Phosphate nephropathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayesha Javid, MBBS[2]

Overview

Phosphate nephropathy is a clinical manifestation of irreversible kidney injury after the consumption of phosphate-containing bowel preparations such as oral sodium phosphate (OSP), leading to acute kidney injury followed by chronic renal failure. It is characterized by diffuse tubular injury with abundant calcium phosphate deposits in the tubules due to which it is also called acute nephrocalcinosis.

Historical Perspective

• In 1990, Oral sodium phosphate purgative got acceptance as a bowel preparation agent prior to colonoscopy.
• This was due to the reason that less amount of drug was required leading to increased patient's compliance, less discomfort and improved bowel cleansing as compared to other available bowel purgatives including polyethylene glycol.
• The first case of acute kidney injury followed by chronic kidney disease due to oral sodium phosphate consumption was reported in 1975. In 2003, deposition of calcium phosphate was observed in the renal tubules after the consumption of the drug.
• Due to repeated acute phosphate nephropathy cases after the oral sodium phosphate ingestion, on 11 December 2008, United States Food and Drug Administration prohibited its over-the-counter purchase of and limited its purchase to prescription only. Soon this product was withdrawn from the market and now it is no longer available as an option for bowel preparation before a colonoscopy or any other procedure.

Pathophysiology

Hyperphosphatemia

Oral sodium phosphate consumption leads to hyperphosphatemia. Particularly, those patients who have to consume a large amount of Oral Sodium Phosphate as a bowel purgative before an elective colonoscopy have markedly elevated phosphate levels in the blood. This is due to increase phosphate absorption from the small intestine and lack of downregulation of sodium-phosphate cotransporters in the small intestine even when a large amount of phosphate has already been absorbed.

Hyperphosphatemia affects the kidneys by increasing the intratubular phosphate concentration, resulting in the deposition of calcium phosphate in the distal tubule and collecting duct. It directly damages the tubular epithelial cells and leads to luminal obstruction. The calcium phosphate crystals activate the innate immune system due to recognition by the epithelial TLRs leading to to tubular injury.

Volume depletion

• Oral sodium phosphate preparations are osmotic purgatives which lead to osmotic diarrhoea. Consumption of a large amount of oral sodium phosphate bowel purgative prior to elective colonoscopy leads to volume depletion. Also before elective colonoscopy, patients are advised not to consume anything by mouth.
• The volume depletion leads to increased reabsorption of sodium chloride and water via the proximal tubule. Also, there is ongoing water reabsorption in the descending limb of the loop of Henle. The combined effect of these results in increased calcium phosphate in the tubules.
• The volume depletion increases the surface expression of hyaluronan and osteopontin which increases the adherence of calcium phosphate crystals to the distal tubule epithelium leading to precipitation and deposition of calcium phosphate in the lumen of the nephrons.

Differentiating Acute Phosphate Nephropathy from other Diseases

• Acute Phosphate Nephropathy needs to be differentiated from other causes of nephrocalcinosis which are associated with hypercalcemia such as;

• Hyperparathyroidism
• Hypervitaminosis D
• Hypercalcemia of malignancy
• Sarcoidosis
• Distal renal tubular acidosis

• It should also be differenitated from a rare case of nephrocalcinosis associated with hyperphosphatemia due to Phosphate supplements for the treatment of hypophosphatemic rickets

Epidemiology and Demographics

Gender

• Several studies report a higher incidence among females as compared to males.
• It could be related to their smaller heights and subsequently lower GFR as compared to men. Hence the same amount of Oral sodium phosphate could be more harmful to the women than men.

Age

Several epidemiological studies have identified advanced age as an independent risk factor of acute phosphate nephropathy, particularly age 55 and more.

Ethnicity

A higher prevalence has been seen among Caucasians.

Risk Factors

Dose of Oral Sodium Phosphate administered

The risk of acute phosphate nephropathy is directly related to the dose of Oral Sodium Phosphate (OSP) administered. The higher the dose administered, more will be blood phosphate levels and hence there would be a higher chance of harming kidneys and resulting in nephropathy.

Chronic Kidney disease

A chronic kidney disease patient will have a decrease glomerular filtration rate (GFR). Oral Sodium Phosphate (OSP) administration is seen to increase the creatinine levels further worsening their kidney functions. Therefore, Oral Sodium Phosphate is contraindicated in chronic renal disease patients. Instead, polyethylene glycol (PEG) has been found to be a good alternative.

Advanced age

Researchers agree that advanced age is an independent risk factor for acute phosphate nephropathy. One research shows the median age to be 64 years, however, although most studies agree on the advanced age is a strong risk factor, but are unable set a particular age limit.

Co-morbid conditions

Co-morbidities such as hypertension and diabetes mellitus have been found to further increase a patient's risk to acute phosphate nephropathy.

Drugs

The following drugs have been found to be a risk factor for acute phosphate nephropathy:

• ACE inhibitors and ARBs
• NSAIDs
• Lithium
• Diuretics

Natural History, Complications and Prognosis

• The patient with acute phosphate nephropathy present with the clinical features of acute kidney injury such as oliguria/or anuria, and volume depletion such as hypotension, cold extremities, dry mucous membrane and increased skin turgidity, following the consumption of oral sodium phosphate bowel purgative for the purpose of bowel cleansing prior to colonoscopy.
• If left untreated, acute phosphate nephropathy can progress to chronic kidney disease and a patient can die of progressive renal failure.

• Acute phosphate nephropathy leads to irreversible kidney damage hence renal replacement therapies, such as hemodialysis and peritoneal dialysis, and renal transplantation is important.

Diagnosis

Diagnostic Criteria

• The diagnosis of acute phosphate nephropathy is made when the following diagnostic criteria is met:

• acute kidney injury or chronic renal failure
• Histopathological findings of acute or chronic tubular injury and deposition of calcium phosphate in the tubules
• History of recent consumption of oral sodium phosphate bowel purgative.

Symptoms

• Acute phosphate nephropathy could be asymptomatic due to which it can be undiagnosed until chronic kidney failure occurs.
• The following symptoms can occur after consumption of oral sodium phosphate which gives a strong suspicion of acute phosphate nephropathy:

• Abdominal pain
• Oliguria,Anuria
• Nausea
• Lethargy
• Drowsiness

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• Hypotension/hypertension
• Pedal and orbital edema
• Inspiratory crackles
• Distended and tender abdomen without guarding
• Tetany is seen in patients with severe hypocalcemia
• Signs of dehydration including; dry mucous membrane, decreased skin turgor, and cool extremities.

Laboratory Findings

Laboratory findings diagnostic of acute phosphate nephropathy include:

Electrolyte disturbances

Following electrolyte abnormalities are diagnostic of acute phosphate nephropathy after the consumption of oral sodium phosphate bowel purgative.

• Hyperphosphataemia
• Hypocalcemia
• Hypernatremia
• Hypokalemia
• Hypomagnesemia
• Anion-gap metabolic acidosis

Urinanalysis

• 0 to 1+ proteinuria
• Hematuria
• Pyuria
• Benign sediments

Renal function test

• Elevated creatinine
• Reduced GFR

Imaging Findings

• Ultrasound is the imaging modality of choice for acute phosphate nephropathy.
• On renal ultrasound, phosphate nephropathy is characterized by increased echogenicity of the renal cortex. However, the renal contour and size are normal.
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Renal biopsy

• Renal biopsy is required for the definitive diagnosis of acute phosphate nephropathy.
• The characteristic finding on the renal biopsy is the extensive deposition of calcium phosphate, mostly in the tubular lumen and less commonly in the peritubular interstitium. The calcium phosphate can be identified using von Kossa stain, also they lack birefringence under polarized light. Other findings can be divided on the basis of the time at which the biopsy is performed:

Early findings (<3 weeks)

The early biopsies show tubular degenerative changes, similar to acute tubular necrosis. Findings include

• luminal ectasia, cytoplasmic simplification, loss of brush border, shedding of cell fragments into the lumina, and enlarged nuclei with prominent nucleoli. The tubular degenerative changes and calcifications are accompanied by interstitial edema and mild to moderate interstitial inflammation that is not typically associated with significant tubulitis.

Late finding (>3 weeks)

• If the time between consumption of Oral sodium phosphate and renal biopsy is more than 3 weeks, then less severe and more localized degenerative changes are observed.
• The findings include, chronic inflammation, extracellular matrix deposition, tubular atrophy and interstitial fibrosis.

Acute Phosphate Nephropathy-Calcium Phosphate deposition dark blue coloured on H&E stain

Treatment

• In patients with cardiovascular collapse and severe electrolyte abnormalities, immediate fluid resuscitation and rapid correction of electrolytes is required.
• It is followed by renal replacement therapy such as haemodialysis or peritoneal dialysis in order to decrease the calcium phosphate deposition process.
• Renal transplantation is also required in some patients.

Prevention

Prevention of acute phosphate nephropathy could be achieved by:

• Identify the higher risk groups and avoid oral sodium phosphate bowel purgative. The higher risk groups include:

• Age >55 years
• Hypovolemia
• Previously existing kidney disease
• Intestinal obstruction
• Active colitis
• Drugs which decrease renal perfusion and function, including diuretics, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and nonsteroidal anti-inflammatory drugs (NSAIDs)

• Oral sodium phosphate are absolutely contrandicated in these patients:

• Pregnancy
• Age <18 years
• Stage 3 to 5 chronic kidney disease (glomerular filtration rate [GFR] <60 mL/min/1.73 m2)
• Inability to maintain adequate fluid intake
• Pre-existing electrolyte disturbances
• Ascites
• Symptomatic congestive heart failure, and
• recent (within <6 months) symptomatic ischemic heart disease (unstable angina or myocardial infarction).

• The relative contraindications include,

• Active inflammatory bowel disease
• Delayed bowel transit
• Parathyroidectomy

• Advice good amount of hydration before, during and after the use of oral sodium phosphate.
• Increase the time gap between the doses.
• Ask patient to avoid the following drugs on the day before and the day after the colonoscopy procedure:

• ACE-I and ARB
• Diuretics
• NSAID

• Order renal function test and serum electrolyte levels after the procedure, in order to look for any renal or electrolyte abnormalities.

References

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