CURICULUM VITAE. Riwayat Pendidikan : Dokter FK UNDIP 1981 Sp.Patologi Klinik 1997 Konsultan Sp2 Patologi Klinik 2007 Doktor 2015

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1 CURICULUM VITAE Nama : Dr dr Purwanto AP, SpPK (K) Tempat/tgl lahir : Solo, 5 April 1953 Alamat pekerjaan: Bagian Patologi Klinik F.K.UNDIP Alamat rumah : Jl Diponegoro II / 18, Semarang, Kepangkatan : Lektor Kepala / IV C Riwayat Pendidikan : Dokter FK UNDIP 1981 Sp.Patologi Klinik 1997 Konsultan Sp2 Patologi Klinik 2007 Doktor 2015 Jabatan : Ketua Program Studi Pendidikan Dokter Spesialis 2 Patologi Klinik FK UNDIP Anggauta Dewan Etik PP PDS Patklin 1 Ketua I IDI Wilayah Jateng

2 Laboratory marker of chronic kidney disease Purwanto AP Bagian Patologi Klinik FK Undip Semarang

3 A Case 76 y/o white female visits clinic. She is distraught. Another MD told her she has stage 3 CKD. She looked it up on the internet and she is afraid she will need dialysis. Has 20 year history of hypertension, on amlodipine. BP 138/72, UA no protein, Cr 1.3 mg/dl Which of following is the next best step? a) Repeat blood test to confirm CR and MDRD egfr b) Repeat blood test for cystatin C level and egfr c) Repeat labs for CKD-epi CR+cystatin C egfr d) 24 Hr urine Cr Clearance e) Encourage her to get another doctor

4 Chronic Kidney Disease How big a problem? 10-15% of US population have non-dialysis dependent CKD In 2011, there were over 620,000 people receiving ESRD Medicare benefits

5 Incidence and Prevalence of End-Stage Renal Disease in the US

6 Which patients are at increased risk for CKD? Risk factors Diabetes Hypertension Autoimmune diseases Systemic infections UTI, nephrolithiasis, lower urinary-tract obstruction Hyperuricemia Acute kidney injury Family history of chronic kidney disease

7 THE KIDNEY COMPASS Get Your Bearings on Kidney Disease HYPERTENSION BONE DISEASE CKD ANEMIA DIABETES PROTEINURIA SAVE YOUR KIDNEYS AND SAVE YOUR HEART

albuminuria Abnormal urine sediment Anatomic defect detected by

8 Chronic Kidney Disease The Basics CKD is defined as either of the following present for 3 months: Markers of kidney damage Pathologic albuminuria Abnormal urine sediment Anatomic defect detected by imaging Histopathologic abnormality Or... Decline in GFR < 60ml/min/1.73m 2

9 What is the definition of CKD? Kidney damage or GFR <60 ml/min / 1.73 m 2 for >3 month Kidney damage can be either functional or structural Functional abnormalities Proteinuria, albuminuria Abnormalities of urinary sediment (dysmorphic red cells) Structural abnormalities On ultrasound scanning or other radiological tests Polycystic kidney disease, reflux nephropathy, or other abnormalities

10 Classification of CKD by Diagnosis Diabetic Kidney Disease Glomerular diseases (autoimmune diseases, systemic infections, drugs, neoplasia) Vascular diseases (renal artery disease, hypertension, microangiopathy) Tubulointerstitial diseases (urinary tract infection, stones, obstruction, drug toxicity) Cystic diseases (polycystic kidney disease) Diseases in the transplant (Allograft nephropathy, drug toxicity, recurrent diseases, transplant glomerulopathy)

11 Classifying CKD: egfr

12 Classifying CKD: Albuminuria Category Albumin/CR (mg/g) Terms A1 <30 Normal A Moderately Increased A3 >300 Severely Increased

13 Primary Diagnoses of CKD need lab. assay Other 17% Diabetes 45% Cystic Disease 3% Glomerulonephritis 7% Hypertension 28% USRDS 2010 Annual Data Report

14 Basic Laboratory of CKD

15 What laboratory tests should use to evaluate CKD? Serum creatinine (to estimate GFR) Serum electrolytes CBC and lipid profile Urinalysis (specific gravity, ph, red cells, leukocytes) If GFR <60 ml/min per 1.73 m 2 Serum calcium, phosphorus, parathyroid hormone, albumin

16 If indicated by findings Antinuclear antibody to evaluate for lupus Serologies for HBV, HCV, and HIV Serum antineutrophil cytoplasmic antibodies for vasculitis Serum and urine protein immunoelectrophoresis for multiple myeloma Stages 4 and 5 CKD: test for hyperkalemia, acidosis, hypocalcemia, hyperphosphatemia

17 Use of sulfosalicylic acid in the detection of proteinuria

18 Result 0 = negative (turbidity 1). + = low turbidity but the whole text can be read (turbidity 2). ++ = moderate turbidity; only some parts of the text can be read (turbidity 3). +++ = the text is illegible but some dots or lines can be seen (turbidity 4) = it is not possible to read through the tube because of strong turbidity, either with a spotted or coagulated pattern (turbidity 5).

19 Turbidity

20 ROC of proteinuria by turbidity

21 Dipstick method for Urinalysis Method Manual Semiquantitative Accuracy problem

23 23

24 Dismorphic erythrocyte : heterogen, hypochromic, distortion Distortion formed when pass abnormal glomerular structure. Indicated glomerular disease as glomerulonephritis.

25 Urinalysis automatic Urisys 2400

26 Electrolyte urine can predict progression and mortality

Laboratory diagnosis - comparison between patologies Developments in the diagnosis of acute myocardial ischemia ACS Leukocytes numbers Developments in the diagnosis of AKF Serum Creatinine Troponin T

27 Laboratory diagnosis - comparison between patologies Developments in the diagnosis of acute myocardial ischemia ACS Leukocytes numbers Developments in the diagnosis of AKF Serum Creatinine Troponin T Troponin I Serum Creatinine In the last 50 years an improvement in the field of new strategies for kidney-cares, has not occured. One of the reasons was the lack of new biomarkers usefull for an early, sensitive and accurate detection of kidney injury

28 The perils of using serum creatinine to guess level of renal function 24-yo Black Man 63-yo White Man 59-yo White Woman SCr 1.3 mg/dl 1.3 mg/dl 1.3 mg/dl GFR as estimated by MDRD Study equation ml/min/1.73 m 2 ml/min/1.73 m 2 ml/min/1.73 m 2

29 Clearance Glomerular Filtration Glomerular Filtration Rate (GFR): ml/min

30 Glomerular filtration First process in the urine formation steps Plasma ultrafiltrate (Bowman capsule) It depens on: PROTEINS 1. MW < 70 kda 2. Molecular configuration 3. Negative electric charge solutes and water passage (urea, sodium, uric acid, free ions etc.) If renal diseases are present, it can occur: Proteinuria plasmatic oncotic pressure reduction edema Proteins loss from glomerular membranes is caused by: Electric charges alteration Intracellular pores changing (ø 5-8 nm)

31 PROTEINURIA PT n.v mg/ 24 h adults Physiological Albuminuria : < 30 mg/24 h spot : < 19 mg/l For the physiological loss of : 10-20% is represented by Albuminuria Glomerular damage: Proteinuria >1gr/ L about 70% is represented by Albuminuria First clinical simptom Albuminuria ( mg/24 h)

32 CLASSIFICATION OF RENAL PROTEINURIA Selective glomerular Proteinuria (glomerulonephritis) : Type of protein Non selective glomerular Proteinuria (nephrotic) : Type of protein Tubular Proteinuria : Type of protein Diabetic nephropathy : Albuminuria M.W KD (1-3 gr/24 h) Albumin, Transferrin M.W. > 100 KD (> 3,5 gr/24 h) Immunoglobulins also M.W. < 50 KD (< 2 gr/24 h) Retinol Binding Protein (RBP), alfa-1- microglobulin, b2-mic Albumin > 1 gr/24 h

33 Laboratory request form for PROTEINURIA Basal investigaton Urine total proteins : diagnosis, stage, monitoring of CRI Urine Albumin (more sensitive and accurate) * Agli esordi della patologia chiedere espressamente la determinazione della microalbuminuria For the differential diagnosis of tubular or glomerular proteinuria it can be useful the detection of: - Beta2-microglobulin and Cistatin C The specific increase of these proteins (P.M. < 50 KDa) in urines means a proximal tubulus reabsorption failure. For using beta2-microglobulin is necessary exclude lymphocytes diseases; generally the plasmatic detection is requested.

34 Urine albumin & protein to creatinine ratio Albumin-to-creatinine ratio Normal to mildly increased <30 mg/g Moderately increased mg/g Severely increased >300 mg/g Protein-to-creatinine ratio Normal to mildly increased <150 mg/g Moderately increased mg/g Severely increased >500 mg/g Type 2 diabetes: screen for albuminuria annually Positive when >30 mg/g creatinine in a spot urine sample

35 Small changes make a big difference A GFR loss of > 1 ml/min/year beginning at age 25 can result in end-stage renal disease within a normal lifespan. Lee A Hebert et al. Kidney International (2001) 59,

36 Albuminuria as a Risk Factor for CVD in PREVEND Hillege HL et al. Circulation 2002: 106:

RENAL CLEARANCE Clearance is considered to be The amount of liquid filtered out of the blood that gets processed by the kidneys or the amount of blood cleaned per time Ideal marker of clearance:

37 RENAL CLEARANCE Clearance is considered to be The amount of liquid filtered out of the blood that gets processed by the kidneys or the amount of blood cleaned per time Ideal marker of clearance: Clearance (ml/min) = 1. Endogenous and costant bio-synthesis 2. Metabolically quiescent in vivo and in vitro 3. Diffusible in the extracellular space 4. Freely filtered by glomerulus 5. Not reabsorpted nor synthesized by tubular cells 6. Detectable with accurated and sensitive simple methods 7. Advantageous cost/benefit relation 8. Simply used in clinical practice [U] V [P] Crearence is typically recorded in units of volume per time, e.g., milliliters per minute ml/min The used solutes are endogenous (creatinine ) and exogenous (inulin) substances

38 GFR and CREATININE CLEARANCE N.R ml/min In clinical practice, to measure GFR, creatinine clearance or estimates of creatinine clearance, based on the serum creatinine level, is used. min It depends on: number of functional nephrons, nephrons functional efficiency and quantity of blood that reaches nephrons

39 Renal disease staging classified through e-gfr Guidelines : Renal damege severity assessment based on GFR 1. Normal Kidney function GFR > 90 ml/min/1,73 m 2 haematuria e proteinuria also detected 2. Mildly reduced GFR ml/min/1,73 m 2 3. Moderately reduced GFR ml/min/1,73 m 2 4. Severely reduced GFR ml/min/1,73 m 2 5. Very severe or end stage kidney failure GFR absent (dialysis)

40 Can be used for screening: Higher precision GFR > 60 ml/min/1,73 m

GFR: velocity measurement Methods Direct GFR measurement Exogenous substances clearence studies (Inulin, iohexol, iotamatus, Cr51-EDA) Endogenous substances clearence studies (ie.

41 GFR: velocity measurement Methods Direct GFR measurement Exogenous substances clearence studies (Inulin, iohexol, iotamatus, Cr51-EDA) Endogenous substances clearence studies (ie.creatinine) Indirect GFR estimated by anthropometric, anthropological and biochemical parametrs Advantages and disadvantages Accurated, but....expensive, long lasting and inapplicable for screening Blood and urine samples are necessary ; a carefull and timed urine collection is required Simple and advantageous Accuracy??

42 Estimating Kidney Function If 24 hr urine can be collected: CrCl = (U cr x Volume) / P cr Time averaged urine urea and Creatinine Cockroft-Gault (0.85 for women) use serum Creatinine CrCl = 0.85 * ( Wt x [140-age] ) / S cr x 72 MDRD Equation: egfr = 170 * S cr * age * sex * race * (Female: 0.762) CKD-EPI Equation: GFR = 141 X min(scr/κ,1) α X max(scr/κ,1) X Age X [if female] X [if black]

43 estimate GFR and the stage of CKD MDRD equation GFR in ml/min per 1.73 m 2 GFR = (serum creatinine in mg/dl) age (1.210 if black) (0.742 if female) CKD-EPI equation GFR = 141 minimum(scr/κ, 1) α maximum(scr/κ, 1) Age (1.018 if female) (1.159 if black) Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is for females and for males minimum indicates the minimum of Scr/κ or 1, maximum indicates the maximum of Scr/κ or 1

45 GFR (ml/min/ ) Early treatment can make a difference 100 No Treatment Current Treatment Early Treatment 10 0 Kidney Failure Time (years)

46 CISTATIN C Low MW protein, it is synthesized by nuclear cells, released in the blood and freely filtered by glomerulus in urines. Not dependent from extrinsic factors: sex, age, diet and infections. Interferences if PCR increases, BMI, steroids, hypothyroidism. Is a better marker in predicting renal function than creatinin in patients affected by Chronic Renal Insufficiency. New formule that used Cistatin C as a GFR indicator has been proposed. Recently it has been found an equation that matching creatinine and cistatin C, it is useful to have a more accurate estimation of GFR.

47 Cystatin C ( mg/l) 13 kda protein produced by all nucleated cells Freely filtered at glomerulus 99% reabsorbed at PCT and catabolized cant be used to measure clearance its not perfect Level rises with age And w/ inflammation/crp

48 CR+Cys C egfr Inker, NEJM 2012;367:20-9 Combined creatinine-cystatin C e-gfr performed better than equations based on either of these alone and may be useful as a confirmatory test for CKD.

49 Cystatin C to Predict CV Death Shlipak, NEJM 2005;352:

NGAL NGAL (Neutrophil gelatinase-associated lipocalin), also known as lipocalin-2 and oncogene 24p3, is a human protein encoded by the LCN2 gene and is expressed by multiple human cells including

50 NGAL NGAL (Neutrophil gelatinase-associated lipocalin), also known as lipocalin-2 and oncogene 24p3, is a human protein encoded by the LCN2 gene and is expressed by multiple human cells including epithelial cells, neutrophils, as well as in various organs of gastrointestinal, respiratory, excretory, and reproductive systems. NGAL serves as a natural immunity protein with antibacterial properties, but it is thought to play several roles in regard to the kidney function. It has been experimentally demonstrated that NGAL may be involved in kidney development. NGAL has also been implicated in renal regeneration and repair after ischemic injury. A protective effect on the kidney from ischemia reperfusion injury has also been demonstrated. These effects are thought to be linked to the role that NGAL plays in iron metabolism in growth and differentiation as well as prevention of cellular death.

51 Receiver operating characteristics curves of egfr, serum neutrophil gelatinaseassociated lipocalin (sngal), and urinary NGAL (ungal) considering progression of CKD as status variable

52 Short message line : Screening and Prevention... Who to screen Individuals > 55 years of age Individuals with hypertension or diabetes How to screen Estimate GFR from serum creatinine, and do a urinalysis In patients with diabetes Screen for proteinuria with urine albumin-tocreatinine or protein-to-creatinine ratio Maintain strict glycemic control to prevent CKD

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