The use of colonoscopy for routine screening for colon and rectal cancer has been one of the most successful public health projects worldwide. Although colonoscopy is the most frequent technique that requires a proper bowel preparation, it could be necessary in others diagnosis tests: CT colonography, barium enema and surgery on the gastrointestinal tract. Effective preparation requires an adequate level of cleansing.

The osmotically balanced, polyethylene glycol-based electrolyte solutions are elected because they are safer and faster than large volume saline-based electrolyte solutions. Many patients have great difficulty to drink the large volume, that can result in unsuccessful preparation and poorly cleansed colon, and therefore, inadequate study assessment.1 The small volume of oral sodium phosphate solution (OSP) was associated with improved patients compliance, less discomfort, and superior colonic cleansing.

The OSPS is not exempt from risks. It can cause transient hyperphosphatemia and can induce intravascular volume contraction. There have been reports of serious adverse events, including death, and there have been case reports of nephrocalcinosis with renal failure associated with the use of oral sodium phosphate.2–4 In fact, in 2008 FDA issued a warning about the use of OSP in patients with chronic kidney disease (CKD) or major cardiovascular comorbidities.

Unfortunately, the results of the available epidemiologic data from large populations are quite confusing some studies reporting a potent association5–7 and others reporting non-significant trends toward better kidney outcomes after OSP compared with other purgatives.2,8 A major limitation of most of theses studies is they just consider renal damage when an acute renal failure happens. However the chronic damage has been well documented with the use of this purgative solution.9,10

Given the large number of patients exposed to OSP annually, clarification of this association is compelling. We present a series of patients with acute and chronic renal damage link to use of OSP.

Twelve cases of phosphate nephropathy were diagnosed: four of them were confirmed by renal biopsy. The baseline characteristics of patients in both groups are shown in Table 1.

There were a predominance of cases of men, 68.2% with mean age 69.44±7.2 years. The main co-morbidities in our patients were high blood pressure 91.6% and DM 33.3%. The 73.3% of the patients received treatment with ACE inhibitors or ARBs, and the 66.5% received treatment with diuretics.

All patients received just one dose of OSP. None of them were subjected to repeated cleanings intestinal in a short period. One patient undergone endoscopy procedures during hospitalization for acute indications (case 1). The other eleven patients received the OSPS preparation and performed the colonoscopy in outpatient regimen.

Renal biopsy findings

In four patients a biopsy was performed. The renal biopsy findings in PN primary involve the tubules and were dependent on the time interval between the preparation with oral sodium phosphate and renal biopsy. The biopsy from patients with AKI acute degenerative changes predominated a resemble findings seen an acute tubular necrosis.11 The renal biopsies performed in patients with chronic course showed tubular atrophy and interstitial fibrosis. Regardless of the degree of acuity of chronicity, the hallmark of PN was abundant tubular and less prominent interstitial calcium phosphate deposits (Fig. 1). The calcifications do not polarize and have a strong histochemical reaction with the von Kossa stain, indicating that they are composed of calcium phosphate.

Fig. 1.

Renal biopsy findings in chronic phosphate nephropathy. (a) Case of chronic phosphate nephropathy with abundant intraluminal and intracellular calcifications in distal tubules accompanied by tubular atrophy and fibrosis (hematoxylin and eosin) and (b) a positive histochemical reaction with the von Kossa stain confirms that the tubular concretions are composed of calcium phosphate.

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Ten years ago some cases of PN began to be published.4 The former cases were presented as an acute illness that manifested as tetany, acute kidney disease or cardiovascular collapse usually within hours of bowel preparation. Patients had marked hyperphosphatemia and hypocalcemia and some patients required even hemodialysis.12

Although case reports and case series provide strong support for an etiological relationship between OSP and the development of PN, epidemiological studies have showed less consistent results. In an retrospective observational study of 9799 patients who filled a prescription for an OSP or PEG (polyethylene glycol), 114 patients (1.16%) developed AKI: 1.29% of the 6432 patients who received OSPS and 0.92% of the 3367 patients who received PEG. The PEG group included patients who were significantly older and had a higher incidence of diabetes mellitus, hypertension, CHF, CKD, diuretics use and ACEi or ARBs use (p<0.05). In the multiple logistic regression models adjusted for covariates and suspected risk factors, OSP was found to be the strongest risk factor for the development or AKI after colonoscopy (OR 2.35, CI 95% 1.51–3.66) when compared with PEG. When a more “strict” definition of AKI was considered (doubling of serum creatinine vs >50% serum creatinine increase), the OSP purgative use remained significantly associated with increased risk for AKI (OR 3.52, CI 95% 1.13–10.93).5

In a recent, large retrospective cohort study using a US-based administrative claims database. The number of the patients included was impressive: 121,226 received OSP pill preparation and 429,430 received PEG. Patients were followed up to 6 months for AKI, renal failure and dialysis. The investigators did not find any increase risk of AKI in OSP pill users compared with PEG (0.2% vs 0.3%). The investigators acknowledged that the study of administrative claims for AKI outcomes may be an insensitive measure of renal dysfunction.8

Brunelli et al. undertook a systematic review and metaanalysis that concluded that it is not possible to discern if an association between OSP exposure and AKI exits. The use of different AKI definitions and significant heterogeneity among the studies referred to choice of bowel preparation, patients populations, baseline renal function, limited the result of the study.13

The chronic form of kidney damage due to OSP agents may present weeks after the initial exposure and may be identified as the result of an investigation of mild or non-specific symptoms such as fatigue. Sometimes, it is just discovered by a casual analysis and the anamnesis is the clue. This was the most frequent pattern in our study. The 65% of the patients were referred for study by nephrologist for increasing in serum creatinine in casual analysis.

This form of presentation requires the inclusion of this entity in the differential diagnosis of CKD. The nephrologist or physician who treats these patients should consider the possibility of PN in patients with renal damage without proteinuria or hematuria when the patient has undergone a digestive test prepared OSD.

Whereas until now to estimate the incidence of kidney disease for OSP we consider just the case presented as AKI, ignoring cases of delaying presentation. It may mean that this problem is more prevalent than is currently recognized. In fact, in the studies that analyze the safe of bowel preparation for colonoscopy the follow up was too short to identify it.

But, the true issue of this complication is not to know the AKI incidence if the secondary chronic loss of renal function over time. The outcomes of these patients are very inconstant: in most of cases of our study represent a substantial and irreversible loss of glomerular filtration. In Hurst et al.,5 just the 16% of patients returned to baseline renal function. They could not know if any of these patients requires renal replacement. In cases reported at least four patients developed ESRD.14 In most of studies this information is not available. In our study one patient (case 3) required renal replacement at diagnosis time and she did not recover renal function. The other patients had an average chronic loss glomerular filtration>20ml/min/1.72m2.

Different options to get an adequate level of cleansing, such as PEG, can also cause renal damage.5,15 The AKI incidence reported for PEG vary between 0.92% and 6%. If we consider that the damage is mainly due to renal hypoperfusion by dehydration, we could think that this injury would less severe and more reversible, although to our knowledge, none study has analyzed the long lasting effect of this injury.

The presence of CKD before the colonoscopy has been considered as the most weighty risk factor to develop kidney damage.6,14,16 However in our study the 63% of the patients had an eGFR>60ml/min/1.73m2. In fact, a lot of cases with normal o nearly normal baseline renal function with kidney injury induced OSP have been published.17 Some studies have suggested that females, above all elderly females, are at greater risk than males for developing PN.14 They might have reduced renal capacity of handle a phosphate load and their smaller body mass makes then more sensitive to fluid loss. This loss of volumen in conjunction with limited oral intake dictated by precolonoscopy protocols, may exacerbate some of the electrolyte abnormalities and the risk of renal failure among patients receiving these agents. Drugs that impact intravascular volumen and renal perfusion may increase the risk of kidney injury after OSP use, including diuretics, ACE inhibitors, angiotensin receptor blockers and non-steroidal anti-inflammatory agents.

The standard dose of OSP contains 11.6g of phosphorus. About 57% of the dose is excreted in feces, 15% in urine and 28% is retained in the body for 24h.18 The total amount of phosphate increases after the first and second doses to fourfold and eightfold of the baseline level respectably and remains elevates at 24h. These results suggest that the second dose of OSP is particularly dangerous because renal reabsorption of phosphate is fully inhibited at the time of dosing and thus the urinary concentrations of phosphate remains elevated for prolonged period.

In summary, the administration of oral sodium phosphate can cause an intense renal injury, sometimes depend of dialysis and often irreversible. This side effect does not always occur in high-risk patients and the most common pattern of presentation was renal chronic disease. The series that study this adverse effect should consider both the acute and chronic pattern damage.

G. Fernandez-Juárez and L. Parejo designed the study. They have drafted and made the critical revision of the manuscript. A. Tato, J. Villacorta, J. Ocaña, R. Cazar, I. Martinez, A. Mendez, J. Ocaña, K. Lopez, E. Gruss, E. Gallego have collected the data and made the critical reviewed of the manuscript. C. Guerrero performed the renal biopsies studies and reviewed the manuscript.

The study has not received any support, grants. None of the authors have received any consulting fees or honoraria related to the study.

The authors declare no conflict of interest.