Chronic Kidney Disease & Diabetic Kidney Disease

Workshop January 2015

Who to test for renal disease?

•

Test for CKD if:

• • • • • • • •

Diabetes (Type 1 & 2) Episode of acute kidney injury (AKI) Hypertension Cardiovascular disease Multisystem diseases Structural renal tract disease Family history CKD Incidental haematuria or proteinuria

NICE Type 2 Diabetes Guidance

• First-pass urine specimen • Once annually • UACR • Request specimen if UTI prevents analysis • Measure serum creatinine (SeCr) and calculate eGFR (MDRD) annually at the time of ACR estimation • Repeat the test if abnormal ACR • Result of MAU confirmed if further abnormal specimen

NICE CKD Guidance

• Report eGFR when measuring SeCr • Use ACR for urinary albumin excretion if: • • Diabetic GFR<60 ml/min/1.73m

2 • Use ACR to quantify proteinuria

Stage 1 2

Interpretation of results - eGFR

3A 3B 4 5 Description Kidney damage, N or



GFR Kidney damage, mild



GFR Moderate



GFR Moderate



GFR Severe



GFR Kidney failure GFR ≥90 60-89 45-59 30-44 15-29 <15 (or dialysis)

Interpretation of results albuminuria

NICE Type 2 Diabetes Guidance NICE CKD Guidance

•Diabetic nephropathy: •≥ 2.5 mg/mmol for men •≥ 3.5 mg/mmol for women •Suspect other renal if •No significant or progressive retinopathy •Blood pressure high or refractory •Heavy proteinuria •Significant haematuria •Rapid worsening of eGFR •Systemic ill health Clinically significant MAU in diabetes patients: ≥ 2.5 mg/mmol for men ≥ 3.5 mg/mmol for women Proteinuria when ACR ≥ 30 mg/mmol or PCR ≥ 50 mg/mmol

NICE CKD Guidance

• eGFR becomes less accurate as true GFR increases • ≥60 ml/min/1.72m

2 • Where GFR >60/ml/min/1.72m

2 , 20% increase in SeCr denotes significant renal function reduction • If extreme muscle mass, GFR should be interpreted accordingly • Ethnicity correction factor should be applied

NICE CKD Guidance

• Confirm new eGFR below 60 ml/min/1.73m

SeCr ( ± 5%) 2 by repetition • Account for biological and analytical variability in • Identify progressive CKD: • 3 eGFR readings over >90 days • Exclude causes of acute GFR deterioration • If new eGFR decline, repeat eGFR test within 2 weeks • Define progression • >5 ml/min/1.73m

2 within 1 year • >10 ml/min/1.73m

2 within 5 years • Determine if rate of decline of GFR continuing at the observed rate will lead to renal replacement therapy within lifetime

Blood pressure targets

NICE CKD Guidance NICE Type 2 Diabetes Guidance

If abnormal ACR, blood pressure target: <130/80 mmHg If CKD, blood pressure target: <140 mmHg SBP < 90 mmHg DBP If diabetes and CKD or ACR ≥ 70 mg/mmol, BP target: < 130 mmHg SBP < 80 mmHg DBP

Blood pressure agents

NICE CKD Guidance NICE Type 2 Diabetes Guidance

Start ACEi if raised albumin excretion rate If intolerant of ACEi, substitute with ARB Treat with ACEi (or ARB if ACEi intolerant) •Diabetes and MAU •Non-diabetic CKD, hypertension and ACR ≥30 mg/ml •Non-diabetic CKD, and ACR ≥70 mg/ml •Titrate to max dose before addition of a 2nd agent •Add agents as per algorithm in NICE/BHS Hypertension Guideline

Stage 1 2 3A 3B 4 5

eGFR Re-testing

eGFR Range (ml/min/1.73m

2 ) ≥ 90 60-89 45-59 30-44 16 - 29 ≤ 15 Retesting Frequency 12 monthly 6 Monthly 3 Monthly 6 Weekly

Referral criteria

NICE CKD Guidance NICE Type 2 Diabetes Guidance

Agree referral criteria between diabetes specialists and nephrologists Referred for assessment: •Stage 4 and 5 CKD •Heavy proteinuria •Proteinuria and haematuria •Rapidly declining eGFR •Poorly controlled hypertension despite 4 agents •Rare or genetic causes of CKD •Suspected renal artery stenosis

Rationale Behind the NICE Guidelines

Who to test for renal disease?

40% 35% 30% 25% 20% 15% 10% 5% 0% Overall Diabetes history Hypertension Neither Diabetes nor Hypertension 40-59 60-69 Age group, years 70+

Adapted from Coresh J,

Am J Kidney

Dis 2003: 41:1-12

Identification: Comparison of testing

Of 1296 individuals with an eGFR <60 ml/min/1.73m

2, the following results were found: 42% Abnormal serum creatinine Despite having significantly impaired eGFR, 38% Abnormal UACR 45% serum creatinine and UACR was measured 62% Abnormal serum creatinine or UACR 0 20 40 Percentage

Baskar V,

Diabetic Medicine

2006: 23 , 1057-1060

60 80

UACR and eGFR as measure of cardiovascular risk

IRR of primary endpoint (cardiovascular death)

Hunt-2 Study 14

‡

12 * P<0.05

†P<0.01

‡P<0.001

10 8 6

‡ ‡

Category of eGFR, mL/min/1.73 m 2 ≥75 60-74 45-59 15-45 Corresponding CKD stage 2 1 & 2 2 3a 3b & 4 4

† * *

2 0 Optimal Microalbuminuria UACR

1. Adapted from Hallan et al.

Archives Internal Medicine

2. NICE Management of CKD:

NICE

2008 2007 167;22;2490-2496

Nephropathy: a gradual progression, a poor prognosis Annual transition rates through stages of nephropathy to death from any cause as described in the UKPDS 1.4% No Nephropathy 2.0% Microalbuminuria 2.8% Macroalbuminuria 2.3% Elevated Plasma Creatinine or RRT 3.0% 4.6% 19.2% Adapted from Adler et al,

Kidney International

2003 63(1); 225-232

BP control and kidney disease

• • • • • • 840 patients Baseline GFR 13-55mls/min Baseline BP 130/80.

Largely non-diabetic kidney disease Trial patients followed until 31 st Dec 2000 Low BP group 32% lower ESRD risk (adjusted, CI 18-43%;P < 0.001) Adapted from Sarnak MJ,

Ann Intern Med.

2005;142:342-351

REIN Study

•

Aim

To address whether glomerular protein traffic influences renal-disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood-pressure control, in reducing proteinuria, limiting GFR decline, and preventing endstage renal disease.

Double-blind Trial

Placebo group (n=88)

Screening/Enrollment

•

1 Month Ramipril (n=78) Conclusion

In chronic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood pressure lowering GISEN Study Group.

Lancet

(1997) 349: 1857-1863

ACEi decrease GFR and proteinuria

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0 N = 61

Conventional Ramipril

N = 36 N = 20 3 – 4.5

4.5 – 7 ≥ 7 Base-line urinary protein excretion (g/24hours) 70 60 50 40 30 20 10 0 N = 87 N = 48 N = 31 3 – 4.5

4.5 – 7 ≥ 7 Base-line urinary protein excretion (g/24hours) Adapted from GISEN Study Group.

Lancet

(1997) 349: 1857-1863

IDNT Study

•

Aim

To determine whether the use of an ARB or a CCB would provide protection against the progression of nephropathy due to type 2 diabetes beyond that attributable to the lowering of the blood pressure

Screening/Enrollment Prospective, randomised double-blind trial

Placebo group (n = 569) Amlodipine 10 mg (n = 567)

•

10 days Irbesartan 300 mg (n = 579) Conclusion

The angiotensin-II –receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes Lewis EJ et al.

NEJM

2001; 345(12): 851-860

Slowing nephropathy progression

70 IDNT Study 60 50 Irbesartan (300mg) Amlodipine (10mg) Placebo RRR 23% p=0.006

p=NS RRR 20% p=0.02

40 30 20 10

• • • •

1715 patients Urinary protein excretion >0.9g/d Creatinine 88-265 µmol/L Target BP <135/85 mmHg 0 0 6 12 18 24 30 Follow-up (months) 36 *(Time to Doubling of Serum Creatinine, ESRD, or Death) 42 48

Adapted from Lewis EJ et al.

NEJM

2001; 345(12): 851-860

54 60

Change in proteinuria for each treatment group

0 -10 -20 -30 IDNT Study Target BP in all groups was <135/85 mm Hg -40 -50 -60 0 6 Irbesartan (300mg) n=579 Amlodipine (10mg) n=567 Placebo n=569 12 18 24 Months P=0.03

P=ns

P=0.103

30 36 42 48 Additional BP lowering agents (other than ACE inhibitors, ARBs, or CCBs) were allowed in all groups

Adapted from Atkins R et al.

AJKD

2005 45: 281-287

The problems…

1.

2.

• Gold standard measurement - inulin clearance • Radio-isotope clearance – not practical • Creatinine clearance – unreliable, overestimates GFR (tubular secretion of creatinine) • Estimated GFR from serum creatinine – Jeliffe 1973 1 , Cockcroft & Gault 1976 2 Jelliffe RW . Creatinine clearance: bedside estimate .

Cockcroft DW , Gault MH . Prediction of creatinine clearance from serum creatinine .

Nephron

1976 ;

16

: 31 – 41 .

Ann Intern Med

1973 ;

79

: 604 –6 05

Modification of Diet in Renal Disease (MDRD) Study 1 • Original equation used 6 variables (including SeCr, age, albumin and urea) • Abbreviated MDRD developed 2 GFR, in mL/min per 1.73m

2 = 186.3 x SCr (exp[ 1.154]) x Age (exp[-0.203]) x (0.742 if female) x (1.21 if black) 1.

2.

Levey AS, Bosch JP, Lewis JB

e t al.

A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group .

Ann Intern Med

1999 ;

130

: 461 –4 70 .

Levey AS , Stevens LA , Schmid CH

et al.

A new equation to estimate GFR from serum creatinine: improved accuracy and updated estimates of prevalence of chronic kidney disease in the United States .

J Am Soc Nephrol

2008 ;

19

: 36A (abstr.) .

The problems…

• Adopted by KDOQI and KDIGO for classification of CKD • eGFR routinely reported with serum creatinine • Allows for diagnosis of stage 3 CKD (ie eGFR<60ml/min) in absence of proteinuria, abnormal imaging, or renal pathology eg. 82 ♀, no proteinuria, stable serum creatinine 92 µmol/L…..

eGFR 54ml/min ie. CKD stage 3….

A Global CKD Epidemic – predicted 13% of US population with CKD stage 3 1 1.

Clase CM, Garg AX, Kiberd BA: Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III).

J Am Soc Nephrol

13: 1338 –1349, 2002

Cardiovascular risk

• PREVEND 1 – no increased CV risk if eGFR<60ml/min and no proteinuria • Rule

et al

2 shows that age and sex also predict outcomes independently of their correlation with estimated or measured Ccr • Proteinuria is key 1.

2.

Brantsma AH , Bakker SJ , Hillege HL

et al.

Cardiovascular and renal outcomes in subjects with K/DOQI stage 1 – 3 chronic kidney disease: the importance of urinary albumin excretion .

Nephrol Dial Transplant

2008 ;

2 3

: 3851 –3 858 .

Rule AD, Bailey KR, Schwartz GL

e t al.

For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics .

Kidney Int

2009 ;

75

: 1071 – 1078 .

CKD IV & V

Anaemia

• Epo produced in interstitium • Falls early in IN, late in PCK • Give Epo pre-dialysis • Maintain Hb above 100 • Requires ferritin >200

Anaemia

• Anaemia – many patients require EPO therapy (Aranesp, NeoRecormon, Eprex) • Target Hb 105 – 125 • Note – excess of cardiovascular deaths in patients with target Hb of 135 1 • ?some associations with cancer progression

1. CHOIR STUDY: N ENGL J MED 2006; 355:2085-2098

Bone disease

• One alpha hydroxylase falls at GFR 50 ml/mn • Phosphate rises, calcium falls • PTH rises • Start one alpha early • Start phosphate binder • Keep Ca & Ph in normal range • Keep PTH <32

Calcification

• Ectopic in soft tissue • Vascular endothelial cells transform into osteoblasts • Coronary, cerebral, peripheral vessels

Acidosis

• Failure to generate bicarb in PT • Causes hyperkalaemia • Reduces appetite, protein malnutrition • Sodium bicarbonate oral • Limitations of oral sodium & overload

Potassium

• Reduced ability to excrete • Drugs – caution with ACEI / ARB • Dietary • Acidosis • Hypoaldosteronism

Summary

• Heightened awareness of CKD • Multiple risk factor management in primary care • NICE referral guidelines • Beware label of “CKD stage 3” – patient may have normal renal function and no evidence of kidney disease

Fluid

• Salt & water retention • Cause hypertension, oedema, LVF • Salt restriction • Loop diuretics - high dose

Nutrition

• Restrict protein?

• Restrict phosphate, potassium • Avoid loss of lean body mass

Mortality/Morbidity

• Hugely increased – 5 yr survival 63% and 24% (under and over 65) – 29 yr old has a life expectancy of 13 yrs • 45% Cardiovascular, then infection – Standard risks – Calcification – CRP high in 70% dialysis patients

Case study 1 – MD 55 ♂

•

Initial GP assessment

• • •

BP = 160/98 mm Hg Creatinine = 121 µmol/L ( eGFR 57ml/min)

•

Proteinuria = 2+

•

Haematuria = 1+

•

Other information:

•

Prior history of headaches

Case study 1 - MD (2 years later)

• • •

Receiving amlodipine No follow-up in 2 years After 2 years attended surgery complaining of ankle swelling – switched to indapamide SR

• •

BP = 170/105 mm Hg eGFR =18 mls/min (Creatinine = 278 µmol/L, Urea = 19.1 mmol/L)

• • •

Severe Proteinuria = 4+ Plasma albumin = 26 g/dl Haematuria = 3+

•

Haemoglobin = 9.9 g/dl

Referred urgently to renal services

Case study 1 – MD (3 months later)

•

Receiving indapamide SR

•

Defaulted on two renal out-patient appointments

•

BP = 170/105 mm Hg

•

eGFR =10 mls/min, Creatinine = 488 µmol/L, Urea = 29.1 mmol/L

• •

Severe Proteinuria = 4+ Plasma albumin = 27 g/dl

•

Haematuria = 3+

•

Haemoglobin = 8.8 g/dl

Case study 1 - MD

• • • • • •

Three months later admitted very unwell Found to have septicaemia caused by dialysis line Mitral valve vegetation (as seen on echocardiography) Emergency surgery to replace the mitral valve Died post operatively Preventable access-related mortality

Learning points

• • • • • •

Inadequate initial investigation Late re-referral Non-engaged patient Unable to offer choice of dialysis or pre-emptive transplantation Intravenous access: no electively formed arteriovenous fistula Preventable vascular access-related mortality

Case study 2 – PD 35 ♂

•

Went to GP with blurred vision

•

Family history: Mother had diabetes, hypertension and had been on dialysis, dying 7 years earlier

•

BP = 260/140 mm Hg

•

Diagnosed with hypertensive retinopathy

Referred urgently to renal services

Case study 2 – PD (admitted to hospital)

•

Raised phosphate and low calcium

•

Urea = 46.7 mmol/L, Creatinine = 1875 µmol/L, HCO 3 = 12 mmol/L, eGFR = 6 ml/min

•

Haemoglobin = 6.9 g/dL

•

Micro-angiopathic haemolytic anaemia

•

9 centimetres kidneys bilaterally, echobright

Case study 2 - PD

•

Education Given “crash-course” on ESRF, diet, fluid restriction and dialysis

•

Dialysis - Line inserted in right internal jugular vein. Converted to tunnelled line

Case study 2 - PD

•

Poor compliance with dialysis schedule, diet and fluid

•

Hyperkalaemic arrest after 4 months causing death

Learning points

•

Poor compliance

•

Lack of screening

–

With a strong family history was he screened (BP, urine dipstick, serum creatinine)?

•

Acute presentation of a treatable chronic kidney disease problem

•

Non-engagement with chronic disease process and died of a preventable cause