Influence of steady-state alterations in acid-base equilibrium on the fate of administered bicarbonate in the dog.

Previous workers have shown that metabolic acidosis increases the apparent space through which administered bicarbonate is distributed. This finding has been ascribed to the accompanying acidemia and to the consequent availability of a large quantity of hydrogen ion that accumulates on nonbicarbonate tissue buffers during the development of acidosis. To test this hypothesis, bicarbonate space was measured in dogs with a broad range of steady-state plasma [HCO-3] in association with alkalemia as well as with acidemia. Appropriate combinations of pH and plasma [HCO-3] were achieved by pretreating the animals to produce graded degrees of each of the four cardinal, chronic acid-base disorders. Metabolic acidosis (n = 15) was produced by prolonged HCl-feeding; metabolic alkalosis (n = 17) by diuretics and a chloride-free diet; and respiratory acidosis (n = 9) and alkalosis (n = 8) by means of an environmental chamber. Animals with normal acid-base status (n = 4) were also studied. Sodium bicarbonate (5 mmol/kg) was infused over 10 min to the unanesthetized animals; observations were carried out over 90 min. The results obtained from animals with metabolic acid-base disturbances demonstrated an inverse relationship between bicarbonate space and initial plasma pH, confirming the previous findings of others. By contrast, the results obtained in animals with respiratory acid-base disturbances demonstrated a direct relationship between bicarbonate space and initial plasma pH. The pooled data revealed that bicarbonate space is, in fact, quite independent of the initial pH but is highly correlated with the initial level of extracellular [HCO-3]; dogs with low extracellular [HCO-3] (congruent to 10 meq/liter) whether acidemic or alkalemic, have a bicarbonate space that is 25% larger than normal and some 50% larger than in dogs with high extracellular [HCO-3] (congruent to 50 meq/liter). We conclude from these results that the increased bicarbonate space in metabolic acidosis (and respiratory alkalosis) does not reflect the availability of more hydrogen ions for release during bicarbonate administration, but merely evidences the wider range of titration (delta pH) of nonbicarbonate buffers that occurs during alkali loading whenever plasma [HCO-3] is low.

Impaired renal vascular reactivity in prehypertensive Dahl salt-sensitive rats.

We have previously shown that renal vascular resistance is less in Dahl salt-sensitive rats than salt-resistant rats fed 1% NaCl diets; however, renal vascular resistance increases before nonrenal vascular resistance as salt-sensitive rats develop hypertension when fed 8% NaCl diets. When salt-resistant rats are given 8% NaCl diets, renal vascular resistance decreases. The current study reports effects of atrial natriuretic peptide, nitroprusside, norepinephrine, angiotensin II, and endothelin-1 on renal and nonrenal vascular resistance in prehypertensive salt-sensitive and salt-resistant rats given 1% NaCl diets; doses used did not affect blood pressure. Resistance of nonrenal vessels in salt-sensitive and salt-resistant rats responded similarly to dilators or constrictors. However, atrial natriuretic peptide and nitroprusside decreased renal vascular resistance of salt-resistant rats (by 65%, p less than 0.01) but not that of salt-sensitive rats. Norepinephrine, angiotensin II, and endothelin-1 increased renal vascular resistance in salt-sensitive rats by 126%, 135%, and 135%, respectively (p less than 0.01); norepinephrine and angiotensin II did not change renal vascular resistance of salt-resistant rats, but endothelin-1 decreased renal vascular resistance in salt-resistant rats by 30% (p less than 0.01). Reactivity of nonrenal blood vessels in prehypertensive salt-sensitive and salt-resistant rats was similar when infused with dilators or constrictors in doses used. By contrast, renal vessels of salt-sensitive rats did not dilate in response to atrial natriuretic peptide and nitroprusside but were hypersensitive to norepinephrine and angiotensin II. Endothelin-1 caused renal vasoconstriction in salt-sensitive rats and renal vasodilation in salt-resistant rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired renal vasodilation and urinary cGMP excretion in Dahl salt-sensitive rats.

We previously have shown that Dahl salt-sensitive rats increase renal vascular resistance in response to excessive salt feeding before total peripheral resistance increases and hypertension occurs. Failure of renal vasculature to dilate, as normally occurs in Dahl salt-resistant rats fed a high salt diet, may play a role in the development of hypertension in Dahl salt-sensitive rats. We also showed that renal vasculature in salt-sensitive rats is hyperreactive to vasoconstrictors and hyporeactive to vasodilators. Atrial natriuretic peptide, by stimulating cell-bound receptors, and nitroprusside, by generating nitric oxide, cause renal vasodilation by generating cGMP. Studies were undertaken to determine whether defective renal vasodilation in Dahl salt-sensitive rats is due to impaired production of cGMP. We examined the influence of nitroprusside infusion and salt intake on renal vascular resistance and cGMP excretion in salt-sensitive rats. Results demonstrate that salt feeding and nitroprusside infusion increase cGMP excretion and decrease renal vascular resistance in salt-resistant rats (P < .01), and, although this relationship was less clear in salt-sensitive rats, there was a reciprocal relationship between renal vascular resistance and cGMP excretion in all animals studied. Salt feeding and nitroprusside infusion caused less of an increase in cGMP excretion in salt-sensitive than in salt-resistant rats (P < .01). In conclusion, these studies support the concept that impairment in cGMP generation may play a primary role in the inability of the kidneys of Dahl salt-sensitive rats to vasodilate in response to increased salt intake. Such an impairment could contribute to salt retention and the development of hypertension.

Demonstration of an antibody to tubular epithelium in glomerulonephritis associated with obstructive uropathy.

It has been postulated that in some patients with obstructive and reflux uropathy proteinuria develops through an intermediate mechanism of immune complex glomerulonephritis involving antigenic material of renal tubular epithelium. A patient with a unilateral ureterocele and nephrotic syndrome underwent bilateral renal biopsies during surgical correction of the obstruction. The obstructed kidney showed mild pyelonephritis, but both kidneys showed a glomerulopathy with electron-dense deposits in the mesangial and paramesangial regions associated with positive immunofluorescence for immunoglobulin M (IgM) and the third component of complement (C3). An IgM antibody was eluted from the biopsy specimens and it reacted by indirect immunofluorescence with normal renal tubular epithelium and with the patient's renal tubular epithelium. The eluate also reacted with pre-eluted glomeruli of the patient, but not with normal glomeruli. All antibody activity could be removed from the eluate by pre-incubation with normal kidney. It is concluded that the unilateral renal obstruction produced tubular injury so that as yet unidentified antigens were recognized by the immune system. The resultant antibody response gave rise to circulating immune complexes which were then deposited in glomeruli with subsequent glomerular damage and nephrotic syndrome.

Soluble HLA antigens, anti-HLA antibodies, and antiidiotypic antibodies in the circulation of renal transplant recipients.

Chronic rejection represents the major threat to long-term survival of organ allografts. It is presumed that this form of rejection is mediated by antibodies against mismatched HLA antigens of the graft. The presence and specificity of anti-HLA-antibodies in posttransplantation sera are, however, difficult to document. We have explored the possibility that anti-HLA antibodies form immune complexes with soluble HLA antigens released from the injured graft and/or that they are blocked by antiidiotypic, anti-anti-HLA-antibodies. Our data demonstrate that the long-term survival of renal allografts is significantly lower in patients who develop anti-HLA-antibodies following transplantation than in patients who do not form antibodies. Following depletion of soluble HLA antigens by magnetic immunoaffinity, we could identify anti-HLA-antibodies in 57% of the sera obtained from patients undergoing chronic rejection of kidney allografts, compared with 41% prior to antigen depletion. In patients tolerating the graft for 4 years or more, the corresponding frequencies of antibody-positive sera was 2% and 5% prior and following depletion of HLA antigens. The presence of HLA antigen/anti-HLA-antibody immune complexes in patients' sera was positively associated with chronic humoral rejection (P less than 0.0001). Patients who tolerated the graft in spite of having developed antibodies against one of its mismatched HLA antigens show specific antiidiotypic (anti-anti-HLA-antibodies). Such antiidiotypic antibodies were not found in sera from patients with chronic rejection (P = 0.005). This indicates that antiidiotypic antibodies may delay the progression of chronic humoral rejection.

Impact of the Libby Zion case on graduate medical education in internal medicine.

Residency training in New York State was substantially altered by the Libby Zion case. Work-hour limitations and augmented supervisory requirements changed the patterns of training--particularly in internal medicine--but with uncertain impacts on the quality of education and patient care. In this historical analysis, we review another major effect of the case: a substantial augmentation of the number of trainees. The need to maintain adequate inpatient staffing--within the ground rules of the Residency Review Committee, and in consideration of the reimbursement formulae and financial climate of New York State--conspired to promote substantial residency program expansion. Similar forces contributed to a national trend to increase the number of trainees. The history, cost and impact of these personnel changes are reviewed.

Persistent hypophosphatemia following parathyroidectomy in end-stage renal disease: report of three patients.

Immediate and persistent hypophosphatemia following subtotal parathyroidectomy, despite discontinuation of phosphate binders, developed in three chronic hemodialysis patients. Although the serum phosphorous level is regularly reduced by parathyroidectomy in such patients, prolonged hypophosphatemia has not previously been reported. This observation supports the concept that parathyroid overactivity in end-stage renal disease is a major determinant of hyperphosphatemia.

Update on renal transplantation.

Renal transplantation has evolved as a preferred mode of long-term therapy for a substantial percentage of chronic renal failure patients. The author reviews recent progress in the field with an emphasis on patient counseling and with the conclusion that the outlook for these patients is bright.

Tuberculous peritonitis in a CAPD patient cured without catheter removal: case report, review of the literature, and guidelines for treatment and diagnosis.

Tuberculous peritonitis in the chronic peritoneal dialysis patient carries a high mortality, which may reflect the diagnostic delay that is often encountered in these cases. Accordingly, a high index of suspicion and an aggressive diagnostic approach (which may include laparoscopic biopsy) should be applied to the patient with persistent culture negative peritonitis. One of the first continuous ambulatory peritoneal dialysis (CAPD) cases involving tuberculous peritonitis successfully treated without interruption of dialysis or removal of the peritoneal dialysis catheter is reported. The literature is reviewed to provide diagnostic and therapeutic guidelines in dealing with this serious infection.

Proteinuria in congestive heart failure.

To clarify the association between proteinuria and congestive heart failure (CHF), 24-hour urinary protein determinations were obtained from 27 patients with objectively documented CHF, before and after therapy of the CHF. The results demonstrate that modest proteinuria is a frequent feature of CHF and that this proteinuria reverses promptly with successful CHF therapy. Proteinuria exceeding 500 mg/day occurred only in patients with acute pulmonary edema. However, there was no other correlation between severity of proteinuria and type or chronicity of CHF. When proteinuria exceeds 1 g/24 h or when proteinuria does not reverse within 2 weeks of successful CHF therapy, intrinsic renal disease should be suspected.

Recurrent IgA nephropathy in living-related donor transplantation: recurrence or transmission of familial disease?

We describe a patient who developed terminal renal failure of two HLA-identical renal allografts due to crescentic IgA nephropathy. The first graft contained IgA deposits at the time of donation, suggesting that transmission of IgA deposits may have contributed to the nephritis of the first allograft. The second graft was free of IgA deposits at the time of donation, but the recipient developed a similar, rapidly progressive nephritis. This case points up the malignant potential of IgA nephropathy and the complex nature of transplant planning for patients with end-stage renal disease (ESRD) secondary to IgA nephropathy. Living-related donor (LRD) transplants seem to be associated with a higher rate of recurrence than cadaveric grafts. This higher rate may partly reflect the inadvertent transmission of subclinical IgA deposits from donor to recipient and a genetic susceptibility of certain HLA types (specifically B35 and DR4) to recurrent disease. Cadaveric transplants may be preferable in the setting of high-risk HLA types or familial patterns of IgA nephropathy.

Posthysteroscopic hyponatremia.

We report a case of severe hyponatremia following hysteroscopic myomectomy for uterine fibroids. This new technique, which requires large volumes of irrigation solution (1.5% glycine in this case), is being more widely applied as an alternative to open surgery. Thus, nephrologists may expect to encounter such cases as the female counterpart to transurethral resection of prostate-associated hyponatremia. Analysis of the dynamic features of this case, in the context of recent knowledge of glycine metabolism, suggests that the early severe hyponatremia is partly spurious, reflecting an osmotic effect of glycine (which is initially restricted to the extracellular space). As glycine progressively enters cells and is metabolized, the later phase of hyponatremia more accurately reflects true hypo-osmolality.

Changes in the plasma anion gap during chronic metabolic acid-base disturbances.

A basic premise in the utilization of the plasma anion gap in the assessment of acid-base disorders is that this parameter remains constant during hyperchloremic metabolic acidosis and metabolic alkalosis. Experimental data under in vitro conditions, however, cast serious doubt on this premise. The purpose of the present study was to characterize the plasma anion gap, estimated as (Na + K) - Cl + HCO3), in two large groups of dogs with graded degrees of chronic, HCl-induced metabolic acidosis or chronic, diuretic-induced metabolic alkalosis. The data indicate that the plasma anion gap decreases significantly in HCl acidosis and increases significantly in metabolic alkalosis; the predicted mean anion gap in animals with a plasma bicarbonate concentration of 10, 21 (normal), and 40 meq/liter approximated 13, 18, and 26 meq/liter, respectively. The observed variation in the plasma anion gap is interpreted as originating mainly from directional changes in the net negative charge of plasma proteins; these changes result from the titration process secondary to the altered plasma acidity and, in the case of metabolic alkalosis, from the additional effect of an increased plasma protein concentration.