1. LINEE GUIDA, KDIGO E DIALISI PERITONEALE
GIANCARLO MARINANGELI
U.O.C. NEFROLOGIA E DIALISI
GIULIANOVA

2. KDOQI and KDIGO 2009 Range of risks
NKF- Kidney Disease Outcome Quality Initiative
2003 Targets for treatment
Kidney Disease Improving Global Outcomes
2009 Range of risks

3. From Renal Osteodystrophy to
Chronic Kidney Disease - Mineral Bone Disorder
(CKD – MBD)
Kidney Int 2006; 69: 3 3

4. Chronic Kidney Disease – Mineral Bone Disorder
(CKD – MBD)
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
Moe et al. Kidney Int 2006;69: 4

5. 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.

6. KDIGO: Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD

7. Key Categories in KDIGO
Diagnosis/Evaluation
Vascular Calcification
Treatment 7

8. 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
There are 9 Evidence Grades in KDIGO.
The Strength of a Recommendation refers to how confident one can be that the recommendation will do more good than harm. Grades for strength of a recommendation are Level 1 and level 2. KI (2009) 76 (Suppl 113), p S19, col 1, para 1.
The Quality of the overall body of evidence was then determined on the basis of the quality grades for the outcomes of interest. There are 4 categories for Evidence Quality. KI (2009) 76 (Suppl 113), p S18, col 2, para 2.
Statements that are Not Graded provide guidance on the basis of common sense. They provide reminders of the obvious, but are not based on a systematic evidence review. KI (2009) 76 (Suppl 113), p S19, col 2, para 1.
Not Graded
“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. Kid Int. 2009; 76 (Suppl 113):S1-S130

9. KDIGO: Diagnosis of CKD-MBD Biochemical Abnormalities

10. 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 (1C); b (not graded);
c (2D)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 10

11. 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
a (2C)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 11

12. 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
There is an emphasis on trends, vs treating a number.
a (1C); b (2D)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 12

13. Evaluation of CKD-MBD: Biochemical Abnormalities
Phosphate and Calcium
CKD Stage
KDIGO 3
Every 6–12 months 4
Every 3–6 months
5 or D
Every 1–3 months
There is an emphasis on trends, vs treating a number. 13

14. Evaluation of CKD-MBD: Biochemical Abnormalities
PTH
CKD Stage
KDIGO 3
Based on baseline level and CKD stage 4
Every 6–12 months
5 or D
Every 3–6 months
There is an emphasis on trends, vs treating a number. 14

15. Treatment of CKD-MBD: Phosphorus and Calcium

16. Definition of “Normal” values
Phosphorus
2.5– 4.5 mg/dl
Calcium
8.5 – 10 (or 10.5) mg/dl
iPTH
(varies with the assay used)
pg/ml
[Centers for Disease Control recommendations]
“Normal” means within the above ranges. These are normal ranges for healthy individuals. 16 16

17. 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 (2C); b (2D);
c (not graded)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 17

18. 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 (2C); b (2D); c (2C)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 18

19. 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 hypercalcemia
a (1B); b (2C)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 19

20. Patients In Whom it is Recommended Calcium Be Restricted
Calcification
Persistently
Low PTH
Hypercalcemia
ABD
1,2,3
2,3,4 2
51% - 83%
57%
16% - 54%
5 – 40% CKD 3,4,6
20 – 50 % HD 6
40 – 70% PD 5
1 Russo D, et al. Am J Neph 2007;27:
2 Chertow GM, et al. Kidney Int. 2002;62:
3 Block GA, et al. Kidney Int. 2005;68:
4 Qunibi W, et al. AJKD. 2008
5 Andress D. Kidney Int. 2008;73:
6 KDIGO. KI 2009; 76 (Suppl 113):S1-S130
Calcium
Restriction 20

21. Phosphate Binding Compounds
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

22. KDOQI / KDIGO - treatment recommendations in 5D:
Laboratory values
KDOQI
Recommend.
Grading
KDIGO
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
Suggested to lower toward the normal range
CaxP (mg2/dL2)
<55
Not suggested to direct clinical practice
N/A
KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

23. PTH Levels

24. 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 (2C); b (not graded); c (2C)
KDIGO. KI 2009; 76 (Suppl 113):S1-S130 24

25. 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 (2C); b (2B)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 25

26. 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 (2B); b (2C)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 26

27. KDOQI / KDIGO - PTH TARGETS
CKD Stage
Target iPTH (pg/ml) KDOQI
Grading
Target iPTH (pg/ml) KDIGO 3
Opinion
Not known 2C 4
5 ND
Evidence 5D
2 to 9 x ULN
KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

28. KDIGO: Diagnosis of CKD-MBD Vascular Calcification

29. 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
Previous CKD-MBD guidelines from KDOQI did not make a recommendation regarding screening for VC.
The KDIGO working group does recommend that screening for VC is done at the discretion of the treating physician, especially when knowledge of the presence of vascular calcification may impact therapeutic decision making.
Clinical trials in CKD patients such as TTG, RIND and even a study in non dialysis patients (Russo et al.) have all demonstrated that prevalence of VC is high (50-83%) in this patient population.
a (2C)
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 29

30. 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
Previous CKD-MBD guidelines from KDOQI did not make a recommendation regarding screening for VC.
The KDIGO working group does recommend that screening for VC is done at the discretion of the treating physician, especially when knowledge of the presence of vascular calcification may impact therapeutic decision making.
Clinical trials in CKD patients such as TTG, RIND and even a study in non dialysis patients (Russo et al.) have all demonstrated that prevalence of VC is high (50-83%) in this patient population.
a (2C)
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 30

31. Calcification prevalence increases as kidney function decreases‡ † *
Chart represents data across three studies of different CKD populations
*Russo D, Corrao S, Miranda I, et al. Progression of coronary artery calcification in predialysis patients. Am J Nephrol. 2007;27:
†Spiegel DM, Raggi P, Mehta R, et al. Coronary and aortic calcifications in patients new to dialysis. Hemodialysis Int. 2004;8:
‡Chertow GM, Burke SK, Raggi P; for Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62:

32. Prevalence of Coronary Artery Calcification in Non-Dialyzed CKD Patients: Meta-Analysis
25%
40%
54%
73%
90%
93% 0%
20%
60%
80%
100%
Patients (%)
Kramer ‘05
Russo ‘04
Spiegel ‘04
Qunibi ‘05
Mehrotra
Non-Diabetics
Diabetics N
GFR Stg Stg < < Stg 3-5
Several published studies show that the process of vascular calcification begins rather early in CKD and is particularly severe among elderly and type 2 diabetic patients.
The above figure, based on a meta-analysis, shows that the prevalence of CAC is predominantly higher in diabetics than in non-diabetics.
Furthermore, among both diabetics and non-diabetics, vascular calcification was seen in patients who were new to dialysis, in patients with CKD, and in patients with established disease on dialysis.
Thus, calcification in early CKD is an important predictor of subsequent progression of CKD, including the rapid increase seen in CKD Stage 5.
Based on data from Mehrotra R et al. Kidney Int. 2004;66; ; Russo D et al. Am J Kidney Dis. 2004;44: ; Kramer H et al. J Am Soc Nephrol. 2005;16: ; Quinibi WY et al. Kidney Int. 2005;68: ; Spiegel DM et al. 2004;2004:
Mehrotra R. J Renal Nutrition. 2006;16: 32

33. The degree of calcification in patients new to dialysis has a significant impact on mortality
CAC=0
CAC 1-400
CAC≥400
P = 0.002
Kaplan-Meier survival curves were generated and a log-rank test was used to detect treatment group differences in time to death.
Baseline CAC score was a significant predictor of mortality in hemodialysis patients.
Figure shows multivariable adjusted survival by baseline CAC score; variables included age, race, gender, and diabetes. The P-value represents statistical significance across 3 stratifications based on baseline CAC:
CAC = 0 (Red Line)
CAC (Blue Line)
CAC ≥400 (Green Line)
Subjects with no evidence of CAC (CAC=0) had a significantly lower mortality rate (3.3/100 patient years, CI ) compared to subjects with a CAC score (7.0/100 patient years, CI ) and those with a CAC score >400 (14.7/100 patient years, CI ) (P=0.002).
After multivariable adjustment, the presence of a baseline CAC score >400 remained significantly associated with increased mortality (HR=4.5, P=0.016, CI ).
Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71(5): 33

34. Treatment of CKD-MBD: What about PD?
4.1.3
…it is probably wise to mantain flexibility with dialysate Ca concentrations…individualized whenever possible…to meet specific patient requirements.
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.

35. Treatment of CKD-MBD: What about PD?
4.1.3
Concentrations between 1.25 and 1.50 mmol/l (2.5 and 3.0) mEq/l are recommended.
PD related points:
more calcium as phosphate binder?
residual renal function
continous, not intermittent, treatment
new solutions, variable Ca

36. Treatment of CKD-MBD: What about PD?
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
S. Bertoli – 2009
O. Simonsen- KI 2003

37. RIMOZIONE DEL FOSFORO IN
DIALISI PERITONEALE
- FUNZIONE RENALE RESIDUA
- PERMEABILITA’ PERITONEALE
- SCHEMA DIALITICO

38. RIMOZIONE DEL FOSFORO IN DP FUNZIONE RENALE RESIDUA
24 pazienti incidenti in DP – GFR start 59,9 L/sett – 7,1 mesi di follow up
Bammens et al, AJKD 2000
CLEARANCE CREATININA
CLEARANCE UREA
CLEARANCE FOSFORO
100
Litri / settimana / 1,73 mq di BSA 80 60
La clearance renale del fosforo è penalizzata dall’essere simile a quella dell’urea e quindi nettamente inferiore a quella della creatinina.
In questo studio longitudinale osservazionale condotto su 24 pazienti incidenti in DP si vede quale sia il rapporto durante i 7 mesi di follow up tra clearance della creatinina, dell’urea e del fosforo. Come si vede la clearance del fosforo è pari a quella dell’urea e circa la metà di quella della creatinina. 40 20 1 2 3 4 5
VISITE 38

39. RIMOZIONE DEL FOSFORO IN DP FUNZIONE RENALE RESIDUA
Analisi cross-sectional su 33 pazienti in DP
una misura - un paziente, 17 in CAPD, 24 M
CLEARANCE CREATININA = 5,15 ± 2,91 ml/min
CLEARANCE UREA = 2,70 ± 1,46 ml/min
CLEARANCE FOSFORO = 2,50 ± 1,73 ml/min
r =0,49
y = 0,6421x
R2 = 0,6848
r =0,94
Più in dettaglio, questo studio riporta, da una analisi cross over condotta su 33 pazienti in DP con una clearance creatinina media di circa 5, il valore numerico di tale relazione che è prossima ad 1 per la clearance della urea ed appunto circa la metà di quella della creatinina.
Ma in termini concreti quanto porta fosforo si rimuove con la FRR ?
Basta osservare la relazione tra clearance del fosforo e GFR (non normalizzato, calcolato come media di clearance urea e creatinina) che è appunto di 0,64 (ovvero per 1 ml/minuto di GFR la clearance del fosforo è di 0,64 ml/minuto)
Neri et al – SIN 2007 39

40. RIMOZIONE DEL FOSFORO IN DP PERMEABILITA’ PERITONEALE
Lilaj et al, AJKD 1999
15 pazienti, PET standard
Gallar et al, Nefrologia 2000
70 pazienti, PET standard
D/P
0,9
0,8
0,7
D/P creat 4 h
Per quanto riguarda la rimozione peritoneale si vede come il comportamento del fosforo sia al contrario che per la FRR simile a quello della creatinina.
0,6
0,5
0,4
ore
0,2
0,4
0,6
0,8
D/P fosforo 4 h 40

41. RIMOZIONE DEL FOSFORO IN DP PERMEABILITA’ PERITONEALE
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
D/P fosforo 4 h
E molto diverso da quello dell’urea. In sostanza il fosforo è svantaggiato in quanto con la FRR si comporta come l’urea e con la membrana peritoneale come la creatinina. Altra osservazione è, come la creatinina, vi è una notevole differenza a secondo della permeabilità peritoneale per cui gli alti permeabili avranno una rimozione di fosforo nettamente superiore a quella dei bassi permeabili.
D/P creatinina 4 h
D/P urea 4 h 41

42. RIMOZIONE DEL FOSFORO IN DP
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

43. KDIGO International Clinical Practice Guidelines
In Summary …
KDIGO International Clinical Practice Guidelines
Phosphorus
Calcium
PTH
Goal = Normal
Evaluate PTH in context of hyperP, hypoCa, vitamin D deficiency
Marked changes should trigger treatment changes
Decrease cinacalcet in event of hypocalcemia
Calcification represents the highest risk
Detect with x-ray/ultrasound
Restrict Calcium in
Hypercalcemia
Calcification
Low PTH
ADBD
Treat the trends: Treat P and Ca to normal, PTH to Goal
KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

44. GRAZIE PER L’ATTENZIONE

45. 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. 45