cin 2013 adult renal programme jamaica

Tropical Medicine Research InstituteThe University of the West Indies 1

Adult Renal Programmein

Jamaica

Monika AsnaniMarvin Reid

Caribbean Institute of Nephrology 5th Annual ConferenceMontego Bay, JamaicaJanuary 24-26, 2013

Tropical Medicine Research InstituteThe University of the West Indies

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)

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.

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

Monika R. Asnani 4

***Powars et al 1991*Thomas et al 1982 **Serjeant 2007


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!!

Monika R. Asnani 5


The Nephron in SCD

Monika R. Asnani 6

Tropical Medicine Research InstituteThe University of the West Indies Monika R. Asnani 7

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

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 Creatinine

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.

Monika R. Asnani 10

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

Monika R. Asnani 11


Determining Glomerular Filtration

Rate in homozygous sickle cell

disease

Monika R. Asnani 12


GFR

Monika R. Asnani

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.

13


GFR

Monika R. Asnani

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

14


Cystatin C

Monika R. Asnani 15

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

Monika R. Asnani

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.

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Objectives of the study

Monika R. Asnani

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.

17


Methods

Monika R. Asnani 18

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

Monika R. Asnani 19

GFR,

mls/min/1.73m2

n Mean Std. Dev. Min Max

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

Monika R. Asnani 20


CKD-EPIsCr/ CKD-EPIsCysC Estimates

Monika R. Asnani 21


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

Monika R. Asnani 22


Estimating GFR in SCD

Monika R. Asnani 23

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

Monika R. Asnani 24


Final points

Monika R. Asnani 25

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

Monika R. Asnani 27

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

Monika R. Asnani 28

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

Monika R. Asnani 29

Variable Females,N=55

Males,N=43

P value

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 (mean ± SD)

111.5 ± 13.5 108.7 ± 11.9 0.28

Diastolic Pressure, mmHg(mean ± SD)

65.7 ± 9.5 60.3 ± 9.3 0.006

Haemoglobin, g/dl (mean ± SD) 7.3 ± 1.5 7.7 ± 1.5 0.22

White blood cells, 109/L (mean ± SD)

12.0 ± 3.9 11.3 ± 3.1 0.35

Serum Creatinine, µmol/L (median, IQR)

49, 45 - 62 61, 53 - 71 0.001

Lactate Dehydrogenase, U/L(median, IQR)

387, 341 - 487 409, 294 - 558 0.31

Cystatin C, mg/L (mean ± SD) 0.84 ± 0.98 0.74 ± 0.40 0.52

Measured GFR, mls/min/1.73m2 (mean ± SD)

95.3 ± 29.6 94.4 ± 24.5 0.87

Albumin: creatinine ratio, mg/g(median, IQR)

5.7, 1.6 – 62.1 5.7, 2.4 – 27.2 0.84


GFR and Alb Excretion

Monika R. Asnani 30

GFR Categories

Albuminuria Categories Total

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

Monika R. Asnani 31

CKD=0(n=22)

CKD=1(n=35)

CKD=2(n=35)

CKD=3(n=4)

CKD=5(n=2)

p-value

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, mls/min/1.73m2

110.3 ± 17.7 112.6 ± 19.8 77.7 ± 8.5 50.2 ± 10.4 7.1 ± 0.98 0.0001

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

Monika R. Asnani 32

050

100

150

0 200 400 600 800Serum Creat in umol/L

Measured GFR adjusted for BSA lowess gfr_bsa SerumCtumol_L

050

100

150

0 2 4 6Cystatin C in mg/L

Measured GFR adjusted for BSA lowess gfr_bsa CysC_mgL

Upper limits of normal values for Serum Creat were 77.7 µmol/L for females and 91.3 µmol/L for males.

Cystatin C levels started rising once GFR started falling below about 100 mls/min/1.73 m2


Pairwise correlations between markers of renal function and disease severity

Monika R. Asnani 33

Measured GFR

Serum Creatinine

LDH Hb Alb:Creat Ratio

Systolic BP

Cystatin C

Measured GFR

1.00

Serum Creatinine

-0.55* 1.00

LDH -0.03 0.06 1.00

Hb 0.28* -0.35* -0.19 1.00

Alb:Creat Ratio

-0.44* 0.77* 0.05 -0.35* 1.00

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

Monika R. Asnani 34

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, µmol/L

-0.17 0.000 -0.22 to -0.11

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

Monika R. Asnani 35

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, mg/L

-17. 6 0.000 -23.2 to -0.11

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

Monika R. Asnani 36

ACR, mg/mmol Coef P value 95% C.I.

Male sex -37.4 0.053 -75.2 to 0.54

Serum Creatinine, µmol/L

1.44 0.000 1.21 to 1.66

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

Monika R. Asnani 37

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.


AcknowledgementsSpecial 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 FundingThe Adult Renal Programme at SCU has been funded largely by the

Caribbean Health Research Council.


THANK YOU

Monika R. Asnani 39

cin 2013 adult renal programme jamaica

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