LINEE GUIDA, KDIGO E DIALISI PERITONEALE

GIANCARLO MARINANGELIU.O.C. NEFROLOGIA E DIALISI

GIULIANOVA

KDOQI and KDIGO

2003 Targets for treatment

2009 Range of risks

NKF- Kidney Disease Outcome Quality Initiative

Kidney Disease Improving Global Outcomes

Kidney Int 2006; 69: 1945-53

From Renal Osteodystrophy to Chronic Kidney Disease - Mineral Bone Disorder

(CKD – MBD)

Moe et al. Kidney Int 2006;69:1945-1953

A systemic disorder of bone and mineral metabolism due to CKD manifested by either one or a combination of the following:

– Abnormalities of Ca, P, PTH, or vit. D metabolism

– Abnormalities in bone turnover, mineralization, volume, linear growth, or strength

– Vascular or other soft tissue calcification

Chronic Kidney Disease – Mineral Bone Disorder(CKD – MBD)

K-DIGO: THE CHALLENGES

The definition CKD-MBD was new and not used in published

clinical studies. Thus each of the three components had

to be addressed separately

The complexity of pathogenesis make it difficult to differentiate a consequence of the disease from a consequence of its treatment

Differences throughout the world in nutrient intake, availability of medications and clinical practice.

KDIGO: Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and

Treatment of CKD-MBD

Key Categories in KDIGO

Diagnosis/Evaluation

Treatment

Vascular Calcification

KDIGO: Grading of Recommendations

Strength of Recommendation

Implications

Level 1

“We recommend …”

“Most patients should receive the recommended course of action.”

Level 2

“We suggest …”

“Different choices will be appropriate for different patients.”

Grade for Quality of Evidence

Quality of Evidence

A High

B Moderate

C Low

D Very Low

Not Graded

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

“The strength of a recommendation is determined not just by the quality of evidence, but also by other, often complex judgments regarding the size of the net medical benefit, values and preferences, and costs.”

KDIGO: Diagnosis of CKD-MBDBiochemical Abnormalities

Diagnosis of CKD-MBD: Biochemical Abnormalities

In the initial CKD stagea, the recommendation is to monitor serum levels of:

– Phosphorus, Calcium, PTH, Alkaline phosphatase

In CKD stages 3-5Db, frequency of monitoring serum calcium, phosphorus, and PTH should be based:

– On the presence and magnitude of abnormalities

– The rate of progression of CKD

In childrenc, the suggestion is to begin monitoring in CKD stage 2

a. 3.1.1 (1C); b. 3.1.2 (not graded); c. 3.1.1 (2D)

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Diagnosis of CKD-MBD: Biochemical Abnormalities

In patients with CKD stages 3-5D, the suggestionsa are to:

– Measure 25(OH)D (calcidiol) levels

– Repeat testing on the basis of:

Baseline values

Therapeutic interventions

– Correct vitamin D deficiency and insufficiency in accordance to treatment strategies recommended for the general population

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130a. 3.1.3 (2C)

Diagnosis of CKD-MBD: Biochemical Abnormalities

In patients with CKD stages 3-5D,

– The recommendationa is that therapeutic decisions should be based on:

Trends versus a single laboratory value

All available CKD–MBD assessments

– The suggestionb is that medical practice should be guided by:

The evaluation of individual values of serum calcium and phosphorus together

Rather than the Ca x P product

a. 3.1.4 (1C); b. 3.1.5 (2D) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Evaluation of CKD-MBD: Biochemical Abnormalities

CKD Stage KDIGO

3 Every 6–12 months

4 Every 3–6 months

5 or D Every 1–3 months

Phosphate and Calcium

Evaluation of CKD-MBD: Biochemical Abnormalities

CKD Stage KDIGO

3 Based on baseline level and CKD stage

4 Every 6–12 months

5 or D Every 3–6 months

PTH

Treatment of CKD-MBD: Phosphorus and Calcium

Definition of “Normal” values

“Normal” means within the above ranges. These are normal ranges for healthy individuals.

Phosphorus 2.5– 4.5 mg/dl

Calcium 8.5 – 10 (or 10.5) mg/dl

iPTH(varies with the assay used)

10 - 65 pg/ml[Centers for Disease Control

recommendations]

Treatment of CKD-MBD:Phosphorus and Calcium

In patients with CKD stages 3-5, the suggestions are to:

– Maintain serum P in the normal range a

– Maintain serum Ca in the normal range b

Phosphate binders are suggested in the treatment of hyperphosphatemia c

For choice of phosphate binder, it is reasonable to take into account c:

– CKD stage

– Presence of other components of CKD-MBD

– Concomitant therapies

– Side-effect profile

a. 4.1.1 (2C); b. 4.1.2 (2D); c. 4.1.4 (not graded) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Treatment of CKD-MBD:Phosphorus and Calcium

In patients with CKD stages 5D, the suggestion is to:

– Lower elevated P levels toward normal range (2C)

– Use a dialysate Ca concentration between 1.25 and 1.5 mmol/l (2.5 and 3.0 meq/L) (2D)

– Increase dialytic phosphate removal in the treatment of persistent hyperphosphatemia (2C)

a. 4.1.3 (2C); b. 4.1.2 (2D); c 4.1.8 (2C) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Treatment of CKD-MBD:Phosphorus and Calcium

In patients with CKD stages 3-5D and hyperphosphatemia, the recommendationa is to:

– Restrict calcium based phosphate binders in the presence of:

Arterial calcification

Adynamic bone disease

Persistently low serum PTH levels

– Restrict the dose of calcium based phosphate binders and/or restrict the dose of calcitriol or vitamin D analog are suggestedb, in the presence of:

Persistent or recurrent hypercalcemiaa. 4.1.5 (1B); b. 4.1.5 (2C) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

51% - 83% 57% 16% - 54%

CalcificationPersistently

Low PTHABDHypercalcemia

1,2,32

2,3,4

Patients In Whom it is Recommended Calcium Be Restricted

1 Russo D, et al. Am J Neph 2007;27:152-1582 Chertow GM, et al. Kidney Int. 2002;62:245-2523 Block GA, et al. Kidney Int. 2005;68:1815-18244 Qunibi W, et al. AJKD. 20085 Andress D. Kidney Int. 2008;73:1345-13546 KDIGO. KI 2009; 76 (Suppl 113):S1-S130

Calcium Restriction

5 – 40% CKD 3,4,6

20 – 50 % HD 6

40 – 70% PD 5

Phosphate Binding Compounds

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

KDOQI / KDIGO - treatment recommendations in 5D:

Laboratory valuesKDOQI

Recommend.Grading

KDIGO

Recommend.Grading

iPTH (pg/mL) 150 to 300 Evidence Suggested range 2 to 9 x ULN 2C

Corrected Ca (mg/dL) 8.4 to 9.5 Opinion Suggested to maintain in

the normal range 2D

P (mg/dL) 3.5 to 5.5 Evidence Suggested to lower toward the normal range

2C

CaxP (mg2/dL2) <55 Evidence Not suggested to direct clinical practice

N/A

KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

PTH Levels

Treatment of Abnormal PTH levels in CKD-MBD

In patients with CKD stages 3-5 not on dialysis, the optimal PTH level is unknown

In patients with levels of intact PTH (iPTH) above the upper normal limit of the assay, the suggestiona is to, first evaluate for:

– Hyperphosphatemia

– Hypocalcemia

– Vitamin D deficiency

It is reasonable to correct these abnormalities with any or all of the followingb:

– Reducing dietary phosphate intake and administering phosphate binders, calcium supplements, and/or native vitamin D

The suggestionc is to treat with calcitriol or vitamin D analogs if:

– Serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors

a. 4.2.1 (2C); b. 4.2.1 (not graded); c. 4.2.2 (2C) KDIGO. KI 2009; 76 (Suppl 113):S1-S130

Treatment of Abnormal PTH levels in CKD-MBD

In patients with CKD stage 5D, the suggestiona is to:– Maintain iPTH levels in the range of approximately two to nine

times the upper normal limit for the assay (2C)

To lower PTH, when it is elevated or rising, the suggestiona is to use:– Calcitriol

– Or vitamin D analogs

– Or calcimimetics

– Or a combination of calcimimetics and calcitriol or vitamin D analogs

In patients with severe hyperparathyroidism who fail to respond to medical/pharmacological therapy parathyreidectomy is suggested (2B)

a. 4.2.3 (2C); b. 4.2.5 (2B) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Treatment of Abnormal PTH Levels In CKD-MBD

In patients with hypocalcemia, the suggestion a is to reduce or stop:

– calcimimetics depending on severity, concomitant medications, and clinical signs and symptoms (2B)

If intact PTH levels fall below two times the upper limit of normal for the assay, the suggestion b is to reduce or stop:

Calcitriol

Vitamin D analogs

And/or calcimimetics

a. 4.2.4 (2B); b. 4.2.4 (2C)KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

KDOQI / KDIGO - PTH TARGETS

KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

CKD StageTarget iPTH

(pg/ml) KDOQIGrading

Target iPTH (pg/ml) KDIGO

Grading

3 35 - 70 Opinion Not known2C

4 70 - 110 Opinion Not known 2C

5 ND 150 - 300 Evidence Not known2C

5D 150 - 300 Evidence 2 to 9 x ULN 2C

KDIGO: Diagnosis of CKD-MBDVascular Calcification

Diagnosis of CKD-MBD: Vascular Calcification

In CKD stages 3-5D, the suggestionsa indicate that:

– It is reasonable to use alternatives to CT-based imaging to detect vascular calcifications, including:

Lateral abdominal radiograph

Echocardiogram

– Patients with known vascular/valvular calcifications can be considered at highest cardiovascular risk

– It is reasonable to use this information to guide the management of CKD–MBD

a. 3.3.1 (2C)KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Diagnosis of CKD-MBD: Vascular Calcification

In CKD stages 3-5D, the suggestionsa indicate that:

– It is reasonable to use alternatives to computed tomography-based imaging to detect the presence or absence of vascular calcification, including:

Lateral abdominal radiograph

Echocardiogram

– Patients with known vascular/valvular calcification can be considered at highest cardiovascular risk

– It is reasonable to use this information to guide the management of CKD–MBD

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 3.3.1 (2C)

4.1.3

…it is probably wise to mantain flexibility with dialysate Ca concentrations…individualized whenever possible…to meet specific patient requirements.

Treatment of CKD-MBD:What about PD?

Similar considerations apply to PD, in which…Ca concentrations…tailored to individual patient’s need.

Compared to HD…PD pts are exposed to a given dialysate calcium concentration for longer periods of time. Therefore…bags with Ca as high as 3.5 mEq/l (1.75 mmol/l) are generally avoided to prevent calcium overload and the induction of ABD.

4.1.3

Concentrations between 1.25 and 1.50 mmol/l (2.5 and 3.0) mEq/l are recommended.

Treatment of CKD-MBD:What about PD?

PD related points:

- more calcium as phosphate binder?

- residual renal function

- continous, not intermittent, treatment

- new solutions, variable Ca

In most cases Calcium balance is slightly positive in CAPD with four exchanges and 1,75 mEq/l Ca…

…and slightly negative with Ca 1,25 mEq/l

Treatment of CKD-MBD:What about PD?

S. Bertoli – 2009

O. Simonsen- KI 2003

RIMOZIONE DEL FOSFORO INDIALISI PERITONEALE

- FUNZIONE RENALE RESIDUA

- PERMEABILITA’ PERITONEALE

- SCHEMA DIALITICO

RIMOZIONE DEL FOSFORO IN DPFUNZIONE RENALE RESIDUA

24 pazienti incidenti in DP – GFR start 59,9 L/sett – 7,1 mesi di follow up

Bammens et al, AJKD 2000

100

80

60

40

20

Litri / settimana / 1,73 mq di BSA

CLEARANCE CREATININA CLEARANCE UREA CLEARANCE FOSFORO

1 2 3 4 5 VISITE

RIMOZIONE DEL FOSFORO IN DPFUNZIONE RENALE RESIDUA

r =0,94

Analisi cross-sectional su 33 pazienti in DPuna misura - un paziente, 17 in CAPD, 24 MCLEARANCE CREATININA = 5,15 ± 2,91 ml/min

CLEARANCE UREA = 2,70 ± 1,46 ml/min

CLEARANCE FOSFORO = 2,50 ± 1,73 ml/min

Neri et al – SIN 2007

r =0,49

y = 0,6421xR2 = 0,6848

RIMOZIONE DEL FOSFORO IN DPPERMEABILITA’ PERITONEALE

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 2 4

fosforo

creatinina

D/P

Lilaj et al, AJKD 199915 pazienti, PET standard

ore 0,4

0,5

0,6

0,7

0,8

0,9

0,2 0,4 0,6 0,8

D/P

cre

at 4

h

D/P fosforo 4 h

Gallar et al, Nefrologia 200070 pazienti, PET standard

y = 0,997 x - 0,03

R2 = 0,7441

0,2

0,4

0,6

0,8

1,0

0,2 0,4 0,6 0,8 1,0

y = 1,136x - 0,41

R2 = 0,282

0,2

0,4

0,6

0,8

1,0

0,2 0,4 0,6 0,8 1,0

D/P creatinina 4 h D/P urea 4 h

D/P

fo

sfo

ro 4

h

Relazione tra il D/P4h del fosforo e D/P4h di creatinina ed urea.Primo PET (a 4.4±3.0 mesi dall’inizio della DP), 57 pazienti.

Neri et al, SIN 2007

RIMOZIONE DEL FOSFORO IN DPPERMEABILITA’ PERITONEALE

Il trasporto peritoneale del fosforo è:

- simile a quello della creatinina (e < a quello dell’urea)- risente molto della permeabilità peritoneale- tanto minore quanto maggiore è l’intermittenza del trattamento

L’eliminazione renale è:

- simile a quella dell’urea- inferiore a quella della creatinina

RIMOZIONE DEL FOSFORO IN DP

In Summary …

Phosphorus

Goal = Normal

Calcium

Calcification represents the highest risk

Detect with x-ray/ultrasound

Restrict Calcium in1. Hypercalcemia2. Calcification3. Low PTH4. ADBD

PTH

Evaluate PTH in context of hyperP, hypoCa, vitamin D deficiency

Marked changes should trigger treatment changes

Decrease cinacalcet in event of hypocalcemia

KDIGO International Clinical Practice Guidelines

Treat the trends: Treat P and Ca to normal, PTH to Goal

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

GRAZIE PER L’ATTENZIONE

K-DIGO (global non-profit foundation)Mission Statement

To improve the care and outcomes of

kidney disease patients worldwide

through promoting coordination,

collaboration and integration of

initiatives to develop and implement

clinical practice guidelines.