Vardaman M. Buckalew

The Familial Risk of End-Stage Renal Disease in African Americans

African Americans have higher overall incidence rates of end-stage renal disease (ESRD) compared with American whites. Hypertensive nephrosclerosis (HN), nephropathy secondary to diabetes mellitus types I and II, and chronic glomerulonephritis (CGN) all occur more frequently in African Americans. To explore the possibility that hereditary factors may play a role in the increased risk of ESRD in African Americans, the family history of 131 African American hemodialysis patients (cases) was compared with 115 age-, sex-, and race-matched non-ESRD controls. Odds ratios (ORs) were calculated to define the prevalence of a relative with ESRD among cases versus controls. Chi-square values were estimated from a log-linear model, while controlling for gender, to test for significance of ORs. Forty percent (12/30) of HN cases, 35% (18/51) of type II diabetes mellitus-induced renal failure cases, and 13% (5/38) of CGN cases had a first-, second-, or third-degree relative with ESRD. The presence of a first-degree relative with ESRD increased an African Americans risk for developing ESRD ninefold (OR, 9.13; 95% confidence interval [CI], 2.6 to 31.8; P < 0.001). The presence of a first- or second-degree relative increased the risk fivefold (OR, 5.23; 95% CI, 2.2 to 12.3; P < 0.0002). First-, second-, or third-degree relatives with ESRD were more prevalent among cases with ESRD due to hypertension and type II diabetes mellitus compared with CGN (P < or = 0.05). Gender differences among the ORs were nonsignificant (P > 0.2) and socioeconomic class (level of education and income) did not differ markedly between cases and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The Syndrome of Distal (Type 1) Renal Tubular Acidosis: CLINICAL AND LABORATORY FINDINGS IN 58 CASES

The clinical and laboratory findings in 14 infants, 2 children and 42 adults with RTA-1 have been retrospectively analyzed and the patients classified as having the hereditary (14%), acquired (31%), or idiopathic (55%) form. In 7 of the 8 hereditary cases, RTA-1 appeared to be a complication of hereditary hypercalciuria. The majority of acquired cases (61%) were secondary to immune-mediated diseases. All of the 14 infants with RTA-1 were classified as idiopathic. All of the idiopathic cases in children and adults were associated with nephrolithiasis and/or nephrocalcinosis, 33% of which had a family history of nephrolithiasis. The 14 infants presented with failure to thrive. Seventy-seven percent of children and adults with RTA-1 had nephrolithiasis and/or nephrocalcinosis and usually presented with symptoms related to this problem. Adults without nephrolithiasis or nephrocalcinosis usually presented with electrolyte disturbances or acidosis. Hypokalemia, the most common electrolyte disturbance, was present in 28% of the entire series. Acidosis was present in all infants and in 70% of children and adults. Clinically apparent bone disease was observed in 3 infants, and in 1 adult with nephrolithiasis. Glomerular function was normal in infants and in the 2 children, but depressed in 40% of adults. Recurrent urinary tract infection was a contributing factor but was not the sole cause of renal failure. Surprisingly, kidney stone number, the number of surgical procedures, and the presence of nephrocalcinosis had no apparent effect on the development of renal failure. Glomerular filtration rate was significantly higher in patients with incomplete RTA-1, and serum total CO2 was significantly correlated with creatinine clearance and minimum urinary pH. Hypercalciuria was present in 32% of patients with nephrolithiasis and/or nephrocalcinosis, and urinary citrate excretion was low in all of 16 patients in whom it was measured. Hypocitraturia appeared to be due in most cases to potassium depletion and renal failure, but may have occurred as a primary defect in 1 patient with hereditary RTA. Urinary uric acid excretion was elevated in 23% of patients with stones in whom it was measured. The mean number of stone-forming events was 51 +/- 14. Although a weak correlation between urinary calcium excretion and stone number was observed, the cause for prodigious stone formation could not be explained. This series emphasizes the variable degree to which the common clinical manifestations of RTA-1 (metabolic acidosis, hypercalciuria, nephrolithiasis, nephrocalcinosis, and potassium depletion) are expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

A digoxin-like immunoreactive substance in preeclampsia

A study has been undertaken of levels of an endogenous substance which immunologically cross reacts with digoxin and may be the putative natriuretic hormone. The possibility that this substance may play a role in the pathophysiology of preeclampsia has been studied by measuring the plasma concentrations in clinically healthy and preeclamptic pregnant patients. A significant difference (p less than 0.001) between these two groups has been found.

Nephrolithiasis in Renal Tubular Acidosis

Renal tubular acidosis is a term applied to several conditions in which metabolic acidosis is caused by specific defects in renal tubular hydrogen ion secretion. Three types of renal tubular acidosis generally are recognized based on the nature of the tubular defect. Nephrolithiasis occurs only in type I renal tubular acidosis, a condition marked by an abnormality in the generation and maintenance of a hydrogen ion gradient by the distal tubule. A forme fruste of type I renal tubular acidosis has been described in which the characteristic defect in distal hydrogen ion secretion occurs in the absence of metabolic acidosis (incomplete renal tubular acidosis). Type I renal tubular acidosis is a heterogeneous disorder that may be hereditary, idiopathic or secondary to a variety of conditions. Secondary type I renal tubular acidosis in sporadic cases is associated most commonly with autoimmune diseases, such as Sjögrens syndrome and systemic lupus erythematosus, and it occurs more frequently in women than men. Nephrolithiasis, which may occur in any of the subsets of type I renal tubular acidosis, accounts for most of the morbidity in adults and adolescents. Major risk factors for nephrolithiasis include alkaline urine, hypercalciuria and hypocitraturia. In addition, we found hyperuricosuria in 21 per cent of the patients with type I renal tubular acidosis with nephrolithiasis. The most frequently occurring risk factor, hypocitraturia, is due to decreased filtered load and/or to increased tubular reabsorption of filtered citrate. While increased tubular reabsorption may be due to systemic acidosis, hypocitraturia occurs in incomplete renal tubular acidosis. Furthermore, alkali therapy (either bicarbonate or citrate salts) increases citrate excretion in complete and incomplete type I renal tubular acidosis. These data suggest that hypocitraturia in type I renal tubular acidosis may be due to a defect in proximal tubule function. Hypercalciuria appears to have 2 causes. It may be due to metabolic acidosis, usually in children with a hereditary defect in urine acidification. In other cases familial idiopathic hypercalciuria causes nephrocalcinosis and nephrolithiasis resulting in distal tubular damage and type I renal tubular acidosis. In these latter cases hypercalciuria is present in complete and incomplete type I renal tubular acidosis. Potassium citrate appears to reduce calcium excretion in both types of hypercalciuric type I renal tubular acidosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Analgesic-Associated Nephropathy and Transitional Cell Carcinoma of the Urinary Tract

Epidemiologic studies from Europe suggest that patients with analgesic-associated nephropathy have an increased risk of developing transitional cell carcinoma of the urinary tract. We did a similar epidemiologic study supporting this association. Six of 115 cases of transitional cell carcinoma diagnosed over 3 years had analgesic-associated nephropathy. The patients were predominantly female, younger, and had renal pelvis tumors instead of bladder tumors (P < 0.002), an mortality rate was higher (P < 0.05). In a historical prospective study, 146 patients with interstitial nephritis diagnosed between 1974 and 1976 were divided into those with and those without analgesic-associated nephropathy. In 4 of 84 patients with analgesic-associated nephropathy transitional cell carcinoma has developed. None of the 98 patients without analgesic associated nephropathy have developed transitional cell carcinoma (P < 0.001). These data strongly incriminate analgesic abuse as a risk factor for the development of transitional cell carcinoma.

Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: treatment with digoxin-binding immunoglobulin.

We report a case of a second trimester multifetal pregnancy with preeclampsia associated with an elevated digoxin-like immune factor. Due to the remoteness from viability the patient was offered therapy with digoxin-binding immunoglobulin. No untoward maternal effects were noted.

Capillary electrophoresis for the determination of glomerular filtration rate using nonradioactive iohexol

High-performance liquid chromatography (HPLC) has been used as an alternative to the isotopic method to calculate glomerular filtration rate (GFR). With the HPLC method, serum iohexol or iothalamate levels are measured, and the plasma clearance rate of the compound is used as a surrogate for GFR. However, HPLC is a labor-intensive procedure, which limits its usefulness in the clinical setting. Capillary electrophoresis, a newer technique in which electrophoretic separations are performed in capillary tubes, is easier and faster than HPLC. We used capillary electrophoresis for the determination of serum iohexol levels and the calculation of GFR. Patients underwent a simultaneous 125I-iothalamate clearance test and a plasma iohexol clearance test to determine GFR. Mean GFR (+/-SD) was 70.9 +/- 29.9 mL/min (range, 14.5 to 131 mL/min) in 52 patients as determined by standard iothalamate clearance methods. For iohexol clearance, the correlation coefficient and standard error were 0.93 and 10.9 mL/min, respectively, using capillary electrophoresis compared with the iothalamate method. Capillary electrophoresis is a simple, rapid method that can be used to calculate GFR and provides results at least as accurate as those obtained by HPLC and x-ray fluorescence.

Measurement of Glomerular Filtration Rate Using Nonradioactive lohexol: Comparison of Two One-Compartment Models

Radioisotopic methods for the determination of the glomerular filtration rate (GFR) are highly accurate but require the collection of multiple blood and urine samples and are costly to perform due to personnel, material, and analysis costs. Nonradioactive methods of GFR determination have the potential of minimizing procedure costs while preserving accuracy. We determined the GFR simultaneously by 125I-iothalamate and nonradioactive iohexol clearance methods in 41 adults. The study group consisted of 54% males, with a mean age of 50.7 (range 28-79) years and a mean GFR by 125I-iothalamate clearance of 66.5 +/- 28.3 (range 10-118) ml/min. The iohexol concentrations were measured by a simplified high-performance liquid chromatography method that did not require sample preparation. The iohexol plasma clearance was calculated by both a new one-compartment model as well as by Jacobssons one-compartment model. Using Jacobssons single-sample model and data from the 240-min point, there was an excellent correlation between 125 I-iothalamate and nonradioactive iohexol clearance values: r2 = 0.95, standard error of the estimate = 11.4 ml/min, and intrapatient coefficient of variation = 16.9%. However, this formula tended to overestimate GFRs < 30 ml/min and to underestimate GFRs > 80 ml/min. The new one-compartment model is a modification of Bubecks model, originally used for the determination of renal plasma blood flow. Using this modified model, there was an excellent correlation between 125I-iothalamate and nonradioactive iohexol clearance values at all levels of GFR tested: r2 = 0.95, standard error of the estimate = 9.2 ml/min, and intrapatient coefficient of variation = 13.7%. In conclusion, the determination of the plasma clearance of iohexol by a nonradioactive technique and a monoexponential model is a simple and accurate method of determining the GFR in patients with varying degrees of renal impairment.

Differential effect of dietary salt on renal growth in Dahl salt-sensitive and salt-resistant rats.

A high salt diet has been shown to increase renal mass of intact rats, although the mechanism by which this occurs has not been investigated. We used Dahl rats that are sensitive (DS) or resistant (DR) to the hypertensinogenic effect of salt to examine changes in renal size and composition caused by a high salt diet. Renal index, deoxyribonudeic add (DNA), protein, water content, protein/DNA ratio, and cell number and size were measured in age-matched DR and DS on a high salt diet for 7,14, or 28 days. The results were compared with those obtained from respective rats on a low salt diet. High salt diet elevated renal index and protein hi DR and DS rats at each time point. After 7 days of a high salt diet, DNA increased in DS only. Protein/DNA ratio was progressively decreased by a high salt diet in DS and remained unchanged in DR rats. Cell number was increased 35% in DS versus only 13% in DR rats at 4 weeks. Cell size decreased 24% in DS and only 11% in DR rats. These results indicate that renal growth due to hyperplasia accompanies ingestion of a high salt diet in both DR and DS rats, but the rate of growth and the mechanism through which it occurs differ between strains. This difference may be important in delineating salt sensitivity and future development of hypertension.

Renal alpha 1- and alpha 2-adrenoceptor mediated vasoconstriction in dogs: comparison of phenylephrine, clonidine, and guanabenz.

The alpha 2-agonist, guanabenz, increases Na and water excretion with little change in renal blood flow, while clonidine has been reported to cause antinatriuresis proportional to renal vasoconstriction. We hypothesized that clonidine-mediated renal vasoconstriction involves alpha 1-receptors. Dose-response curves were constructed correlating decreases in renal blood flow with doses of phenylephrine, clonidine, and guanabenz injected as boluses into renal arteries of anesthetized dogs. Changes in renal blood flow before and after prazosin, yohimbine or verapamil were recorded. Guanabenz was a 10-fold weaker vasoconstrictor than clonidine, but was still effective when alpha 1-receptors were blocked. Tenfold differences were found between phenylephrine, clonidine, and guanabenz for dependence on alpha 1-receptors. Denervation did not significantly shift the curves. Verapamil markedly attenuated only clonidine and guanabenz, which supported their dependence on calcium channels for vascular smooth muscle contraction. Thus, postsynaptic alpha 2-adrenoceptors can contribute to renal vasoconstriction in the dog but the receptors are either less numerous on the vasculature or are less efficiently coupled to contractile elements than are alpha 1-receptors. Clonidine constricts the renal vasculature through both adrenoceptor subtypes.