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Keywords:

  • Kidney graft function;
  • phosphorus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

Acute phosphate nephropathy following a large phosphate load is a potentially irreversible cause of kidney failure. Here, we report on the unfavorable graft outcome in two recipients of deceased donor kidneys from a donor who had evolving acute phosphate nephropathy at the time of organ procurement. The donor, a 30-year-old with cerebral infarction, developed hypophosphatemia associated with diabetic ketoacidosis and was treated with intravenous phosphate resulting in a rise in serum phosphorus from 0.9 to 6.1 mg/dL. Renal biopsies performed on both recipients for suboptimal kidney function revealed acute tubular injury and diffuse calcium phosphate microcrystal deposits in the tubules, which were persistent in subsequent biopsies. A retrospective review of preimplantation biopsies performed on both kidneys revealed similar findings. Even though initial renal histology in both recipients was negative for BK virus, they eventually developed BK viremia with nephropathy but both had a substantive virologic response with therapy. The first patient returned to dialysis at 6 months, while the other has an estimated glomerular filtration rate of 12 mL/min, 17 months following his transplant. We conclude that unrecognized acute phosphate nephropathy in a deceased donor contributed substantially to poor graft outcome in the two recipients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

Nephrocalcinosis is defined histopathologically by deposits of calcium salts in the renal parenchyma, typically resulting in tubulointerstitial injury (1). When the precipitating factor for nephrocalcinosis is an acute phosphate load, it has come to be known as acute phosphate nephropathy (APN) (2,3). Although several cases of phosphate nephropathy have been reported after treatment with oral phosphates, this condition is rarely described after intravenous phosphate therapy and has not been described in a deceased donor whose kidneys were used for transplantation. Here, we report on the unfavorable graft outcome in two recipients of deceased donor kidneys from a donor who had evolving acute phosphate nephropathy at the time of organ procurement.

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

Donor

The donor was a 30-year-old Caucasian female, who came to the emergency room of a local hospital with history of severe headaches, nausea, mental status changes, tachypnea and slurred speech. Her past history was significant for leukemia diagnosed at age 4, which was successfully treated with chemotherapy and radiation therapy. She also had a history of type I diabetes mellitus for 9 years and of hypothyroidism, and her outpatient medications included insulin and levothyroxine. She had no history of smoking or alcohol or illicit drug use. She worked as a sales agent at a local store. Her family history was remarkable for history of ovarian cancer in her paternal grandmother, lung cancer in her paternal grandfather and stroke affecting her maternal grandfather.

Hospital course

In the emergency room of the local hospital, the vital signs recorded included a height of 67 inches, weight 88 kg, temperature 96.8°F, pulse rate 62/min, respiratory rate of 20/min and a blood pressure 114/77 mmHg. Initial laboratory studies were as follows: serum sodium 129 mEq/L, serum potassium 4.8 mEq/L, serum chloride 86 mEq/L, serum bicarbonate 6 mEq/L, blood urea nitrogen 31 mg/dL, serum creatinine 1.7 mg/dL, blood glucose 596 mg/dL, serum calcium 9.3 mg/dL, serum albumin 4.5 g/dL, anion gap of 37, hemoglobin 14.8 g/dL and white blood cell count 27.8 K/mm3 with 9% bands. The arterial blood gas on admission was as follows: pH 7.18, pCO2 11 mmHg, pO2 152 mmHg, HCO3 4.2 mEq/L, O2 Sat 99%. The urinalysis showed clear urine with pH of 5, specific gravity 1.02, trace protein, 3+ glucose, small amount of blood, 0–2 red blood cells and no white blood cells. The first recorded serum phosphate was 1.0 mg/dL at 12 h following admission. She initially received insulin, morphine, vancomycin, ondansetron and intravenous fluids. Shortly after presentation, she had a seizure episode that lasted for 13 min. She was intubated, started on intravenous mannitol and transferred to the intensive care unit. A CT scan of the head revealed cerebral edema, ischemic infarction of both hemispheres and an old subarachnoidal hemorrhage. In the intensive care unit she became hypotensive and was started on a dopamine infusion and given intravenous ceftriaxone. On hospital day 1, she was started on a phosphorus infusion for a serum phosphorus of 1 mg/dL (0.32 mmol/L) and over the next 2 days she received 120 mmols of intravenous phosphate as potassium phosphate. Her serum creatinine improved to 0.9 mg/dL by hospital day 2. Her phosphorus infusion was discontinued 60 h after admission when her serum phosphorus was noted to be 3.9 mg/dL (1.26 mmol/L). An MRI of brain on hospital day 4 showed generalized narrowing and tapering of the major intracranial vessels. Brain flow study performed on hospital day 5 was consistent with brain death. By the time brain death was declared, her serum phosphorus had risen to 6.2 mg/dL (2.0 mmol/L) and her serum calcium had declined to 5.8 mg/dL with a rise in serum creatinine to 1.4 mg/dL (Table 1).

Table 1.  Laboratory data of the donor prior to organ procurement
 0 h17 h29 h42 h60 h68 h73 h81 h89 h92 h
  1. 1The first serum phosphorus was 1 mg/dL obtained approximately 12 h after admission.

Sodium (mEq/L)129142147152164 146 142143
Potassium (mEq/L)4.843.13.133.73 5.74.5
Chloride (mEq/L)86111109116127126104 108106
CO2 (mEq/L)661519212828 2323
BUN (mg/dL)3112754511 1517
Creatinine (mg/dL)1.71.00.90.90.90.81.1 1.41.7
Glucose (mg/dL)59616116022690102249 239237
Calcium (mg/dL)9.38.78.37.176.76.15.8  
Phosphorus (mg/dL)11.70.9 3.94.1 6.26.1 
Magnesium (mg/dL) 2.12     1.8 
Albumin (g/dL)4.53.73.5    2.22.1 
Hemoglobin (g/dL)14.813.6 12.610.611.110.5   
Arterial blood pH7.18 7.487.467.517.45 7.39 7.42
Arterial pC02 (mmHg)11 25252738 41 40
Arterial p02 (mmHg)152 14111916374 142 590
Arterial HC03 (mEq/L)4.2 19182226 25 26
Urine output (mL/h) 9217590  92 175100

In accordance with the decedent's wishes, her heart, liver, lungs and kidneys were procured for transplantation on day 5. Prior to procurement, she continued to have a good urine output although the final serum creatinine was 1.7 mg/dL. In view of the history of diabetes, both donor kidneys underwent postprocurement biopsy, which was reported as showing an adequate number of glomeruli and normal-appearing arteries, arterioles and tubules. A subsequent retrospective review of this renal biopsy at our institution revealed numerous intratubular calcium phosphate deposits.

Recipient 1

The first recipient was a 65-year-old HLA-mismatched Caucasian male with end-stage renal disease (ESRD), who had no sensitization history and had no antibodies to a standard panel of class I and class II HLA antigens. The cold ischemia time was 16 h. The patient had a past history of type II diabetes mellitus for 25–30 years, complicated by nephropathy, retinopathy and polyneuropathy, hypertension, coronary artery disease, hyperlipidemia, peripheral vascular disease, benign prostatic hypertrophy, osteomyelitis, anxiety and depression.

Hospital course

He was given antithymocyte globulin and intravenous methylprednisolone as induction immunosuppression and then begun on prednisone and mycophenolate mofetil with tacrolimus added on postoperative day 6. The first postoperative serum phosphorus obtained on day 1 was 5.3 mg/dL. His immediate preoperative serum creatinine was 6.3 mg/dL and his creatinine slowly improved to 2.9 mg/dL (estimated glomerular filtration rate [eGFR] 23 mL/min) by day 10, the best renal function he achieved. A kidney biopsy on day 17 showed acute tubular injury and diffuse intratubular microcrystal deposits. These deposits stained basophilic with hematoxylin and eosin stain, were nonrefractile and showed strong black staining with Von Kossa stain, consistent with calcium phosphate crystal deposits (Figure 1A, B). A simian virus 40 (SV40) T antigen stain for BK virus was negative. A blood polymerase chain reaction (PCR) for BK virus was negative on postoperative day 20.

image

Figure 1. Renal allograft histopathology. (A) Recipient 1: Intratubular calcium phosphate microcrystal deposits (hematoxylin and eosin stain, 200 × magnification). (B) Recipient 1: Intratubular calcium phosphate microcrystal deposits showing strong black staining with Von Kossa stain for calcium (200 × magnification). (C): Recipient 2: Intratubular calcium phosphate microcrystal deposits (hematoxylin and eosin stain, 200 × magnification).

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A second kidney biopsy was performed 3.5 months following his transplant because of continued slow decline in graft function (eGFR 14 mL/min). This showed persistent diffuse calcium phosphate microcrystal deposits in the tubules, minimal interstitial inflammation and no evidence of rejection. C4d stain was negative in peritubular capillaries. Rare tubular cell atypia was suspicious for polyoma virus. The SV40 stain for polyoma virus was positive. His blood BK viral load was measured at 69 500 copies/mL. At this time his tacrolimus dose was reduced, mycophenolate discontinued and he was started on leflunomide. His renal function continued to deteriorate, despite a virologic response with a BK viral load 2 months later of less than 5000 copies/mL.

He returned to hemodialysis at about 6 months posttransplant because of uremic symptoms and an eGFR of 9 mL/min. He subsequently underwent transplant nephrectomy and is currently listed for a second kidney transplant. The explanted kidney showed diffuse and persistent tubular calcium phosphate deposits. There was no evidence of BK virus by immunohistochemical staining.

Recipient 2

The second recipient was a 52-year-old Hispanic man with ESRD secondary to focal segmental glomerulosclerosis. He had no sensitization history and had no antibodies to a standard panel of class I and class II HLA antigens. His past history was also significant for hypertension, schizophrenia and hyperlipidemia.

Hospital course

He received induction immunosuppression with antithymocyte globulin and intravenous methylprednisolone and then was begun on prednisone and mycophenolate mofetil with tacrolimus added on postoperative day 7. The first postoperative serum phosphorus obtained on day 0 was 5.5 mg/dL. The early postoperative course was complicated by delayed graft function and he required renal replacement therapy for 8 days. Serum creatinine stabilized at 3.5 mg/dL (eGFR 20 mL/min) by day 15 and a kidney biopsy performed at this time revealed intratubular microcrystal deposits with staining characteristics typical of calcium phosphate (Figure 1C). There was no evidence of acute rejection. There were no viral cytopathic changes concerning for BK virus nephropathy and an SV40 T-antigen immunostain was negative. A second kidney biopsy performed 40 days posttransplant showed no evidence of rejection or viral cytopathic changes. Numerous calcium phosphate microcrystal deposits were still present in the tubules.

A third kidney biopsy was performed 3 months posttransplant for persistent suboptimal renal function (eGFR 16 mL/min). This showed viral cytopathic changes present predominantly in medullary tubules consistent with BK virus nephropathy and once again persistent intratubular deposits of calcium phosphate. Blood BK viral load was 871 832 copies/mL. At this time his tacrolimus dose was reduced and mycophenolate discontinued. He was started on oral leflunomide and he received a short course of intravenous cidofovir. A repeat kidney allograft biopsy 5 months posttransplant stained negative for polyoma virus with absence of any viral cytopathic changes. However, prominent calcium phosphate deposits in the tubules were present. BK viremia gradually improved (BKV PCR blood 699 copies/mL at 8 months posttransplant and negative at 11 months posttransplant). At 17 months posttransplant, he remains relatively asymptomatic with a serum creatinine of 5.2 mg/dL (eGFR 12 mL/min).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

We believe that the two patients reported here received kidneys from a deceased donor in whom APN had developed. The persistence of poor graft function with intratubular calcium phosphate deposits in two recipients from the same donor prompted us to carefully review the clinical course of the donor during her terminal illness. It became evident that prolonged and substantive administration of intravenous phosphorus had led to a rise in serum phosphorus from 0.9 to 6.2 mg/dL over 72 h and a serum creatinine that rose to 1.7 mg/dL consistent with acute tubular injury. The fall in serum calcium that accompanied the rapid rise in serum phosphorus following intravenous replacement is well described in the older literature and may be associated with metastatic calcium phosphate deposition and renal failure (4–6). The kidney biopsies that were performed at organ procurement and read at an outside hospital were subsequently reviewed by one of us and both kidneys demonstrated the same intratubular calcium phosphate deposits that were recognized in recipients’ kidney biopsies. Morphologically, the calcium phosphate deposits in both donor and recipients appeared to be in the distal convoluted tubules although no specific tubule markers were used to confirm this.

APN is a recently recognized cause of acute kidney injury, which appears to occur after exposure to a high oral phosphorus load. In its most dramatic and easily recognized form, severe hyperphosphatemia and hypocalcemia follows a large oral phosphorus load with almost immediately apparent acute renal failure (7). More recently, it has been reported in some patients given oral sodium phosphate solutions as laxatives or bowel cleansing preparations and occasionally following rectal phosphorus administration (2,8,9).

The ingestion of a large phosphorus load leads to a rapid increase in phosphaturia, mediated by a phosphorus sensor in the gut that can regulate renal phosphorus excretion even without changes in serum phosphorus (10, 11). The development of nephrocalcinosis following intravenous phosphorus administration is almost certainly related to an increase in urinary phosphorus excretion, presumably through activation of PTH- and FGF23-stimulated pathways, although the factors that contribute to calcium phosphate precipitation within the tubules are not completely understood. Experimental animals develop acute tubular injury and intratubular calcium phosphate deposition within 1 to 3 days of a large oral or intraperitoneal phosphorus load (12,13). Repeated administration of phosphate supplements is the likely basis for the nephrocalcinosis and progressive renal impairment that occurs in children with vitamin D-resistant hypophosphatemic rickets as it is also seen in an animal model of vitamin D-resistant hypophosphatemia (14).

The kidney donor in this report was admitted with diabetic ketoacidosis and volume depletion and the correction of hyperglycemia, metabolic acidosis and volume depletion with insulin and intravenous fluids may have led to hypophosphatemia seen on hospital day 1. Thereafter, she received 120 mmol of intravenous potassium phosphate over the next approximately 48 h, which was in excess of the recommended treatment for hypophosphatemia of 7–56 mmol (0.08–0.64 mmol/kg) of phosphorus (15,16). The history of diabetes along with volume depletion and the use of mannitol, a proximal tubular natriuretic may have made her particularly susceptible to the development of APN, as these have been considered as risk factors in some studies (2,3,9,17,18). Furthermore, the subsequent additive effects of tubular injury that occurred following procurement, cold preservation and reperfusion as well as the use of tacrolimus may have contributed to the poor recovery of renal function in the recipients of these kidneys.

Interestingly, both recipients subsequently developed BK virus nephropathy later in their course, which may have had a further detrimental effect on kidney function. Although there is unlikely to be a relationship between APN and BK virus infection, we cannot exclude the possibility that the tubular injury associated with calcium phosphate deposition may have been a risk factor for BK virus disease. Both patients responded to reduction in immunosuppression and antiviral therapy to control BK viremia and nephropathy although renal function continued to deteriorate.

In summary, this case demonstrates that intravenous administration of phosphorus can lead to the development of acute phosphate nephropathy, a problem that has not been recognized in recent publications. The serious consequences of overcorrection of hypophosphatemia should be recognized by critical-care physicians and others, who embark on the use of intravenous phosphorus therapy, especially in cases where the hypophosphatemia, as in this case, is in part due to transcellular shifts and may not need aggressive correction. Although the development of APN in this donor occurred prior to the declaration of brain death, intensivists and organ procurement coordinators also need to be aware of this danger when contemplating the correction of hypophosphatemia as part of a deceased donor management protocol. Finally, transplant physicians should be aware of the histological signs of acute phosphate nephropathy and recognize that this particular form of acute tubular injury in a kidney donor may have long-term adverse consequences in the recipients of these kidneys.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References

This work is supported, in part, with resources at the VA Medical Center, Iowa City. We thank Lori Markham for helpful discussions about this case.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Acknowledgments
  7. References