Medical Nutritional Therapy for Patients with Chronic Kidney Disease not on Dialysis: The Low Protein Diet as a Medication.

The 2020 Kidney Disease Outcome Quality Initiative (KDOQI) Clinical Practice Guideline for Nutrition in chronic kidney disease (CKD) recommends protein restriction to patients affected by CKD in stages 3 to 5 (not on dialysis), provided that they are metabolically stable, with the goal to delay kidney failure (graded as evidence level 1A) and improve quality of life (graded as evidence level 2C). Despite these strong statements, low protein diets (LPDs) are not prescribed by many nephrologists worldwide. In this review, we challenge the view of protein restriction as an "option" in the management of patients with CKD, and defend it as a core element of care. We argue that LPDs need to be tailored and patient-centered to ensure adherence, efficacy, and safety. Nephrologists, aligned with renal dietitians, may approach the implementation of LPDs similarly to a drug prescription, considering its indications, contra-indications, mechanism of action, dosages, unwanted side effects, and special warnings. Following this framework, we discuss herein the benefits and potential harms of LPDs as a cornerstone in CKD management.

[Hyperphosphatemia in dialysis: which binder?]

Several studies have evidenced the association between high serum phosphorus concentrations and adverse events especially in patients on dialysis. Recent K-DIGO guidelines suggest lowering elevated phosphate levels toward the normal range. This goal should be achieved by combining dietary counseling, optimizing dialysis procedures and prescribing phosphate binders. Despite the availability of several binders, the "ideal" phosphate binder that combines high efficacy, low pills burden, minimal side effects and low cost is still not available. In clinical practice it is crucial to reach a high patient's compliance to therapy. The pill burden is the most relevant factor contributing to low compliance. This is the case of phosphate binder therapy that represents almost 50% of total pills prescribed to patients on dialysis. It has been evidenced an association between pills of phosphate binder and poor control of phosphorus and PTH. In recent years sucroferric oxyhydroxide is available as a new phosphate binder. Its peculiarity is an high phosphate binding capability that requires prescription of low number of pills per day. This characteristic has been confirmed by several randomized controlled trials. These trials have also evidenced that sucroferric oxyhydroxide may cause some gastrointestinal side effects. There is an ongoing study to confirm in "the real world" the incidence of side effects reported by controlled trials.

Low vitamin K1 intake in haemodialysis patients.

BACKGROUND & AIMS: Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis. METHODS: In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins). RESULTS: Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency. CONCLUSIONS: Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated.

Calcimimetic and vitamin D analog use in hemodialyzed patients is associated with increased levels of vitamin K dependent proteins.

Matrix Gla protein (MGP) and bone Gla protein (BGP) are two vitamin K-dependent proteins (VKDPs) involved in the regulation of vascular calcification (VC). We carried out a secondary analysis of the VIKI study to evaluate associations between drug consumption and VKDP levels in 387 hemodialyzed patients. The VIKI study assessed the prevalence of vitamin K deficiency in hemodialysis patients. We evaluated drug consumption, determined BGP and MGP levels, and verified the presence of any vertebral fractures (VF) and VC by spine radiographs. Total BGP levels were twice as high with calcimimetics versus no calcimimetics (290 vs. 158.5 mcg/L, p < 0.0001) and 69 % higher with vitamin D analogs (268 vs. 159 mcg/L, p < 0.0001). Total MGP was 19 % higher with calcimimetics (21.5 vs. 18.1 mcg/L, p = 0.04) and 54 % higher with calcium acetate (27.9 vs. 18.1 mcg/L, p = 0.003); no difference was found with vitamin D analogs (21.1 vs. 18.3 mcg/L, p = 0.43). Median Total BGP level was 29 % lower in patients with ≥1 VF (151 vs. 213 mcg/L, p = 0.0091) and 36 % lower in patients with VC (164 vs. 262.1 mcg/L, p = 0.0003). In non-survivors, median BGP and MGP were lower, but only for MGP this difference reached the statistical significance (152 vs. 191 mcg/L, p = 0.20 and 15.0 vs. 19.7 mcg/L, p = 0.02, respectively). Pending studies on vitamin K supplementation, calcimimetics, and vitamin D analogs may play a role in preserving vitamin K-dependent protein activity, thus contributing to bone and vascular health in CKD patients.

Management of CKD-MBD in non-dialysis patients under regular nephrology care: a prospective multicenter study.

BACKGROUND: Knowledge about mineral bone disorder (MBD) management in non-dialysis chronic kidney disease (ND-CKD) patients is scarce, although essential to identifying areas for therapeutic improvement. METHODS: We prospectively evaluated current management of CKD-MBD in two visits, performed 6 months apart, in 727 prevalent ND-CKD stage 3b-5 patients from 19 nephrology clinics. Therapeutic inertia was defined as lack of treatment despite hyperphosphatemia and/or hypocalcemia, and/or hyperparathyroidism. The primary endpoint was the prevalence of achieved target for CKD-MBD parameters and related treatments (phosphate binders, vitamin D and calcium supplements). The secondary endpoint was the assessment of prevalence and clinical correlates of therapeutic inertia. RESULTS: Over 65 % of patients did not reach parathormone (PTH) targets, while 15 and 19 % did not reach phosphate and calcium targets, respectively. The proportion of untreated patients decreased from stage 3b to 5 (at baseline, from 60 to 16 %, respectively). From baseline to the 6-month visit, the achievement of targets remained stable. Low protein diet was prescribed in 26 % of patients, phosphate binders in 17.3 % (calcium-based binders 15.5 %, aluminium binders 1.8 %), and vitamin D in 50.5 %. The overall prevalence of therapeutic inertia at the 6-month visit was 34.0 % (for hyperphosphatemia, 54.3 %). Compared to CKD stage 3, the likelihood of therapeutic inertia was 40 and 68 % lower at stage 4 and 5, respectively. CONCLUSIONS: PTH, calcium and phosphate targets were not reached in a significant proportion of patients. One-third of patients with at least one MBD parameter not-at-target remained untreated. Therapeutic inertia regarding CKD-MBD treatment may be a major barrier to optimizing the prevention and cure of CKD-MBD.

Vitamin K and cardiovascular calcification in CKD: is patient supplementation on the horizon?

The vitamin K-dependent proteins (VKDPs) matrix Gla protein and osteocalcin protect from cardiovascular calcifications and bone fractures. A vitamin K recycling system maintains sufficient vitamin K levels for activation of VKDPs through γ-glutamyl carboxylase (GGCX). Kaesler et al. demonstrate that uremia per se can interfere with GGCX activity, contributing to vitamin K deficiency in chronic kidney disease and opening the path to the clinical use of vitamin K, currently tested in randomized trials.

Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks?

Calcium supplements may induce hypercalcaemia in patients with chronic kidney disease (CKD) or patients on hemodialysis. Even in the absence of overt hypercalcaemia, calcium supplementation may be associated with a positive calcium balance and intracellular calcium overload. There is an increased risk of complex supraventricular, ventricular arrhythmias or the risk of suffering a cardiac arrest in the presence of hypercalcaemia and calcium overload in subjects with impaired or absent renal function. A maximum intake of 1000 mg elemental calcium, combining supplements and dietary calcium, together with a 1.5 mmol/l level in the dialysate, may be a safer (opinion based) recommendation in CKD patients. This is especially the case if the patient already shows signs of extra-skeletal calcification or if they present cardiac comorbidities. Lower calcium levels in the dialysis fluid might reduce the positive calcium balance but can increase intradialytic plasma calcium changes and therefore increase the risk of arrhythmias.

Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics.

BACKGROUND: Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement. METHODS: We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from ≥6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID. RESULTS: Age was 69 ± 13 years and GFR 27.5 ± 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively). CONCLUSIONS: This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment.

Phosphate control in dialysis.

Prevention and correction of hyperphosphatemia is a major goal of chronic kidney disease-mineral and bone disorder (CKD-MBD) management, achievable through avoidance of a positive phosphate balance. To this aim, optimal dialysis removal, careful use of phosphate binders, and dietary phosphate control are needed to optimize the control of phosphate balance in well-nourished patients on a standard three-times-a-week hemodialysis schedule. Using a mixed diffusive-convective hemodialysis tecniques, and increasing the number and/or the duration of dialysis tecniques are all measures able to enhance phosphorus (P) mass removal through dialysis. However, dialytic removal does not equal the high P intake linked to the high dietary protein requirement of dialysis patients; hence, the use of intestinal P binders is mandatory to reduce P net intestinal absorption. Unfortunately, even a large dose of P binders is able to bind approximately 200-300 mg of P on a daily basis, so it is evident that their efficacy is limited in the case of an uncontrolled dietary P load. Hence, limitation of dietary P intake is needed to reach the goal of neutral phosphate balance in dialysis, coupled to an adequate protein intake. To this aim, patients should be informed and educated to avoid foods that are naturally rich in phosphate and also processed food with P-containing preservatives. In addition, patients should preferentially choose food with a low P-to-protein ratio. For example, patients could choose egg white or protein from a vegetable source. Finally, boiling should be the preferred cooking procedure, because it induces food demineralization, including phosphate loss. The integrated approach outlined in this article should be actively adapted as a therapeutic alliance by clinicians, dieticians, and patients for an effective control of phosphate balance in dialysis patients.

Prevalence and progression of cardiovascular calcifications in peritoneal dialysis patients: A prospective study.

BACKGROUND: Patients on dialysis may have abnormal serum levels of Ca, P and parathyroid hormone, with related bone diseases. This population has an increased risk of death, with cardiovascular calcification (CC) a contributing factor. Patients on peritoneal dialysis appear to be at increased risk of hyperlipidemia, a contributing factor to atherosclerotic plaque formation. Although several studies have described the presence and progression of CC in hemodialysis populations, there are fewer data in patients on peritoneal dialysis. STUDY DESIGN: The Renal Osteodystrophy and Calcifications: Key factors in Peritoneal Dialysis (ROCK-PD) study was a 36-month, prospective observational study conducted in Italy. The study examined the presence and progression of CC in two cardiac valves and five arterial sites. The potential associations of serum Ca and P with mortality and cardiovascular morbidity, demographic, clinical and blood chemistry variables was investigated. RESULTS: CC was present in 77% of patients at baseline (N=369) and in 90% of patients by study end (N=145), progressing in 73% of patients. There were 42 deaths (11%). Analyses showed a marked correlation between baseline P levels and the presence of left ventricular hypertrophy. However, there were no consistent correlations between serum Ca or P with mortality or morbidity. CONCLUSIONS: CC was common in peritoneal dialysis patients and progressed in a majority of patients.

Bleeding, vertebral fractures and vascular calcifications in patients treated with warfarin: hope for lower risks with alternative therapies.

Anticoagulant therapy in patients with atrial fibrillation requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHA(2)DS(2)VASc, coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score. In addition to bleeding, other risks have been associated with the use of warfarin, including an increased susceptibility to vascular calcifications and fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP). In fact, while on one side warfarin is used to prevent embolism, on the other hand acting as a vitamin K antagonist it blocks the inhibitory effect of MGP on vascular calcification. Similarly, patients treated with warfarin carry a greater risk of developing osteoporosis and fractures, due to reduced BGP activity. Recently, a new generation of anticoagulant drugs has been developed, such as dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor-Xa inhibitor. They offer an interesting alternative to warfarin, because they do not require frequent blood tests for monitoring while offering similar results in terms of efficacy. Lacking the inhibitory effect on the vitamin K cycle, the consequent side effects can be avoided. If, compared to warfarin treated patients, a lower incidence of vascular calcifications and fractures will be demonstrated, the advantages over warfarin may be even greater, leading to further benefits in terms of morbidity and mortality.

[Vascular calcification in chronic kidney disease]. / La calcificazione vascolare nel paziente con insufficienza renale cronica.

Patients affected by chronic kidney disease (CKD) suffer by secondary hyperparathyroidism and hyperphosphatemia. The new KDIGO guidelines identify a new definition in CKD-MBD (Mineral Bone Disorder), in which vascular calcification plays a central role. In fact, CKD patients that present vascular calcification have highest risk of cardiovascular morbility and mortality. Recently, it has been elucidated that the control of phosphate is one of the major problems for the nephrology community. Furthermore, new markers, such as FGF-23, have been identified as inducers of vascular calcification and cardiovascular disease in CKD. Therefore, the use of calcium-free phosphate-binders may reduce the risk of cardiovascular disease by reducing both serum phosphate and FGF-23 levels.

Arterial accelerated aging in dialysis patients: the clinical impact of vascular calcification.

Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in Chronic Kidney Disease (CKD). In addition to abnormalities in serum calcium (Ca) and phosphate (P) profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification (VC). Indeed, the co-localization of bone markers such as Osteopontin, Alkaline Phosphatase and Osteocalcin along with osteoblast-like cells in the contest of the arterial wall of uremic patients, indicate that VC is an active biological process with peculiar analogies with bone mineralization. Thus, VC represents a plausible link between Ca and P derangements and the increased mortality associated with CKD-MBD. The process of VC starts in early stages of CKD and patients with CKD-3, -4 and -5 not undergoing haemodialysis may present a significant burden of calcification in the coronaries. Considering that presence and extent of VC in CKD portend poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent VC deposition and progression. Indeed, careful control of calcium load, serum P and parathyroid hormone along with the use of calcium-free P binders and vitamin D analogs represent our current armamentarium to improve quality of life and reduce mortality in CKD. We herein summarize the current understanding and evidence supporting strategies available for VC treatment.

Management of calcium refilling post-parathyroidectomy in end-stage renal disease.

BACKGROUND: Management of post-parathyroidectomy hypocalcemia in dialysis patients is not well defined. We reviewed published approaches to treatment in an effort to define a clinical algorithm for controlling serum calcium levels post-operatively. METHODS: We conducted a PubMed search for the years 1980-2003 with the keywords "hypocalcemia" and "parathyroidectomy". Only English language and human subject abstracts were analyzed, and only those articles dealing with secondary or tertiary hyperparathyroidism (HPTH) were reviewed further. Other articles were extracted from cross-referencing. RESULTS: We initially examined 146 articles. This review summarizes the findings of the relevant articles along with our own practice regarding post-parathyroidectomy hypocalcemia management in dialysis patients. The vast majority of patients require intravenous (i.v.) calcium supplements after surgery. There are no available controlled studies on calcium supplementation for post-parathyroidectomy hypocalcemia in this patient population. Calcitriol supplementation proved valuable in two studies. CONCLUSIONS: Post-parathyroidectomy hypocalcemia is a common complication, which can be prevented and treated with oral and i.v. calcium supplementation and/or active vitamin D metabolites. Daily follow-up of both serum calcium and phosphorus are mandatory to prevent this major post-operative complication. Based on the available evidence, we propose a protocol for the prevention and treatment of post-parathyroidectomy hypocalcemia, for use in clinical practice. This approach requires validation by a controlled clinical trial.