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

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

From Renal Osteodystrophy to Chronic Kidney Disease - Mineral Bone Disorder (CKD – MBD) Kidney Int 2006; 69: 1945-53 3 3

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;69:1945-1953 4

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 Vascular Calcification Treatment 7

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

KDIGO: Diagnosis of CKD-MBD Biochemical 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 10

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. 3.1.3 (2C) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 11

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. 3.1.4 (1C); b. 3.1.5 (2D) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 12

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

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

Treatment of CKD-MBD: Phosphorus and Calcium

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) 10 - 65 pg/ml [Centers for Disease Control recommendations] “Normal” means within the above ranges. These are normal ranges for healthy individuals. 16 16

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 17

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 18

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. 4.1.5 (1B); b. 4.1.5 (2C) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 19

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;27:152-158 2 Chertow GM, et al. Kidney Int. 2002;62:245-252 3 Block GA, et al. Kidney Int. 2005;68:1815-1824 4 Qunibi W, et al. AJKD. 2008 5 Andress D. Kidney Int. 2008;73:1345-1354 6 KDIGO. KI 2009; 76 (Suppl 113):S1-S130 Calcium Restriction 20

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

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)

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 24

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 25

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 26

KDOQI / KDIGO - PTH TARGETS CKD Stage Target iPTH (pg/ml) KDOQI Grading Target iPTH (pg/ml) KDIGO 3 35 - 70 Opinion Not known 2C 4 70 - 110 5 ND 150 - 300 Evidence 5D 2 to 9 x ULN KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

KDIGO: Diagnosis of CKD-MBD Vascular 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 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. 3.3.1 (2C) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130 29

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. 3.3.1 (2C) KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130 30

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;27:152-158. †Spiegel DM, Raggi P, Mehta R, et al. Coronary and aortic calcifications in patients new to dialysis. Hemodialysis Int. 2004;8:265-272. ‡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;62:245-252.

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 28 85 56 55 73 130 13 GFR Stg 3-5 Stg 2-5 <15 48 <15 47 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;2022-2031; Russo D et al. Am J Kidney Dis. 2004;44:1024-1030; Kramer H et al. J Am Soc Nephrol. 2005;16:507-513; Quinibi WY et al. Kidney Int. 2005;68:271-277; Spiegel DM et al. 2004;2004:265-272 Mehrotra R. J Renal Nutrition. 2006;16:100-118 32

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 1-400 (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 0.4-6.1) compared to subjects with a CAC score 1-400 (7.0/100 patient years, CI 2.7-11.4) and those with a CAC score >400 (14.7/100 patient years, CI 8.1-21.4) (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 1.33-15.14). 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):438-441. 33

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.

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

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

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

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

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

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

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

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

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

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. 45