—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 4 - Acute and Chronic Tubulointerstitial Nephropathy with Abundant Tubular Deposits of Calcium Phosphate

Glen S. Markowitz
Columbia University





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Case History
A 64-year-old Caucasian female presented with unexplained renal failure, a creatinine of 2.6 mg/dl, malaise, and weight loss. Four months prior, the patient had a creatinine of 0.9 mg/dl. Past medical history was significant for hypertension for 6 months and a remote history of chronic urethritis and cystitis requiring urethrotomy (40 years prior). At the time of evaluation the patient's medications included amlodipine, metoprolol, and esomeprazole (as needed), although she had recently been switched from lisinopril to amlodipine and metoprolol due to poor blood pressure control. Physical examination revealed a blood pressure of 194/74 and no edema. Urinalysis revealed rare WBC's, no RBC's, and no proteinuria. There was no evidence of a monoclonal serum spike. The patient had an albumin of 4.3 g/dl, calcium 9.9 mg/dl, hematocrit 27.3%, platelet count 301,000, normal C3 and C4, negative ANCA, and negative anti-GBM antibody. The kidneys measured 9.5 and 8.8 cm in length by ultrasound. During the following 2 months the patient's creatinine declined to 2.3 mg/dl, at which time renal biopsy was performed.


Case 4 - Slide 1
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Case 4 - Figure 1 - A low magnification view displays disproportionate tubulointerstitial scarring. There is mild to moderate interstitial chronic inflammation. Prominent tubular calcifications are seen in the upper left and lower right portions of the field.
Case 4 - Figure 2 - A glomerulus appears histologically unremarkable.
Case 4 - Figure 3 - An intermediate magnification view shows abundant tubular calcifications. The calcifications do not polarize and are mainly confined to distal tubules.

Case 4 - Figure 4 - A high power view shows that the calcifications have an intra-cellular (within tubular epithelia), intra-luminal, and interstitial distribution.
Case 4 - Figure 5 - The tubular calcifications stain intensely with the von Kossa stain, consistent with calcium phosphate.
Case 4 - Figure 6 - A periodic acid Schiff stain demonstrates the prominent tubular atrophy and interstitial fibrosis. Glomeruli appear unremarkable. There is no significant tubulitis.


Pathologic Findings:
Sampling for light microscopy consists of 3 cores of renal cortex containing 40 glomeruli, 2 of which are globally sclerotic. The majority of glomeruli appear histologically unremarkable. In contrast, a minority of glomeruli exhibit mild ischemic-type wrinkling of the GBM and thickening of Bowman's capsule. There is diffuse, moderate to severe tubular atrophy and interstitial fibrosis involving approximately 60% of the cortex sampled. Residual non-atrophic tubules exhibit mild degenerative changes. The acute and chronic tubular injury is accompanied by abundant non-polarizing calcifications. The calcifications are located in tubular lumina, within the cytoplasm of tubular epithelia, and focally within the interstitium, and exhibit a strong histochemical reaction with the von Kossa stain, consistent with calcium phosphate. There is mild interstitial inflammation composed of mainly lymphocytes and predominantly confined to zones of tubulointerstitial scarring. Vessels exhibit mild to moderate arteriosclerosis.

Sampling for immunofluroescence consisted of 16 glomeruli, none of which were globally sclerotic. There was no significant glomerular or tubular immunofluorescence positivity for IgG, IgM, IgA, C3, C1, kappa, lambda, fibrinogen, or albumin. On ultrastructural evaluation, no significant glomerular abnormalities were noted. There was only 10% foot process effacement and no electron dense deposits were seen. Multiple calcifications were identified within tubular epithelia and the interstitium.

Diagnosis:
Acute and chronic tubulointerstitial nephropathy with abundant tubular deposits of calcium phosphate, consistent with acute phosphate nephropathy.

Clinical Follow-up:
Upon further questioning, additional clinical history was obtained. Two months prior to the discovery of renal failure, the patient underwent colonoscopy that was preceded by bowel cleansing with oral sodium phosphate solution (OSPS). Following the biopsy, the patient's serum creatinine slowly declined but has not returned to baseline levels. At present, the patient is 58 months post-colonoscopy & OSPS exposure and she has a creatinine of 1.7 mg/dl.

Discussion:
The renal biopsy findings are notable for acute tubular injury and chronic tubular damage as manifest by tubular atrophy and interstitial fibrosis. Within this acute and chronic tubulointerstitial nephropathy, the most distinctive finding is abundant tubular and interstitial calcifications. When tubular calcifications are seen on renal biopsy, the precipitating calcium salt typically contains either phosphate or oxalate. The two anions can be differentiated pathologically. Calcium oxalate is identified as refractile crystals under polarized light. In contrast, calcium phosphate is non-polarizable but gives a positive histochemical reaction to the von Kossa stain. The term nephrocalcinosis applies specifically to renal parenchymal calcium phosphate deposition.

The two major patterns of calcium phosphate deposition within the kidney are nephrocalcinosis and nephrolithiasis. Nephrocalcinosis is a tubulointerstitial nephropathy characterized by tubular degeneration with subsequent atrophy, interstitial fibrosis, and prominent tubular calcifications. The calcifications form intraepithelial, intraluminal, and interstitial concretions. The usual clinical presentation for nephrocalcinosis is gradual onset of renal insufficiency with minimal proteinuria. Nephrocalcinosis is generally thought to occur secondary to diverse conditions associated with chronic hypercalcemia including hyperparathyroidism, hypercalcemia of malignancy, vitamin D intoxication, sarcoidosis, milk alkali syndrome, and distal renal tubular acidosis.

In 2003, we saw 5 distinctive cases of nephrocalcinosis which differed from the usual form of disease [1]. The cohort consisted of 2 males and 3 females with a mean age of 69.2 years. All 5 patients had a history of hypertension and 4 were receiving either an angiotensin converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The cohort was distinctive in that all of the patients had recently undergone colonoscopy, none had a history of hypercalcemia, and the renal failure had an acute onset, unlikely the usual insidious presentation of nephrocalcinosis. Patients had a mean baseline creatinine of 0.9 mg/dl at a mean of 4 months prior to colonoscopy. Acute renal failure with a mean creatinine of 4.9 mg/dl was documented at a mean of 3 weeks post-colonoscopy. Importantly, in all 5 patients, bowel cleansing with OSPS preceded colonoscopy. Thus, while hypercalcemia was not present, an exogenous source of hyperphosphatemia was identified. The changes were referred to as "acute nephrocalcinosis" to emphasize the rapidity of onset. At a mean of 6 weeks post-colonoscopy, the patients had a mean creatinine of 4.7 mg/dl.

Oral sodium phosphate solution (OSPS) is the most widely utilized purgative agent for bowel cleansing prior to colonoscopy in the United States. The over-the-counter preparation consists of two 45 ml doses taken 12 hours apart on the evening before and morning of colonoscopy. Each 45 ml dose contains 21.6 g of monobasic sodium phosphate and 8.1 g of dibasic sodium phosphate. Following the second administration, serum phosphorus levels increase transiently by 3.0 to 3.5 mg/dl [2, 3, 4]. Contra-indications to the use of OSPS include clinically significant renal impairment, while caution is encourage prior to use in the elderly or patients with electrolyte disorders.

In 2004, Desmueles et al. described a similar case of ARF following OSPS use in a 71-year-old woman [5]. Renal biopsy findings were identical to acute nephrocalcinosis, but the authors utilized the more appropriate term "acute phosphate nephropathy" which emphasizes the important pathogenic role of exogenous phosphate administration [5]. We subsequently adopted this terminology.

More recently, we reviewed the archives of the renal pathology laboratory at Columbia University from 2000 – 2004 in an effort to identify additional cases of acute phosphate nephropathy (APhN). A major goal was to understand the long-term outcome of this condition. Criteria for the diagnosis of APhN included: 1) ARF; 2) Renal biopsy findings of acute and chronic tubular injury with abundant calcium phosphate deposition; 3) No other significant pattern of renal injury; 4) Recent exposure to OSPS or Visicol, a tablet form of identical composition that is available only by prescription; and 5) the absence of hypercalcemia [6]. During this 5-year period, 7,349 native renal biopsies were processed, of which 31 met the criteria of acute and chronic tubular injury with abundant calcium phosphate deposition. Among the 31 cases, 10 were excluded for the following reasons: 4 met criteria for APhN but had a second, significant disease process on renal biopsy (i.e. post-infectious glomerulonephritis); 2 had recent colonoscopy prior to the development of ARF but information was not available on the bowel preparation regimen; 2 had a history of hypercalcemia; and 2 had no recent history of colonoscopy. Thus, out of 31 cases that previously would have been classified as "nephrocalcinosis", a history of hypercalcemia was present in only 2 patients. In contrast, a history of recent colonoscopy was present in 27 [6].

The 21 patients with acute phosphate nephropathy consisted of predominantly Caucasian (81%) females (81%) with a history of hypertension (76.2%) [6]. Among the 16 patients with hypertension, 14 were treated with an ACE-I or ARB. The mean baseline serum creatinine was 1.0 mg/dl and was available within <1 month of colonoscopy in 11 patients and <4 months of colonoscopy in 19 patients. Patients presented with acute renal failure and a mean serum creatinine of 3.9 mg/dl at a median of <1 month following OSPS use. Specifically, 8 patients presented with ARF <2 weeks after colonoscopy while 18 presented within <2 months of OSPS use. The mean 24 hour urine protein was 256 mg, and microscopic evaluation of the urine revealed either a bland sediment or rare RBC's or WBC's. The mean duration of post-colonoscopy follow-up was 16.7 months. During this time, 4 patients progressed to ESRD, requiring dialysis. Sixteen of the remaining 17 patients had a decline in serum creatinine to a mean of 2.4 mg/dl. Only 4 patients reached a creatinine <2.0 mg/dl and no patient returned to baseline. Of note, the case presented herein is patient #21 from this report [6].

There are multiple lines of evidence connecting the use of OSPS and the development of acute phosphate nephropathy. First and foremost is the tight temporal relationship between the administration of OSPS and the development of acute renal failure. Second, phosphate is being administered and phosphate is the anion precipitating in the kidney. Third is the finding that in at least one large center, OSP preceded the development of nephrocalcinosis in at least 25 of 31 cases. There is also human data to support this concept, in that children with hypophosphatemic rickets are treated with oral phosphate and vitamin D and may develop biopsy-documented nephrocalcinosis [7]. Similarly, animal models have shown that exogenous phosphorus administration leads to tubular calcium phosphate deposition and nephrocalcinosis in mice, rats, rabbits, and dogs [8, 9, 10, 11, 12].

The pathophysiology of acute phosphate nephropathy involves multiple factors. The use of OSPS leads to diarrhea and volume depletion, which undoubtedly plays a large role in the development of APhN. As such, the importance of adequate hydration before, during, and after OSPS use cannot be overemphasized. Volume depletion is likely to be exacerbated by the frequent concurrent treatment with an ACE-I or ARB, and less commonly diuretics or NSAID's. Calcium phosphorus product (CPP) is generally regarded as a marker of the risk for calcium phosphate precipitation, and a transient increase in CPP following OSPS administration is well recognized. It is noteworthy that in APhN, the calcium phosphate precipitation occurs mainly in the distal tubule and collecting duct [1] where, due to avid proximal tubular water and sodium resorption and the permeability of the descending limb of the loop of Henle to water but not calcium or phosphate, the highest intratubular CPP is likely to be achieved [13]. The observation that APhN appears to occur more commonly in females is interesting and raises the possibility that dosing of OSPS should be adjusted for body size. Last but certainly not least, age plays an important role in the development of APhN. Older patients achieve greater levels of hyperphosphatemia following the use of OSPS [14]. For instance, in one study the mean increase in serum phosphorus following OSPS administration was 3.4 mg/dl in patients between the age of 25-35 years, compared to an increment of 5.5 mg/dl in individuals over the age of 56 [14].

There is undoubtedly significant under-recognition of acute phosphate nephropathy. Elderly patients who present with unexplained renal failure without significant proteinuria or active urine sediment may or may not be referred to a nephrologist and if referred, are unlikely to undergo renal biopsy. If biopsied, a diagnosis of nephrocalcinosis is likely to be rendered and etiologies of hypercalcemia will be sought. Based on the experience of a single large center, a history of recent OSPS exposure should be sought in all renal biopsies which seemingly reveal nephrocalcinosis.

The role of exogenous phosphate administration (i.e. OSPS) in the development of APhN is gaining increased recognition. In May of 2006, the United States Food and Drug Administration issued an alert regarding the potential for OSP products to lead to acute renal failure and APhN [15]. Clearly further studies are needed to determine the true incidence of APhN, to better understand risk factors for the development of APhN, and to provide guidelines for the most appropriate bowel preparation regimen in different patient populations. Existing data strongly suggest that the mechanism of disease is likely to be dose-dependent. As such, newer bowel preparations of OSP solution & tablets have become available which have equal efficacy but a 16.7 – 20% decrease in phosphate content (i.e. Phospho-soda EZ Prep, C.B. Fleet Inc; Osmoprep, Salix Pharmaceuticals).

References:
  1. Markowitz GS, Nasr SH, Klein P, et al.: Renal failure and acute nephrocalcinosis following oral sodium phosphate bowel cleansing.Human Pathol 35:675-684, 2004

  2. Vanner SJ, MacDonald PH, Paterson WG, et al.: A randomized prospective trial comparing oral sodium phosphate with standard polyethylene glycol-based lavage solution (Golytely) in the preparation of patients for colonoscopy. Am J Gastroenterol 85:422-7, 1990

  3. Cohen SM, Wexner SD, Binderow SR, et al.: Prospective, randomized, endoscopic- blinded trial comparing precolonoscopy bowel cleansing methods. Dis Colon Rectum 37:689-696, 1994

  4. Beloosesky Y, Grinblat J, Weiss A, et al.: Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients. Arch Intern Med 163:803-8, 2003

  5. Desmeules S, Bergeron MJ, Isenring P: Acute phosphate nephropathy and renal failure. N Engl J Med 349:1006-7, 2003

  6. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD: Acute phosphate nephropathy following oral sodium phosphate bowel purgative: An underrecognized cuase of chronic renal failure. J Am Soc Nephrol 16:3389-3396, 2005

  7. Alon U, Donaldson DL, Hellerstein S, et al.: Metabolic and histologic investigation of the nature of nephrocalcinosis in children with hypophosphatemic rickets and in the Hyp mouse. J Pediatr 120:899-905, 1992

  8. Ritkes-Hoitinga J, Lemmens AG, Danse LHJC, et al.: Phosphorous-induced nephrocalcinosis and kidney function in female rats. J Nutr 119:1423-1431, 1989

  9. Ritkes-Hoitinga J, Mathot JNJJ, Van Zutphen LFM, et al.: Inbred strains of rats have differential sensitivity to dietary phosphorus-induced nephrocalcinosis. J Nutr 122:1682-1692, 1992

  10. Cramer B, Husa L, Pushpanathan C: Nephrocalcinosis in rabbits -- Correlation of ultrasound, computed tomography, pathology and renal function. Pediatr Radiol 28:9-13, 1998

  11. Alon U, Donaldson DL, Hellerstein S, et al.: Metabolic and histologic investigation of the nature of nephrocalcinosis in children with hypophosphatemic rickets and in the Hyp mouse. J Pediatr 120:899-905, 1992

  12. Schneider P, Ober KM, Ueberberg H: Contribution to the phosphate-induced nephropathy in the dog. Comparative light and electron microscopic investigations on the proximal tubule after oral application of K2HPO4, Na2HPO4, KCl, and NaCl. Exp Pathol 19:53-65, 1981

  13. Asplin JR, Mandel NS, Coe FL: Evidence of calcium phosphate supersaturation in the loop of Henle. Am J Physiol 270:F604-F613, 1996

  14. Gumurdulu Y, Serin E, Ozer B, Gokcel A, Boyacioglu S. Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation. J Gastroenterol Hepatol 19:68-72, 2004

  15. http://www.fda.gov/cder/drug/infopage/osp_solution/default.htm