Proteinuria. Dr. Kelvin kai-leung. HO Honorary Consultant in Nephrology Hong Kong Sanatorium Hospital. Dr Kelvin Ho 1

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1 Proteinuria Dr. Kelvin kai-leung HO Honorary Consultant in Nephrology Hong Kong Sanatorium Hospital 1

2 Normal value of protein in urine <150mg/day 30-50mg is mucoprotein secreted by the Loop of Henle <15mg is albumin The remaining protein is normally filtered at the glomeruli 2

3 Isolated proteinuria Aetiology: Proteinuria usually reflects an increase in glomerular permeability that allows the filtration of normally non-filtered macromolecules such as albumin, across the capillary wall 3

4 Proteinuria The increase in permeability can be due to: Structural injury of the glomeruli Loss of the charge barrier ( - ve charge) across the membrane 4

5 Isolated proteinuria (I) Presentations: (1) Obvious signs of glomerular disease: Heavy proteinuria (>3gm/day) Frothy urine Dependent oedema Active urinary sediments e.g. red cell casts, hyaline casts 5

6 Microscopy hyaline cast 6

7 Red blood cell cast Granular cast Marker of glomerular injury 7

8 Urine microscopy - rbc 8

9 Isolated proteinuria (II) Presentations: (2) Asymptomatic: Presence of protein is discovered incidentally by routine dipstick urinalysis e.g. body check for insurance or job application 9

10 What to do? Questions to ask: 1. How does the protein being produced? 2. How much protein is excreted? 3. What type of protein is excreted? 10

11 Conditions under which protein is excreted 1. Transient/intermittent proteinuria: Most common. 4% men. 7% women Single episode with resolution in subsequent examinations Stress; fever; exercise 11

12 Conditions under which protein 2. Orthostatic proteinuria: is excreted Mainly in adolescents and is uncommon over the age of 30. Increase in protein excretion in the upright position but normal protein excretion when supine. Separate collection of urine during the day time (upright for 8 hrs) and at night (supine 8hrs). It s s a benign condition. The increase in protein excretion resolves spontaneously in most patients. 12

13 Conditions under which protein is excreted 3. Persistent proteinuria: Most likely to reflect renal diseases: Diabetic nephropathy Glomerulonephritis e.g. IgA nephropathy, membranous nephropathy, lupus nephritis etc Hypertensive nephrosclerosis Polycystic kidney disease Analgesic nephropathy or systemic disorder e.g. CHF 13

14 Degree of proteinuria (I) Amount of protein excreted is measured with a 24-hour urine collection Calculating the total protein-to to-creatinine ratio (mg/mg) on a random urine specimen ( a drawback of less accurate with different variables e.g. body sizes and state of nutrition) (Urine dipstick is less predictive because it reflects the urine protein concentration which is influenced by the urine volume) 14

15 Degree of proteinuria (II) The quantity of protein is important because: It reflects the severity of the renal disease: the lower the degree of proteinuria the better (e.g. of < 1gm/day usually reflects a less severe form of the renal disease) It is prognostically important in patients with a glomerular disease e.g IgA nephropathy (the higher the degree of proteinuria at presentation predicts a higher chance of ESRF in the future), membranous nephropathy, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy the higher the degree of proteinuria reflects a less favourable prognosis guides whether the use of immunosuppressive drugs in an individual disease e.g. when proteinuria > 3gm/day. 15

16 Types of protein excreted 1. Non selective in size of protein molecules in various types of glomerulonephritis 2. Highly selective of small size protein molecules in minimal change disease 3. Low-molecular molecular-weight protein due to over production of immunoglobulin light chains in multiple myeloma 16

17 Analysis of proteinuria by urinalysis Urine dipstick primarily detects albumin for protein. A positive test usually indicates glomerular protein. However, dipstick is relatively insensitive. Not becoming positive until total protein excretion is > mg/day (can miss microalbuminuria in DM) Results may be variable with urine protein concentration. False +ve+ results in patients after contrast medium has been administrated (to repeat after 24 hrs) 17

18 Urine analysis Microscopic study: Red blood cells Urine sediments: Red cell casts Hyaline casts 18

19 Workup of the patient with proteinuria Evaluation of mild proteinuria should test the urine on at least 2 other occasions. Elevate by 24hup if persistent proteinuria (consider orthostatic proteinuria in adolescents and young adults): Separate collection of urine during the day time (upright for 8 hrs) and at night (supine 8hrs). Examine the urine for sediments, red blood cells, red cell casts etc Take a careful medical history including: HT, DM, CHF, prior history of renal diseases 19

20 Persistent proteinuria +/- a negative history U/S or IVU to look for a structural lesions e.g PKD, chronic pyelonephritis (cystoscopy if isolated haematuria only exists) If all negative Monitor 24hup; urinalysis & sediments; BP & Cr Renal biopsy: if increasing protein excretion or worsening of renal function e.g CrCl or plasma Cr 20

21 Monitoring of urine protein excretion Is a very useful measurement Establish the diagnosis Follow the course of glomerular disease e.g. diabetic nephropathy; IgA nephropathy 21

22 Diabetic nephropathy The presence of microalbuminuria = diagnosis of diabetic nephropathy. Gross proteinuria is a finding of later stage of the renal disease 22

23 Diabetic Nephropathy: : albumin excretion rates Dipstick for protein 24-hour protein (mg) 24-hour albumin (mg) Timed collection (ug/min) Spot collection Normal -- <150mg <30mg <20 <30ug alb/mg Cr Micro- albuminuria Overt Nephropathy -- <500mg mg ug alb/mg Cr + 500mg >300mg > ug alb/mg Cr 23

24 Continuum of the renal injury STAGE STAGE II RISK RISK (R) (R) STAGE STAGE II II INJURY INJURY (I) (I) STAGE STAGE III III FAILURE FAILURE (F) (F) STAGE STAGE IV IV LOSS LOSS (L) (L) STAGE STAGE V ESRD ESRD (E) (E) Severity Outcome 24

25 25

26 Renal failure 26

27 Definition Chronic renal failure (CRF) is defined as a substantial and irreversible reduction in renal function over a period of months to less than 20% of normal. It is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. 27

28 Causes of CRF Primary or seconday glomerulonephritis Diabetic nephropathy Hypertensive nephrosclerosis PKD Chronic pyelonephritis Analgesic nephropathy Vesicoureteric reflux Renal tuberculosis Nephrocalcinosis Obstructive uropathy 28

29 Percent Distribution of Incidence of ESRD by Primary Diagnosis in yr 2004 in Hong Kong Primary Etiology Diabetes Glomerulonephritis Hypertension Unknown Others Incidence(%)

30 Incidence of ESRF in H.K. Annual incidence of new cases require RRT: 100 per million population (PMP) in PMP in 2003 Currently > 7000 patients require RRT in

31 Staging of chronic kidney disease Stage Description GFR (ml/min/1.73 sq.m) 1 Slight kidney damage with normal or increased filtration >90 2 Mild decrease in kidney function Moderate decrease in kidney function Severe decrease in kidney function Kidney failure requiring dialysis or transplantation <15 31

32 CRF typically occurs in three stages: 1. Compensatory stage. 50ml/min<GFR<80ml/min, Cr<178umol/L(2mg/dl), BUN<9mmol/L (25mg/dl), and no symptoms. 2. Decompensatory stage. 25ml/min<GFR<50ml/min, Cr>178umol/L, BUN>9mmol/L, lightly gastrointestinal signs(anorexia, nausea, and vomiting) and anemia. 3. Uremic stage. GFR<25ml/min, Cr>445umol/L(5mg/dl), BUN>20mmol/L(55mg/dl), typical uremic symptoms. 32

33 Symptoms early stages of renal failure are often completely asymptomatic malaise, loss of energy loss of appetite insomnia nocturia and polyuria due to impaired concentrating ability itching nausea, vomiting and diarrhoea paraesthesiae due to polyneuropathy 'restless legs' syndrome (overwhelming need to frequently alter position of lower limbs) 33

34 bone pain due to metabolic bone disease paraesthesiae and tetany due to hypocalcaemia symptoms due to salt and water retention - peripheral or pulmonary oedema symptoms due to anaemia amenorrhoea in women; erectile dysfunction in men In more advanced uraemia (serum urea > mmol/l), these symptoms become more severe, and CNS symptoms are common: mental slowing, clouding of consciousness, and seizures myoclonic twitching. 34

35 Physical signs short stature - in patients who have had chronic renal failure in childhood pallor - due to anaemia brown discoloration of the nails scratch marks due to uraemic pruritus signs of fluid overload pericardial friction rub murmurs - mitral regurgitation due to mitral annular calcification; aortic and pulmonary regurgitant murmurs due to volume overload peripheral sensory loss (rare). 35

36 Symptoms and signs of chronic renal failure 36

37 Physical signs In CRF 37

38 Haematology Investigations Full blood count: normochromic normocytic anemia Haematinics: : folic acid, Vit B12, Iron Biochemistry Blood Urea, electrolytes and creatinine: : to assess the severity of renal failure- blood ureana nd creatinine elevated; hyperuricemia, hyperkalemia,, decrease bicarbonate Blood Calcium, phosphate and albumin: hypocalcemia, hyperphosphatemia Lipids, glucose ± HbA1c 38

39 Microbiology Hepatitis and HIV serology: if dialysis is needed (vaccination against hepatitis B if no previous infection; isolation of dialysis machine if positive) Imaging Renal ultrasound: usually shrunken kidneys; but in diabetic glomerulosclerosis, amyloidosis,, polycystic kidney diseases, bilateral hydronehrosis kidney size may be normal. Chest X-ray: X heart size, pulmonary oedema ECG: if > 40 years or there are risk factors for cardiac disease Renal artery imaging: if renovascular disease is suspected 39

40 Immunology : Blood Grouping Tissue typing Cytomegalovirus, Epstein-Barr virus, varicella zoster virus Renal biopsy: If transplantation is considered/ If diagnosis is not known: Immunoglobulins and protein electrophoresis Urinary Bence Jones protein Complement ANA: and dsdna if ANA is positive ENA (extractable nuclear antigens ): if a connective tissue disorder is suspected Rheumatoid factor ANCA: in all possible inflammatory renal disease Anti-GBM: in all possible inflammatory renal disease Cryoglobulins: : if cryoglobulinaemia is clinically suspected 40

41 Treatment A. Treatment of any underlying reversible cause of renal failure B. Slowing the rate of progression C. Treating the complications of CRF D. Renal replacement therapy Dialysis: Hemodialysis and Peritoneal dialysis Renal Transplantation 41

42 Reversible factors in chronic renal Hypertension Reduced renal perfusion failure Renal artery stenosis Hypotension due to drug treatment Sodium and water depletion Poor cardiac function Urinary tract obstruction Urinary tract infection Other infections: increased catabolism and urea production Nephrotoxic medications 42

43 Slowing the rate of progression of CRF Control of blood pressure and proteinuria: ACE inhibitors: Enalapril, Ramipril Angiotensin-II receptors blocker: Losartan Diet : Low salt diet Moderate protein restriction (to 60 g protein per day) Adequate intake of calories 43

44 Treatment of complications of CRF 1. Anaemia 2. Fluid and electrolyte balance 3. Acidosis 4. Cardiovascular disease and lipids 5. Infection 6. Bleeding 7. Renal osteodystrophy 8. Myopathy 44

45 Anaemia A normocytic, normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4. Causes of anemia in CRF: relative deficiency of erythropoietin diminished erythropoiesis due to toxic effects of uraemia on marrow precursor cells reduced red cell survival increased blood loss due to capillary fragility and poor platelet function reduced dietary intake and absorption of iron and other haematinics. 45

46 Anemia: Treatment Iron supplementation Recombinant human Erythropoietin (EPO) and modified EPO products, such as darbopoetin- alpha Vitamin B12 and Folate Blood transfusions 46

47 Cardiovascular Abnormalities Cardiovascular disease is the leading cause of morbidity and mortality in patients at every stage of CKD 45% of patients reaching stage 5 CKD already have advanced cardiovascular complications Ischemic vascular disease: occlusive coronary artery, cerebrovascular,, and peripheral vascular disease Heart failure: Abnormal cardiac function secondary to myocardial ischemia, left t ventricular hypertrophy, and frank cardiomyopathy,, in combination with the salt and water retention that can be seen with CKD, often results in heart t failure or even episodes of pulmonary edema HTN and LVH Hypertension develops in approximately 80% of patients with CRF Chronically diseased kidneys also tend to hypersecrete renin,, leading to high circulating concentrations of renin, angiotensin II and aldosterone 47

48 Fluid and electrolyte balance Limitation of potassium intake (e.g. 70 mmol/day), sodium intake (e.g. 2-3g 2 or mmol/day) and PO4 800mg/d may be required in late CRF Fluid restriction may be required In some cases, high sodium and water intake : for salt wasting diseases (renal cystic disease, obstructive uropathy,, reflux nephropathy or other tubulo-interstitial diseases) g/day NaCl by oral. It is usual to start with g/day and increase the dose as required. Sodium bicarbonate may be substituted in part for sodium chloride when acidosis requires correction 48

49 Renal osteodystrophy It is a mixture of osteomalacia, hyperparathyroid bone disease (osteitis fibrosa), osteoporosis and osteosclerosis Diminished activity of 1α-hydroxylase 1 enzyme (cholecalciferol( to its active metabolite, 1,25-dihydroxycholecalciferol ) Due to deficiency of calcitriol there is diminished intestinal absorption of calcium, hypocalcaemia and reduction in the calcification of osteoid in bone Hypocalcaemia is corrected by giving 1α-hydroxylated 1 synthetic analogues of vitamin D Hyperphosphataemia is controlled by dietary restriction of foods with high phosphate content (milk, cheese, eggs) and the use of phosphate-binding drugs administered with food (e.g. calcium carbonate and aluminium hydroxide). 49

50 Pathophysiology : renal osteodystrophy 50

51 Neuromuscular Abnormalities Generalised myopathy is due to a combination of poor nutrition, hyperparathyroidism, vitamin D deficiency and disorders of electrolyte metabolism Hiccups, cramps, and fasciculations or twitching of muscles. Advanced stage: asterixis, myoclonus,, seizures, and coma Restless leg syndrome is characterized by ill-defined sensations of sometimes debilitating discomfort in the legs and feet relieved by frequent leg movement Evidence of peripheral neuropathy without another cause (e.g., diabetes mellitus) is a firm indication for starting renal replacement therapy 51

52 Gastrointestinal Abnormalities Anorexia followed by nausea, and vomiting is commonly seen Higher incidence of peptic ulcer disease in uraemic patients : treat with H2-receptor H antagonists or proton pump inhibitors 52

53 Endocrine-Metabolic Disturbances Glucose metabolism is impaired in CKD Kidney contributes to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic patients In women with CKD, estrogen levels are low,, and menstrual abnormalities and inability to carry pregnancies to term are common (spontaneous abortion) Men with CKD have reduced plasma testosterone levels, and sexual dysfunction and oligospermia In both sexes there is loss of libido and sexual function 53

54 Strategies for preventing progressive nephropathy in diabetic patients Major treatment strategies Blood pressure control: <130/85 in DM, and <125/75mmHg,? the lower the better Potentially better choice of ARB Glycaemic control Low-protein diet Reduction in proteinuria predicts slower decline in GFR ARBs e.g. Irbesartan (IRMA 2 PRIME), Losartan (RENAAL) a very useful indicator of therapeutic response 54

CHRONIC KIDNEY DISEASE (CKD)

CHRONIC KIDNEY DISEASE (CKD) CKD implies longstanding (more than 3 months), and usually progressive, impairment in renal function. In many instances, no effective means are available to reverse the primary