Molecular and cell biology of acute renal failure: new therapeutic strategies.

Acute renal failure (ARF) commonly occurs in critically ill patients. Despite improved dialysis techniques and recent advances in intensive care medicine, mortality from this condition remains unacceptably high. Increased understanding of the factors that mediate cellular injury, such as adenosine triphosphate depletion, intracellular calcium accumulation, and generation of reactive oxygenation species, as well as those that mediate recovery, such as locally produced and systemically released growth factors, provide fresh insights that can be used to develop new strategies to limit renal damage after acute insults and speed the repair process. Exogenous administration of growth factors, adenine nucleotides, and thyroxine, each of which can facilitate recovery of experimental ARF, in addition to factors yet to be identified, is a potentially exciting new therapeutic strategy to improve survival of patients with this condition.

Unilateral renal papillectomy via laser or incisional techniques: chronic functional effects in the dog.

OBJECTIVE: To determine if selective renal papillectomy would impair urinary concentrating ability, thereby decreasing urinary calcium concentration. METHODS: Left papillectomy was performed in dogs using either incisional (n = 6) or Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (n = 5) techniques. Split renal function studies were then performed four months postoperatively to determine the effect on multiple parameters including inulin and para-aminohippurate (PAH) clearance, free water reabsorption, and calcium concentrations. Partially infarcted kidneys (n = 6) were evaluated in a similar fashion to determine the role of impaired glomerular filtration rate (GFR) in the observed concentrating defect occurring after papillectomy. RESULTS: Papillectomized kidneys demonstrated impaired free water reabsorption, resulting in a decreased urinary osmolality and an increased fractional excretion of water. Osmolar clearance [Na+] and Na+ excretion were unaffected by papillectomy, whereas [Ca++] was significantly reduced. While a slight defect in free water reabsorption existed following partial infarction, urinary osmolality was only minimally decreased, fractional excretion of water was unchanged, and Na+ excretion was decreased. CONCLUSIONS: The concentrating defect induced by papillectomy via either sharp excision or laser ablation is due to loss of medullary tissue and is greater than the defect resulting from impaired GFR, which is presumably due to decreased medullary solute delivery and increased flow of water in remaining nephrons. Since the physiologic consequences of papillectomy (formation of less concentrated urine with decreased [Ca++]) have potential clinical applicability, further study of this concept is warranted.

Diuretics and cation transport in hypertensive blacks.

Thiazide diuretics are particularly efficacious in the treatment of hypertension in blacks. A number of observations suggest that many hypertensive blacks have features consistent with a status of "corrected" volume expansion. Our studies, as well as those of other investigators, show that the Na,K pump is inhibited in leucocytes and erythrocytes of blacks with essential hypertension. This observation is also consistent with the concept of volume expansion in hypertensive blacks, since the Na,K pump is inhibited in many forms of experimental volume expansion, including the administration of salt in normal humans. We postulate that the efficacy of thiazide diuretics may be related to their ability to stimulate the Na,K pump. We present data obtained in 13 black hypertensive men in whom Na efflux, and Na,K-ATPase in the erythrocyte rose significantly after 7 days of treatment with hydrochlorothiazide, 50 mg/day. Diuretic therapy may indirectly result in reduced intracellular calcium in the vascular smooth muscle.

Stimulation of erythrocyte and renal Na+,K+-adenosine triphosphatase activity by antidigoxin antibody in normal rats.

1. A circulating ouabain-like factor which inhibits the Na+,K(+)-pump has been implicated in volume-expanded states. To assess the role of this putative factor in normovolaemic rats, we measured erythrocyte and renal Na+,K(+)-adenosine triphosphatase activity after the infusion of a mixture of high-affinity digoxin-binding Fab fragments (Digibind) capable of removing digoxin from pump sites. 2. Compared with either saline (vehicle) or sheep immunoglobin G, infusion of the antidigoxin antibody caused a moderate increase of Na+,K(+)-adenosine triphosphatase activity in the erythrocyte (saline 348 +/- 12; immunoglobulin G 339 +/- 16; antidigoxin antibody 432 +/- 22 nmol h-1 mg-1; P less than 0.005 by analysis of variance) and a larger increase in the renal cortex (saline 9.7 +/- 0.9; immunoglobulin G 9 +/- 1.4; antidigoxin antibody 24.3 +/- 1.8 mumol h-1 mg-1; P less than 0.0005 by analysis of variance) without a change in blood pressure. 3. These results are consistent with the presence of a digoxin-like inhibitor of the Na+,K+-pump in normal rats.

Severe pulmonary hypertension with diffuse smooth muscle proliferation of the lungs. Pulmonary tuberous sclerosis?

A 49-year-old man with normal intelligence and no cutaneous lesions had symptoms and signs of cor pulmonale. The chest roentgenogram showed an interstitial pattern. Hemodynamic studies revealed increased pulmonary arterial and wedge pressures. The patient died in shock, and the postmortem findings were a diffuse smooth muscle proliferation in the lungs as the cause of the pulmonary hypertension. We presume that this is a form of pulmonary tuberous sclerosis of which few cases are reported with such severe pulmonary hypertension as shown by our measurements.