Multiaxial diagnosis and the psychosomatic model of disease.

Current medical diagnosis reflects the prevailing biomedical model of disease. A need exists for a new system of diagnosis that, instead, is based on the psychosomatic model. This article presents an analysis of the underlying framework of the multiaxial system developed in recent years for diagnosis in Psychiatry that indicates its relevance to the psychosomatic model. It goes on to describe a new multiaxial system of diagnosis derived from that analysis that allows diagnosis to be stated as a process of adaptation in the environment, which includes biological, psychological, and social factors. The practical application of this system to the broad range of medical illnesses is explained and illustrated. This multiaxial approach represents a first step toward, and a stimulus for, the development of a better diagnostic system that can provide one basis for the crucial transformation of medical care to reflect the psychosomatic model of disease.

Renal and extrarenal considerations in high-dose mannitol therapy.

It is well recognized that the large doses of mannitol used in treating cerebral edema alter extracellular fluid (ECF) volume, osmolality, and composition to a degree which, under some circumstances, can lead to acute renal failure, cardiac decompensation, and other difficulties. It is less well appreciated that the patient's body habitus, age, total body water content relative to body weight, pretreatment plasma sodium concentration and plasma osmolality, and the presence of edema or ascites also can influence the degree of ECF change and the rate of mannitol excretion to a significant degree. Here, we show how these changes occur and the way in which their magnitude can be predicted prior to therapy so as to minimize the risk of an adverse result.

Renal epithelial amino acid concentrations in mercury-induced and postischemic acute renal failure.

The concentration of 18 alpha-amino acids (AAs) in plasma and renal cortical cell water were measured 3 or 24 hr after 1 hr of unilateral renal artery clamping or 24 or 48 hr after 15 mg/kg body weight HgCl2 injection sc as a test of epithelial integrity. Cellular glycine (Gly), hydroxyproline (Hpr), ornithine (Orn), phenylalanine (Phe), serine (Ser), and tryptophan (Trp) concentrations were depressed 24 hr after HgCl2 (p less than 0.05), but the remaining 12 AAs were not distinguishable from control despite the presence of severe renal failure. ARginine (Arg), glutamic acid (Glu), and valine (Val) also were decreased (P less than 0.05) 24 hr later, but concentrations of half of all measured AAs were still normal. Cellular alanine (Ala), Arg, Glu, Gly, Phe, and Ser concentrations were decreased 3 hr after ischemia, p less than 0.05, but 12 AAs were unchanged and only Arg, Phe, Ser, and threonine (Thr) were reduced 24 hr after ischemia was reversed. Concentrations of even the most affected AAs remained notably higher than in plasma in both forms of acute renal failure (ARF). Total loss of AAs from a small proportion of tubular cells would be hidden by essentially normal concentrations in the rest, and such losses may well have occurred. Unless cellular AAs in ARF are almost completely bound, however, the well-maintained cell:plasma AA concentration ratios indicate that cellular energetics were adequate for AA uptake and that epithelial permeability to AAs in the vast majority of cells was not greatly disturbed. Such findings suggest that most of the epithelium, although seriously damaged, had remained viable.

Glomerular hemodynamics in established glycerol-induced acute renal failure in the rat.

The glomerular dynamic correlates of failed filtration were studied in volume replete rats with established glycerol-induced acute renal failure (ARF). Over one-half of all nephrons formed virtually no filtrate, while the single nephron glomerular filtration rate (SNGFR) of fluid-filled nephrons, measured at the glomerulotubular junction to preclude the possibility of covert tubular leakage, averaged one-sixth of control (P less than 0.001). Even that low mean value was elevated by a few nephrons with a near normal SNGFR. Renal failure thus reflected both total filtration failure in the majority of nephrons and massively reduced filtration in most of the remainder. Glomerular capillary pressure (Pg) averaged some 14 mmHg below control (P less than 0.001), whereas the arterial colloid osmotic and Bowman's space pressures were not significantly altered. Renocortical and whole kidney blood flow were also unchanged. Marked internephron functional heterogeneity precluded estimates of the ultrafiltration coefficient. However, the fall in SNGFR correlated well with the markedly depressed Pg and afferent net filtration pressure (delta PnetA, P less than 0.001), which in turn were caused by increased preglomerular resistance and a reciprocal fall in efferent arteriolar resistance. This complex change in intrarenal resistances was largely, if not entirely, responsible for failed filtration in this ARF model.

Does the ultrafiltration coefficient play a key role in regulating glomerular filtration in the rat.

Various experimental maneuvers, hormones, and pharmacological agents are reported to exert their effects on glomerular filtration largely or exclusively by changing the ultrafiltration coefficient (Kf) of the filtration barrier. In light of a number of uncertainties discussed in this review, however, it is by no means certain that the Kf actually does play this central role in the physiological regulation of glomerular function.

Microcomputer simulation as an aid in analyzing data and teaching the principles of glomerular dynamics.

This report describes a simple program, written in BASIC language, that closely emulates a previously published network thermodynamic model of glomerular dynamics. While the latter requires the SPICE 2 simulation program and a mainframe computer for its execution, the present program operates on any IBM-compatible microcomputer. It has equal utility as an aid in the interpretation of laboratory studies of glomerular dynamics and as a tool for teaching the intricacies of the control of glomerular function. The program is available in 'user friendly' format that obviates the need for any expertise in the use of computers.

Glomerular hemodynamics in mercury-induced acute renal failure.

As manifest by tubular collapse and the virtual absence of flow into the glomerulotubular junction (GTJ), filtration in most nephrons (SNGFR) of rats poisoned with 9 mg/kg body wt HgCl2 16 to 28 hours earlier was virtually absent. Arterial colloid osmotic pressure (COPA) and Bowman's space pressure (PBS) were modestly depressed (P less than 0.05 or below), and mean blood pressure was reduced from 115 +/- 2 mm Hg (SEM) to 97 +/- 1 mm Hg (P less than 0.001). Glomerular capillary hydraulic pressure (Pg), 25.6 +/- 1.3 mm Hg was some 24 mm Hg lower than control (P less than 0.001) and yielded a net afferent effective filtration pressure (Pnet) of 4.1 +/- 1.2 mm Hg. Excluding three rats with values greater than 10 mm Hg, Pnet averaged 2.0 +/- 0.9 mm Hg (N = 17 rats) versus 20.0 +/- 1.8 mm Hg in controls (N = 10, P less than 0.001), the former being statistically almost indistinguishable from 0 mm Hg and barely able to support any filtration. This decrease in Pg was caused by a major increase in preglomerular resistance (RA) and a reciprocal fall in efferent arteriolar resistance (RE), the RA/RE ratio of 7.2 +/- 0.8 being fourfold higher than control (P less than 0.001). Renocortical blood flow was not different from control (P greater than 0.2). A wide spread of Pg values in individual glomeruli and the absence of tubular flow despite the appearance of i.v. injected lissamine green in a quadrant of surface glomeruli suggested the possibility of a greatly increased, glomerular capillary resistance. It is concluded that reciprocal changes in RA and RE are the immediate cause of filtration failure in this form of ARF and that, in the virtual absence of filtration, tubular leakage can play no important role. Since PBS was depressed in both the developmental and established phases of ARF, tubular obstruction appears to play no direct role in the pathogenesis of this particular model of murine acute renal failure.

Effects of intra-animal nephron heterogeneity on studies of glomerular dynamics.

Quintuplicate determinations of the parameters measured in studies of glomerular dynamics revealed that the intra-animal coefficients of variation for Bowman's space and star vessel pressures, nephron filtration rate, and filtration fractions were 54 to 72% larger than the corresponding interanimal coefficients of variation; those for glomerular capillary pressure were more nearly equal. With a net efferent filtration pressure (delta PE) of 10.6 +/- SEM 1.9 mm Hg, the rats were far from filtration pressure equilibrium and the calculated ultrafiltration coefficient (Kf) of 2.1 +/- SEM 0.2 nl/min X mm Hg was lower than in many other studies. Statistical analysis revealed that the precision of estimates of both the measured and the derived parameters in glomerular dynamic studies is affected appreciably by ignoring the intra-animal effect. The importance of the intra-animal variance in glomerular dynamic studies is greatest when only one or two samples of each measured parameter are obtained in every rat (k = 1 or 2) and least when k is large. Triplicate sampling provides combined SEMs that are not greatly larger than those obtained with k = 5, however, and offers the greatest economy in studies of glomerular dynamics. The number of animals required to provide values with delta PE and Kf that are within +/- 20% of the "true" values is rather large.

An alternate method for estimating efferent arteriolar plasma colloid osmotic pressure.

The colloid osmotic pressure (COP) of efferent arteriolar plasma in glomerular dynamic studies generally is estimated from the measured protein concentration (CE) while the nephron filtration fraction (SNFF) is derived from CE and the systemic plasma protein concentration (CA) according to the equation SNFF = (1 - CA/CE). Estimates of both SNFF and COPE are quite sensitive to small errors in protein measurement, however, with a putative coefficient of variation of +/- 5% in protein measurement at a typical SNFF of 0.33, for example, providing an uncertainty (i.e., +/- SD) of +/- 14% in the SNFF estimate and +/- 2.4 mmHg in the estimated COPE value. In this study, we evaluated in vitro the precision with which the COP of plasma samples can be estimated after ultrafiltration by coupling direct oncometry of native plasma with isotopically measured filtration fractions derived employing nanoliter and microliter volumes and applying a modification of the equation of Ladegaard-Pedersen (Scand. J. Clin. Lab. Invest. 23: 153-158, 1969). The measured and estimated oncotic pressures were then compared. The mean differences between theoretic and measured COP values at filtration fractions of less than 0.1, 0.1-0.2, 0.2-0.3 and greater were: -0.4 +/- 0.8 (SE) (n = 22); 1.8 +/- 1.1; 3.9 +/- 1.0; and 6.0 +/- 1.7%, respectively. It is concluded that the coupling of direct oncometric measurement of arterial plasma colloid osmotic pressure with isotopically determined filtration fractions provides a satisfactory estimate of COPE that is suitable for studies of glomerular dynamics.

Hemodynamic basis for human acute renal failure (vasomotor nephropathy).

Oliguric acute renal failure in man is characterized by intense outer cortical vasoconstriction and a marked increase in preglomerular resistance. The degree of preglomerlar resistance change needed to cause the expected 50 to 80 percent fall in blood flow far exceeds the level that would totally abolish filtration. By contrast, equal 3.0-fold increases in both pre- and postglomerular resistance provide this same degree of ischemia but leave filtration very well maintained. Such a scenario seems unlikely, however, since it would entail a mere 15 to 25 percent decrease in preglomerular resistance vessel caliber rather than the extreme attenuation observed. By contrast, there are reasons to believe that preglomerular constriction may be accompanied by postglomerular vascular relaxation. In sum, unless cortical ischemia reflects precisely matched increases in pre- and postglomerular resistances, filtration failure is inevitable in human vasomotor nephropathy.

Theoretical analysis of pathogenetic mechanisms in experimental acute renal failure.

A network thermodynamic model of glomerular dynamics has been employed to determine the degree of change in individual glomerular vascular resistances, hydraulic conductivity and proximal tubule pressure that, singly or in concert, could lower GFR to the degree expected in experimental acute renal failure (ARF). In both the rat and dog, the analysis shows that filtration failure is not achieved until preglomerular resistance (RA) is increased at least twofold or postglomerular resistance (RE) is decreased by 74% or more with all other determinants held at control values. Tubular obstruction alone will not provide failed filtration until tubule pressure is increased to 30 to 40 mm Hg in the rat and 44 mm Hg in the dog. A much smaller change in tubular pressure can contribute greatly to the development of filtration failure, however, when occurring in association with major change in individual vascular resistances. Glomerular capillary resistance must be increased to a value more than twice the normal sum of RA and RE (greater than fivefold in the dog), and glomerular capillary hydraulic conductivity lowered to below 5% of control, as isolated changes, before full filtration failure is approached. There is no reason to believe that most forms of ARF relate to only a single abnormality, however, and the effect of concomitant changes in individual resistances, hydraulic conductivity and proximal tubule pressure on glomerular filtration and blood flow is presented in the text and figures. A possible mechanism by which altered blood viscosity at the efferent arteriole may contribute to ARF is discussed and quantified. The degree of change in any determinant required to exert a given effect on filtration is independent of etiology, thus rendering the results of this analysis equally valid for any other pathological event which causes a significantly reduced GFR in the rat or dog.

An analysis of glomerular dynamics in rat, dog, and man.

A network thermodynamic model was utilized to assess similarities and dissimilarities in the predicted response of human, rat, and dog glomeruli to change in the independent variables regulating glomerular filtration. The analysis in rat and dog employed basal values reported in the micropuncture literature. The analysis in man was based on a calculated total nephron vascular resistance (Rt) of 1.2 X 10(10) dyne sec cm-5 with a range of pre- (Ra) and postglomerular (Re) resistances and capillary hydraulic conductivities (Kf) that would provide a nephron blood flow (GBF) of approximately 550 nl/min and single nephron filtration rate (SNGFR) of approximately 65 nl/min. The maximal putative value for Ra/Re in man was approximately 1.1, a ratio demanding a Kf greater than 20 nl/min mm Hg to obtain the required SNGFR. Solitary changes in Ra and Re, glomerular capillary resistance, proximal tubule pressure, serum protein concentration, total vascular resistance, and Kf were induced and the resultant effect on SNGFR was examined in the three species. The relationship between changes in individual resistances, glomerular blood flow, glomerular filtration, and glomerular capillary pressure also was assessed. The patterns of response in man and dog, determined by the model, were remarkably similar and distinct from those of the rat in many regards. Except when the maximal possible Ra/Re ratio is assumed for man, filtration pressure equilibrium was not found; plasma flow dependence of SNGFR was not evident in rat, dog, or man. The differences in SNGFR control predicted for the rat, on the one hand, and dog and man on the other may have distinct physiologic significance.