an adaptive response to increased workload 2° to loss of other nephrons sustained glomerular hypertension increased mesangial matrix production glomerulosclerosis

17. final common pathways of glomerular injury • secondary focal segmental glomerulosclerosis • tubulointerstitial inflammation and fibrosis (tubulointerstitial fibrosis)

18. final common pathways of glomerular injurysecondary focal segmental glomerulosclerosis • nephron loss compensatory changes in surviving nephrons 1. vasodilation of afferent arterioles 2. glomerular hypertension 3. glomerular hyperfiltration sustained glomerular hypertension and hyperfiltration TGF-β, angiotensin II, PDGF, CTGF, endothelins accumulation of extracellular matrix focal and segmental glomerulosclerosis global sclerosis proteinuria, hypertension, progressive renal insufficiency

19. final common pathways of glomerular injurysecondary focal segmental glomerulosclerosis • glomerular hypertrophy intracapillary microthrombi recruited macrophages hyperlipidemia glomerulosclerosis

20. Nephrotic syndrome-ifferential diagnosis of nephrotic and nephritic syndrome Nephrotic syndrome is a group of symptoms including protein in the urine (more than 3.5 grams per day), low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling. * Increased permeability of the basement membrane-podocyte system to albumine Structural damage to the glomerulus due to inflammatory processes NEPHROSIS NEPHRITIS

21. Differential diagnosis of nephrotic and nephritic syndrome * • Urine: proteinuria (>3.5g, v. 40mg/m2/h) • Serum: hypoproteinemia, hypalbuminemia, hypercholesterinemia • Urine: hematuria, proteinuria, erythrocyte casts • Serum: normal total protein level NEPHROSIS NEPHRITIS

22. Differential diagnosis of nephrotic and nephritic syndrome * NEPHROSIS NEPHRITIS • GFR normal • BP: no hypertension • Decreased intravascular volume • GFR decreased • BP: hypertension • Increased intravascular volume

23. Conditions leading to nephrotic syndrome * • Conditions causing heavy proteinuria • Primary nephrosis: • Idiopathic nephrotic syndrome (INS) (=MCNS, lipoid nephrosis) • FSGS • Membranosus nephropathy • Membranoproliferatíve GN • Secondary nephrosis • SLE, Schönlein-Henoch nephropathy, amiloid nephropathy, diabetic nehropathy

24. Mechanisms of proteinuria • Structure of the filtration barrier • Role of the basement membrane • Humoral factors • Role of the podocyte

25. Structure of the filtration barrier Podocyte Foot processes Fenestrated endothelium

26. Mechanisms of proteinuria • Structure of the filtration barrier • Role of the basement membrane • Humoral factors • Role of the podocyte

27. Treatment-Hypovolemia/hypervolemia? * • (Donckerwolcke 2001 [110 MCNCS]) • Because of dynamic change of intravascular volume in nephrosis, treatment should be tailored in according to the volume state • Evaluation: • Blood pressure, CVP • U[K+]/(U[K+]+U[Na+]) correlates with plasma aldosterone level and is useful in monitoring hyovolemic states • Clinical estimate

28. Treatment of nephrotic syndrome • Supportive treatment • Treatment of steroid sensitive cases • Treatment of steroid resistant NS (FSGS)

29. Supportive tretment • Restore plasma volume/decrease edema • Decrease proteinuria • Prevent renal damage

30. Supplementary measures • Sodium restriction • Protein restriction 1g/kg + losses • Decreases proteinuria • Decreases sodium retention • Decreases the danger of development of secondary FSGS • Decreases the compensatory protein synthesis of the liver (hypoercholesterinemia& thrombophylia)

31. Supplementary measures • ACE inhibitors • Decreases proteinuria • Hemodynamic effect • Direct effect on podocytes • Decreases fibrosis • Indomethacin • Decreases GFR and proteinuria • Steroid: prednisone • Remission within 4 weeks

32. Definitions- Renal failure • Azotemia: Elevated blood urea nitrogen • (BUN>28mg/dL) & Creatinine (Cr>1.5mg/dL) • Uremia: azotemia with symptoms or signs of renal failure • End Stage Renal Disease (ESRD): uremia requiring transplantation or dialysis • Chronic Renal Failure (CRF): irreversible kidney dysfunction with azotemia >3 mos. • Creatinine Clearance (CCr): rate of filtration of creatinine by the kidney (marker for GFR) • Glomerular Filtration Rate (GFR): the total rate of filtration of blood by the kidney.

33. Renal Failure • Acute Renal Failure • Prerenal azotemia • An abnormally high level of nitrogen-type wastes in the bloodstream. It is caused by conditions that reduce blood flow to the kidneys. • Postrenal azotemia • An obstruction of some kind (i.e., bladder cancer, uric acid crystals, urethral stricture etc) • Intrinsic Renal Disease • Usually glomerular disease • Usually leads to End Stage Renal Disease

34. Chronic Renal Failure-Definition • CRF is defined as a permanent reduction in glomerular filtration rate (GFR) sufficient to produce detectable alterations in well-being and organ function. This usually occurs at GFR below 25 ml/min. • About 100 to 150 per million persons in the U.S. develop CRF annually • Average annual cost is $25,000 – 35,000 per patient per year • Progressive and irreversible deterioration in glomerular +/- tubular function measured over months and years

35. Chronic Renal Failure-Causes • Diabetic Nephropathy • Diabetes most common contributor to ESRD • Hypertension • CFR with Hypertension causes 23% of ESRD annually • Glomerulonephretis: 10% • Polycystic Kidney Disease: 5% • Rapidly progressive glomerulonephrities (vasculitis): 2% • Renal Vascular Disease (i.e., renal artery stenosis) • Medications • Analgesic Nephropathy (progression after many years) • Pregnancy: high incidence of increased creatitine and HTN during pregnancy associated with CRF

36. Stages of Chronic Renal Failure • Silent – GFR up to 50 ml/min. • Renal insufficiency – GFR 25 to 50 ml/min. • Renal failure – GFR 5 to 25 ml/min • End-stage renal failure – GFR less than 5 ml/min.

37. Diabetic Nephropathy • What can be done to reduce the risk of problems? • Blood glucose control • Blood pressure control • Using ACE inhibitors and AT II antagonists • Diet • Controlling blood lipids and cholesterol • Smoking

38. Treatment for Diabetic Nephropathy

39. Metabolic changes • Na+ excretion initially increased • Edema occurs when GFR continues to diminish. • NH4+ excretion declines adding to metabolic acidosis. • Bone CaCO3 begins to act as a buffer for the acidosis and leading to chronic bone loss and bone lesions develop (renal osteodystrophy). • Accumulations of normally secreted uremic toxins

40. Uremic Syndrome • Uremia occurs in stage 3 & 4 of CRF. It means literally “urine in the blood” • Symptomatic azotemia • Fever, Malaise • Anorexia, Nausea • Mild neural dysfunction • Uremic pruritus (itching)

41. Associated problems with CFR • Immunosuppression • Increased risk of infection • People with CFR should be vaccinated regularly • Anemia • Due to reduced erythropoietin production by kidney. Usually doesn’t occur until 6-12 mos prior to dialysis • Hyperuricemia (Gout) • Increased uric acid in system • Pain in joints, may contribute to renal dysfunction • Hyperphosphatemia • Increased parathyroid hormone levels • Increased phosphate load from bone metabolism • Hypertension • Poor coagulation • Proteinuria

42. Chronic Renal Failure • Chronic Renal Failure and Its Progression • Functional Adaptation to Nephron Loss • Increased amount of sodium that escapes reabsorption • Excessive amount of potassium in blood • Increased ammonia concentration • Calcium and phosphorus metabolism are markedly altered

43. Complications

44. Management of complications • Erythropoietin • Sodium bicarbonate • Calcium-based phosphate binders • Vitamin D supplementation • Statins • Anti-hypertensives

45. Treatment of Chronic Renal Failure • Metabolic Acidosis • Anemia • Renal Osteodystrophy • Uremic Neuropathy • Sexual Dysfunction • Hypertension

47. Treatment of End Stage Renal Failure • Hemodialysis • Uses a mechanized filter to remove impurities from the blood system • Essentially replaces kidney with a machine • Dialysis usually occurs a couple times per week.

48. Treatment of End Stage Renal Failure • Peritoneal Dialysis • Uses the abdominal cavity as a filter

49. Treatment of End Stage Renal Disease • Survival of People with ESRD • Data show a mean expected remaining life span of just under 8 years for people 40-44 beginning dialysis and just over 4 years for people 60-64 • Adequacy of Dialysis • Nutrition

50. Chronic Renal Failure • Physical Rehabilitation – benefits of exercise • Vocational Rehabilitation • The goal should be to help the person with chronic renal failure to resume all the duties, responsibilities and benefits he or she enjoyed prior to the illness • Gainful employment is extremely important for an adult in the earning period of his or her life, to regain self-esteem and to interact with society confidently • Fear of losing financial benefits may deter some people • Some research has shown that multidisciplinary predialysis intervention leads to maintenance of job