Proteinuria in the Diagnosis & Management of Kidney Disease

1. Proteinuriain the Diagnosis & Management of Kidney Disease Dr Shamila De Silva Consultant Physician Senior Lecturer in Medicine Faculty of Medicine, Ragama

2. Proteinuria • Marker of renal disease • Mediates progressive renal dysfunction • Independent risk factor for CVD

3. In this lecture… • Causes of proteinuria • Evaluating a patient with proteinuria • Managing proteinuria

4. Pathophysiology • Low molecular weight proteins in plasma filtered in to tubules • Almost completely re-absorbed in PCT • Normal daily protein excretion <150 mg • Of this albumin = 10 mg

5. Types of Proteinuria • ‘Functional’ • Orthostatic • Overflow • Tubular • Glomerular

6. ‘Functional’ Proteinuria • Transient • Sub-nephrotic • Exercise • Fever • Heart failure

7. Orthostatic Proteinuria • Proteinuria only in upright position • Benign • Early morning samples normal, but proteinuria in samples collected during day

8. Overflow Proteinuria • Increased filtration of LMW protein through a normal glomerulus • Free light chains in Myeloma (Bence-Jones proteinuria) • No albumin – dipstick negative

9. Tubular Proteinuria • Injury to tubulo-interstitial compartment • Loss of normal filtration & reabsorption of proteins • Loss of proteins released by tubular epithelial cells in response to injury

10. Glomerular Proteinuria • Increased permeability of glomerular capillary wall to macromolecules, sp albumin • Persistent • May be associated with haematuria & ↓ GFR

11. Classification of Pathological Proteinuria

12. Presentation of Renal Disease with Proteinuria • Asymptomatic • Symptomatic - Nephrotic Nephritic

13. Asymptomatic • Most • Routine testing • Screening high risk patients

14. High Risk in… • Diabetes • Hypertension • CVD – IHD, CHF, PVD, CVD • Structural renal tract disease, calculi or prostatic hypertrophy • Multi-system disease - SLE • Family h/o Stage 5 CKD or hereditary kidney disease

15. Nephrotic Syndrome • Proteinuria >50 mg/kg/day (>3.5 g/d in 70 kg adult) • Hypoalbuminaemia • Oedema • Hyperlipidaemia

16. Clinically.. • Oedema – peri-orbital, ankle, sacral, genital • Pleural effusions, ascites • Leukonychia • Xanthelasma • Frothy urine

17. Causes of Nephrotic Syndrome • Diabetic nephropathy • Membranous nephropathy • Minimal change disease • Focal segmental glomerulosclerosis • Mesangiocapillary GN • Renal amyloidosis

18. Nephritic Syndrome • Oedema • Hypertension • Proteinuria + significant haematuria • ↓ GFR

19. Clinically.. • ↓ urine output • Smoky urine • Ankle oedema • Evidence of systemic disease +/-

20. Causes of Nephritic Syndrome • Post-infectious GN • IgA Nephropathy • ANCA-associated vasculitis - Wegener’s , MPA • Anti-GBM disease - Goodpasture’s

21. Evaluating Proteinuria • Repeat dipstick • Urine culture & ABST • Quantify proteinuria • Measure excretory renal function

22. Quantifying Proteinuria • 24 h urine protein • Albumin or Protein concentration in ‘spot’ urine sample Corrected for hydration state  (1) albumin/creatinine ratio (ACR)– more sensitive, for detection & identification (2) protein/creatinine ratio (PCR)– for quantification & monitoring

23. Normal Proteinuria • <150 mg/day • Urine PCR <15 mg/mmol

24. Nephrotic-range Proteinuria • >3.5 g/d (PCR >350 mg/mmol) • Predominantly albumin in glomerular disease

25. Non-nephrotic Proteinuria • 150 mg – 3.5 g/d • PCR 15 – 350 mg/mmol • Glomerular disease • Non-glomerular parenchymal renal disease • Urinary tract disease

26. Cause of Proteinuria Related to Quantity

27. Microalbuminuria • Albumin excretion 30 – 300 mg/d • ACR - 2.5 – 30 mg/mmol for men 3.5 – 30 mg/mmol for women • Not detected by dipsticks • Early DM nephropathy • Indicator of CVD risk in at-risk populations

30. Cardiovascular survival (Kaplan-Meier) according to microalbuminuria status in a population-based cohort aged 50 to 70 yr.

31. Measuring Excretory Renal Function • Plasma Creatinine • Calculate eGFR • Categorize according to CKD stage

32. Classification of CKD – NKF-KDOQI 2000 Stage Description GFR • Normal GFR + other evidence of CKD* >90 • Mild Impairment 60-89 • Moderate Impairment 30-59 • Severe Impairment 15-29 • Established Renal Failure (ERF) <15 *persistent microalbuminuria persistent proteinuria persistent haematuria structural abnormalities of kidneys biopsy-proven chronic GN

34. When to Refer for Specialist Renal Assessment • ACR >70 unless due to diabetes and already treated • ACR >30 with haematuria • Stage 4 or 5 CKD with or without diabetes irrespective of level of proteinuria • Rapidly declining eGFR 5 ml/min in 1 year or 10 ml/min within 5 years irrespective of level of proteinuria

36. Management - Aims • Identify underlying cause  treat where possible • Minimise risk of renal function deterioration  control HPT, ↓ proteinuria • Minimise risk of CVD • Prepare patients with progressive renal disease for RRT

37. General Management • Exercise • Healthy weight • Stop smoking

38. BP Control in Non-diabetics • Aim <140/90 • ACR >30  ACEI (ARB if intolerant) • ACR >70  ACEI + ARB is better • ACR >70 but NOT hypertensive  ACEI + ARB is reno-protective

39. BP Control in Diabetics • ACR >2.5 (men) & >3.5 (women)  ACEI or ARB (even if not hypertensive) • Increase ACEI/ARB to maximum tolerated dose before adding second agent • DM + CKD or ACR ≥ 70 mg/mmol  Aim to keep BP <130/80

40. Limit dietary sodium to 50-70 mmol/d • Check S.K+ & eGFR 1-2 weeks after commencing or increasing dose of ACEI or ARB • If K >6 mmol/l or eGFR ↓ by >25% from baseline (s.creatinine ↑ by >30%)  stop ACEI/ARB

43. CVD Risk Management • Major cause of mortality in patients with proteinuric renal disease • Statins for primary & secondary prevention • Low dose Aspirin for secondary prevention • Avoid multiple antiplatelet drugs in CKD  high bleeding risk

44. In Summary… • Proteinuria is a powerful risk factor for development of progressive renal dysfunction and CVD • Measurement of urine albumin to creatinine ratio (or protein to creatinine ratio) on a ‘spot’ urine sample has made 24-hour urine collections for proteinuria quantification unnecessary • Screening for proteinuria should be undertaken in patients with risk factors for development of CKD

45. Early identification of patients with proteinuria offers the best chance of preventing progressive renal dysfunction • BP control, blockade of RAAM & CVD risk factor management are the key therapeutic goals in proteinuric patients

46. References • Topham P. Proteinuric renal disease. Clinical Medicine 2009;9(3):284-7 • Early identification and management of chronic kidney disease in adults in primary and secondary care. Clinical guideline CG73. London: NICE, 2008. www.nice.org.uk/Guidance/CG73 • Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Review. Kidney International 2005;67:799–812.

47. Acknowledgements • Colleagues at the Department of Medicine, Ragama, sp Prof Janaka De Silva • Mentors throughout my career, sp Dr Sivakumaran & Prof Ken Farrington • My husband