Cin 2013 adult renal programme jamaica
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Cin 2013 adult renal programme jamaica Cin 2013 adult renal programme jamaica Presentation Transcript

  • Adult Renal Programme in Jamaica Monika Asnani Marvin Reid Caribbean Institute of Nephrology 5th Annual Conference Montego Bay, Jamaica January 24-26, 2013Tropical Medicine Research InstituteThe University of the West Indies 1
  • Sickle Nephropathy In the USA:  Approximately 4 to 5% of persons with SCD have or will develop stage 5 chronic kidney disease (CKD),  0.11% of patients who are on long-term maintenance renal replacement therapy have SCD-associated nephropathy (Abbott 2002) Locally, in Jamaica:  The estimated crude point prevalence of CRF in persons 20 years and over at the end of 1999 was 327 per million population. (based on creatinine >150 mmol/L). (Barton et al 2004 WIMJ)  0.7 % attributable to SCD (rank =11)Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 2
  • Sickle Nephropathy  Functionally– Glomerular Hyperfiltration and Albuminuria (micro- and macroalbuminuria).  Histologically, FSGS is the predominant glomerular lesion in patients with SCD and proteinuria .  Glomeruli are much enlarged in SCD presumably by hypertrophy  Glomerular enlargement and early hyperfiltration are thought to play important roles in subsequent chronic glomerular injury and progressive CKD in SCD.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 3
  • Sickle Nephropathy  An important cause of morbidity and mortality  Renal failure has contributed to death in ~18% of Jamaican patients with SS disease over 20 years of age.*  Renal insufficiency rises to 85% in those over the age of 60 years **  Once diagnosis of chronic renal failure (Serum Ct>132 µmol/l) is made, life expectancy thereafter is about 4 years*** (despite dialysis).  With the increasing patient survival, renal failure will play a greater role in the morbidity and mortality of SCD in the future.  Therefore, important for early detection *Thomas et al 1982 **Serjeant 2007 ***Powars et al 1991Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 4
  • Sickle Nephropathy  Current markers of early nephropathy NOT validated in SCD  In fact, most studies in the literature ASSUME methods that work in other populations work the same way in SCD  The kidney in SCD has some unique features and hence this assumption may be incorrect!!Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 5
  • The Nephron in SCDTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 6
  • Kidney in SCD In SCD, reno-tubular abnormalities exist which could theoretically impact on the usefulness of current recommendations:  Hyposthenuria which would affect albumin conc in urine  Increased tubular secretion of creatinine  Increased prevalence of bacteriuria  Increased prevalence of hematuriaTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 7
  • Measures of Renal Function  Microalbuminuria  Glomerular Filtration Rate  Serum CreatinineTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 8
  • Our work  Validating utility of Spot/ Timed Urine ACR to determine MA  Validating 99_Tc DTPA (diethylene-triamine-penta- acetic acid) scan to determine GFR  Utility of Cystatin C in determining GFR  Creating Estimating equations using commonly measured parameters: such as age, weight, serum creatinine  Predictors of MA/GFR  Normative values of Serum CreatinineTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 9
  • Albuminuria in Adults-JSCCS1 By mean age ~29 years, 25.9% with HbSS and 10.8% with HbSC disease had microalbuminuria whereas 16.5% of HbSS and 2.7% of HbSC disease had macroalbuminuria Mean arterial pressure, haemoglobin levels, serum creatinine, reticulocyte counts and white blood cell counts were statistically significant predictors of albuminuria in HbSS White blood cell counts and serum creatinine predicted albuminuria in HbSC disease. Both markers of chronic haemolysis, i.e. AST and LDH levels, showed no associations with albuminuria in either genotype. Asnani et al PLoS one 2011Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 10
  • Validating MA measurements  Prelim data suggest that 2 hour collection of urine is better than spot urine for classification of MA status in SCD….however both can be recommended  Alb:Creat Ratio can be confidently utilizedTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 11
  • Determining Glomerular Filtration Rate in homozygous sickle cell diseaseTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 12
  • GFR Glomerular filtration rate (GFR) is widely accepted as the best overall measure of kidney function. As GFR cannot be measured in any direct way, usual methods have included estimations from urinary clearance of exogenous markers such as inulin, iohexol, Chromium-51-EDTA, 99m-Tc DTPA renal scan, and iodine-125–iothalamate. Due to the complexities of the measurement of the clearance of exogenous markers for routine clinical practice, alternative endogenous markers such as urea and creatinine, and more recently, Cystatin-C, have all been utilized to estimate GFR.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 13
  • GFR Several formulae have also been developed to estimate GFR from serum creatinine concentration, age, sex, and body size. The Cockcroft-Gault (CG) and the modified Modification of Diet in Renal Disease (MDRD) equations have been widely used in adults, with the latter gaining greater popularity since its inception in 1999Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 14
  • Cystatin C  A non-glycosylated low molecular weight (13 kD) basic protein that inhibits cysteine proteases and correlates closely to GFR in children and adults.  All nucleated cells synthesize cystatin C at a constant rate.  Cystatin C crosses the glomerular membrane and it is reabsorbed and metabolized in the renal tubules and not returned to the bloodstream.  Unlike creatinine, cystatin C is not secreted by the tubules, even in cases of reduced GFRTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 15
  • Cystatin C use in SCD Cystatin-C has been used very infrequently in small studies in SCD, involving mainly children, and seems to have had good utility. A single study among Kuwaiti adults with SCD has shown Cystatin- C to be a superior marker of GFR than other commonly used measures, including the CG and MDRD equations.  MDRD and Cockcroft-Gault equations: Unsure of utility in estimating GFR in SCD. Still being used to determine GFR in studies however.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 16
  • Objectives of the study We compare GFR levels measured using the 99m-Tc DTPA renal scan (mGFR_DTPA) to estimates using:  modified MDRD (eGFR_MDRD),  Cockcroft-Gault (eGFR_CG),  Chronic Kidney Disease Epidemiology Collaboration (eGFR_CKDEPI),  and various Cystatin C based equations We hypothesize that due to the differences in serum creatinine handling by the sickle kidney, these equations will not show good limits of agreement in persons with SCD, and we therefore propose to generate serum creatinine and/or serum Cystatin C based GFR estimating equations specific for SCD.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 17
  • Methods  98 patients with the homozygous SS disease (55 females: 43 males; mean age 34±2.3 years) were recruited to the study in their steady state.  All had serum measurements of creatinine and Cystatin C, as well as had GFR measured using 99mTc-DTPA nuclear renal scan.  The Bland-Altman limit of agreement method was used to determine agreement between measured and estimated GFR values.  Linear regressions were used to construct GFR predictive models using serum creatinine, Cystatin C and height as predictor variables.  Accuracy was further studied by determining what percentage of GFR values estimated from these equations fell within 30% of the measured values.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 18
  • GFR measured and estimated GFR, n Mean Std. Dev. Min Max mls/min/1.73m2 Measured GFR 98 94.9 27.4 6.4 159.0 eGFR_MDRD 98 165.3 54.6 7.1 315.2 eGFR_CG 98 132.8 40.4 8.7 233.9 eGFR_CKDEPIsCr 98 136.1 27.4 6.5 180.4 eGFR_larssonCysC 98 170.9 131.7 8.1 656.1 eGFR_hoekCysC 98 140.6 85.7 9.1 433.2 eGFR_CKDEPIcysC 98 123.3 43.9 7.6 240.0Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 19
  • MDRD/ CG EstimatesTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 20
  • CKD-EPIsCr/ CKD-EPIsCysC EstimatesTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 21
  • Dot Plot showing range of GFR values as well as means and sdTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 22
  • Estimating GFR in SCD  eGFR1 Equation: -0.84 + (2704.1/ Serum Ct) + (1.3x106/ height2) where Serum Ct is in µmol/L; height is in cm.  eGFR2: -40.7 + (40.7/√Cys C) + (2.4 x 106/ height2) where Serum Cys C is in mg/L; height is in cm.  eGFR3 Equation: -25.1 + (1840.8/ Serum Ct) + (28.2/√CysC) + (1.4x106/ height2) where Serum Ct is in µmol/L; Serum Cys C is in mg/L; height is in cm.  The P30 for eGFR1, eGFR2 and eGFR3 was 82.7, 83.7 and 86.7 respectively.  Their utility needs to be further tested in other SCD groups as well as longitudinally.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 23
  • Dot Plot showing range of GFR values as well as means and sdTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 24
  • Final points  The recommended MDRD and the CG equations grossly overestimate the GFR, and in fact the CKD-EPI equations using either serum creatinine or serum Cystatin C measures to estimate GFR are probably the closest.  One of the main limitations of the study is that it was conducted in a very narrow age group of young adults, ranging from about 29 years to 39 years.  No independent validation group was used to test the performance of the recommended equations.  Application of the new equations in further studies will allow for their further refinement, as well as allow study of their accuracy and precision in monitoring renal function in this population.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 25
  • Chronic Kidney Disease in adult Jamaicans with homozygous sickle cell diseaseTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 26
  • Introduction Chronic kidney disease (CKD) comprises a continuum of renal function and is usually determined based on estimated glomerular filtration rate (CKD). Important to screen and diagnose CKD early in its course so potentially therapeutic interventions can be applied and therefore prevent complications of CKD such as kidney failure and worsening cardiovascular diseases. In this study:  We propose to determine CKD categories for a birth cohort of persons with homozygous SS disease.  We also aim to determine possible predictors and associated factors for GFR and albumin excretion in this population.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 27
  • Methods 98 patients with the homozygous SS disease (55 females: 43 males; mean age 34±2.3 years) recruited in their steady state. Investigations:  MSU for albumin: creatinine ratio (ACR) as well as for culture if needed  Blood for: Haematology, Serum Creatinine and Cystatin C, LDH  99m Tc DTPA renal scan ‘ Low GFR’ was defined as measured GFR < 60 mls/min adjusted for BSA, ‘normal GFR’ between 60-130 mls/min adjusted for BSA, and ‘high GFR’ (Hyperfiltration) by measured GFR > 130 mls/ min adjusted for BSA. Albumin excretion was categorized as ‘nil albuminuria’ if albumin: creatinine ratio (ACR) < 2.5 mg/mmol for men and < 3.5 mg/mmol for women, ‘microalbuminuria’ if ACR > 2.5 & < 25 mg/mmol for men and > 3.5 & < 35 mg/mmol for women and ‘macroalbuminuria” if ACR > 25 mg/mmol in men and > 35 mg/mmol in women.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 28
  • Demographic and Clinical characteristics by Gender Variable Females, Males, P value N=55 N=43 Weight, Kg (mean ± SD) 58.6 ± 9.4 60.2 ± 12.6 0.47 Height, cm (mean ± SD) 166.7 ± 6.7 172.6 ± 8.0 0.0002 Systolic Pressure, mmHg 111.5 ± 13.5 108.7 ± 11.9 0.28 (mean ± SD) Diastolic Pressure, mmHg 65.7 ± 9.5 60.3 ± 9.3 0.006 (mean ± SD) Haemoglobin, g/dl (mean ± SD) 7.3 ± 1.5 7.7 ± 1.5 0.22 White blood cells, 109/L 12.0 ± 3.9 11.3 ± 3.1 0.35 (mean ± SD) Serum Creatinine, µmol/L 49, 45 - 62 61, 53 - 71 0.001 (median, IQR) Lactate Dehydrogenase, U/L 387, 341 - 487 409, 294 - 558 0.31 (median, IQR) Cystatin C, mg/L (mean ± SD) 0.84 ± 0.98 0.74 ± 0.40 0.52 Measured GFR, mls/min/1.73m2 (mean ± 95.3 ± 29.6 94.4 ± 24.5 0.87 SD) Albumin: creatinine ratio, mg/g 5.7, 1.6 – 62.1 5.7, 2.4 – 27.2 0.84 (median, IQR)Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 29
  • GFR and Alb Excretion GFR Albuminuria Categories Total Categories Normal Micro Macro Low GFR 1 0 5 6 Normal GFR 31 32 19 82 High GFR 2 4 4 10 Total 34 36 28 98Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 30
  • Demographic and Clinical characteristics by CKD category CKD=0 CKD=1 CKD=2 CKD=3 CKD=5 p-value (n=22) (n=35) (n=35) (n=4) (n=2) Sex (F:M) 16:6 17:18 19:16 1:3 2:0 0.17 Age, yrs. 33.7 ± 1.9 34.1 ± 2.4 33.9 ± 2.3 35.9 ± 2.9 32.1 ± 2.3 0.45 Measured GFR, 110.3 ± 17.7 112.6 ± 19.8 77.7 ± 8.5 50.2 ± 10.4 7.1 ± 0.98 0.0001 mls/min/1.73m2 Serum Creatinine, µmol/L 52.0 ± 12.0 51.0 ± 11.8 62.8 ± 16.1 107.0 ± 51.5 632.5 ± 153.4 0.0003 Cystatin C, mg/L 0.50 ± 0.23 0.65 ± 0.26 0.81 ± 0.30 1.19 ± 0.90 5.60 ± 0.53 0.0004 ACR, mg/mmol 1.78 ± 0.93 52.4 ± 86.2 51.2 ± 118.1 73.3 ± 69.2 914.0 ± 100.2 0.0001 Hb, gm/dl 7.95 ± 1.3 7.5 ± 1.2 7.4 ± 1.7 7.4 ± 2.0 3.8 ± 0.3 0.057 Systolic BP, mmHg 107.9 ± 13.3 107.8 ± 9.6 110.9 ± 11.5 121 ± 18.2 147 ± 12.7 0.060 Diastolic BP, mmHg 62.7 ± 10.0 62.5 ± 8.9 63.0 ± 10.1 68.5 ± 10.1 79.0 ± 7.1 0.23 WBC, 109/L 10.7 ± 2.7 13.1 ± 4.6 11.3 ± 2.6 11.4 ± 0.4 7.6 ± 0.8 0.06 Retics, % 10.6 ± 3.5 11.0 ± 3.5 11.5 ± 4.1 12.4 ± 3.9 7.7 ± 6.1 0.87 LDH, U/L 345.8 ± 89.0 538.1 ± 789.7 483.6 ± 164.9 429.5 ± 205.7 667.5 ± 24.8 0.004Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 31
  • Scatterplots with Smoothed Lowess Curves150 150100 100 50 50 0 0 0 200 400 600 800 0 2 4 6 Serum Creat in umol/L Cystatin C in mg/L Measured GFR adjusted for BSA lowess gfr_bsa SerumCtumol_L Measured GFR adjusted for BSA lowess gfr_bsa CysC_mgL Upper limits of normal values for Serum Cystatin C levels started rising once GFR Creat were 77.7 µmol/L for females and started falling below about 100 mls/min/1.73 91.3 µmol/L for males. m2Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 32
  • Pairwise correlations between markers of renal function and disease severity Measured Serum LDH Hb Alb:Creat Systolic Cystatin C GFR Creatinine Ratio BP Measured 1.00 GFR Serum -0.55* 1.00 Creatinine LDH -0.03 0.06 1.00 Hb 0.28* -0.35* -0.19 1.00 Alb:Creat -0.44* 0.77* 0.05 -0.35* 1.00 Ratio Systolic BP -0.46* 0.46* 0.14 -0.19 0.42* 1.00 Cystatin C -0.61* 0.91* 0.08 -0.32* 0.79* 0.38* 1.0000 * p value: 0.01Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 33
  • Multiple linear regression for associations of GFR and serum creatinine Measured GFR Coef P value 95% C.I. Male sex 4.33 0.368 -5.2 to 13.8 Height, cm -1.09 0.001 -1.7 to -0.48 Serum Creat, -0.17 0.000 -0.22 to -0.11 µmol/L Constant 288.6 0.000 187.1 to 390.0 N = 98 Adj R-squared = 0.37 F( 3, 94) = 20.01 Prob > F = 0.0000Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 34
  • Multiple linear regression for associations of GFR and serum Cystatin C Measured GFR Coef P value 95% C.I. Male sex 2.09 0.64 -6.8 to 11.0 Height, cm -0.87 0.004 -1.5 to -12.1 Serum Cystatin C, -17. 6 0.000 -23.2 to -0.11 mg/L WBC, 109/L 1.24 0.03 0.12 to 2.37 Systolic BP, mmHg -0.39 0.034 -0.75 to -0.03 Constant 283.2 0.000 190.7 to 375.7 N = 98 Adj R-squared = 0.49 F( 3, 94) = 19.24 Prob > F = 0.0000Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 35
  • Multiple linear regression for associations of albuminuria ACR, mg/mmol Coef P value 95% C.I. Male sex -37.4 0.053 -75.2 to 0.54 Serum Creatinine, 1.44 0.000 1.21 to 1.66 µmol/L WBC, 109/L 7.0 0.01 1.6 to 12.4 Constant -160.8 0.005 -180.9 to -32.6 N = 98 Adj R-squared = 0.63 F( 3, 94) = 56.64 Prob > F = 0.0000Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 36
  • Discussion  By the time SS persons are in the fourth decade of life, there is 6% prevalence of CKD Stage 3 and above and just over 65% of them have albuminuria.  This same cohort has been shown to have a prevalence of albuminuria of 26% determined 15 years ago, and 42% at determination 5 years ago  10% prevalence of hyperfiltration (defined as measured GFR >130 mls/min/1.73 m2 in females; and GFR > 140 mls/min/1.73 m2 in males)  Lower values for normal Serum Creatinine levels need to be utilized in clinical practice  Serum creatinine is not a very sensitive marker of kidney function in SS disease  None of the multiple regression models showed any effect of increasing haemolysis, as evidenced by lactate dehydrogenase levels or reticulocyte counts, on GFR or ACR.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 37
  • Acknowledgements Special thanks to late Nurse Norma Lewis and Nurse Margaret Phipps for assistance with patient recruitment and data collection, and Medical Technologists Marjorie Beckford, Sheldon Kelly, Walworth Duncan, Diahann Knight, all of the TMRI laboratories, for collection and processing of samples. Thanks also to staff at Central Medical laboratories and Apex X-Ray for assistance in performing measurements as well. Project Funding The Adult Renal Programme at SCU has been funded largely by the Caribbean Health Research Council.Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 38
  • THANK YOUTropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 39