Prostaglandins inhibit renal ammoniagenesis in the rat.

We describe the inhibitory effect of prostaglandins (PGs) on in vivo rat renal ammonia synthesis. The influence of systemic pH upon urinary PG excretion and ammoniagenesis was also investigated. Finally, PG production by incubated rat renal cortical slices was suppressed to investigate the PG-ammonia interplay in the absence of changes in renal blood flow, glomerular filtration rate, ambient electrolyte concentrations or extrarenal hormonal factors. In vivo ammonia synthesis doubled and PG excretion fell by 44% in normal rats, after intravenous administration of 1 mg/kg of meclofenamate. Higher doses of meclofenamate further augmented ammonia production and further reduced PG excretion. PG depletion was also associated with an increase in fractional excretion of ammonia (FENH3) that was independent of changes in urine flow rate or pH. Acute metabolic acidosis (AMA) increased total ammonia synthesis but also stimulated PG production. Administration of meclofenamate to rats with mild AMA markedly reduced urinary PG excretion, further augmented ammonia synthesis, and significantly increased the FENH3. Inhibition of stimulated PG synthesis during severe AMA did not increase ammoniagenesis or FENH3. Acute metabolic alkalosis did not alter production of PGs or ammonia, but reduced the FENH3 by 42%. Meclofenamate nearly normalized the FENH3 but stimulated synthesis to a lesser degree than was seen in nonalkalotic rats that received meclofenamate. Inhibition of PG synthesis in incubated rat renal cortical slices also stimulated ammoniagenesis. Conversely, stimulation of PG synthesis decreased ammonia production and acidification of the incubation medium increased prostaglandin F2 alpha production. Thus, in vitro findings support the in vivo results. We conclude that PGs inhibit ammonia synthesis in normal rats and in those undergoing mild AMA. Severe acidosis overrides this inhibitory effect of PGs, whereas metabolic alkalosis suppresses the stimulatory effect of PG synthesis inhibition.

The pathophysiology of acid-base changes in chronically phosphate-depleted rats: bone-kidney interactions.

Acid-base disturbances may develop secondary to the changes in renal tubular function and bone dynamics which attend phosphate depletion (PD). This work characterizes the acid-base status of rats fed a low phosphate diet. After 18 days, PD rats had marked calciuria (pair-fed controls: 0.3 +/- 0.2; PD 32.2 +/- 2.5 mueq/h; P less than 0.001), severe bicarbonaturia (controls: 0; PD 17.6 +/- 0.2 meq/h; P less than 0.001), and negative net acid excretion (controls: 44.5 +/- 2.9; PD: --6.6 +/- 2.5 meq/h; P less than 0.001), but plasma pH, HCO3, and PCO2 were equal in both groups. After 45 days, plasma HCO3 fell to 21.1 +/- 0.9 meq/liter in PD (controls: 23.6 +/- 0.5 meq/liter; P less than 0.05), while bicarbonaturia (controls: 0.4 +/- 0.2; PD: 3.8 +/- 1 mueq/h; P less than 0.02) and calciuria were present but diminished. These data suggested the coexistence of bone HCO3 mobilization and renal HCO3 wasting in PD. To test this thesis, bicarbonaturia was eliminated by nephrectomy. 24 h later plasma HCO3 was higher in PD rats (controls: 19.3 +/- 0.02; PD: 22.6 +/- 0.8 meq/liter; P less than 0.05), consistend with the presence of extrarenal HCO3 production. After inhibition of bone resorption with colchicine (1 mg/kg), plasma HCO3 decreased to 16.8 +/- 0.6 meq/liter in PD rats (controls): 26.4 +/- 1 meq/liter; P less than 0.001) while bicarbonaturia persisted. These data indicate that the plasma HCO3 in PD is the net result of renal HCO3 wasting and bone HCO3 mobilization. These combined effects maintain normal blood HCO3 initially (18 days) but with time (45 days), bone resorption diminishes and the acidifying renal tubular defect predominates.

Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat.

To define the interplay of glomerular hypertension and hypertrophy with mesangial extracellular matrix (ECM) deposition, we examined the effects of glomerular capillary distention and mesangial cell stretching on ECM synthesis. The volume of microdissected rat glomeruli (Vg), perfused ex vivo at increasing flows, was quantified and related to the proximal intraglomerular pressure (PIP). Glomerular compliance, expressed as the slope of the positive linear relationship between PIP and Vg was 7.68 x 10(3) microns 3/mmHg. Total Vg increment (PIP 0-150 mmHg) was 1.162 x 10(6) microns 3 or 61% (n = 13). A 16% increase in Vg was obtained over the PIP range equivalent to the pathophysiological limits of mean transcapillary pressure difference. A similar effect of renal perfusion on Vg was also noted histologically in tissue from kidneys perfused/fixed in vivo. Cultured mesangial cells undergoing cyclic stretching increased their synthesis of protein, total collagen, and key components of ECM (collagen IV, collagen I, laminin, fibronectin). Synthetic rates were stimulated by cell growth and the degree of stretching. These results suggest that capillary expansion and stretching of mesangial cells by glomerular hypertension provokes increased ECM production which is accentuated by cell growth and glomerular hypertrophy. Mesangial expansion and glomerulosclerosis might result from this interplay of mechanical and metabolic forces.

Clinical features and health-care costs of diabetic nephropathy.

The nephropathy complicating insulin-dependent diabetes mellitus (IDDM) has been well studied, but that complicating non-insulin-dependent diabetes mellitus (NIDDM) is less well defined. In patients with IDDM, the glomerular filtration rate is often increased early in the course of the disease, approaches normal with insulin therapy, but tends to remain slightly elevated throughout the ensuing 10-15 yr of insulin dependency. After the onset of overt azotemia, end-stage renal disease (ESRD) develops in approximately 5 yrs. Proteinuria may be intermittently positive in the earliest stages of diabetes, evolving into intermittent and then persistent microalbuminuria, which in turn blossoms into macroalbuminuria. Because 40-50% of IDDM patients develop proteinuria and two-thirds of this subpopulation develop ESRD, some 20-30% of any given cohort of IDDM patients eventually need dialysis or transplantation. Evidence indicates that diabetic nephropathy is associated with a greater incidence of eye, nerve, heart, and peripheral vascular disease. Nondiabetic renal disease complicating IDDM and NIDDM is associated with a lesser frequency and severity of these extrarenal manifestations. The prevalence of retinopathy increases with advancing nephropathy. Roughly two-thirds of the deaths from IDDM are related to renal failure, and most of the remainder are caused by associated cardiovascular disease. Transplantation from living relatives carries the best prognosis for survival, and little difference is seen between hemodialysis, peritoneal dialysis, and cadaver transplantation. The health-care costs of treating diabetic nephropathy are also reviewed.

Clinical use of the anion gap.

The concepts underlying the clinical use of the anion gap (AG) and those disorders associated with its alteration are reviewed. A substantial increase in the AG usually indicates the presence of a metabolic acidosis, unless large doses of certain antibiotics or sodium salts of organic acids are being used. The etiology, pathogenesis and diagnosis of high AG metabolic acidoses are discussed. Stress is placed upon the utility of the AG in defining the cause of the acidosis, and as a guide to therapy in certain organic acidoses. A decrease in the normal AG occurs in dilutional states, hypoalbuminemia, hypercalcemia, hypermagnesemia, hypernatremia, diseases associated with hyperviscosity, bromide intoxication, and in certain paraproteinemias. The important clue provided by a low or negative AG in the diagnosis of certain of these life-threatening disorders is emphasized.

Simple and mixed acid-base disorders: a practical approach.

Metabolic and respiratory acid-base disorders occur as single and mixed entities. When induced perturbations in PCO2, HCO3(-), pH, and serum electrolytes are interpreted in the light of sound physiologic principles, even the most complicated mixed disorders may be easily diagnosed. The pathophysiology underlying the simple disturbances is defined and used as a framework for discussion of the mixed metabolic, respiratory acid-base derangements. Formulae are presented which allow one to predict what the appropriate degree of metabolic compensation should be for any primary respiratory disorder, or what the PCO2 should be for any given degree of primary metabolic acidosis or alkalosis. The various clinical settings in which mixed acid-base disorders occur most commonly are discussed.

Diabetic nephropathy: can the natural history be modified?

Those diabetic patients who progress to advanced kidney disease constitute a subpopulation that is particularly vulnerable to the angiotoxic effects of the insulin-dependent disorder. Until the predisposing factors are identified, the most effective way to arrest renal deterioration is by controlling those currently recognized risk factors that accelerate the glomerulopathy. Treatments that normalize blood pressure, reduce dietary protein intake, and control hyperglycemia have been shown to retard the progression of diabetic nephropathy.

Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis.

Our understanding of the physiology and biochemistry of acid-base and fluid-electrolyte regulations has greatly expanded in recent years. Key physiologic principles have emerged that now permit rational diagnosis and therapy of clinical disorders of serum electrolyte concentration. This paper describes diagnostic strategies based upon these principles. The etiology of the myriad factors in hyponatremia is best derived by first measuring serum tonicity and then assessing extracellular fluid volume. The hyper-, iso- and hypotonic hyponatremia are defined, and the hypotonic group is subclassified into hypo-, iso- and hyper volemic forms. The hypernatremias are best categorized by their state of volume expansion. Classification into the hypo-, hyper- and isovolemic hypernatremias simplifies their diagnosis. Metabolic acidoses are classified in terms of the anion gap. Clinical and chemical aspects of increased and normal anion gap acidoses are described. Metabolic alkaloses require a source of new bicarbonate and its retention by the kidney. The means by which new alkali is synthesized and urinary loss prevented serve to effectively classify the alkaloses. Hypokalemic syndromes are defined in terms of associated changes in body potassium. The potassium-depleted states are further subclassified by whether normotension or hypertension is associated. Hyperkalemia is produced by redistribution of cellular and extracellular potassium or by increased body potassium. Defects in the renin-angiotensin-aldosterone-distal renal tubule effector arm usually underlie hyperkalemic states, which are than classified in terms of this regulatory hormonal cascade. Classifications for disordered serum concentrations of calcium, magnesium, phosphorus and uric acid are presented. Hormonal, metabolic and renal regulatory factors form the basis for an organized approach to these disorders.

Development and progression of chronic renal disease: can it be prevented or attenuated?

Following its initiation, renal disease tends to progress relentlessly to end stage, necessitating dialysis or transplantation or causing death. Studies have shown that metabolic, hematologic and hemodynamic adaptations by the damaged kidney underlie the progressive nature of the disease. This review underscores the hemodynamic maladaptations and consequences and the evidence that suggests that glomerular hypertension is a necessary accompaniment to renal damage. The evidence reviewed indicates that high pressure develops in fragile glomerular capillaries after loss of a critical amount of renal mass and causes progressive sclerosis and destruction of remaining nephrons. This maladaptive renal response ensures progressive destruction in a variety of renal diseases including diabetes mellitus. Reduced protein intake and converting enzyme inhibitor therapy may prevent or attenuate the progression of these diseases.

Diuretic use in critical care.

Diuretics have found wide application in critical care medicine. The use of mannitol and loop diuretics in a variety of life-threatening disorders is reviewed. The combined venodilatory and natriuretic effects of bumetanide, furosemide and ethacrynic acid relieve congestive symptoms in pulmonary edema. Although commonly administered to prevent development of acute tubular necrosis or in varying stages of evolving disease, few data are available to demonstrate the efficacy of mannitol or loop diuretics. An approach to the oliguric patient with acute tubular necrosis is described. The dangers of hyponatremia are reviewed, and the rational use of loop diuretics and hypertonic saline is outlined. The 3 loop-active agents inhibit calcium reabsorption in the thick ascending limb of Henle's loop and therefore have proved useful in treating hypercalcemia. A practical approach to the diuretic-saline treatment of severe hypercalcemia is outlined. The kaliuretic effect of loop diuretics can be used to advantage in patients with acute or chronic hyperkalemia. A guide to such therapy is described.

Hypokalemia and cardiovascular disease.

A growing body of experimental, epidemiologic and physiologic evidence testifies to the hazards of hypokalemia and other electrolyte disorders that can complicate the chronic use of diuretic drugs in patients with cardiovascular disease. This study reviews the complex renal and extrarenal mechanisms that regulate potassium balance in normal persons with special attention to the role of stress-related hormones. Disturbances of potassium balance are common in patients taking diuretics; indeed, the potential number of people in this country at risk of diuretic-related hypokalemia approaches 9 million. The magnitude of this problem is of particular concern, because of the compelling data that link hypokalemia in such patients to electrical instability of the heart and to a fatal outcome after an acute cardiac injury. Therefore, aggressive correction of hypokalemia is warranted in patients with cardiovascular disorders.

The development and progression of chronic renal disease. Can it be prevented or attenuated?

Many forces contribute to the immutable progressive deterioration of renal diseases. This review focuses on the pernicious haemodynamic response of the kidney to an initial loss of mass. Afferent arteriolar dilatation, coupled with relative or absolute efferent arteriolar constriction, causes the hydrostatic pressure in the intervening glomerular capillaries to increase. While sustaining the glomerular filtration rate, the glomerular hypertension may ultimately scar and destroy the kidney. Experimental studies in animals persuasively argue that the high glomerular capillary pressures do indeed contribute to progressive renal damage. Whether this observation is translatable into human renal diseases is the subject of ongoing clinical investigation. The role of dietary protein restriction and converting enzyme inhibitors in reducing this glomerular hypertension and in potentially attenuating the progression of a wide range of renal diseases is also discussed.

Selective review of key perioperative renal-electrolyte disturbances in chronic renal failure patients.

The medical care of chronic renal failure patients is often complicated by the comorbid conditions of hypertension and coronary artery disease in the perioperative period. The limitations on solute and water excretion imposed by renal dysfunction increase the susceptibility of this population to both salt deficit and surfeit, as well as hyponatremia and hypernatremia perioperatively. Accurate assessment and successful treatment of these complications in renal failure patients require understanding of the concept of electrolyte-free water, proper utilization of diuretics, and calculated prescription of fluid therapy. The presence of hyperkalemia in the adapted renal failure patient generally indicates a severe reduction in glomerular filtration, such that nonrenal hypokalemic treatments are imperative. IV calcium-based therapy and infusion of insulin with glucose represent the mainstays of immediate therapy, and sodium bicarbonate therapy should be given only when severe acidemia is present. Perioperative aggravation of preexistent hypertension is common. Rebound hypertension attributable to injudicious adjustment of the medical regimen should be diligently searched for first, before any new therapies are recommended. Relief of pain or anxiety may be all that is necessary. Briefly acting calcium channel blocker therapy should not be employed in these cases, and smooth IV control by a variety of agents is preferable, the choice of the agent contingent on the clinical scenario.

Diabetic nephropathy. The basis for dietary and converting enzyme inhibitor therapy.

Once initiated, renal disease progresses in most patients to end-stage over a matter of months or years. This progressive consumption of renal mass seems to result from maladaptations to the initial insult by the remaining kidney. This review stresses the hemodynamic underpinnings of this progression of renal disease. The evidence is reviewed that indicates that loss of renal mass from surgical reduction in kidney tissue or from diabetes mellitus results in increased blood flow, filtration, and glomerular pressure in the remaining nephrons. Prevention of this glomerular hypertension by reduction in dietary protein or by the addition of converting enzyme inhibitors affords protection. The clinical implications of these observations are reviewed.

Pre- and postoperative renal failure.

The acute onset of oliguria and azotemia in the postoperative setting may be caused by pre-renal causes or intrinsic renal damage. The first step in arriving at a diagnosis is to review the history as noted above for clues regarding fluid balance, treatment with nephrotoxins, etc. The typical patient with prerenal azotemia will present with evidence of the recent onset of worsening of pre-existing cardiac disease, renal or gastrointestinal fluid loss, or the accumulation of acites, edema, or retroperitoneal fluid. In the absence of very recent diuretic therapy, he will be excreting a scant amount of concentrated (greater than 400 mOsm per L) sodium free (less than 10 to 20 mEq per L) urine. The serumBUN/Cr ratio is often greater than 15 to 20:1, and their urinary sediment will be bland. In an occasional patient in whom these studies give equivocal results, additional help may be obtained with measurements of central venous pressure (CVP) or pulmonary wedge pressure (PWP) and by noting their response to intravenous fluid loading. A rising CVP or PWP in the face of salt loading is, of course, evidence against prerenal azotemia. Patients with obstructive uropathies may be oligoanuric or polyuric-occasionally a characteristic alternating polyuria and oliguria is found (due to displacement of a stone or relief of edema). When oliguric their urine typically contains substantial amounts of sodium (greater than 20 mEq per L), is isotonic, and their OsmU:OsmP is les s than or equal to 1.2. Their urinary sediment will reflect the cause of their obstruction as noted above. A renal scan, ultrasound study, or infusion IVP are mandatory to rule out the possibility of obstructive uropathy. If these nonivasive studies are equivocal, one must consider doing a unilateral retrograde. The development of ATN usually occurs in the setting of hypotension, sepsis, dehydration, and with exposure to nephrotoxins. Most patients with be excreting scant amounts of isotonic urine containing more than 20 to 30 mEq per L of sodium. Their CrU:CrP is less than or equal to 20:1 and their urinary sediment reveals many epithelial cells and casts. Those patients with nonoliguric ATN have urine outputs which may exceed 2 liters per day. Despite this output they demonstrate a stepwise increase in serum urea and creatinine. Urine sodium and osmolality are not very helpful in this setting. Many such patients do have low (less than 20 mEg per L) urine sodium concentration and excrete isotonic urine.

Acute metabolic acid-base disorders.

Metabolic acid-base disturbances commonly and predictably complicate the course of many intensive care unit patients and plague the intensivists, surgeons, and anesthesiologists beset with the task of caring for them. In this article, we offer a systematic approach to the patient with the metabolic acid-base disorders that are likely to be encountered in the setting of the intensive care unit. The discussions are in no way presented as through treatments of all metabolic disorders, but rather focus on the more practical aspects, namely, clinical scenarios, diagnostic clues, and therapeutic goals. Additionally, we interject a discussion of some of the more controversial topics with regard to the therapy of metabolic disorders.