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In J.F., atorvastatin would be an appropriate choice.

Post-transplant Osteoporosis

CASE 34-5, QUESTION 4: Would osteoporosis and bone fractures be a concern and what would be

appropriate therapies in this patient?

Rapid bone loss with the subsequent development of osteopenia or osteoporosis is

another common post-transplantation disorder. Osteoporosis increases bone fragility

and eventually leads to fracture. Studies estimate that osteoporosis occurs in 11% to

56% and fractures 5% to 44%, and increases in time in the transplant population.

Osteoporosis risk factors for transplant recipients are similar to those in the general

population included. Additional risk factors in kidney transplant include time on

hemodialysis before transplant, vitamin D deficiency, pretransplant PTH and FGF-23

levels, diabetes, and steroid dose. Patients with ESRD commonly have at least some

evidence of renal osteodystrophy, which includes hyperparathyroidism,

osteomalacia, osteosclerosis, and adynamic or aplastic bone disease. Many kidney

transplant recipients have already been exposed to medications that can affect bone

and mineral metabolism, such as corticosteroids and/or loop diuretics.

Drugs used to prevent organ rejection predispose patients to osteoporosis,

especially corticosteroids. The most dramatic reduction in bone loss after

transplantation occurs within the first 3 to 6 months, when high doses of steroids are

tapered to prednisone doses equivalent to 7.5 to 10 mg every day. As noted,

corticosteroid-free or rapid-taper corticosteroid immunosuppressant regimens are

being used to minimize or prevent post-transplant bone disease. Most studies suggest

a minor effect of CNI on bone. Other currently used agents appear to have little or no

effect. Most recommendations are based on the American College of Rheumatology’s

guidelines for the prevention and treatment of corticosteroid-induced osteoporosis.

These recommendations focus on providing calcium and vitamin D (variable dosing

depending on kidney and liver functions) to patients who will be receiving

continuous corticosteroid therapy. Patients with osteopenia or osteoporosis with

bone mineral density scans using dual-energy X-ray absorptiometry (DXA) scans,

calcium, and vitamin D analogs are recommended in conjunction with either a

bisphosphonate or calcitonin or teriparatide.

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Clinical trials have demonstrated that bisphosphonates and vitamin D or activated

vitamin D analogs are effective in reducing or stabilizing bone loss but fail to show

significant improvement in bone fracture rates, bone pain, or immobility owing to

bone disease.

Although J.F. is young and likely may not have severe bone disease, a DXA scan

should still be performed, as well as FRAX score should be determined. Phosphate,

calcium and parathyroid levels, 25OH vitamin D levels, and eGFR should be

assessed prior to initiation of any therapy. He could be given calcium and vitamin D

because he is receiving steroids, unless he has a contraindication to this therapy.

Based on the results of J.F.’s DXA scan, he may need to receive either a

bisphosphonate or an activated vitamin D analog, such as calcitriol, vitamin D, and

possibly calcium supplementation. A repeat DXA scan should be performed in 1 to 2

years. J.F. should be carefully counseled on how to take his medicine correctly and

monitored for adverse effects.

BK Polyomavirus Infection

CASE 34-6

QUESTION 1: K.T., a 45-year-old white man, is now 16 months post-transplant. His post-transplant course

has been complicated by two rejection episodes. The first was severe and required rabbit

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antithymocyte globulin therapy; the second was a mild rejection several weeks later that was adequately treated

with three pulse doses of 500 mg IV methylprednisolone. His current immunosuppressant regimen consists of

tacrolimus 8 mg PO BID, MMF 1 g PO BID, and prednisone 10 mg PO daily. In addition, he is receiving

amlodipine 10 mg PO daily, benazepril 10 mg PO daily, pravastatin 40 mg PO at bedtime, and calcium with

vitamin D 500 mg/400 IU PO BID. Today, he is in the transplant clinic for a routine follow-up visit. He has no

complaints and says he has been feeling “great,” although he has noticed some blood in his urine during the past

couple of weeks. Because of this, a urinalysis is ordered in addition to the standard laboratory values. The

results are as follows:

Na, 145 mEq/L

K, 4.2 mEq/L

Cl, 104 mEq/L

HCO3, 26 mEq/L

BUN, 32 mg/dL

SCr, 2.7 mg/dL

Ca, 10.1 mEq/L

Phosphorus, 4.5 mg/dL

Glucose, 110 mg/dL

Amylase, 50 IU/L

Lipase, 32 IU/L

WBC count, 7.7 cells/μL

Hgb, 10.4 g/dL

Hct, 31%

Tacrolimus trough, 9 ng/mL

Urinalysis, color yellow

Specific gravity, 1.013

pH, 7.0

Protein, 100 mg/dL

Glucose, negative

Ketones, negative

Bilirubin, negative

Blood, moderate

Nitrite, negative

Leukocyte, negative

Squamous epithelial cells, 3 cells/high-power field

Bacteria, negative

Urinalysis revealed “decoy” cells, and plasma BK virus–PCR was greater than 10

4

. Because of an

increased serum creatinine, a percutaneous kidney biopsy is performed. The pathologist reviews the histology of

the tissue sample and determines that it is consistent with polyoma-associated nephropathy. What is BK

polyomavirus? How is it diagnosed and what are its clinical manifestations?

BK virus is a human polyomavirus, first isolated in 1971. Polyomaviruses are

small, nonenveloped viruses with a closed, circular, double-stranded DNA

sequence. Little is known about the transmission or about the primary infection of BK

virus. It is believed that viremia during the initial exposure results in systemic

seeding and subsequently becomes a latent infection. The kidney is the main site of

BK virus latency in healthy people. More than 50% of the general population express

BK virus antibodies by age 3 years. Immunosuppression after transplantation

probably leads to the reactivation of the virus, but other factors, such as organ

ischemia and coinfection with other pathogens, may contribute to reactivation.

Reactivation inevitably leads to viruria or viral shedding into the urine.

Asymptomatic viruria occurs in approximately 10% to 45% of kidney transplant

recipients.

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Diagnosis of polyoma-associated nephropathy is made by careful review of

clinical, laboratory, and histologic findings. Patients are often asymptomatic,

although hematuria has been noted in some patients. Clinically, BK virus nephritis

mimics acute rejection, and increases in serum creatinine often lead to a tissue

biopsy. Tissue histology is similar to cases of acute rejection and BK virus nephritis,

with mononuclear infiltration as the predominant finding. The abundance of plasma

cells, prominent tubular cell apoptosis, collecting duct destruction, and absence of

endarteritis are features that may distinguish BK virus nephritis from acute cellular

rejection. Although BK virus has been implicated in up to 5% of all cases of

interstitial nephritis (of which 30% go on to graft failure), it is still unclear whether

asymptomatic biopsy findings in the kidney transplant recipient are a prognostic

indicator. Decoy cells in the urine and BK virus–PCR in blood are used as screening

tools. Blood or plasma BK virus–PCR is a more sensitive and stable test, and

correlates better with renal dysfunction than decoy cells. The American Society of

Transplantation recommends screening for BK virus in all kidney transplants, by

measuring serial BK PCRs monthly for the first 3 to 6 months post-transplant, then

every 3 months until the end of the first year post-transplant, whenever there is an

unexplained risk in serum creatinine and after treatment of acute rejection. If the BK–

PCR is consistently >10,000 copies/mL, it is recommended to reduce

immunosuppression.

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Most cases of polyoma-associated nephropathy occur within the first 3 months

after transplantation, although a number of cases have been reported as long as 2

years after transplantation. The major risk factor for the development of polyomaassociated nephropathy and subsequent graft dysfunction or loss is the degree of

immunosuppression. In addition, accelerated graft loss has been demonstrated in

patients who received antilymphocyte antibodies in the presence of polyomaassociated nephropathy misdiagnosed as an acute rejection episode. K.T., like many

patients with BK virus, is asymptomatic with an elevated serum creatinine. Because

K.T. has received higher doses of immunosuppression recently to treat two acute

rejection episodes, he is at higher risk for developing BK virus nephritis.

TREATMENT

CASE 34-6, QUESTION 2: K.T. is told to stop taking MMF and to reduce his tacrolimus dose to 4 mg PO

BID with target trough levels less than 6 ng/mL. Why was K.T.’s immunosuppressive regimen significantly

reduced?

Because BK virus reactivation and BK nephritis are strongly associated with the

degree of immunosuppression, reduction in, or removal of, immunosuppressant

agents is considered first-line therapy and most effective approach. Beneficial

clinical responses have been demonstrated in some patients when the dose of CNI is

reduced and/or other agents removed. Not all patients, however, respond to this

maneuver. In addition, reduction in immunosuppression puts patients at higher risk

for an acute rejection episode. Close clinical follow-up after reduction of

immunosuppression is important to ensure adequate response and to make sure the

patient does not experience an acute rejection episode. In K.T.’s case, an

improvement of renal function can be expected, as seen by a reduction in serum

creatinine over time. Also, monitoring viral loads from both the urine and the serum

has been shown to correlate with clinical disease.

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