PRESENTATION OF CASE
Dr. Yin Ge (Medicine): A 69-year-old man with a history of diabetes mellitus, heart disease, peripheral vascular disease, and renal transplantation was admitted to this hospital because of increasing weakness, malaise, anorexia, diffuse pain, and a history of falling.
Twenty months before this admission, renal transplantation was performed because of renal failure caused by diabetic and hypertensive nephrosclerosis; a myocardial infarction occurred intraoperatively. Immunosuppression was begun with the administration of antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. The next month, coronary-artery bypass grafting of three vessels was performed for unstable angina. During the next 18 months, the patient was admitted to this hospital multiple times for recurrent sternal osteomyelitis; cultures were positive for methicillin-sensitive Staphylococcus aureus, Candida tropicalis, and 3 months before admission, coagulase-negative staphylococcus. Treatment included antimicrobial agents, surgical débridement, and chest-wall reconstruction. Thirteen months before this admission, testing of the blood for BK virus nucleic acids was positive. Two months later, worsening renal failure and congestive heart failure occurred. Pathological examination of a biopsy specimen of the allograft kidney showed glomerulitis, with mononuclear cells, scattered neutrophils, and swollen endothelial cells; there were also dilated peritubular capillaries containing mononuclear cells, plasma cells, and occasional neutrophils. Immunofluorescence microscopy revealed widespread, intense staining of the peritubular capillaries for C4d; the results were thought to represent acute cellular and humoral rejection. Plasmapheresis was performed, and methylprednisolone, immune globulin, and rituximab were administered.
Five months before admission, increasing fatigue, anorexia, and failure to thrive developed. The patient had recurrent fevers and chills and felt cold, all in association with sternal and central-catheter infections. During this time, he saw numerous physicians, including generalists and specialists; however, his condition continued to deteriorate. The results of testing 8 weeks before admission are shown in Table 1TABLE 1
Laboratory Data.
. Increasing fatigue and diffuse weakness that was worse in the legs developed 6.5 weeks before admission. The patient tripped, hit his head, and lacerated his parietal scalp on the right side; the results of computed tomography (CT) of the head, performed at another hospital, were reportedly normal. During the remaining weeks before this admission, chronic pain and anorexia worsened, associated with weight loss of 9.1 kg. The patient reported pain in the lower abdomen, constipation, nausea with recurrent retching, and decreased urination, and he required increasing narcotic analgesia. One week before admission, he had difficulty arising from bed and fell several times. Four days before admission, he saw his primary care physician for pain, weakness, and anorexia. The blood pressure was 112/70 mm Hg and the pulse 70 beats per minute. The physician prescribed megestrol acetate for anorexia. According to the patient's wife, he had had constipation, a depressed mood, and hair loss for the past several months. The day before this presentation, his wife noted slurred speech and increasing somnolence.
Diabetes mellitus had been diagnosed 16 years earlier. The patient also had hypertension, hypercholesterolemia, hyperkalemia, peripheral vascular disease (for which angioplasty of the left superficial femoral artery and bilateral stent placements in the common iliac arteries had been performed), and prostatic hypertrophy. Medications on admission included tacrolimus (0.5 mg daily), mycophenolate mofetil (250 mg twice daily), prednisone (5 mg daily), fluconazole, simvastatin, amlodipine, carvedilol, isosorbide mononitrate, acetylsalicylic acid, acetaminophen, furosemide, fentanyl patch, tamsulosin hydrochloride, omeprazole, insulin, fludrocortisone (prescribed 9 months earlier for hyperkalemia), megestrol acetate, polyethylene glycol, zinc sulfate, sodium bicarbonate, ferrous sulfate, narcotic analgesia, trimethoprim–sulfamethoxazole, stool softeners, and fluticasone by inhalation. He lived with his wife and was retired. He drank alcohol in moderation until this recent illness and had stopped smoking 7 years earlier; he had not used illicit drugs. His mother had had diabetes mellitus and died at 81 years of age of throat cancer; his father died at 80 years of age of prostate cancer.
On examination, the patient was somnolent but arousable. The blood pressure was 93/45 mm Hg, the pulse 43 beats per minute and regular, the temperature 36.0°C, the respiratory rate 16 breaths per minute, and the oxygen saturation 99% while the patient was breathing ambient air. Trace erythema over the inferior sternal incision and a healing laceration over the right parietal scalp were noted. There were minimal crackles in the lung fields and diffuse muscle wasting; the remainder of the examination was normal, although the neurologic examination was limited owing to the patient's decreased ability to concentrate.
The platelet count and the activated partial-thromboplastin time were normal, as were blood levels of calcium, total and direct bilirubin, aspartate and alanine aminotransferase, amylase, lipase, and lactic acid. The tacrolimus level was 7.0 ng per milliliter; other test results are shown in Table 1. Urinalysis revealed a pH of 5.0 and a specific gravity greater than 1.030; the results were otherwise normal. An electrocardiogram showed sinus rhythm at a rate of 44 beats per minute (decreased from 64 beats per minute 5 weeks earlier), with a PR interval of 200 msec, a QRS complex of 88 msec, and QT and QTc intervals of 517 and 442 msec, respectively; new nonspecific T-wave abnormalities appeared in leads V1, V2, and V3 as compared with 5 weeks earlier. A chest radiograph showed mild interstitial pulmonary edema, with surgical clips in the mediastinum and a tortuous aorta with atherosclerotic calcification. CT of the head without the administration of contrast material revealed periventricular and subcortical microangiopathic changes and atherosclerosis in the carotid siphons, with no evidence of intracranial hemorrhage, mass lesion, or territorial infarct. Ultrasonography of the transplanted kidney revealed resistive indexes of the arcuate arteries throughout the kidney of 0.84 to 1.00 (normal range, 0.6 to 0.7), which were increased as compared with a study from 5 months previously, which showed indexes of 0.74 to 0.83; these findings suggested the possibility of transplant rejection.
Within 80 minutes after arrival, the patient's blood pressure decreased to 83/35 mm Hg and the pulse to 40 beats per minute. Normal saline (4 liters intravenously within the first 6 hours), vancomycin, cefepime, fluconazole, and methylprednisolone were administered. Hypotension and bradycardia persisted. Calcium gluconate, atropine, dopamine (followed by norepinephrine), vasopressin, glucagon, and ondansetron were added. Screening of the blood for toxins revealed the presence of dextromethorphan, methylprednisolone, and amlodipine. The patient was admitted to the coronary intensive care unit (ICU). Ciprofloxacin, metronidazole, sodium bicarbonate, calcium gluconate, insulin, and glucose were administered intravenously. Anuria occurred, despite bumetanide challenge, and continuous venovenous hemofiltration was begun.
Transthoracic echocardiography revealed a left ventricular ejection fraction of 64% and an estimated right ventricular systolic pressure of 68 mm Hg, which were unchanged from a previous study. Regional wall-motion abnormalities seen on the previous study were improved. Cultures of the blood and urine were obtained.
Diagnostic tests were performed.
DIFFERENTIAL DIAGNOSIS
Dr. Jeffrey L. Greenwald: May we see the imaging studies?
Dr. Shaunagh McDermott: The chest radiograph obtained on admission shows perihilar fullness and loss of definition of the pulmonary vasculature, features consistent with mild interstitial pulmonary edema (Figure 1FIGURE 1
Chest Imaging.
). The CT scan of the brain without the administration of contrast material shows periventricular and subcortical white-matter hypodensities, most likely representing chronic microangiopathic changes. There is also mild prominence of the ventricles and sulci, a feature consistent with diffuse parenchymal volume loss (Figure 2FIGURE 2
CT of the Brain.
).
Ultrasonography of the transplanted kidney on admission shows resistive indexes of the arcuate arteries of 0.84 to 1.00, as compared with 0.74 to 0.83 on ultrasonography performed 5 months earlier (Figure 3A and 3BFIGURE 3
Renal Ultrasonography.
). This increase in the resistive index is worrisome with regard to transplant rejection.
Dr. Greenwald: This case is particularly challenging, since our patient presented with a several-month course of the following largely nonspecific problems: weakness, fatigue, weight loss, depressed mood, and malaise. According to the Institute of Medicine, our patient had the geriatric clinical syndrome of failure to thrive, which is defined as “weight loss, decreased appetite and poor nutrition, and inactivity, often accompanied by dehydration, depressive symptoms, impaired immune function, and low cholesterol. Occurring in both acute and chronic forms, failure to thrive leads to impaired functional status, morbidity from infection, pressure sores, and, ultimately, increased mortality.”1 This syndrome is challenging to address, since it often has multiple contributing causes, including clinical, psychosocial, and environmental elements. Identifying potential causes requires bearing in mind that the principle of Occam's razor may not apply. That is, multiple underlying contributing factors may coexist.
We are given several clues that I will use to