Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. Anoop M
MBBS, MD, DNB Consultant - Nephrology & Transplant Physician Nephroplus, Bangalore.
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Abstract
Hyperphosphatemia is an electrolyte disorder where serum phosphorus levels get elevated caused due to chronic kidney disease, hypoparathyroidism, metabolic or respiratory acidosis, Excessive phosphate load, pseudo hypoparathyroidism or transcellular shifting. The most common cause of hyperphosphatemia is chronic kidney disease (CKD) as it is very prevalent in patients with CKD. CKD patients with hyperphosphatemia have to take multiple number of pills due to multiple associated comorbidities which consequently cause poor adherence to therapy. The high pill burden is associated with the non-adherence to therapy and poor treatment outcomes. In patient with chronic diseases, non-adherence to medications is quite common, and it may be seen in almost over 50% of the patients.
There are different types of phosphate binders available which reduce the serum phosphorus levels but these phosphate binders contribute to the highest number of pills taken by patient among all the therapies. The central problem associated with the phosphate binder treatment is the insufficient patient adherence caused by usually high pill burden and ensuing gastrointestinal adverse events. The measure to reduce pill burden and increase adherence to therapy is to decrease the number of pills. Zerofos-DS (by Alniche Life Sciences) is a double strength medicine 1st time in India which offers effective treatment to hyperphosphatemia in half the number of pills as compared to conventional phosphate binders. In conclusion, Zerofos-DS is an advanced approach to treat hyperphosphatemia as well as to increase the patient adherence to therapy by reducing the pill burden.
Keywords: Hyperphosphatemia, Chronic Kidney Disease, Phosphate binders, Serum phosphorus, Pill burden, Non-adherence, Zerofos-DS
Introduction
Inorganic phosphorus is an intracellular anion that plays an important role in energy production, functioning of cells, signal transduction, and membrane transport.
Hyperphosphatemia - Hyperphosphatemia is an electrolyte disorder in which there is an elevated level of phosphate in the blood or when there is too much phosphate in your blood. [1] It is a common complication in CKD (Chronic kidney disease) patients, particularly in those patients who requires therapy for renal replacement. Most people have no symptoms while others develop calcium deposits in the soft tissue, low calcium levels which can result in muscle spasms [1].
Causes of Hyperphosphatemia includes:
Chronic Kidney Disease is the major cause for hyperphosphatemia as function of phosphorus homeostasis is lost in this condition in last stages. The pool size for phosphorus exchange is decreased by the kidney disease by inhibiting the bone formation [2]. With the progression of chronic kidney disease (CKD), bone and mineral metabolism becomes dysregulated and to maintain normal phosphorus and calcium levels increasing levels of parathyroid hormone serve as an adaptive response. This response becomes maladaptive and high level of phosphorus may occur [3]. The consequences of hyperphosphatemia can be numerous, uremic bone disease, development of secondary hyperparathyroidism, and the promotion of vascular and visceral calcifications (figure 1).
Figure 1: Development and consequences of hyperphosphatemia in Chronic Renal Disease
The association between increased risk of death by cardiovascular disease/vascular calcification and hyperphosphatemia has been well established for a long time.
The serum phosphorus has now consistently been shown to be an independent predictor of the risk for death [4].
Etiology
The most common cause of Hyperphosphatemia is renal failure. The filtration of inorganic phosphate is reduced significantly by glomerular filtration rate of less than 30 mL/min, increasing serum phosphorus levels. Some other less common cause of Hyperphosphatemia includes increased renal reabsorption or high intake of phosphorus.
Excessive use of phosphate-containing laxatives or enemas, and vitamin D intoxication can cause high intake of phosphate. Vitamin D increases intestinal phosphate absorption. Renal phosphate reabsorption is enhanced by hypoparathyroidism, acromegaly and thyrotoxicosis resulting in hyperphosphatemia. Hyperphosphatemia can also be due to genetic causes as several genetic deficiencies can lead to decreased FGF-23 activity, hypoparathyroidism and pseudo hypoparathyroidism.
Epidemiology
Hyperphosphatemia is a prevalent condition in kidney patients and a common laboratory abnormality encountered by nephrologists. The prevalence of hyperphosphatemia is 50 to 74% in patients with end- stage renal disease (ESRD) [5].
After excluding patients with end-stage renal disease (ESRD), with acute kidney injury (AKI) or whose phosphate did not get measured at admission, David E. Leaf and Myles Wolf found that 12% of all patients at admission to a tertiary care hospital, had incidence of hyperphosphatemia [6].
Pathophysiology
Hyperphosphatemia, in general, can be caused due to: Decreased renal excretion, Excessive phosphate load, Hypoparathyroidism and pseudo hypoparathyroidism or Transcellular shifting.
1. Decreased renal excretion: The 90% of the daily phosphate load in the body gets excreted by kidneys, and when renal function becomes diminished it causes decreased secretion and increased retention of phosphate.
2. Excessive phosphate load: As phosphate is the major intracellular anion in human body, the massive tissue breakdown due to any cause can result into the release of intracellular phosphate into extracellular fluid. The cause for massive tissue breakdown can be severe hemolysis, tumor lysis syndrome, or rhabdomyolysis.
3. Hypoparathyroidism: Hypoparathyroidism is a rare disease that results in hypocalcaemia. The most possible common cause is the injury or dysfunction of the parathyroid gland, removal of the parathyroid gland during anterior neck surgery. Symptoms include muscle cramps, seizures, paresthesia and laryngospasm.
4. Transcellular shift: Diabetic ketoacidosis and lactic acidosis can rarely cause phosphate massive cellular shifts out of the cells.
Pill Burden in CKD Patients and Quality of life
Due to complex chronic illness and multiple associated comorbidities, kidney patients have a high pill burden. One study found that maintain hemodialysis (MHD) patients had a median pill burden of 19 pills /day (figure 2) [7]. Complex medication regime has been shown to impair adherence caused by increase healthcare cost, poor quality of life and mortality also in chronic conditions. Increasing adherence to medication regimens is important to achieve treatment outcomes [8].
Figure 2: Percentage of pill burden from different classes of medications
In patient with chronic diseases, non-adherence to medications is quite common, and can be seen in almost over 50% of the patients [9]. Together with managing the comorbidities and complications, the major goal of treatment in CKD is slowing the rate of progression of disease. According to researches, it was shown that non-adherence in CKD caused increase in expense of medications and hospitalizations, uncontrolled hypertension and more frequent dialysis [10] and can eventually lead to CKD progression and occurrence of End stage renal disease (ESRD). Worldwide, the variation of adherence to medication in CKD patients has been reported 3 % to 83 % [11]. The major predictors for the poor adherence or non-adherence to medication includes high pill burden, high cost, forgetfulness, not feeling well, complex dosing schedule, poor knowledge of disease/treatment, adverse effects, and taking alternative medicine among others. Therefore, adherence to medications in CKD patients remains a major concern to therapy.
Dialysis patients, are prescribed many medications and poor health-related quality of life (HR-QOL) because of a very high burden of co-existing diseases. It is reported that, in dialysis population the daily pill burden is one of the highest as compared to any other chronic disease like diabetes mellitus and congestive heart failure [12] [13] [14]. For uncontrolled serum phosphorus levels, increasing the number of prescribed pill does not seem to improve control over kidney and it may also come at the cost of poorer Health related – quality of life (HR-QOL) [15].
Serum phosphorus control may be complicated by pill burden and non-adherence [16] [17]. On an average, over 50% of the dialysis patients are not adherent to their pill burden regimes, but depending on the patient measurement method and patient population this level ranges from 21 to 74% [18][19]. Pill burden affects the adherence of patients and often pose a large pill burden which is associated with lower health-related quality of life.
So, there is a direct relation between medication adherence and burden, and health-related quality of life (HRQOL) in predialysis chronic disease (CKD). There was a significant association between the prevalence of polypharmacy and the maintenance of polypharmacy over a period of time, also during CKD stage and also by taking care of other aspects of patient like age, BMI, diabetes mellitus, cardiovascular disease and a history of smoking. Comorbid diabetes mellitus was a significant risk factor for the initiation of polypharmacy in CKD patients.
Pill Burden by current phosphate binders and their limitations
There are different kind of phosphate binders available like Calcium acetate, Sevelamer hydrochloride, Sucroferric oxyhydroxide, lanthanum carbonate, Calcium carbonate and Calcium chloride. The mechanism of action of an effective phosphate binder is that they reduce the absorption of dietary phosphate in the gastrointestinal tract by exchange of the anion phosphate with an active cation (carbonate, acetate, oxyhydroxide, and citrate) to excrete them through feces by converting it into non-absorbable compound. In patients with end-stage renal disease, phosphate binders are widely used to achieve serum phosphorus control. Phosphate binders are probably the single largest contributor to the daily pill burden as suggested by clinical experiences. Also, prediction of risk of death has now also been consistently shown by the serum phosphorus levels independently. According to the current KDIGO clinical practice guideline, it recommends lowering elevated serum phosphorus levels toward the normal range in patients with ESRD on dialysis through restriction of dietary phosphorus intake, increase in clearance by dialysis, and the use of phosphate-binding medications [4]. The high pill burden from phosphate binders may affect patient's ability to maintain serum phosphorus levels and adherence to the therapy [20].
The central problem associated with the phosphate binder treatment is the insufficient patient adherence caused by usually large pill size, high pill burden and ensuing gastrointestinal adverse events [21]. In a study, many patients were found to adhere completely to phosphate binder prescription even under supervised study conditions [22].
The major limitation of the current available phosphate binders is the pill burden they cause to the patient which contributes to the poor treatment outcomes, impaired health related – quality of life in maintenance dialysis patients. Thus, a high pill burden may be one of the factors that limit the ability to optimize serum phosphorus levels as it is likely that high pill burden and hyperphosphatemia is bidirectional. There are various sources through the phosphorus intake becomes high and different types of treatments are available for its cure but every treatment has its own limitation (figure 3).
Figure 3: Sources of high phosphorus and their treatments and limitations
Measures to reduce pill burden (Zerofos DS)
The oral phosphate binders are effective in decreasing serum phosphorus levels but they also have high pill burden and low adherence rates. As reduced adherence to the prescribed phosphate binder therapy is associated with the increase in concentrations of serum phosphorus.
The double strength medicine can be an option when it comes to decrease the pill burden as if patient is taking 6 tablet per day then he/she will have to take the half tablets of double standard medicine i.e., 3 tablet which will reduce the pill burden of phosphate binders by 50% Zerofos-DS (composed of Calcium acetate, by Alniche Life Sciences) is a first double strength medication in India, which comes in a form of 1334mg where the conventional Calcium Acetate tablet comes in 667mg. With the composition of two tablet in one.
It belongs to a class of medications called phosphate binders. The phosphate is retained by the people with advanced kidney failure, which leads to too much phosphate in their bodies (hyperphosphatemia). Hyperparathyroidism is caused by high phosphate levels, which leads to calcium deposits in tissue and abnormal bone formation. Zerofos-DS is a natural mineral that works by holding onto phosphate from the diet so that it can pass out of your body. In dialysis some phosphate is removed from blood, but to keep phosphate levels balanced it is difficult to remove enough phosphate. ZEROFOS-DS is used to prevent high blood phosphate levels in patients who are on dialysis due to severe kidney disease.
Calcium acetate is a first line treatment for hyperphosphatemia in patients with ESRD on maintenance dialysis as it more cost-effective when compared to other phosphate binders, has higher binding capacity and can effectively work in high pH. Zerofos-DS is a very effective measure to reduce the pill burden in CKD patients as the patients normally taking 6 tablets when move to Zerofos-DS will now take 3 tablets reducing the pill burden of phosphate binders by 50%.
Mechanism of Action
ZEROFOS-DS (Calcium Acetate, by Alniche Life Sciences) belongs to a class of medications called phosphate binders. Zerofos-DS is a natural mineral that works by holding onto phosphate from the diet so that it can pass out of your body. Dialysis removes some phosphate from blood, but it is difficult to remove enough to keep phosphate levels balanced.
ZEROFOS-DS is used to prevent high blood phosphate levels in patients who are on dialysis due to severe kidney disease. It works by binding with the phosphate in the food patient eat, so that it is eliminated from the body without being absorbed. Binding phosphate in the intestines reduces absorption of phosphate into the body.
Salient Features
Conclusion
As we have discussed above, the CKD patients have to take number of pills due to multiple associated comorbidities and due to the high pill burden, they suffer from poor adherence to drug and therapy. Among all the pills CKD patients take, phosphate binders have highest number of pills hence have the higher pill burden. The measures for reducing pill burden is decrease the number of pills the patient is taking and Zerofos-DS (by Alniche Life Sciences) comes in double strength which offers composition of 2 tablets in one thus reduce the pill burden of phosphate binders by 50%. The combination of two conventional tablet of calcium acetate is provided in one tablet of Zerofos-DS. It is concluded that Zerofos-DS is an effective approach to reduce serum phosphorus levels with the benefit of low pill burden and better patient compliance.
References
