Cin 2013 adult renal programme jamaica

Adult Renal Programme
in
Jamaica

Monika Asnani
Marvin Reid

Caribbean Institute of Nephrology 5th Annual Conference
Montego Bay, Jamaica
January 24-26, 2013

Tropical Medicine Research Institute
The 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)

The 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.


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 1991


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!!


The Nephron in SCD


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 hematuria


Measures of Renal Function

 Microalbuminuria
 Glomerular Filtration Rate
 Serum Creatinine


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 Creatinine


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 2011


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 utilized


Determining Glomerular Filtration Rate in
homozygous sickle cell disease


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.


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 1999


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 GFR


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.


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.


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.


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 7.6 240.0


MDRD/ CG Estimates


CKD-EPIsCr/ CKD-EPIsCysC Estimates


Dot Plot showing range of GFR values as well as
means and sd


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.


Dot Plot showing range of GFR values as well as
means and sd


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.


Chronic Kidney Disease in adult Jamaicans
with homozygous sickle cell disease


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.


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.


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)


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 98


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 0.004


Scatterplots with Smoothed Lowess
Curves
150

150
100

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. m2


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: 0.01


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 = 0.0000


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


F( 3, 94) = 19.24

Prob > F = 0.0000


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


F( 3, 94) = 56.64

Prob > F = 0.0000


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.


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.


THANK YOU


Cin 2013 adult renal programme jamaica

Recomendados

Recomendados

Más contenido relacionado

La actualidad más candente

La actualidad más candente (20)

Similar a Cin 2013 adult renal programme jamaica

Similar a Cin 2013 adult renal programme jamaica (20)

Más de Caribbean Institute Of Nephrology

Más de Caribbean Institute Of Nephrology (10)

Cin 2013 adult renal programme jamaica