Characterization of an immortalizing N-terminal domain of polyomavirus large T antigen.

Polyomavirus large T antigen has an N-terminal domain of approximately 260 amino acids which can immortalize primary cells but lacks sequences known to be required for DNA binding and replication. Treatment of full-length large T with either V8 protease or chymotrypsin yields an N-terminal fragment of 36 to 40 kDa and a C-terminal fragment of approximately 60 kDa. This finding suggests a division of the protein into two domains. Proteolysis experiments show that the N-terminal domain does not have strong physical association with the rest of the protein. It also does not self-associate. A construct expressing only the N-terminal 259 amino acids is sufficient for immortalization. The independently expressed N-terminal domain is multiply phosphorylated, although at a lower level than the same region in full-length large T. The 259-residue protein binds to both pRb and p107 with somewhat lower efficiency than the full-length protein.

Wegener's granulomatosis with severe renal failure: clinical course and results of dialysis and transplantation.

Nine patients with Wegener's granulomatosis have developed chronic renal failure and undergone chronic hemodialysis and transplantation. These patients are all young (less than 43 years); all except one are male. They present with acute renal failure that resolves with hemodialysis and immunosuppression, but then slowly develop chronic renal failure in spite of adequate immunosuppression. On chronic dialysis no manifestations of Wegener's granulomatosis occur despite low or no immunosuppression in most of them. After transplantation the usual post-transplant immunosuppression regimen (azathioprine and prednisone) not only prevents rejection, but also controls the disease. In only one patient has it been necessary to change from azathioprine to cyclophosphamide because of recurrence.

Severe hypokalemia induced by hemodialysis.

During dialysis, it is assumed that the serum electrolyte levels asymptotically approach the concentration in the dialysate. In five patients, we observed an average 20% fall in serum potassium level, although the dialysate contained 42% more potassium than the predialysis serum. One patient had quadriplegia and near respiratory arrest as a complication of hypokalemia. The cause of the hypokalemia was a rapid shift of potassium from the extracellular to the intracellular space secondary to correction of acidosis. All patients entered dialysis with a history suggesting prolonged potassium loss, marked acidosis, and moderate hypokalemia; thus, the dialysate potassium concentration should be higher than normal, and frequent determinations of the serum potassium level should be performed. Therapy resulting in rapid correction of acidosis in uremic patients undergoing hemodialysis may cause large transcompartmental shifts of potassium. Potassium transfer across the dialysis membrane may be inadequate to compensate for such shifts, and life-threatening hypokalemia may occur.

Recovery from acute renal failure.

Acute tubular necrosis is the most common cause of acute renal failure making up two-thirds of such cases. Mortality is best correlated to basic disease. Surgery, particularly in the abdomen, carries an unusually sinister prognosis. The influence of age on outcome is controversial. Intensified dialysis, early reoperations, hyperalimentation, and possibly continuous dialysis and antibiotic barrage deserves close investigation as tools of improving survival. Almost all surviving patients recover renal function within 30 days and beyond two months recovery almost never occurs. Approximately 3% of the patients initially suspected of having acute tubular necrosis will need chronic hemodialysis indefinitely or have a transplant to regain renal function. The older patient seems to be more susceptible to this problem. Delayed recovery and chronic renal failure is unusual. High dose loop diuretic therapy and hyperalimentation with intravenous amino acids may shorten the time for recovery, although considerable controversy exists.

Time of death, recovery of renal function, development of chronic renal failure and need for chronic hemodialysis in patients with acute tubular necrosis.

We analyzed 432 patients with acute tubular necrosis, dialyzed at the University of Minnesota Dialysis Unit between 1968-1979. Only 135 patients or 31% survived. The median time to death was 5 days and to recovery of renal function was 12 days. Serum creatinine continued to fall for one month after the last dialysis and then stabilized. Ultimate serum creatinine level was directly related to age of patient but not duration of need for dialysis. One-fourth of the patients were left with moderate renal insufficiency (creatinine 1.5-3 mg/dl). Eight of 82 (10%) of the patients with long term (greater than 1 mo follow-up) had severe renal failure (creatinine over 3 mg/dl) and 4 other patients never recovered renal function but needed chronic hemodialysis. Acute renal failure is numerically important but not very time demanding on the capacity of dialysis units. The majority of the patients have no clinical problem of renal dysfunction if they survive their basic disease leading to acute tubular necrosis.

Treatment of intractable uremic pericardial effusion. Avoidance of pericardiectomy with local steroid instillation.

Forty-five patients with uremic pericardial effusion were treated with local instillation of nonabsorbable steroid through an indwelling pericardial drainage catheter and followed up from one to 54 months. In these patients previous intensive dialysis and other attempts at control of the effusions were unsuccessful. The average hospitalization for percutaneous therapy was eight days. An asymptomatic internal mammary artery fistula developed in one patient. Another had resolution of her pericardial effusion but not of associated pericardial pain. She subsequently underwent pericardiectomy (stripping), without resolution of her pain. One patient had a recurrence of her effusion six months after therapy. Complications of this technique are rare. The relatively noninvasive drainage and local instillation of a nonabsorbable steroid is almost universally effective.

Long-term dialysis and renal transplantation in lymphatic leukemia.

With increasing experience and skill with renal transplantation and dialysis, many disorders that were previously thought to contraindicate these procedures are no longer regarded as contraindications. We have previously reported that transplantation can successfully be performed in patients who have had malignant diseases if they seem to be cured after approximately 12 months. Although incurable malignancies have usually been regarded as absolute contraindications, successful dialysis and transplantation have been achieved in a patient with chronic lymphatic leukemia.