Glomerular diseases

General Medicine

1. Glomerular Diseases Natangwe Shimhanda MBChB V

2. Glomerulus A tuft of capillaries situated within a Bowman's capsule at the end of a renal tubule in the vertebrate kidney that filters waste products from the blood and thus initiates urine formation. T he basic filtration unit of the kidney.

3. Anatomy and Function

4. Molecules <1.8nm are freely filtered e.g water, sodium, insulin, glucose Molecules > 3.6nm are not filtered e.g hemoglobin

5. Renal Corpuscle

6. 3 Layers of the Glomerulus

7. Ultrafiltration Barrier Capillary Endothelium with fenestration pores filters everything except blood cells Basement membrane prevents filtration of large proteins Podocytes make the outer layer, and they have pedicels that allow only small molecules to pass through.

8. Filtration forces Filtration Depends on the Starling forces Oncotic pressure exerted by the plasma proteins in the glomerular capillaries and bowman’s capsule Hydrostatic pressure exerted by the fluid in the capillary walls

9. Glomerular Filtration Rate Total amount of filtrate in all the renal corpuscles in both kidneys per minute. Assesses kidney function Takes into account Net Filtration pressure (NFP), the surface area available for filtration and the permeability of the glomeruli

10. Creatinine Clearance Males {(140-age)* wt *1.22}/Cr Females {(140-age)* wt *1.22}/Cr multiply the answer by 0.85 Ranges M 97-137 F 88-128

11. GFR Normal GFR varies according to age, sex, and body size, and declines with age . The formula eGFR = k × height (cm) ÷ creatinine ( μmol /L) provides estimate of GFR .

12. Glomerular Diseases Glomerulonephritis is an inflammation of the glomerulus, while glomerulopathy is a term for disorders affecting this structure. Glomeruli may be injured by variety of factors and in course of several systemic diseases. Most of the glomerular diseases are immunologically mediated, whereas tubular and interstitial disorders are frequently caused by toxic or infectious agents.

13. Classification Focal (affecting only some of glomeruli) or Diffuse (affecting most or all glomeruli) Segmental / Global Primary glomerular disease (glomeruli are the predominant site of involvement) or Secondary glomerular disease (includes certain systemic and hereditary diseases which secondarily involve the glomeruli)

14. Immune mechanisms underlie most forms of primary glomerulopathies and many of secondary glomerular disorders . Damage by immune complexes Damage by cytotoxic antibodies Cell-mediated immune injury (delayed type hypersensitivity ) Damage by complement and proinflammatory mediators PATHOGENESIS OF GLOMERULAR INJURY

15. METABOLIC GLOMERULAR INJURY Diabetic nephropathy, Fabry’s disease HAEMODYNAMIC GLOMERULAR INJURY Systemic hypertension DEPOSITION DISEASES Amyloidosis , cryoglobulinaemia . INFECTIOUS DISEASES HBV, HCV, HIV, E.coli -derived nephrotoxin INHERITED GLOMERULAR DISEASES Alports syndrome NON IMMUNE MECHANISM OF CELLULAR INJURY IN GLOMERULUS

16. 1. Proteinuria Transient proteinuria may occur during febrile illnesses or after exercise and does not require investigation. Persistent proteinuria is significant and should be quantified by measuring the urine protein/ creatinine ratio in an early morning sample (protein should not exceed 20 mg/ mmol of creatinine ).

17. Causes of proteinuria Orthostatic proteinuria Glomerular abnormalities – Minimal change disease – Glomerulonephritis – Abnormal glomerular basement membrane (familial nephritides) Increased glomerular filtration pressure Reduced renal mass Hypertension Tubular proteinuria.

18. (i) Nephrotic syndrome A nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of  protein  from the blood into the urine . Clinical state characterised by: Heavy proteinuria, 50mg/kg Hypoalubinaemia , 25gm/l Oedema Generalised hyperlipaedaemia

19. Primary causes Minimal-change nephropathy Focal glomerulosclerosis Membranous nephropathy Hereditary nephropathies Nephrotic syndrome

20. Secondary causes Diabetes mellitus Amyloidosis and paraproteinemias Post infectious- Group A beta haem strep and other bacteria eg . Typhoid and syphilis Malaria Viral-chickenpox, HIV, Hep B, EBV Renal vein thrombosis Collagen vascular-SLE, Nephrotic syndrome

21. Causes Cont ’ Hereditary nephritis- nail patella and Alport’s Sickle cell disease Malignancy : leukaemia , lymphoma, wilm’s Toxins: Bee stings, poison ivy, oak, snake vernom Drugs: probrnicid , captopril, heroin, mercury, gold, penicillamine etc

22. Signs and symptoms Hypoalbuminemia Edema Hypercholesterolemia Hypoalbuminemia Tiredness Leukonychia Breathlessness fluid overload Dyslipidaemia Nephrotic syndrome

23. TREATMENT Supportive Treatment Monitoring and maintaining euvolemia Monitoring urine output, BP regularly Fluid restrict to 1L. Diuretics (IV furosemide ). Nephrotic syndrome

24. TREATMENT Supportive Treatment Monitoring kidney function Do U &E daily and calculating GFR Treat hyperlipidemia to prevent further atherosclerosis. Prevent and treat any complications Nephrotic syndrome

25. TREATMENT Specific Treatment Immunosuppression for the glomerulonephritides Corticosteroid therapy: 60 mg/m2 per day of prednisolone Nephrotic syndrome

26. T reatment The steroid sensitive Nephrotic Syndrome resolves spontaneously after a corticosteroid therapy course. A renal biopsy must be done if unresponsive or atypical features. Steroid-resistant nephrotic syndrome: Management of the oedema is by diuretic therapy , salt restriction, ACE inhibitors and sometimes NSAIDs which may reduce proteinuria

27. (ii) Congenital nephrotic Syndrome Presents in utero , from birth up to 3/12 Infantile: 4/12 up to 1 year of life . Primary Causes Infantile microcytic disease Diffuse mesangial sclerosis ( Drash ) Minimal change lesion Focal Glomerulosclerosis

28. Secondary congenital and infantile: Infections: syphilis, Toxoplasmosis, CMV, Rubella, Malaria Toxic: mercury SLE HUS Drug reaction Hepatoblastoma Syndromes: Nail patella, Lowe syndrome etc

29. Epidemiology: 2-7 children per 100,000 children/year 15 times more common in children than adults Incidence higher in black children M:F=2:1

30. Pathophysiology : Protein : normal urine in children has 100mg protein/24hrs (adults 150mg). Consists of albumin and Tamm- Horsfall protein of tubular origin. Increased protein loss is due to: Increased capillary permeability. Increased in size of pores of GBM

31. Pathophysiology continue: Selectivity: type of protein lost varies with the underlying glomerular disease. Minimal change- highly selective, other glomerular disease non selective. Hypoalbuminaemia : due to excessive urinary loss of albumin. Oedema: cardinal feature of nephrotic d ue to decreased plasma oncotic pressure

32. Clinical manifestations: Oedema usual and a predominant features Gastrointestinal disturbances e.g Dirrhoea (oedema of intestinal mucosa) hepatomegaly Abdominal pain- peritonitis, UTI Tachypnoea –pleural effusions, ascites , infection Poor appetite Psychological functional disturbances

33. Investigations : Proteinuria may be selective or non selective Urine Protein/ creatinine ratio < 0,2 normal 0,1-0,5 minimal 0,2-2,0 moderate > 2,0 nephrotic FBC+ diff, ESR, u+e , Total protein, albumin, cholesterol, INR, C3/C4, ASOT, Anti- DNASe B, Hepatitis B, WR, HIV, ANA, CXR, TST, CMP

34. Complications : Renal failure: acute renal failure, HPT Infections: bacterial Thromboembolism : platelets, protein S&C def FTT and malnutrition Premature atherosclerosis from hyperlipemia Calcium and Vitamin D metabolism

35. 2. Hematuria Urine that is red in colour or tests positive for haemoglobin on urine sticks should be examined under the microscope to confirm haematuria (>10 red blood cells per high-power field ). Glomerular haematuria is suggested by brown urine, the presence of deformed red cells (which occurs as they pass through the basement membrane ) and casts, and is often accompanied by proteinuria .

36. Causes of Hematuria Non-glomerular Infection (bacterial, viral, TB, schistosomiasis ) Trauma to genitalia, urinary tract or kidneys Stones Tumours Sickle cell disease Bleeding disorders Renal vein thrombosis Hypercalciuria . Glomerular Acute glomerulonephritis (usually with proteinuria ) Chronic glomerulonephritis (usually with proteinuria ) IgA nephropathy Familial nephritis, e.g. Alport syndrome Thin basement membrane disease.

37. Acute nephritis Increased glomerular cellularity restricts glomerular blood flow and therefore filtration is decreased . This leads to: decreased urine output and volume overload hypertension , which may cause seizures oedema , characteristically around the eyes haematuria and proteinuria.

38. Causes Post-infectious (including streptococcus ) Vasculitis ( Henoch – Schönlein purpura or, rarely, SLE , Wegener granulomatosis , microscopic polyarteritis , polyarteritis nodosa ) IgA nephropathy and mesangiocapillary glomerulonephritis Anti-glomerular basement membrane disease ( Goodpasture syndrome) – very rare.

39. Management Management is by attention to both water and electrolyte balance and the use of diuretics when necessary. Rarely, there may be a rapid deterioration in renal function (rapidly progressive glomerulonephritis). This may occur with any cause of acute nephritis, but is uncommon when the cause is post-streptococcal. If left untreated, irreversible renal failure may occur over weeks or months, so renal biopsy and subsequent treatment with immunosuppression and plasma exchange may be necessary.

40. Post-streptococcal and post-infectious nephritis Usually follows a streptococcal sore throat or skin infection and is diagnosed by evidence of a recent streptococcal infection (culture of the organism, raised ASO/ anti- DNAse B titres ) and low complement C3 levels that return to normal after 3–4 weeks. Streptococcal nephritis is a common condition in developing countries, but has become uncommon in developed countries. Longterm prognosis is good.

41. Treatment Phenoxymethylpenicillin 250mg/5ml P.O Q.I.D 5/7 or Azithromycin 10mg/kg P.O 3/7

42. Henoch – Schönlein purpura It usually occurs between the ages of 3 and 10 years, is twice as common in boys, peaks during the winter months and is often preceded by an upper respiratoryinfection . Despite much research, the cause is unknown. It is postulated that genetic predisposition and antigen exposure increase circulating IgA levels and disrupt IgG synthesis. The IgA and IgG interact to produce complexes that activate complement and are deposited in affected organs, precipitating an inflammatory response with vasculitis .

43. Henoch – Schönlein purpura Henoch – Schönlein purpura is the combination of some of the following features: • Characteristic skin rash • Arthralgia • Periarticular oedema • Abdominal pain • Glomerulonephritis.

44. Clinical Findings At presentation, affected children often have a fever. The rash is the most obvious feature. It is symmetrically distributed over the buttocks, the extensor surfaces of the arms and legs, and the ankles. The trunk is spared unless lesions are induced by trauma . The rash may initially be urticarial, rapidly becoming maculopapular and purpuric .

45. Management if severe, can be treated with corticosteroids All children with renal involvement are followed for a year to detect those with persisting urinary abnormalities (5–10 %), who require long-term follow-up. This is necessary as hypertension and declining renal function may develop after an interval of several years.

46. IgA nephropathy This may present with episodes of macroscopic haematuria , commonly in association with upper respiratory tract infections. Histological findings and management are as for Henoch – Schönlein purpura , which may be a variant of the same pathological process but not restricted to the kidney .

47. Vasculitis The commonest vasculitis to involve the kidney is Henoch – Schönlein purpura (see above). However, renal involvement may occur in rarer vasculitides such as polyarteritis nodosa , microscopic polyarteritis and Wegener granulomatosis . Characteristic symptoms are fever , malaise, weight loss, skin rash and arthropathy with prominent involvement of the respiratory tract in Wegener disease . ANCA ( antineutrophil cytoplasm antibodies ) are present and diagnostic in these diseases. Renal arteriography, to demonstrate the presence of aneurysms, will diagnose polyarteritis nodosa . Renal involvement may be severe and rapidly progressive. Treatment is with steroids , plasma exchange and intravenous cyclophosphamide , which may need to be continued for many months.

48. Systemic lupus erythematosus (SLE) SLE is a disease that presents mainly in adolescent girls and young women. It is much commoner in Asians and Afro- Caribbeans than Caucasians. It is characterized by the presence of multiple autoantibodies, including antibodies to double-stranded DNA. The C3 and C4 components of complement may be low, particularly during active phases of the disease. Haematuria and proteinuria are indications for renal biopsy, as immunosuppression is always necessary and its intensity will depend on the severity of renal involvement.

49. Glomerulonephritis Also known as glomerular nephritis  (GN) or  glomerular disease It is a disease of the kidney, characterized by inflammation of the glomeruli

50. Acute Glomerulonephritis Cause infections such as strep throat Lupus erythematous Goodpasture's syndrome Wegener's disease polyarteritis nodosa Glomerulonephritis

51. Acute Glomerulonephritis Symptoms Puffy face in the morning hematuria (or brown urine) oliguria Glomerulonephritis

52. Chronic Glomerulonephritis Cause This condition may develop after survival of the acute phase of rapidly progressive glomerulonephritis Glomerulonephritis

53. Chronic Glomerulonephritis Signs and symptoms Proteinuria/ hematuria High blood pressure oedema nocturia Very bubbly or foamy urine Glomerulonephritis

54. Diagnosis Urine test Blood test  Throat swab  Renal function tests Kidney biopsy  Imaging tests  Glomerulonephritis

55. Treatment Diet salts restrictions and adequate fluid intake  The following medications may also be prescribed to treat possible underlying causes: Bacterial infections - a targeted  antibiotic Lupus or vasculitis - corticosteroids and immunosuppressants Glomerulonephritis

56. Treatment IgA - possibly fish oil supplements. Goodpasture's syndrome - plasmapheresis is a procedure designed to reduce blood plasma levels without depleting the body of its blood cells. Antibodies are removed and donated plasma replaces the depleted plasma Glomerulonephritis

57. Investigations of Hematuria All patients • Urine microscopy (with phase contrast) and culture • Protein and calcium excretion • Kidney and urinary tract ultrasound • Plasma urea, electrolytes, creatinine , calcium, phosphate , albumin • Full blood count, platelets, clotting screen, sickle cell screen. If suggestive of glomerular haematuria • ESR, complement levels and anti-DNA antibodies • Throat swab and antistreptolysin O/anti- DNAse B titres • Hepatitis B and C screen • Renal biopsy if indicated • Test mother’s urine for blood (if Alport syndrome suspected ) • Hearing test (if Alport syndrome suspected).

58. Hemolytic Uraemic Syndrome Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive renal failure that is associated with microangiopathic ( nonimmune , Coombs-negative) hemolytic anemia and thrombocytopenia. It predominantly, but not exclusively, affects children. Most cases are preceded by an episode of infectious, sometimes bloody, diarrhea acquired as a foodborne illness or from a contaminated water supply caused by E. coli O157:H7, other non-o157:H7 E. coli serotypes, Shigella , and Campylobacter.

59. The typical pathophysiology of HUS involves the binding of Shiga-toxin to the globotriaosylceramide (Gb3; also called ceramide trihexoside which accumulates in Fabry disease) receptor on the surface of the glomerular endothelium.

60. Hereditary Glomerulopathies Predominant hematuria Alport’s syndrome Benign Familial hematuria Hemolytic Uraemic Syndrome

61. Alport’s syndrome Genetically heterogeneous disease arising from mutations of the gene coding for type IV collagen , a major constituent of the basement membrane. Persistent hematuria often progressing proteinuria, hypertension and renal failure. Often associated with high frequency sensori -neural deafness and ocular defects

62. Benign Familial hematuria is usually due to the thin basement membrane. No associated deafness and the condition is inherited as an autosomal dominant.

63. References Lissauer T, Clayden G, 2012. Illustrated Textbook Of Paediatrics . Fourth edition . © 2012 Elsevier Ltd Wittenberg D.F. (2009), Coovadia’s Paediatrics and Child Health. Oxford University Press Southern Africa ( pty ) Ltd