Michael M. Friedlaender

Temporary regression of Merkel cell carcinoma metastases after cessation of cyclosporine.

A 46-year-old male received two preemptive living-donor kidney transplants in 1989 and in 1998 and was treated with prednisone, cyclosporine (CsA), and azathioprine. Pulse methylprednisolone and ATG therapy were given in 1992 for acute cellular rejection. In September 1999, a cervical swelling was removed and recurred 3 months later. Histology of the removed tissue showed Merkel cell carcinoma (MCC) (sheets of closely packed small cells with round nuclei containing finely dispersed chromatin, scant cytoplasm, and mitotic figures and immunohistochemistry showing scattered staining with chromogranin and prominent paranuclear dot-like staining with cytokeratin, epithelial membrane antigen moderately to intensely positive and negative for leukocyte common antigen, desmin and S-100). Azathioprine therapy was stopped. Five courses of cyclophosphamide, adriamycin, vincristine, and etoposide had no effect on the neck swelling, which increased in size during therapy. Local radiotherapy to a total dose of 50 Gy caused reduction in the swelling. Oral prednisone 7.5 mg and CsA 100 mg twice daily were continued. The patient remained in good general condition without local tumor recurrence for over 6 months. In October 2000 the patient returned with recent onset of anorexia, weight loss, and diffuse bone pains that were unresponsive to analgesics. He was unable to walk. There was a painful swelling in his neck at the site of the previously resected tumor. Multiple new growths protruding from his skull had appeared. One of these was excised and confirmed the metastatic spread of the MCC. Immunohistochemistry performed on this biopsy material showed positive staining for transforming growth factor (TGF)(Fig. 1). Tc-99 M-MDP bone scan showed multiple areas of increased uptake including in the skull, right acromion, several ribs, and left sacroiliac joint. Biochemistry showed normal renal function and no change in mildly elevated liver enzymes (chronic biopsy verified hepatitis C). The patient received further palliative radiotherapy to his left shoulder region and to his sacrum. CsA was stopped and only 5 mg of prednisone was continued. Carboplatin therapy was advised but the patient opted not to receive this because, soon after stopping CsA, he became free of pain. All visible signs of his MCC metastases disappeared, he was freely mobile, and gained weight. External examination of his cranium revealed no signs of the previous multiple metastatic growths. His kidney function was excellent. The whole blood-specific CsA levels before cessation of therapy were 96–130 ng/ml. The patient remained in excellent condition for 8 months after withdrawal of CsA therapy. In May 2001 sudden paraparesis occurred. CT scan showed thoracic spinal compression by a soft tissue lesion and several hypodense liver lesions. Palliative radiotherapy did not prevent total paraplegia and the patient died at home 1 month later. His renal function remained normal until his death. MCC is a rare skin cancer arising from cells of neuroendocrine origin and seems to be especially aggressive after organ transplantation (1). The value of reduction in immunosuppressive therapy, especially cessation of azathioprine, has been shown mostly in tumors associated with oncogenic viruses such as Kaposi’s sarcoma and posttransplantation lymphoproliferative disease (2, 3), but there are very few reports of regression of solid tumors. CsA therapy has been associated with more rapid growth of hepatic tumors (4) and stimulates tissue expression of TGF(5). A nonimmunologic mechanism whereby CsA promoted phenotypic changes in several types of malignant cells in vitro and increased tumor growth and metastatic spread of malignant cells in vivo has recently been described (6). Treatment with anti-TGFmonoclonal antibodies prevented these effects of CsA. The MCC metastases in our patient showed positive staining for TGF, and it is thus possible that the dramatic regression of the MCC metastases in our patient were via such a CsA-induced TGFmechanism. Withdrawal of CsA therapy enabled a terminally ill patient to return to good health for an 8-month period until a new spinal metastasis caused a rapid fatal outcome.

Successful renal transplantation from two donors with methanol intoxication

Two patients with acute methanol intoxication are reported, one with acute renal failure. Both were declared brain-dead and kidneys were harvested at 80 and 130 hr after hospital admission. All four kidneys were transplanted and subsequently functioned well. In both donors who had received ethanol treatment, thrombocytopenia was present. The reluctance to use kidneys from such donors and from donors with acute renal failure before harvesting is discussed. Waiting lists for renal transplantation are growing and there is a world-wide shortage of cadaver organs. We were recently surprised to find reluctance to consider two local patients dying from methanol intoxication as suitable organ donors, and we report the outcome of four kidneys transplanted from these donors. We were unable to find any similar cases reported in the English literature.

Oncogenous osteomalacia: a case study.

A case of oncogenous osteomalacia due to a fibrosarcoma of the maxilla is reported, with a 19 year course before treatment. Metabolic studies of calcium and phosphorus were performed 3 and 19 years after the first symptomology. There was a negative balance for both phosphorus and calcium with low serum levels of 1,25-dihydroxyvitamin D which were corrected by resection of the tumor. Portions of the tumor were cultured and the supernatant did not affect phosphorus transport by a proximal tubule kidney cell line. Other portions were injected into athymic nude mice where they resulted in hypophosphatemia and phosphaturia, thus confirming the endocrine nature of the oncogenous osteomalacia factor.

End-Stage Renal Interstitial Fibrosis in an Adult Ten Years after Ifosfamide Therapy

A 33-year-old male presented with end-stage renal failure. Renal biopsy showed severe interstitial fibrosis without glomerulopathy or vasculopathy. More than 10 years previously the patient had been successfully treated for recurrent rhabdomyosarcoma. The treatment included ifosfamide, a drug known to cause acute tubular dysfunction. Though a possible synergistic effect of previous radiation which was well within accepted tolerance limits cannot be excluded, it would appear that ifosfamide was almost certainly the major cause of the late onset chronic renal disease.

Renal Transplantation Is Not Contraindicated in Asymptomatic Carriers of Hepatitis B Surface Antigen

Recent reports showing that the presence of positive tests for hepatitis B surface antigen (HBsAg) is associated with prohibitively high morbidity and mortality suggest that such patients should not be considered for kidney transplantation. The clinical outcome and serology including hepatitis B DNA assays of 11 patients who were HBsAg-positive at the time of transplantation, as well as the hepatic complications in all 200 kidney transplantations during the same period, were analyzed. In the 11 HBsAg-positive patients, no clinical or laboratory evidence suggesting deterioration in liver function over a mean follow-up period of 8.0 +/- 1.7 years was found. Of six patients with fatal or severe chronic liver disease, only one was HBsAg-positive at the time of transplantation and showed no deterioration over 9 years. Two immunosuppressed patients developed anti-HBs antibodies after acute hepatitis B infection. A review of the literature leads to the conclusion that previous reports of poor patient prognosis may represent patients who first showed HBsAg positivity after transplantation or who had preexisting HBsAg-related liver disease. The present findings suggest that asymptomatic patients with positive tests for HBsAg should not be excluded from kidney transplantation programs.

Amelioration of familial Mediterranean fever during hemodialysis.

FAMILIAL Mediterranean fever is characterized by recurrent polyserositis and fever1 2 3 and is a potentially fatal illness, owing to a high incidence of renal involvement.1 2 3 4 5 The main cause o...

Improved Renal Function in Patients with Primary Renal Disease after Control of Severe Hypertension

Renal function and life expectancy can be improved by aggressive antihypertensive therapy in severe hypertension. However, most reports of severe hypertension and renal failure concern primary hypertensive states. 3 cases of primary renal disease, 1 glomerular, 1 obstructive and 1 of chronic pyelonephritis, are described here. In all 3 cases, severe hypertension and renal failure were present. Adequate reduction in blood pressure resulted in substantial improvement in renal function.

Noninvasive Assessment of Skin Iron Content in Hemodialysis Patients. An Index of Parenchymal Tissue Iron Content

Iron overload has been described in patients undergoing chronic hemodialysis. The present study was undertaken to evaluate a rapid, noninvasive method for determination of skin iron by the technique of diagnostic x-ray spectrometry (DXS). Thirty-five patients receiving chronic hemodialysis treatment entered the study and were compared with 25 normal controls. Since pathological skin iron deposition occurs mainly at the dermal-epidermal junction in the basal cells of the epidermis, measurements were made in the thenar eminence representing mainly epidermal tissue (FeE), and in the forearm representative mainly of dermis (FeD). The mean +/- SD FeE iron concentrations were equivalent to 14.5 +/- 8.8 and 18.2 +/- 10.2 parts per million wet weight tissue (ppm) and both were significantly higher than in normal controls in which they averaged 9.2 +/- 2.5 ppm (P less than 0.005) and 10.2 +/- 3.2 ppm (P less than 0.001), respectively. There was significant positive correlation between individual skin iron determinations with the total number of blood transfusions received, the rate of blood transfusion, and with serum ferritin levels. Bone marrow hemosiderin was examined in six patients and showed a similar trend. Despite correlation only with indirect indices of tissue iron, our findings suggest that DXS may serve as a reliable quick method for noninvasive estimation of nonreticuloendothelial tissue iron deposition in hemodialysis patients suspected of having transfusional iron overload. The method may be valuable in monitoring the effects of chelation therapy.

Combined Cyclophosphamide and Corticosteroid-Induced Remission in Severe Glomerulopathy Associated with Systemic Vasculitis

Three patients with systemic vasculitis and severe renal disease as major manifestations are reported. In 2 cases, rapidly progressive glomerulonephritis presented as oliguric renal failure. In the third case, the clinical picture was severe nephrotic syndrome with decreased renal function. Combined cyclophosphamide and corticosteroid treatment resulted in dramatic improvement of renal function and remission of nephrotic syndrome. In 2 cases, histological improvement was documented by repeated kidney biopsy. The optimal duration of cyclophosphamide therapy has to be determined.

The in vivo and in vitro effect of calmodulin antagonists on the renal actions of 25(OH) vitamin D3 in the rat.

Previous work from this laboratory has demonstrated that 25(OH) vitamin D3 [25(OH)D3] acutely suppresses the phosphaturic action of parathyroid hormone (PTH) and interferes with the PTH-induced activation of adenylate cyclase (AC). Calmodulin inhibitors block vitamin D-induced Ca2+ transport in the gut and phosphorus uptake in renal BBMVs. We have examined whether calmodulin antagonists affect the renal action of 25(OH)D3. Acute clearance experiments were performed in PTH-infused parathyroidectomized rats receiving 25(OH)D3 after pretreatment with trifluoperazine (TFP) or promethazine (P). In vitro PTH-induced activation of renal AC was also studied in membrane preparations from pretreated rats in the presence of 25(OH)D3. 25(OH)D3 reduced the PTH-stimulated increase in fractional excretion of phosphorus (CP/CIn) from 0.292±0.024 to 0.195±0.018 (p<0.005) and urinary cAMP from 149.3±20.3 to 78.1±10.4 pmol/min (p<0.01) and also blunted AC activation in vitro. TFP but not P abolished the effects of 25(OH)D3 both in vivo and in vitro. R 24571 also abolished the in vitro effect of 25(OH)D3. Thus, (1) TFP abolishes both the antiphosphaturic and the AC/cAMP-related actions of 25(OH)D3, (2) P does not have these effects, and (3) R 24571 abolishes the in vitro effect of 25(OH)D3. These results suggest that the antiphosphaturic effect of 25(OH)D3 acting via the AC/cAMP system may be calmodulin dependent.