Dvora Rubinger

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.

Sympathetic Nervous System Function and Dysfunction in Chronic Hemodialysis Patients

Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality.

Transient Exercise-Induced Water Intoxication and Rhabdomyolysis

Water loading only rarely results in adverse effects due to the high efficiency of the kidney in excreting free water. However, when renal diluting ability is impaired, such as in inappropriate vasopressin secretion, water intoxication can occur in otherwise normal individuals. We report the case of a 19-year-old man with acute voluntary water intoxication following exercise, which resulted in a transient defect in renal diluting capability. Hyponatremia was further complicated by rhabdomyolysis. We review the literature regarding other cases of hyponatremia following excessive water intake, and discuss the possible association between hyponatremia and rhabdomyolysis. We conclude that monitoring of muscle enzymes is indicated in acute hyponatremia, to allow for timely intervention intended to prevent rhabdomyolysis-associated acute renal failure.

IgM Nephropathy: Morphological Study Related to Clinical Findings

This study describes 10 cases of IgM nephropathy in whom the main morphological findings consisted of diffuse mesangial deposition of IgM and varying degrees of mesangial cell proliferation. In addition, focal segmental sclerosis was present in 1 patient and global sclerosis in another. An ill-defined electron-dense deposit was seen within the mesangial area in 1 case. Except for 1 patient, who had hematuria only, all suffered from nephrotic syndrome without deterioration of renal function. In view of the constant and characteristic finding of a diffuse mesangial IgM deposition, it is suggested that this form of nephropathy constitutes an entity separate from focal glomerulosclerosis or minimal change disease.

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.

Restoration of baroreflex function in patients with end-stage renal disease after renal transplantation

BACKGROUND Renal transplantation improves the uraemic autonomic dysfunction and heart rate variability (HRV). The effects of successful transplantation on blood pressure variability (BPV) and baroreflex function are not well defined. METHODS BPV, HRV and baroreceptor indices were determined in (1) 52 non-diabetic chronic haemodialysis patients, (2) 44 transplanted patients, 24 in the first year after renal transplantation (< or =1 year) and 20 at least 1 year (>1 year) after renal transplantation, and (3) 41 control individuals with normal renal function, age-matched to (1) and (2). Power spectrum analysis of interbeat intervals (IBI) and systolic blood pressure (SBP) was performed in the low-frequency (LF 0.04-0.15 Hz) and the high-frequency (HF 0.15-0.40 Hz) bands. Spontaneous baroreceptor sensitivity (BRS) was determined by the sequence (slope) and spectral (alpha coefficient) techniques. RESULTS In haemodialysis patients, BPV was increased, while HRV, BRS slope and LF alpha and HF alpha coefficients were markedly decreased as compared to control individuals. Renal transplantation was associated with normalization of BPV at short term (< or =1 year) and long term and with improvement of HRV at a long-term (>1 year) follow-up. In patients with long-standing functioning grafts (>1 year), baroreceptor indices were significantly increased and returned to values similar to those of the control subjects. CONCLUSIONS Our data show that renal transplantation improves blood pressure and HRV and restores baroreflex function to near normal range on the long-term follow-up. These effects may contribute to the improvement of blood pressure control and survival after successful transplantation.

Sympathetic activation and baroreflex function during intradialytic hypertensive episodes.

Background The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes. Methodology/Principal Findings Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of- dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension. Conclusion/Significance Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of- dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension.

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Background/Aims: Dent’s disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. Methods: Eighteen probands with Dent’s disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. Results: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. Conclusions: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease in this patient cohort.

Pseudo-Normal Osmolal and Anion Gaps following Simultaneous Ethanol and Methanol Ingestion

Methanol, ethylene glycol, and isopropyl alcohol are associated with acute intoxication. The diagnosis is dependent upon high anion-gap metabolic acidosis, and an osmolal gap between the calculated and the measured osmolality. Normal anion gap has been reported in some cases of concomitant methanol and ethanol ingestion, where the high serum levels of ethanol inhibited the metabolism of methanol by alcohol dehydrogenase. The osmolal gap in these cases was higher than expected for methanol, and served as a constant marker for a metabolic derangement. Herewith, we present a patient who presented with normal osmolal and anion gaps 36 h after ethanol and methanol ingestion, yet progressively developing ocular toxicity. Normal anion and osmolal gaps should not rule out earlier methanol poisoning.

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.