Paolo Monardo

Salivary Phosphate-Binding Chewing Gum Reduces Hyperphosphatemia in Dialysis Patients

In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders, only half of hemodialysis (HD) patients achieve recommended serum phosphate levels. A hyperphosphoric salivary content, which correlates linearly with serum phosphate, has been reported in HD patients. We hypothesized that binding salivary phosphate during periods of fasting in addition to using phosphate binders with meals could improve the treatment of hyperphosphatemia. We assessed the phosphate-binding capacity of the natural polymer chitosan by (31)P nuclear magnetic resonance and established that 10 and 20% (wt/vol) middle viscosity chitosan solutions bind 30 and 50% of the phosphate contained in PBS, respectively. Thirteen HD patients with serum phosphate levels >6.0 mg/dl despite treatment with sevelamer hydrochloride chewed 20 mg of chitosan-loaded chewing gum twice daily for 2 wk at fast in addition to their prescribed phosphate-binding regimen. Salivary phosphate and serum phosphate significantly decreased during the first week of chewing; by the end of 2 wk, salivary phosphate decreased 55% from baseline (73.21 +/- 19.19 to 33.19 +/- 6.53; P < 0.00001), and serum phosphate decreased 31% from baseline (7.60 +/- 0.91 to 5.25 +/- 0.89 mg/dl; P < 0.00001). Salivary phosphate returned to baseline by day 15 after discontinuing the chewing gum, whereas serum phosphate levels took 30 d to return to baseline. Parathyroid hormone and serum calcium concentrations were not affected by the gum. In conclusion, adding salivary phosphate binding to traditional phosphate binders could be a useful approach for improving treatment of hyperphosphatemia in HD patients.

Salivary Glands: A New Player in Phosphorus Metabolism

In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders and dietary phosphate limitation in addition to dialysis, only 50% of dialysis patients achieve recommended serum phosphate levels. The identification of other approaches for serum phosphorus reduction is therefore necessary. We have approached this issue by taking into account the relationships between serum phosphate, kidney function, and saliva. Saliva was chosen because the anatomy and/or physiology of acini, the secretive units of salivary glands, shares similarities with that of the renal tubules. Salivary fluid contains electrolytes including phosphate that, when related with the amount of salivary secretion per day, raises the interest in identifying another possible approach for phosphorus removal in uremic patients. This article reports studies from our laboratory in the last 3 to 4 years, which have demonstrated a hyperphosphoric salivary content in patients with chronic renal failure and those with end-stage renal disease under chronic dialysis that, in patients with chronic renal failure, linearly correlates with serum phosphate in patients with chronic renal failure and negatively with GFR. The ingestion of the saliva and later its absorption in the intestinal tract starts a vicious circle between salivary phosphate secretion and fasting phosphate absorption, thereby worsening hyperphosphatemia. Therefore, salivary phosphate binding could be a useful approach to serum phosphate level reduction in dialysis patients. The reduction of salivary phosphate with the salivary phosphate binder, chitosan-loaded chewing gum, chewed during fasting periods, as an add-on to phosphate binders could lead to a better control of hyperphosphatemia, as demonstrated in our study, which confirms the importance of this approach.

A new approach to the evaluation of hyperphosphatemia in chronic kidney disease.

AIMS Hyperphosphoremia, main contributor to cardiovascular calcifications, has a major impact on the morbidity and mortality of chronic renal failure (CRF) patients. Phosphate binders and dietary phosphate limitation are not effective enough to abolish hyperphosphoremia-induced cardiovascular abnormalities, therefore, the identification of other and more timely approaches for serum phosphorous reduction is necessary. Salivary fluid contains phosphate which, if related to the daily salivary secretion (1,000 - 1,800 ml), deserves attention as a marker for an earlier start of pharmacologic treatment for phosphorous removal. In ESRD patients under dialysis we have shown increased salivary phosphate closely to be related with serum phosphorous and interpreted as compensatory. This study evaluates salivary phosphate secretion in 77 nondialyzed CRF compared with healthy subjects and its relationship with renal function. METHODS Saxons test confirmed normal salivary function in patients and controls. Serum phosphorous, creatinine and GFR were also measured. RESULTS Salivary phosphorous was significantly higher in CRF patients compared with controls: 38.60 mg/dl (range 12.20 - 95.60) vs 16.30 (10.30 - 27.10), p < 0.0001; serum phosphate was also significantly higher: 3.70 (2.10 - 6.80) vs 3.50 (2.3 4.6), p = 0.013. In CRF patients, salivary phosphorous positively correlated with serum phosphorous (r - 0.45, p < 0.0001) and with serum creatinine (r = 0.72, p < 0.0001), while negatively correlated with GFR (r = -0.72, p < 0.0001). CONCLUSIONS The results of our study show also in CRF patients increased salivary phosphate secretion, which is related with renal function. On this basis the use of salivary phosphate secretion as a marker for an earlier start of the abnormal phosphate, metabolism pharmacologic treatment could be proposed.

Salivary phosphorus and phosphate content of beverages: implications for the treatment of uremic hyperphosphatemia.

BACKGROUND Hyperphosphatemia provides relevant and dangerous evidence of end-stage renal disease (ESRD) in patients undergoing periodic hemodialysis. The relationship between hyperphosphatemia and cardiovascular calcification, with the consequences of high morbidity and mortality after cardiovascular events, is well-defined. Hyperphosphatemia is treated by dietary limitation of phosphorus ingestion and by phosphate binders, but only half of ESRD patients fall within the range of K/DOQI guidelines. OBJECTIVE AND METHODS We summarize the results of our studies on salivary phosphate secretion in hemodialysis (HD) and chronic kidney disease (CKD) patients, and on the habit of HD patients to drink beverages with a high or low phosphate content. We also examine the correlation between hyperphosphoremia and the phosphate content of common beverages consumed by HD patients. RESULTS AND CONCLUSIONS Higher levels of salivary phosphate secretion were found in HD and in CKD patients, along with a relationship between serum phosphorus levels and a high phosphate content of beverages in HD patients.

An update on calcium metabolism alterations and cardiovascular risk in patients with chronic kidney disease: questions, myths and facts

In 2006, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines introduced, for the first time, the definition and diagnostic and therapeutic criteria for a systemic complication of the mineral metabolism dysfunction, such as vascular calcification, caused by chronic renal insufficiency. Abdominal x-ray and echocardiography rather than the more complex CT scan is suggested to make the diagnosis. This condition is associated with high cardiovascular risk and consequent poor prognosis. An alteration in total body calcium (Ca) content is one of the key factors in the cardiovascular complications observed in uremic subjects. In the general population, the addition of Ca to the diet has been to shown to improve bone mineral density (BMD) compared to controls, but it does not appear to reduce the risk of bone fractures. In patients with CKD, there are certainly some theoretical justifications for administering calcium salts: vitamin D deficiency, which reduces the intestinal absorption of Ca; hypocalcemia, which increases the risk of hyperparathyroidism; and hyperphosphatemia, which justifies the use of Ca-based P binders. There is already a large body of evidence pointing against the use of Ca-based binding agents, when there is a positive Ca balance because of the development of vascular calcification.

Sevelamer carbonate in the treatment of hyperphosphatemia in patients with chronic kidney disease on hemodialysis

Sevelamer carbonate is an anion exchange pharmaceutical, developed to improve on the performance of the non-absorbable, non-calcium, and metal-free phosphate binder sevelamer hydrochloride. Sevelamer carbonate is expected not to worsen metabolic acidosis, as previously reported during long-term treatment with sevelamer hydrochloride in hemodialysis (HD) patients. Carbonate is the alternate counterion to chloride on the sevelamer polymeric backbone, but the active poly(allylamine) responsible for phosphate (PO4) binding remains unaltered. Therefore, sevelamer carbonate is expected to reduce elevated serum phosphorus level, similarly to sevelamer hydrochloride. Sevelamers are prescribed in uremic HD patients to control hyperphosphatemia, but the carbonate has also been proposed for the treatment of chronic kidney disease (CKD) non-dialysis patients. Although hyperphosphatemia is regarded as a main contributor to increased mortality in the HD population because of cardiovascular calcification, metabolic acidosis has also been advocated as a major player in the increased mortality in this population, by engendering malnutrition, negative nitrogen balance, and inflammation. This paper reviews the evidence showing that sevelamer carbonate is as good as sevelamer hydrochloride in terms of hyperphosphatemia control in CKD, but with a better outcome in serum bicarbonate balance.

Subcutaneous Low Doses of Recombinant Human Erythropoietin in Predialysis Patients Do Not Interfere with the Progression of Renal Failure

This paper reports a study on the treatment of predialysis patients with recombinant human erythropoietin (r-HuEPO). The haematocrit, haemoglobin, reticulocyte and platelet values as well as creatinine and creatinine clearance evaluated by standard and radio-isotopic methods before, during and after r-HuEPO treatment were determined. The slope of the inverse creatinine versus time curves was studied too. The authors did not observe any variation of the renal function parameters during and after study and suggest their protocol of r-HuEPO administration for predialysis patients.

Time-dependent effect of sevelamerHCl on the cardiovascular system.

These potential benefits of newer agents, including sevelamer, and other anion-exchange resins, as discussed by Drs Wrong and Harland [5], are supported, only in part, by very large-scale observational studies, where lower levels of serum calcium, phosphorus, and less so parathyroid hormone, are associated with improved survival for people with chronic kidney disease [1,6]. As we have previously discussed extensively, this is not enough [7–9]. What remains important is that the direct relationship between modification of calcium, phosphorus or PTH with improved survival and cardiovascular outcomes in randomized, controlled trials is still far from proven. This is despite the largest trial in this area, the Dialysis Clinical Outcomes Revisited (DCOR) trial enrolling over 2100 patients to either sevelamer or calcium salts, which showed no difference for mortality between treatment arms [10] and the meta-analyses of phosphate binders [11], calcimimetics [9] and vitamin D compounds [8]. The ongoing search for efficacious and cost-effective agents, such as anion exchange resins, is laudable. Therefore, the suggestion of Wrong and Harland that colestipol, or other cheaper alternatives, could be promoted in preference to the more expensive sevelamer, is appealing. However, while these and other measures may be temporarily supported, the real priority for resources in this area should be directed at understanding the effects of the treatment for altered mineral metabolism on patient centred outcomes, including bone pain, cardiovascular events and mortality in chronic kidney disease. Do any of these drugs, which can control phosphorus levels, really have any effect on reducing the excess mortality which is attributable to high serum phosphorus levels in chronic kidney disease? Certainly there are numerous resins that can be used to absorb intestinal phosphorus, but just as well there are now numerous data to support that adequately powered, randomized trials investigating either pharmaceutical agents or the serum targets of calcium, phosphorus and parathyroid hormone levels should be developed.

Renal Function Evaluation in an Adult Female with Cat-Eye Syndrome

Cat-eye syndrome is a rare congenital anomaly involving the kidney. It is rarely reported in literature, while renal function has never been studied up to now. Shown here are the morphofunctional renal alterations observed in a female patient affected by cat-eye syndrome.