Phosphate nephropathy or nephrocalcinosis[1] is an adverse renal condition that arises with a formation of phosphate crystals within the kidney's tubules. This renal insufficiency is associated with the use of oral sodium phosphate (OSP) such as C.B. Fleet's Phospho soda and Salix's Visocol, for bowel cleansing prior to a colonoscopy.[2]
According to the U.S. Food and Drug Administration (FDA), the potential risk factors of this complication include pre-existing kidney disease, increased age, female gender, dehydration, comorbidities such as diabetes mellitus and hypertension, and concurrent treatment with hypertensive medications (ACE inhibitors and angiotensin receptor blockers) and medications that affect renal perfusion (Nonsteroidal anti-inflammatory drug or NSAIDs and diuretics).[2] This complication can be diagnosed with renal tests and biomarkers in laboratories including histochemical staining of renal biopsy specimens,[3] the measure of creatinine level, GFR level, and urine output,[4][5] urine microscopy,[1] CT scanning,[6] and urinalysis.[3]
Phosphate nephropathy may also lead to further renal complications including acute kidney diseases and chronic kidney diseases, or the abrupt and gradual loss of kidney function over time.[7] Different management approaches involve the use of alternative bowel preparation agents and increasing patients' risk assessment among healthcare professionals, including nephrologists, gastroenterologists, and renal pathologists.[8] Other agents used for bowel preparation (e.g. magnesium citrate or PEG-3350 & electrolyte-based purgatives such as Colyte or Golytely) do not carry this risk.[4][8]
According to the U.S. Food and Drug Administration (FDA), "acute phosphate nephropathy is a rare, serious adverse event that has been associated with the use of OSPs. The occurrence of these events was previously described in an Information for Healthcare Professionals sheet and an FDA Science Paper issued in May 2006. Additional cases of acute phosphate nephropathy have been reported to FDA and described in the literature since these were issued."[2]
Signs and symptoms
Patients with phosphate nephropathy have variable outcomes, either being recognised as developing acute kidney injury, the abrupt loss in renal failure, or being undiagnosed.[4] As the deposition of calcium phosphate crystals are detected at the renal tubules following the use of OSP, the symptoms of phosphate nephropathy are similar to acute tubular necrosis, an intrinsic renal injury.[9] For example, events including diarrhea, vomiting, dehydration, sepsis, and hypotension following the colonoscopy, can indicate the risk of phosphate nephropathy and raise the concern for acute tubular necrosis.[9] The results of hypotension and dehydration are dry mucous membrane, decreased skin turgor, and cool extremities, which can be used to notify the abnormal renal perfusion.[9] As there is a gap between the first administration of OSP and recognisable symptoms, many phosphate nephropathy incidences[spelling?] are overlooked and not proceeded to biopsy for further investigation.[8]
The transient hyperphosphatasemia, the electrolyte disorder with elevated phosphate level in the blood, is found to be correlated with the use of OSP after colonoscopy.[10] Significant electrolyte abnormalities including hypocalcemia, hypernatremia, and hypomagnesemia are also the outcomes of the use of OSP.[4] As these detection tests are mostly operated at the laboratory level, phosphate nephropathy incidents are widely under-recognized and overlooked.[10]
Depiction of different adverse renal conditions. Phosphate nephropathy or deposition of calcium phosphate within renal tubules belongs to the urinary stone problems.
Risk factors
According to the FDA, caution is required to consider prior use of OSP, especially in patients with the following potential risk factors. For instance, people older than 55, female gender,[6] people with a history of kidney diseases if their GFR level is less than 60 mL/min,[1] people who recurrently on antihypertensive treatment with NSAIDs, ARBs, ACEIs, and diuretics, people who have lower fluid intake and less bowel movements,[2][1] people who have underlying systemic and gastrointestinal diseases,[1] and a short interval between OSP administrations (less than 12 hours interval).[11] The risk of acquiring phosphate nephropathy was reported to increase in parallel with the number of these listed risk factors.[11]
Older people are particularly at risk when using OSP for colonoscopy, as they have lower fluid intake, have intrinsically less bowel movements, and often have antihypertensive or nephrotoxic drugs.[1] It is also reported that people with comorbidities including diabetes mellitus, hypertension, and other metabolic syndromes will have a higher risk of phosphate nephropathy.[12]
Pathophysiology
The efficient elimination of phosphorus depends on the kidney’s filtration rate and the phosphorus bioavailability in the blood.[6] Most renal phosphorus is absorbed at the proximal tubules in comparison to the distal nephron.[11] The elevated phosphorus load, or hyperphosphatemia, can reduce the phosphorus reabsorption in the kidney’s proximal tubular within minutes of OSP ingestion.[1] This leads to hypovolemia, a large distribution of phosphate at the distal nephron without being completely reabsorbed at the proximal tubules.[11] Hypovolemia results in an increase of proximal salt and water at the descending limb of the loop of Henle, where calcium and phosphate are unable to permeate.[11] Hypovolemia collectively combines with the ongoing water and salt reabsorption in the proximal tubules, enhances the calcium phosphate precipitation within the renal tubular lumen.[11][9]
Parathyroid hormone-induced calcium precipitation also contributes to the formation of calcium phosphate crystals, which thus impairs the renal function.[1] An excess phosphorus triggers calcium precipitation and reduces calcium absorption in the gastrointestinal tract.[1] This reduces the ionized calcium concentration in blood, which further induces a compensatory parathyroid hormone response.[1] Parathyroid hormone is reported to accelerate urinary calcium load, which results in the formation of calcium phosphate crystals in the renal distal tubules and collecting ducts.[1]
When the calcium phosphate crystals bind to the tubular epithelial cells, the reactive oxygen species are released, which further impair the renal excretory pathway.[1] The use of OSP causes an increase in phosphatemia and impairs renal perfusion, which later leads to acute kidney injury and chronic kidney disease.[6] The calcification of major arteries like coronary arteries and cardiovascular complication risks can be the result of impaired kidney function in excreting calcium and phosphate.[13]
Diagnosis
Phosphate nephropathy can be diagnosed via different types of assessment, most of which are also used to detect acute kidney injury and chronic kidney disease.[1] Most phosphate nephropathy incidents are diagnosed weeks or months after taking OSP, due to its clinical silence.[8] For example, these assessments include the measurement of serum phosphorus with an elevation of more than 3mmol/L,[4] the finding of an elevated serum creatinine level and a decrease in glomerular filtration rate (GFR),[4]urine microscopy for crystallization detection,[1] the image of calcium phosphate crystals deposited through CT scanning,[6]urinalysis,[3] renal biopsy specimens with histochemical staining for calcium phosphate.[8][3] These assessments are generally carried out within the laboratory environment, in which longer waiting time is required to attain the results.[citation needed]
The measurement of serum creatinine level and GFR are used to indicate the severity stage of acute kidney injury or the duration of impairment of kidney function, when early-onset phosphate nephropathy occurs.[12] The more than 1.5 fold increase in serum creatinine level, or the more than 25% decrease in GFR, or the decrease in urine output less than 0.5mL/kg/h within 6 hours, signify the risk of attaining acute kidney injury after ingestion of OPS.[5]
Urine microscopy is reported to be an accurate diagnostic assessment for underlying crystalline-induced nephropathy, either endogenous or drug-induced calcium phosphate crystals.[14] Via examining the urinary sediments, calcium phosphate crystals are identified, and the associated phosphate nephropathy is determined.[14]
For phosphate nephropathy with nonspecific symptoms, renal biopsy is reported as an important diagnosis due to the normal levels of both calcium and phosphorus.[12] Following renal biopsy, the calcium phosphate crystals are distinguished from calcium oxalate crystals via staining with haematoxylin and eosin, as calcium phosphate deposits lack birefringence under polarized light.[3] Then, the positive staining with the von Kossa stains can be used to display the presence of abnormal calcium and phosphate deposits respectively via light illumination.[8]
Prevention
As phosphate nephropathy is considered an irreversible complication when starting to progress into acute kidney injury and chronic kidney disease, prevention strategies can help to avoid the undesired outcomes.[1] According to the FDA, it is recommended for both healthcare professionals and patients, particularly high-risk individuals, to obtain adequate information about the adverse effect of OSP before administering and consuming this agent.[2] Monitoring of renal function weeks or months after the administration of OSP also helps to early detect and treat the condition appropriately.[1]
Withholding the antihypertensive medications (ARBs, ACEIs), diuretic medications, and NSAIDs before and after the use of OSP for colonoscopy, is reported to minimize the risk of phosphate nephropathy.[4]
As ingestion of OPS can potentially induce osmotic diarrhea and result in depletion of body fluid, adequate hydration is recommended before and after the procedure to prevent episodes of hypotension.[10] It is unknown whether water or electrolyte-containing solutions would adequately compensate the electrolyte imbalance following the use of OSP.[6] The recommended volume of fluid when using OSP as a bowel preparation agent varies from 0.7 to 2.2 L, with the optimal amount greater than 3.7 L.[6] It is still unknown whether lowering the standard doses of OSP from 45/45 ml to 45/30 mL in 9–12 hours apart would be safer to use, as lower OSP dose was reported to cause moderate elevation of serum phosphorus.[6][15]
In addition, there are other relevant bowel-preparation agents that can be used in line with the colonoscopy guidelines including electrolyte-based purgatives such as Golytely, Polyethylene glycol (PEG), sodium picosulfate,[8] and sodium laxatives.[4] These bowel preparation alternatives show the same efficacy with OSP and cause less frequently and significantly side effects and complications than OSP.[15]
Mannitol and large volume of saline were first used as bowel preparation agents prior to colonoscopy.[6] As the use of Mannitol causes the production of methane, hydrogen, and other flammable gases, it was reported to be associated with colonic explosion.[6] Large volume of saline was also reported to significantly impact the electrolyte balance and net fluid within the body.[6] Later in the 1990, the polyethylene-glycol electrolyte lavage solution or PEG-ELS, was formulated with more effectiveness and safety to use.[7] PEG-ELS was not widely adopted due to its requirement of consuming an enormous volume.[6] Then, OSP (C.B. Fleet's Phospho soda) in the form of tablets with the same efficacy as PEG-ELS, was chosen as a safe alternative bowel preparation agent.[7]
Later, in 1975, acute kidney injury and potential chronic kidney disease were first found to be related to the ingestion of OSP.[8] Then, in 2003, an adverse incident of calcium phosphate deposition within the renal tubules was first reported following the use of OSP.[8] This was linked to the tubular injury and other renal complications as well as the emergence of the term “phosphate nephropathy”.[8]
Related Research Articles
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retroperitoneal space, and in adult humans are about 12 centimetres in length. They receive blood from the paired renal arteries; blood exits into the paired renal veins. Each kidney is attached to a ureter, a tube that carries excreted urine to the bladder.
Kidney stone disease, also known as renal calculus disease, nephrolithiasis or urolithiasis, is a crystallopathy where a solid piece of material develops in the urinary tract. Renal calculi typically form in the kidney and leave the body in the urine stream. A small calculus may pass without causing symptoms. If a stone grows to more than 5 millimeters, it can cause blockage of the ureter, resulting in sharp and severe pain in the lower back or abdomen. A calculus may also result in blood in the urine, vomiting, or painful urination. About half of people who have had a renal calculus are likely to have another within ten years.
Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds in the blood. It is largely related to insufficient or dysfunctional filtering of blood by the kidneys. It can lead to uremia and acute kidney injury if not controlled.
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure called Bowman's capsule. The renal tubule extends from the capsule. The capsule and tubule are connected and are composed of epithelial cells with a lumen. A healthy adult has 1 to 1.5 million nephrons in each kidney. Blood is filtered as it passes through three layers: the endothelial cells of the capillary wall, its basement membrane, and between the foot processes of the podocytes of the lining of the capsule. The tubule has adjacent peritubular capillaries that run between the descending and ascending portions of the tubule. As the fluid from the capsule flows down into the tubule, it is processed by the epithelial cells lining the tubule: water is reabsorbed and substances are exchanged ; first with the interstitial fluid outside the tubules, and then into the plasma in the adjacent peritubular capillaries through the endothelial cells lining that capillary. This process regulates the volume of body fluid as well as levels of many body substances. At the end of the tubule, the remaining fluid—urine—exits: it is composed of water, metabolic waste, and toxins.
Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and can cause acute kidney injury.
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly and can often be irreversible. Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications of acute and chronic failure include uremia, hyperkalaemia, and volume overload. Complications of chronic failure also include heart disease, high blood pressure, and anaemia.
Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess in the blood of amino acid and protein metabolism end products, such as urea and creatinine, which would be normally excreted in the urine. Uremic syndrome can be defined as the terminal clinical manifestation of kidney failure. It is the signs, symptoms and results from laboratory tests which result from inadequate excretory, regulatory, and endocrine function of the kidneys. Both uremia and uremic syndrome have been used interchangeably to denote a very high plasma urea concentration that is the result of renal failure. The former denotation will be used for the rest of the article.
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include high blood pressure, bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization.
Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off (lysed) from the treatment, releasing their contents into the bloodstream. This occurs most commonly after the treatment of lymphomas and leukemias and in particular when treating non-Hodgkin lymphoma, acute myeloid leukemia, and acute lymphoblastic leukemia. This is a potentially fatal complication and patients at increased risk for TLS should be closely monitored while receiving chemotherapy and should receive preventive measures and treatments as necessary. TLS can also occur on its own although this is less common.
Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in nephrons of the kidneys. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.
Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys to excrete excess acids. Metabolic acidosis can lead to acidemia, which is defined as arterial blood pH that is lower than 7.35. Acidemia and acidosis are not mutually exclusive – pH and hydrogen ion concentrations also depend on the coexistence of other acid-base disorders; therefore, pH levels in people with metabolic acidosis can range from low to high.
A sodium phosphate is a generic variety of salts of sodium and phosphate. Phosphate also forms families or condensed anions including di-, tri-, tetra-, and polyphosphates. Most of these salts are known in both anhydrous (water-free) and hydrated forms. The hydrates are more common than the anhydrous forms.
Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.
Phospho soda was an over the counter saline laxative produced by the C.B. Fleet Company in Lynchburg, Va. Phospho soda consisted mostly of monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate. Phospho soda is often taken in a double dose, to prepare for colonoscopy. It is still used outside the US.
Milk-alkali syndrome (MAS), also referred to as calcium-alkali syndrome, is the third most common cause of hypercalcemia. Milk-alkali syndrome is characterized by elevated blood calcium levels, metabolic alkalosis, and acute kidney injury.
Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe the deposition of poorly soluble calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined by progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. It may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium salts.
Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.
A renal diet is a diet aimed at keeping levels of fluids, electrolytes, and minerals balanced in the body in individuals with chronic kidney disease or who are on dialysis. Dietary changes may include the restriction of fluid intake, protein, and electrolytes including sodium, phosphorus, and potassium. Calories may also be supplemented if the individual is losing weight undesirably.
"Acute phosphate nephropathy and renal failure". New England Journal of Medicine. 2003 Sep 4;349(10):1006-7.
"Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing". Human Pathology. 2004 Jun;35(6):675-84.
"Renal failure following bowel cleansing with a sodium phosphate purgative". Nephrology Dialysis Transplantation. 2005 Apr;20(4):850-1.
"Acute Phosphate Nephropathy following Oral Sodium Phosphate Bowel Purgative: An Underrecognized Cause of Chronic Renal Failure". Journal of the American Society of Nephrology. 2005 Nov 1;16(11).
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