The measurement of nephron filtration rate and absolute reabsorption in the proximal tubule of the rabbit kidney.

Micropuncture studies were performed in the rabbit to determine nephron filtration rate and absolute fluid reabsorption in the proximal tubule in order to compare the latter value with data obtained with the in vitro microperfusion technique. New Zealand white rabbits, 2-2.8 kg, were studied. Nephron filtration rate was 21 nl/min (n equal to 48) and absolute reabsorption along the length of the accesible portion of the proximal convoluted tubule was 10.3 nl/min. Correcting this value for tubular length gives a fluid reabsorption of approximately 1.9 nl/mm per min. In view of the marked difference between the in vivo and in vitro techniques and the various sources of error with each, this is reasonably similiar to the value of 1.3 nl/mm per min obtained in the isolated proximal convoluted tubule.

Recognition of hypertension and abnormal blood pressure burden with ambulatory blood pressure recordings in type I diabetes mellitus.

Ambulatory blood pressure (AMBP) measurements were obtained at 20-min intervals for 24 h in 25 subjects with insulin-dependent (type I) diabetes mellitus and 21 control subjects. The diabetic patients had normal kidney function (glomerular filtration rate 112.1 +/- 7.2 ml.min-1.1.73 m-2, renal plasma flow 459.0 +/- 23.4 ml.min-1.1.73 m-2) and were normotensive according to standard sphygmomanometer examinations. Mean +/- SE AMBP (systolic/diastolic in mmHg) measurements in diabetic patients (24 h, 131.7/77.2 +/- 2.9/1.8; 0600-2200, 132.3/78.4 +/- 2.9/3.4; 2200-0600, 125.1/75.7 +/- 3.9/3.4) significantly exceeded control values during all times (24 h, 121.8/70.3 +/- 2.9/1.9; 0600-2200, 120.7/71.8 +/- 2.6/2.0; 2200-0600, 108.2/61.5 +/- 6.6/2.7). Mean 24-h AMBP exceeded 135/85 mmHg in 49% of diabetic patients. The same threshold of 135/85 mmHg was used to determine the prevalence of abnormal measurements per time period (pressure burden). Pressure burden was increased twofold in diabetic patients compared with control subjects. Mean AMBP was significantly reduced at night in control subjects but not in diabetic patients. Changes in blood pressure were not related to kidney function in diabetic patients. AMBP recordings uncovered an increased prevalence of abnormal mean blood pressure, increased pressure burden, and a lack of diurnal variation of blood pressure in subjects with type I diabetes mellitus. These findings have important implications for early intervention strategies in diabetes mellitus because AMBP recordings correlate well with end-organ damage.

Ambulatory blood pressure in type I diabetes mellitus. Comparison to presence of incipient nephropathy in adolescents and young adults.

AMBP measurements were obtained at 20-min intervals during the day and at 60-min intervals during the night in 38 adolescents and young adults (12-25 yr old) with type I diabetes, and in 36 healthy, nondiabetic control subjects of comparable age. The group of patients with elevated AER (greater than 15 micrograms/min) had higher mean 24-h sBP, dBP, and BPB (defined as the prevalence of systolic readings greater than 130 mm Hg or diastolic readings greater than 85 mm Hg) compared with both the group of patients with type I diabetes and AER less than 15, and the control group. The normal diurnal variation in BP and BPB was observed in the control group and the group with type I diabetes and AER less than 15, whereas the nocturnal decrease observed in the group with type I diabetes and AER greater than 15 was not statistically significant. Elevations in AMBP of the patient group with AER greater than 15 were reflected in random BP measurements. Even though the mean random BP measurements of all groups were within the normal range for age, the mean random sBP and dBP of the type I diabetes patients with AER greater than 15 was higher than both the control group and the group with type I diabetes and AER less than 15. The GFR, determined by the clearance of 99Tc-DTPA, was associated negatively with measures of AMBP and AER in the group with AER greater than 15.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of angiotensin-converting enzyme inhibition on renal function and albuminuria in normotensive type I diabetic patients.

Normotensive patients with insulin-dependent (type I) diabetes mellitus (n = 18) were given 25 mg captopril (b.i.d.) and placebo for 3 mo in a randomized double-blind crossover study. Patients had normal renal function, and none had retinopathy. Albuminuria was less than 20 micrograms/min in 12 patients and between 20 and 200 micrograms/min in the other 6. Patients were examined at the end of the placebo and captopril phases. Captopril caused little reduction in blood pressure obtained by 24-h ambulatory monitoring (systolic 126.0 +/- 2.7 to 123.9 +/- 2.4 mmHg, P less than 0.08; diastolic 74.2 +/- 1.9 to 72.1 +/- 1.9 mmHg, P less than 0.09). Captopril lowered glomerular filtration rate from 99.5 +/- 7.7 to 71.0 +/- 5.5 ml.min-1. 1.73 m-2 (P less than 0.01), whereas renal plasma flow (443.9 +/- 15.2 ml.min-1. 1.73 m-2) remained unchanged. Filtration fraction was reduced from 22.4 +/- 1.4 to 17.4 +/- 1.4% (P less than 0.01). Urinary albumin excretion was reduced from 59.1 +/- 0.15 to 27.7 +/- 13.9 micrograms/min (P less than 0.1). Reduction was related to the extent of initial albuminuria (r = 0.997, P less than 0.001), a relationship that remained significant after logarithmic transformation (r = 0.540, P less than 0.02). Dextran clearance was used to determine glomerular capillary function. Angiotensin inhibition caused reduction in effective glomerular pore size and also reduced flow via the nondiscriminatory shunt. Angiotensin inhibition in normotensive patients with type I diabetes was well tolerated. Reduction in albuminuria is mediated by a combination of hemodynamic changes and alterations in glomerular capillary function.

Comparison of albumin excretion rate obtained with different times of collection.

This study was undertaken to assess the usefulness of different techniques for determination of albumin excretion rate (AER). Ninety patients with type I (insulin-dependent) diabetes mellitus and 45 with type II (non-insulin-dependent) diabetes mellitus, with AER/24 h of less than 200 micrograms/min, were included. All patients were free of major systemic complications of diabetes and overt kidney disease (mean serum creatinine 1.1 +/- 0.1 mg/dl, range 0.4-1.2 mg/dl). We compared timed day, night, and 24-h specimens, as well as timed spot specimens during water-induced diuresis. Most patients with type I (75 of 90) and type II (30 of 45) diabetes had AER less than 20 micrograms/min and showed significant differences in AER that were dependent on the collection time. Differences were diminished or absent with AER less than 20 micrograms/min. Sensitivity, specificity, and prediction rates of AER in different specimens were evaluated against 24-h AER. Use of albumin concentrations and albumin-creatinine ratios did not improve test performance in comparison with AER. Sampling time and the overall rate of AER influenced measurement of urinary albumin excretion. Day or 24-h AER is most useful to determine the presence of abnormal AER. AER and albumin concentration in spot samples are of limited use for initial screening and frequently require day or 24-h specimens of AER for confirmation. Day or 24-h AER should be used for long-term follow-up of the diabetic patient.

Prune belly syndrome and retroperitoneal germ cell tumor.

The prune belly syndrome is a congenital set of anomalies that includes cryptorchidism. Despite the known risk of testicular tumors in cryptorchid testes, what may be the first case of a germ cell tumor complicating the prune belly syndrome is described herein.

Urate secretion in isolated rabbit renal tubules.

The flux of radioactive urate from bath to lumen was measured in isolated proximal convoluted (PCT), proximal straight (PST), and cortical collecting tubules (CCT). Urate was secreted in the PST as evinced by a) accumulation of urate in the lumen of perfused tubules to levels 2-4 times greater than in the bath, and b) inhibition of urate flux (bath to lumen) by cooling, by probenecid (2.5 X 10(-4) M), and by ouabain (10(-4) M). Urate secretion was strongly dependent on the rate of urinary flow, diminishing as flow rate was reduced below 2 nl/min, and reaching maximal rates when flow exceeded 5 nl/min. The isotopic urate (either [2-14C]urate or [6-14C]urate) was secreted without modification. Luminal urate was not impressively elevated above the concentration of the bath in PCT. Cortical collecting tubules were relatively impermeable to urate. It is concluded that urate secretion occurs predominantly in the PST of this species by a mechanism dependent on the uphill transport of the molecule from the bath into the urine.

Autopsy diagnosis of Legionnaires' disease in immunosuppressed patients. A paleodiagnosis using Giemsa stain (Wohlbach modification).

A diffuse pneumonia characterized by short Giemsa-stained, gram-negative rods that were not cultured was diagnosed at autopsy in the fall of 1975 in three immunosuppressed patients who had had renal transplants. An acute fibrinous exudate was found, with macrophages, neutrophils, and numerous short bacilli in each inflamed alveolus as shown by Giemsa's stain (Wohlbach modification). Transplantation was stopped for 1 month. The institutional infection control committee discussed the cases, and increased observation. After the Legionnaires' disease agent was identified in 1977, the bacteria were stained by Dieterle's method and identified as Legionnaires' disease bacteria by direct fluorescent antibody test. No further cases have been identified in the succeeding 62 renal transplantations at this medical center. Although Wohlbach's modification of Giemsa has given consistently good staining of the Legionnaires' disease bacterium in our cases, unclarified factors may interfere with good staining, and the May-Grünwald Giemsa stain was unsatisfactory.

Basis for heterogeneity of para-aminohippurate secretion in rabbit proximal tubules.

Para-aminohippurate (PAH) is secreted at different rates in S1, S2, and S3 segments of isolated perfused proximal tubules of rabbit kidney. To characterize PAH transport we determined the maximal rate of secretion (Vmax) and the apparent Michaelis constant (Km) for each segment by examining the relationship between bath concentration of PAH and net PAH secretion (Jb leads to lPAH) transposed for Lineweaver-Burk analysis. The passive component of secretion for all segments was estimated by slope analysis at relatively high concentrations of PAH, by the component of PAH secretion insensitive to inhibition by probenecid, and, additionally, in S2 segments, from PAH efflux from lumen to bath. Subtraction of the passive component from Jb leads to lPAH (probenecid method) gave Vmax values for S1, S2, and S3 segments of 1,097 +/- 336 (n = 6), 7,430 +/- 1,338 (n = 6), 1,647 +/- 138 (n = 8) X 10(-15) mol.min-1.mm-1 (+/- SE) and apparent Km values of 139 +/- 37 (n = 6), 195 +/- 37 (n = 6), and 113 +/- 16 (n = 6) X 10(-6) M, respectively. Thus, Vmax for S2 greater than S3 congruent to S1, whereas apparent Km was not consistently different among the segments. On the basis of these results we suggest that axial heterogeneity of PAH secretion may reflect an increased basolateral membrane density of PAH transporters of common affinity in the S2 segment of the proximal tubule.

Renal cancer complicating acquired cystic kidney disease.

Acquired cystic kidney disease (ACKD) occurs in the setting of prolonged azotemia and is therefore common in dialysis patients. It is characterized by epithelial proliferation, and its major complication is the development of renal cancer. The incidence of renal cancer is significantly increased in ACKD patients and is probably increased overall in the ESRD population as well. Those ESRD patients with suspicious symptoms, prolonged predialysis azotemia, or a dialysis duration of longer than 3 yr, or those who are candidates for a renal transplant should be screened for ACKD. Sonography or computed tomographic scanning are useful as initial screening tools. However, although more expensive and requiring contrast administration, the contrast-enhanced computed tomographic scan is the definitive imaging procedure by which to initially evaluate a renal mass. A suspicious renal mass is a patient who is a surgical candidate is an indication for a radical nephrectomy.

Renin and the kidney.

The factors involved in renin release have been extensively evaluated. The primary determinants are the transmural pressure at the afferent arteriole, sodium delivery to the macula densa, and the activity of the adrenergic nervous system. Other possible factors include circulating catecholamines, the serum and cerebrospinal fluid sodium concentration, serum potassium concentration, angiotensin II concentration, and antidiuretic hormone release. There is no convincing evidence that the renin-angiotensin system mediates renal autoregulation. Plasma renin activity is altered in a number of clinical settings. This parameter is elevated in most patients with cirrhosis and the nephrotic syndrome as well as in individuals with severe congestive heart failure. Despite inappropriately large weight gains, plasma renin suppresses normally with increased salt intake in edematous patients who have a normal glomerular filtration rate. The mechanisms of the alteration in the renin-angiotensin system in Bartter's syndrome is still not clear.

The effect of water loading on albumin excretion in type I diabetes mellitus.

An increased albumin excretion rate is recognized as an important early marker for incipient kidney disease in patients with diabetes mellitus. Many different techniques have been used, and a single void technique has been proposed as the simplest method for screening for increased albumin excretion. We evaluated a previous observation that single void samples during water diuresis yield increased albumin excretion rates. Timed day, night, and 24 hour albumin excretion rates (AER) were obtained in 35 patients with Type I diabetes mellitus. This was followed by examination of 8 consecutive half-hour specimens obtained during continued water diuresis. We compared 26 patients with low AER (less than 20 micrograms/min/24 hr sample) to 9 patients with high AER (greater than 20 and less than 200 micrograms/min/24 hr). Sampling began 60 min after the initiation of the waterload. At first, the AER in the low AER group was significantly higher than it was at night, but it decreased over 60 to 90 min of sampling to levels comparable with daytime AER. This was paralleled by a similar pattern in urine flow rate, sodium, and solute excretion. The AER in the high AER group did not increase with the water load and remained high throughout the study periods. The pattern of urine flow rate, sodium, and solute excretion was similar to that of the group with low AER. The study demonstrates that early sampling after water-induced diuresis leads to overestimation of AER in patients with low AER as compared to patients with high AER.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for an inhibitor of renal urate and PAH secretion in rabbit blood.

Results of previous studies of urate secretion in isolated perfused S2 segments of the rabbit proximal tubule suggested that a bath of rabbit serum may inhibit urate transport in comparison to a synthetic medium. In the current study we tested for a urate transport inhibitor by determining the steady-state tissue-to-medium ratio (T/M) of [14C]urate in nonperfused S2 segments during incubation in synthetic medium (BSA-Burg) and commercial rabbit serum (RS-PF). With 80-120 microM urate in the bath the T/M ratio was 7.66 +/- 0.53 (n = 29) in BSA-Burg and 5.29 +/- 0.40 (n = 29) in RS-PF. RS-PF decreased the influx of urate into the cells but had no effect on urate efflux. Freshly drawn rabbit serum and plasma also inhibited urate accumulation, and the inhibition was reversible. p-Aminohippurate accumulation was inhibited by RS-PF, but tetraethylammonium bromide uptake was not. RS-PF inhibited transepithelial secretion of urate and PAH, but net fluid absorption was not decreased. The inhibitory material in rabbit serum could not be removed by extensive dialysis (14,000-dalton exclusion), by ultrafiltration (50,000-dalton exclusion), or by charcoal or ethanol extraction. Inhibitory activity was detected in both albumin and globulin fractions of rabbit serum. The relation between bath and intracellular urate concentrations of nonperfused tubules in rabbit serum was sigmoidal, whereas the relation in the BSA-Burg medium was more nearly hyperbolic. We conclude that organic anion transport in rabbit S2 segments is inhibited or suppressed by normal serum and suggest that urate secretion and excretion may be subject to allosteric modification by serum proteins.

The role of disease duration and hypertension in albumin excretion of type I diabetes mellitus.

The objective of this study was to examine the relationship between blood pressure, albumin excretion, and renal function in patients with type I diabetes mellitus. The study design was as follows: nonselected consecutive patients with type I diabetes mellitus were divided into three groups by level of albumin excretion rate (AER): less than 20 micrograms/min, 20 to 200 micrograms/min, and greater than 200 micrograms/min. The setting for the study was an outpatient diabetic clinic in a tertiary referral center. There were 166 patients studied: 53% men, 47% women, 86% white, 17% treated for hypertension. Seventy-six percent had an AER less than 20 micrograms/min, 18% had an AER of 20 to 200 micrograms/min, and 6% had an AER of greater than 200 micrograms/min. Glycosylated hemoglobin did not differ between groups. AER was increased with age and disease duration (P less than 0.005 by analysis of variance) after 10 yr of disease. Serum creatinine (P less than 0.005) and systolic (P less than 0.005) and diastolic (P less than 0.01) blood pressures were also increased with AER. Serum creatinine and blood pressure were found to be increased in parallel after 10 yr of disease, but both remained within the normal range overall. A comparison of individual blood pressures in patients not taking antihypertensive drugs (N = 138) with age-related blood pressures of nondiabetic subjects revealed increased systolic and diastolic blood pressures at all ages. Group comparison demonstrated a significant link between increased AER and serum creatinine (declining renal function) and increased blood pressure after a latent period of 10 yr. Blood pressure appears to be increased from the earliest age in diabetes compared with healthy populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of linking practice data to published evidence. A randomized controlled trial of clinical direct reports.

OBJECTIVES: The purpose of this study was to evaluate the effect of clinical direct reports (practice data with pertinent evidence from the literature) on dialysis modality selection for patients with end-stage renal disease. METHODS: A randomized controlled clinical trial was conducted at five dialysis centers. Five of the 10 physician participants were assigned through centralized computerized randomization to the intervention group (who received 12 center-specific clinical direct reports encouraging the consideration of peritoneal dialysis), and five were assigned to the control group, who received usual information but no similar report. One hundred fifty-two patients were eligible for monitoring. RESULTS: The number of patients allocated to peritoneal dialysis was significantly higher in the intervention group than in the control group (15.3% versus 2.4%; P = 0.044). Due to a need for transient initial hemodialysis by some patients, the percentage of patients receiving peritoneal dialysis further increased through the end of the 3-month follow-up (18.0% versus 4.9%, P = 0.041). CONCLUSIONS: There were no significant differences between the intervention and control groups in meeting patient preferences, metabolic status, and complication rates. The results of this study show that linking pertinent published evidence to actual practice data can support the implementation of practice recommendations and influence the selection of dialysis treatment for new patients.

Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome.

Antiglomerular basement membrane (GBM) antibodies can cause glomerulonephritis or pulmonary hemorrhage by themselves or Goodpasture syndrome when they occur together. It is unknown if variations in antibody reactivity contribute to the different patterns of organ involvement seen in this disease. This study examines the reactivity of the alpha 1-alpha 6 NC1 domains of Type IV collagen, the putative autoantigen, in sera from patients with anti-GBM antibodies after various clinical presentations of lung hemorrhage and renal injury. Serum or plasma containing anti-GBM antibodies from 35 patients with combined glomerulonephritis and pulmonary hemorrhage, 19 with glomerulonephritis alone, and 4 with pulmonary hemorrhage alone were compared with samples from 19 normal controls and 32 patients with other kidney diseases. Four different immunologic assays were performed with bovine alpha 1-alpha 6(IV) and recombinant human type alpha 1-alpha 5(IV) collagen NC1 domains. The study found that the anti-GBM antibodies from all patients reacted with the alpha 3(IV) NC1 (85% exclusively). Additional limited reactivity with the alpha 1(IV) NC1 and alpha 4(IV) NC1 was found in 15 and 3%, respectively. This non-alpha 3(IV) NC1 reactivity was most frequent in the patients with anti-GBM antibodies and glomerulonephritis alone. None of the patients had reactivity to other basement membrane components like laminin, fibronectin, heparan sulfate proteoglycan, entactin, or the 7S and triple helical fragments of Type IV collagen. The observed alpha-chain NC1 reactivity was confined to patients with anti-GBM antibodies with no additional reactivities detected among a large number of other kidney diseases controls. The correlation of alpha 1-alpha 6(IV) NC1 reactivity in a large number of patients with anti-GBM antibodies defined by classic assays definitively establishes that reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for the expression of autoimmune disease directed to the NC1 domain of Type IV collagen. On the basis of the evidence, the classification of antibasement membrane disease and Goodpasture syndrome as anti-Type IV collagen disease is proposed.

Glomerular basement membrane. Identification of dimeric subunits of the noncollagenous domain (hexamer) of collagen IV and the Goodpasture antigen.

The noncollagenous (NC1) domain hexamer of glomerular basement membrane (GBM) collagen is composed of a multiplicity of monomeric and dimeric subunits, and specific subunits are the targets for anti-GBM autoantibodies of patients with Goodpasture (GP) syndrome. The identity of GBM monomers has been established and the alpha 3(IV)NC1 monomer identified as the one that binds GP antibodies (Gunwar, S., Saus, J., Noelken, M. E., and Hudson, B. G. (1990) J. Biol. Chem. 265, 5466-5469). In the present study, the chain origin of 25 dimeric components and the identity of those that bound the anti-GBM antibodies from two GP patients were determined. This was accomplished by NH2-terminal sequence analysis and immunoblotting analysis of dimeric components that were resolved by two-dimensional electrophoresis in combination with high pressure liquid chromatography. The results revealed that (a) the components are mainly homodimers of the NC1 domains of alpha 1, alpha 2, alpha 3, alpha 4, and probably alpha 5 chains of collagen IV, reflecting a specificity of promoter-promoter association and (b) each homodimer had several size and charge isoforms. The GP antibodies bound exclusively to both alpha 3(IV)NC1 monomers and dimers and not to other basement membrane constituents. These findings provided new insights about the structure of GBM collagen and together with our previous findings firmly established the alpha 3(IV) chain as the target for the anti-GBM antibodies that mediate glomerulonephritis and pulmonary hemorrhage in patients with Goodpasture syndrome.

Percutaneous transluminal angioplasty in transplant renal artery stenosis: experience and review of the literature.

Percutaneous transluminal angioplasty (PTA) was performed in five instances of renal transplant artery stenosis (RTAS) in four patients. Hypertension was present in all cases and improved after angioplasty together with reduction in medicine requirements. Abnormal renal function in four instances also improved after PTA. This reflects the current literature in which 76 of 90 patients were successfully treated by PTA (follow-up to 24 months), with two cases of recurrent stenosis, no mortality, and only a single case of graft loss. Vascular surgical repair succeeded in 130 to 180 patients, but graft loss occurred in 20 cases and recurrent stenosis in 11. Mortality was reported in five cases. Our review of the literature and experience suggests that PTA may be preferred in the treatment of RTAS.