Adam L. Linton

Acute Interstitial Nephritis Due to Drugs: Review of the Literature with a Report of Nine Cases

Acute interstitial nephritis due to drugs commonly presents as acute renal failure and may be commoner than is presently realized. Drugs implicated include not only methicillin and other penicillins but also diuretics and nonsteroidal anti-inflammatory agents. The mechanism of injury likely involves an immunologic disturbance, possibly a delayed hypersensitivity reaction. Differential diagnosis from other causes of acute renal failure may be difficult, but coincident evidence of an acute allergic reaction may help, as may the detection of eosinophils in the urine or avid uptake of 67Ga by the kidneys. Definitive diagnosis may require renal biopsy, which will reveal normal glomeruli and a patchy but usually heavy interstitial infiltrate with lymphocytes, plasma cells, and eosinophils. Diagnosis of acute interstitial nephritis is important, because withdrawal of the offending agent will usually result in rapid improvement in renal function, and steroid therapy may reduce residual chronic renal damage.

Vasoactive Hormones in the Renal Response to Systemic Sepsis

The pathophysiology of renal dysfunction in generalized sepsis remains unknown. In this study, 24 hours after surgical induction of peritonitis in 20 volume-loaded sheep, three patterns of renal function were seen. In group 1 (n = 8), glomerular filtration rate (GFR) decreased by 70%, urine volume by 85%, absolute sodium excretion by 95%, and fractional sodium excretion by 83%. Group 2 (n = 4) exhibited similar sodium retention but GFR did not fall. Group 3 (n = 8) showed no change in GFR or urine volume and only minimally reduced sodium excretion. Mean arterial pressure fell 17% in group 1 only; central venous pressure, pulmonary capillary wedge pressure, and plasma volume were maintained at or above presepsis values in all groups. Cardiac index was either increased or unchanged, and renal plasma flow was maintained in all groups; there was thus no hemodynamic evidence to suggest volume contraction. Histologic examination showed only minor changes with no consistent pattern. Renal functional changes correlated with other manifestations of severe sepsis--GFR and sodium retention correlated significantly with increased cardiac index, decreased systemic vascular resistance, pulmonary arterial hypertension, leukopenia, hypoproteinemia, and hypoglycemia. All of these changes were most marked in group 1. In groups 1 and 2, plasma renin activity (PRA) increased and urinary kallikrein excretion decreased. PRA correlated inversely with GFR, urine volume, and sodium excretion; urinary kallikrein excretion correlated positively with urine volume and sodium excretion. Urinary excretion of 6-keto-PGF1 alpha was increased in groups 1 and 2 and correlated inversely with mean arterial pressure in group 1 animals. During sepsis, urinary thromboxane B2 excretion continued at presepsis values in all groups. The results suggest that unusual reciprocal changes in activity of the renin-angiotensin and renal kallikrein-kinin systems may play a role in the renal response to sepsis. PGI2 synthesis is increased and may affect systemic hemodynamics and renal function; the role of thromboxane A2 in this context is unknown.

Nephrotoxicity of High- and Low-Osmolality Contrast Media

Nephrotoxicity of radio-opaque contrast media (CM) is generally believed to involve toxic injury of proximal tubular cells. Measurement of urinary tubular enzyme excretion has been advocated as a sensitive marker of such toxic injury. It has been claimed that the new low-osmolality or nonionic CM reduce the incidence of nephrotoxicity but this remains uncertain. We studied 23 patients with normal renal function undergoing coronary angiography; patients were randomized into three groups receiving either diatrizoate (1,800 mmol/kg H2O), ioxaglate (600 mmol/kg H2O) or iohexol (850 mmol/kg H2O). Urinary excretion of a panel of enzymes increased significantly in all groups by 20 h (p less than 0.05 to less than 0.005). Alanine aminopeptidase excretion at 20 h was greater after the administration of high osmolality ionic CM than with the others but all three CM produced a similar pattern of enzyme excretion. No significant change in glomerular filtration rate was found in any group so the significance of the enzymuria remains uncertain.

The Renal Response Produced by Nonhypotensive Sepsis in a Large Animal Model

We describe an animal model of generalized sepsis, induced in the sheep by cecal perforation, which reproduces the high systemic flow and peripheral vasodilation seen in early human sepsis. Despite volume loading, animals demonstrate a fall in glomerular filtration rate, oliguria, low fractional sodium excretion, maintained urine osmolarity, and increased plasma renin activity. Histologically, kidneys show no consistent abnormality; overall the findings suggest volume contraction or hypoperfusion. This is contradicted, however, by maintained blood pressure and pulmonary capillary wedge pressure, increased cardiac output, and reduced peripheral resistance. Increased Fc lysozyme and low molecular weight proteinuria suggest tubular damage. These paradoxical observations are currently unexplained.

Patterns of Urinary Protein Excretion in Patients with Sepsis

Urine protein excretion patterns have been studied in 42 patients with sepsis and compared with that in 21 healthy controls. Patients with sepsis were shown to have highly significant increases in fractional clearances for beta 2-microglobulin, albumin, amylase and immunoglobulin G as compared with the controls. Analysis of the pattern of protein excretion demonstrates that the proteinuria is of the tubular rather than the glomerular type. There was no evidence that administration of aminoglycoside antibiotics contributed to the production of tubular proteinuria, and in particular these drugs did not appear to affect the excretion of beta 2-microglobulin.

Association between renal and sympathetic responses to nonhypotensive systemic sepsis

We investigated the association between plasma catecholamines and the renal response to nonhypotensive sepsis. Arterial plasma catecholamines were measured in 16 sheep, before and 24 h after surgical induction of peritonitis. Animals were volume loaded with lactated Ringers solution (8 L/24 h) before and after surgery; non became hypotensive. For analysis, animals were retrospectively divided into those with increased serum creatinine after 24 h of sepsis (group 1, n = 8) and those without (group 2, n = 8). Group 1 showed increased cardiac index and decreased systemic vascular resistance typical of severe sepsis, with decreased glomerular filtration rate (GFR), oliguria, sodium retention, increased plasma renin activity (PRA), decreased urinary kallikrein excretion, and increased urinary 6-keto-prostaglandin-F1 alpha excretion. Group 2 showed insignificant hemodynamic disturbance, and no significant renal response. Plasma catecholamines were equal in both groups at baseline. In group 1, there were uniform increases after 24 h in plasma norepinephrine (474 +/- 115 to 1183 +/- 158 [SEM] pg/ml; p less than .01) and plasma epinephrine (108 +/- 8 to 309 +/- 70 pg/ml; p less than .05). In group 2, neither plasma norepinephrine (343 +/- 59 to 330 +/- 56 pg/ml) nor plasma epinephrine (116 +/- 16 to 116 +/- 13 pg/ml) changed significantly. Plasma norepinephrine correlated inversely with GFR; plasma epinephrine correlated with PRA. The sympathetic nervous system may be involved in the renal response to nonhypotensive sepsis, both directly and via effects on other vasoactive hormone systems.

The Protective Effect of Thromboxane Synthetase Inhibition on Renal Function in Systemic Sepsis

To study the role of thromboxane in systemic sepsis and renal failure, peritonitis was induced surgically in 22 sheep, leading to local and systemic sepsis. A selective thromboxane synthetase inhibitor, U63,557A (Upjohn Co, Kalamazoo, MI) was given before surgery in five animals and 30 minutes after surgery in five animals. A typical picture of volume-loaded, normotensive, vasodilated septic shock developed in all animals. Twenty four hours after induction of sepsis, the control group showed a marked reduction in glomerular filtration rate (GFR), urine volume, and urinary sodium excretion. Pretreated animals showed no change in GFR and a smaller reduction in urine volume and sodium excretion. The posttreatment group showed no change in any parameters of renal function. Plasma renin activity, urinary TXB2 excretion, and urinary 6-keto PGF1 alpha excretion increased after 24 hours only in the control group. Urinary TXB2 excretion was reduced by 80% in animals given U63,557A before surgery. The results indicate a significant protective effect of U63,557A on renal function during septic shock, probably related to reduced thromboxane synthesis, with no apparent deleterious systemic effects. The results support a role for thromboxane in the pathogenesis of acute renal failure in systemic sepsis.

Early Hepatic Dysfunction in a Large Animal Model of Nonhypotensive Sepsis

Sepsis was induced in 12 sheep by cecal devascularization and perforation. Intravenous crystalloid was administered to maintain th e pulmonary capillary wedge pressure at preseptic levels. By 24 h there was a significant drop in albumin and alkaline phosphatase with increases in aspartate aminotransferase (AST), lactate dehydrogenase and bilirubin. By 48 h the alkaline phosphatase had returned to presepsis levels, the bilirubin continued to rise, the AST and lactate dehydrogenase had plateaued while the alhumin remained low. These biochemical alterations were confirmed by examining data from 25 sheer used in similar sepsis experiments. These data revealed that marked elevations in AST were associated with a higher central venous pressure and worse renal impairment, but there was no relationship with any other hemodynamic parameter, PO2, pH or serum lactate. Histologically these biochemical alterations were associated with extensive microvesicular fatty change at 24 h and centrilobular necrosis at 48 h. Electron microscopy revealed mitochondrial degeneration, hyperplasia of the smooth endoplasmic reticulum and intracellular cholestasis.

Fluid Overload in Acute Renal Failure

Amid the broad spectrum of patients who suffer acute reduction of renal function for a variety of reasons, there exists a group in whom fluid balance becomes one of the clamant problems of management. Fluid overload occurs frequently, particularly in patients with renal failure in the context of sepsis, liver disease, heart failure, or bums, where sodium retention may be part of the pathophysiological disturbance (1). The demahds of circulatory support and nutrition lead to the administration of much more fluid than the kidneys can excrete; and the patient may become so bloated as to resemble the “Mchelin man.” It is seldom easy to cope with this problem when using ordinary hemodialysis procedures, even with isolated ultrafiltration periods, because of hemodynamic instabilThese grossly edematous patients are usually first flogged with massive doses of diuretics, despite considerable evidence to suggest that they are seldom diureticresponsive, and that diuretics may adversely afkt renal function. The emergence of effective techniques to deal with fluid retention would be of great value in intensive care units, and a number of possible contenders have appeared.