John D. Conger

Interventions in clinical acute renal failure: What are the data?

A variety of therapeutic approaches have been used both to prevent acute ischemic and nephrotoxic renal injury and to improve renal function and reduce mortality once acute renal failure (ARF) has developed. Unfortunately, there have been few rigorous assessments of the efficacy of these treatment interventions. The reasons for the lack of abundant critical data regarding treatment effects in ARF are several. First, ARF is a functional disorder. It has a spectrum of etiologies, occurs in a variety of clinical settings and varies in severity. Second, selected endpoints of treatment success vary and co-morbid factors frequently determine outcome. Third, it had been difficult to carry out prospective controlled studies in a disorder in which the mortality rate approaches 50%. In this review, an effort was made to analyze the available literature with a primary focus on controlled studies to determine significant prophylactic and treatment effects of various interventions in ARF. Three endpoints of therapy (change in renal function, change in course of azotemia, and change in mortality) were examined for pharmacologic agents. Changes in course of azotemia and mortality were assessed in evaluating different dialysis modes. Effect on nitrogen balance, change in course of azotemia, and change in mortality were used as endpoints to determine treatment effects of different nutritional regimens. When weight was given to prospective controlled studies, some insights emerged as to treatment interventions that are most likely to have beneficial effects in specific settings of ARF. Among pharmacologic agents, mannitol appears to have a positive prophylactic effect in kidney transplantation. There are no other significant beneficial effects of diuretics for prophylaxis or as treatment in early or established ARF. Of vasoactive agents, there is a relatively small amount of data suggesting that diltiazem may have a positive prophylactic effect in kidney transplantation, and dopamine possibly is beneficial early in the evolutionary phase of ARF. Atrial natriuretic peptide and calcium channel blockers may have beneficial effects in established disease. No other pharmacologic interventions are supported by substantial data. At best, the results are equivocal regarding the use of early and vigorous dialysis in ARF. However, there are recent impressive data indicating that the use of biocompatible membranes is efficacious in recovery and survival. There is no clear evidence that one form of nutritional therapy has advantages over others, but some level of amino acid supplementation in addition to basic energy replacement is supported by the overall data.

Acute Uric Acid Nephropathy

Uric acid, as the end-product of purine metabolism in humans, presents a clinical problem because of its relative insolubility, particularly in the acid environment of the distal nephron of the kidney. As a result, states of enhanced purine catabolism increase the urate load on the kidney, leading to intrarenal precipitation. Major causes of increased purine metabolism are malignancies with rapid cell turnover, such as leukemias and lymphomas, and the added acceleration of cell lysis that occurs with chemotherapy and radiation. Serum urate levels rise rapidly, and acute renal failure occurs as a consequence of tubular deposition of urate and uric acid. The keys to the diagnosis of acute uric acid nephropathy are the appropriate clinical setting of increased cell lysis, oliguria, marked hyperuricemia, and hyperuricosuria. A urinary uric acid-to-creatinine ratio greater than 1 helps to distinguish acute uric acid nephropathy from other catabolic forms of acute renal failure in which serum urate is elevated. Preventive treatment involves pharmacologic xanthine oxidase inhibition with allopurinol and alkaline diuresis. Occasionally, acute renal failure occurs despite allopurinol because of the tubular precipitation of the precursor metabolites, such as xanthine, which accumulate with xanthine oxidase inhibition. Dialysis therapy may be required both to correct azotemia and to reduce the body burden of urate. Hemodialysis is preferred because it can achieve greater clearance than other dialysis modes.

Is parenteral nutrition therapy of value in acute renal failure patients

A patient with oliguric acute renal failure (ARF) following mitral valve surgery is presented. The patient was treated with parenteral nutrition and hemodialysis. While the patient survived, there were several complications of nutrition therapy. In this review, the benefits, risks, and uncertainties regarding parenteral nutrition in ARF are considered. First, the differences in metabolism in complicated and uncomplicated acute uremia are discussed. The important roles of alterations in intermediary metabolism and of proteases in the catabolism of ARF are emphasized. The historical basis of parenteral nutrition treatment in ARF is reviewed. The results are divided regarding the relationship among nutritional support, improvement in renal function, and enhanced patient survival. A critical analysis of nitrogen metabolism results reported in the literature does not convincingly support the effectiveness of parenteral nutrition formulae in generating positive nitrogen balance. The complications of parenteral nutrition therapy are outlined. In light of the uncertain efficacy and recognized risks of prolonged parenteral nutrition, a rationale for approaching therapy is presented that is based on the estimated metabolic stress and protein-energy requirements of the individual ARF patient.

Glomerular and Tubular Factors in Urine Flow Rates of Acute Renal Failure Patients

Distinguishing between oliguric and nonoliguric acute renal failure (ARF) has clinical relevance. However, there is a paucity of data regarding the pathophysiologic basis for variations in urine flow rates in ARF. This study was designed to determine whether differences in residual levels of glomerular filtration rate (GFR) or differences in tubular reabsorption of filtered solutes and H2O accounted for the variations in urine flow rates among ARF patients. Twenty-five patients with ARF of 3 to 6 days duration having ischemic and nephrotoxic etiologies, increasing serum creatinines of more than 0.7 mg/dL/d, urine sodium concentrations and fractional excretions of sodium (FENa) of more than 20 mEq/L and more than 1%, respectively, 12 hours after stopping diuretics and urine sediments consistent with acute tubular necrosis were studied. Urine and serum collections were made over an 8-hour period to determine creatinine clearance (Ccr), filtered osmolar load, urine to serum creatinine ratio (U/Scr), urine to serum creatinine osmolality (U/Sosm), and FENa. These were compared with urine flow rates. Creatinine clearance was validated as an estimate of GFR in ARF with simultaneous inulin clearances x 12 measurements (r = 0.935, P < 0.001). Residual Ccr was strongly correlated with urine flow rate (r = 0.857, P < 0.001), as was filtered osmolar load (r = 0.810, P < 0.001). However, the latter relationship was totally dependent on Ccr. There was no correlation between U/Scr, U/Sosm, or FENa and urine flow rates. It is concluded that the residual level of GFR is the primary determinant of variations in urine flow rate in patients with ARF.

Intrarenal infusion of gallopamil in acute renal failure : a preliminary report

SummaryIn order to ascertain the protective role of a potent calcium entry blocking agent in human acute renal failure, 10 patients were randomised to treatment with either intrarenal gallopamil plus intravenous furosemide (frusemide) 0.5 mg/kg/h for 24 hours, or furosemide alone. Gallopamil was infused into each kidney at the rate of 40 to 80 µg/min for 4 hours. During 7 days of post-treatment follow-up, the gallopamil treatment group exhibited a significantly higher urine output [257 ml/h vs 81 ml/h (p < 0.001) after 2 days, and 199 ml/h vs 120 ml/h (p < 0.005) after 7 days] and creatinine clearance [20 vs 4 ml/min (p < 0.005) after 2 days, and 38 vs 14 ml/min (p < 0.001) after 7 days] than the furosemide-only control group. Furthermore, gallopamil treatment accelerated the decline of serum creatinine after renal failure and reduced the requirement for dialysis.Although patient numbers were small, these results indicate that the addition of intrarenal gallopamil to intravenous furosemide treatment enhances the recovery of renal function after acute renal failure.

The Protective Mechanism of Thyroidectomy in a Rat Model of Chronic Renal Failure

Selective thyroidectomy (Tx) has been shown to attenuate proteinuria and disease progression in models of chronic renal failure (CRF). In this investigation, four groups of Munich-Wistar rats were studied to determine if glomerular dynamics or another renal metabolic consequence of Tx was responsible for the protective effect as measured by 24-hour protein excretion (UPROT). The groups were TxT4, thyroxine-replaced Tx rats with five-sixths nephrectomy; Tx, Tx rats not receiving replacement thyroxine with five-sixths nephrectomy; TxI, Tx rats not receiving replacement thyroxine with five-sixths nephrectomy that were given continuous intraperitoneal isoproterenol to restore systemic and renal hemodynamics; and TxT4(C), two-kidney Tx rats receiving replacement thyroxine that served as normal controls. Five-sixths nephrectomy was carried out 2 weeks after Tx, and experiments were carried out 1 week later. Serum T4 was profoundly reduced and there was failure to gain weight in Tx and TxI rats, despite similar protein intakes in all groups. Cardiac output was reduced in Tx, but was similar in TxI to levels in TxT4 rats. Whole-kidney glomerular filtration rate was lower in Tx, at 0.145 +/- 0.052 mL/min (P less than 0.05), but similar in TxI (0.305 +/- 0.147 mL/min) to that in TxT4 rats (0.317 +/- 0.135 mL/min). Twenty-four-hour urinary protein, which was 129 +/- 57 mg in TxT4, was reduced in Tx to 9 +/- 3 mg (P less than 0.01) but restored in TxI to 89 +/- 30 mg, a level similar to that in TxT4.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial Glomerular and Tubular Dynamics in Thyroidectomized Rats With Remnant Kidneys

Serial measurements were performed in Munich-Wistar rats with five-sixths nephrectomy that had undergone prior selective thyroidectomy (Tx group) or thyroidectomy with thyroxine replacement (TxT4 group) to determine the effects of Tx on glomerular and tubular dynamics in relation to Tx attenuation of renal failure progression. At 1 week, inulin clearance rates (Cin) in TxT4 and Tx rats were 0.367 +/- 0.171 and 0.120 +/- 0.036 mL/min, respectively, different at P less than 0.01. Corresponding single-nephron filtration rate (SNGFR), glomerular plasma flow (QA), glomerular transcapillary hydraulic pressure (delta P), and proximal tubular reabsorption (Jv) were all reduced in Tx compared with TxT4 rats (P less than 0.01). Protein excretion (UPROT) was 151 +/- 40 in TxT4 rats, and 9 +/- 5 mg/d in Tx animals. Glomerular mesangial matrix expansion and focal tubulointerstitial changes were more frequent in TxT4 than Tx rats. By 4 weeks, Cin, SNGFR, QA, glomerular ultrafiltration coefficient (Kf) and Jv were similar in Tx and TxT4. Only glomerular capillary pressure (PGC) remained lower in Tx rats (35 +/- 3 v 50 +/- 3 mm Hg in TxT4, P less than 0.001). UPROT was 161 +/- 24 in TxT4 and 17 +/- 12 mg/d in Tx rats. While 7% +/- 4% of glomeruli showed focal sclerosis in TxT4 rats, there was none in the Tx group. Maximal glomerular planar area increased between 1 and 4 weeks in the TxT4 group, but not in the Tx group. However, this measurement was not significantly different between TxT4 and Tx glomeruli at 1 or 4 weeks. Minimal focal tubulointerstitial changes were found in TxT4, but there were not progressive from those observed at 1 week. The reduced PGC at 1 week was the result of a disproportionately greater increase in afferent (RA) than efferent arteriolar resistance (RE) in Tx rats (P less than 0.025); however, at 4 weeks, both RA and RE had decreased to values identical to those in TxT4 animals and the lower PGC in Tx rats was the result of a reduced mean arterial pressure. In conclusion, a reduced PGC was the sole functional correlate of decreased proteinuria and glomerulosclerosis afforded by Tx in this partial nephrectomy model. Suppression of either nephrectomy-related hypertrophy or tubulointerstitial injury by Tx could not be excluded as at least partially protective factors.

Effects of Natriuretic Peptides in Acute Renal Failure

The natriuretic effects of an extract of mammalian atrial myocytes was first reported by de Bold et al. (1) in 1981. This substance was subsequently characterized as a polypeptide. The basic structure of the precursor molecule contains approximately 150 amino acids (152 amino acids in humans and rats) (2). The active portion of the polypeptide is the COOH terminus which contains approximately 25 amino acids (28 amino acids in humans) and a cys-cys disulfide bond (3). There are several natural and synthetic variations of the active peptide component. The primary stimulus to atrial natriuretic peptide (ANP) synthesis and release is distention of the atria where storage granules have been identified. Infusion of normal saline into human volunteers increased plasma ANP twofold from basal levels of less than 25 pg/mL (4). Shenker et al. (5) found that plasma ANP levels were elevated in edematous states that involved increased intravascular volume and atrial enlargement such as congestive heart failure. However, plasma ANP in edematous states not involving atrial stretch (cirrhosis, nephrotic syndrome) has not been found consistently to be increased. In addition to atrial enlargement, endothelins have been found to be potent direct stimuli of cardiac ANP release (6). Atrial natriuretic peptide has a relatively short plasma half-life of approximately five minutes. Clearance receptors are located primarily in the lung, liver and kidney (7). Neutral endopeptidase is the principal ANP degradative enzyme in these tissues (8). Natural and synthetic atrial natriuretic peptides cause dose-dependent reductions in systemic arterial pressure. The mechanism involves both peripheral vasorelaxation and a reduction in cardiac output (9, 10). The magnitude of arterial pressure reduction is dependent upon the state of basal vascular tone. The vasorelaxing effect of ANP is greater when there is an increase in peripheral vascular resistance (1 1, 12). Atrial natriuretic peptide has been shown to inhibit both secretion and activity of the renin-angiotension-aldosterone (13) and adrenergic nervous systems (14), as well as that of vasopressin (15) and endothelin-1 (16).