Urine is a saturated equilibrium and not a metastable supersaturated solution: evidence from crystalluria and the general composition of calcium salt and uric acid calculi.

A computer algorithm is described which allows urine to be modelled as a saturated equilibrium solution with respect to any combination of the solids calcium oxalate, calcium hydrogen phosphate (brushite), amorphous calcium phosphate, uric acid, sodium hydrogen urate and ammonium hydrogen urate. It is demonstrated that this model of urine, unlike the widely accepted metastable supersaturated solution model, explains the long-known calcium salt crystalluria versus pH curves of both non-stone-forming and stone-forming urine. Further, the saturation model accounts for why most "infection" stones do not contain calcium oxalate and why most "urate" stones are composed solely of uric acid and not admixed with alkali metal hydrogen urate salts. The supersaturation model of urine cannot explain satisfactorily these well-known phenomena. For example, the supersaturation model predicts that virtually all "infection" stones should contain calcium oxalate along with calcium phosphate and, perhaps, struvite.

Acute volume expansion and salt-loading studies in rats. The role of atrial natriuretic peptide and catecholamines.

Differences have been postulated for the mechanism of natriuresis due to atrial natriuretic peptide (ANP), salt loading with high salt diet (HS) and acute volume expansion (AcVE), in particular between AcVE and ANP based on the observed synergism between the two. Therefore the effects of and the interaction between the three were investigated in rats. ANP and AcVE produced the same natriuresis in HS as in normal salt (NS) rats and, in both, the actions of ANP and AcVe were significantly additive showing similarity in mechanisms. Synergism [(AcVE + ANP) - AcVE] was, however, present only in the NS rats. Proximal tubular sodium transport was the same with AcVE and ANP+AcVE suggesting that synergism is a property of more distal nephron segments. In conscious HS rats, plasma ANP was significantly less but natriuresis was higher than in NS rats. ANP therefore probably has some causative role in the natriuresis of AcVE but none in that of HS loading. Urinary dopamine was significantly increased by HS and further increased by AcVE in both NS and HS rats, the relationship between dopamine and natriuresis being significantly positive (r2 = 0.328) reaching equivalent levels in both NS and HS rats. Systemic benserazide prevented the increase in urinary dopamine but only attenuated the natriuresis of AcVE. We conclude that HS does not potentiate the natriuresis of AcVE or ANP, synergism between AcVE and ANP is not a proximal tubule event and dopamine accounts for significant natriuresis of VE in addition to other natriuretic factors.

Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis.

Primary distal renal tubular acidosis (dRTA) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Kindreds showing either autosomal dominant or recessive transmission are described. Mutations in the chloride-bicarbonate exchanger AE1 have recently been reported in four autosomal dominant dRTA kindreds, three of these altering codon Arg589. We have screened 26 kindreds with primary dRTA for mutations in AE1. Inheritance was autosomal recessive in seventeen kindreds, autosomal dominant in one, and uncertain due to unknown parental phenotype or sporadic disease in eight kindreds. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive dRTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the one known dominant dRTA kindred, in one sporadic case, and one kindred with two affected brothers. In the dominant kindred, the mutation Arg-589/Ser cosegregated with dRTA in the extended pedigree. An Arg-589/His mutation in the sporadic case proved to be a de novo mutation. In the third kindred, affected brothers both have an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1. These mutations were not detected in 80 alleles from unrelated normal individuals. These findings underscore the key role of Arg-589 and the C terminus in normal AE1 function, and indicate that while mutations in AE1 cause autosomal dominant dRTA, defects in this gene are not responsible for recessive disease.

Recognition and management of IgA nephropathy.

IgA (immunoglobulin A) nephropathy is the most common form of primary glomerulonephritis worldwide. It generally has a good prognosis, with 15-year rates of kidney survival from the apparent onset of disease usually well in excess of 70%. Progression, when it occurs, is usually a slow, indolent process, and spontaneous remission of disease activity occurs in 7% of patients. It is possible to predict, from the initial presenting features and laboratory findings, renal biopsy and clinical course during follow-up, which patients are likely to have progressive renal disease. Identification of the factors likely to be associated with progression is of importance in helping to establish which patients will benefit from specific therapeutic intervention. For all patients, attention should be directed toward general health issues in an endeavour to reverse factors that are likely to have an adverse impact on renal function. This should include early detection and tight control of hypertension (present in 50% of all patients with IgA nephropathy during the course of their disease), along with utilisation of antihypertensive agents that have specific renoprotective effects, namely ACE inhibitors or calcium antagonists. Such therapy should also be considered in normotensive patients with heavy proteinuria, as a reduction of proteinuria is often achieved by this means. Other aims should include maintenance of desirable bodyweight, correction of hyperlipidaemia, cessation of smoking, participation in an active exercise programme, avoidance of exposure to nephrotoxins and maintenance of a high fluid intake. A low protein/low phosphate diet together with phosphate binder therapy should be commenced early in the course of renal impairment. Corticosteroid and/or cytotoxic drug therapy should be considered in the small percentage of patients with heavy proteinuria or a rapid decline in renal function. Such therapeutic endeavours are likely to delay the onset of renal failure in patients with progressive IgA nephropathy.

Sublingual nifedipine in human pregnancy.

BACKGROUND: Nifedipine is widely used for acute lowering of blood pressure in obstetric hypertensive emergencies. It has not been approved for this indication or widely assessed. AIMS: To examine retrospectively the efficacy of nifedipine over a 12 month period in a high risk obstetric service. METHODS: Chart review of all patients admitted to hospital in the antenatal period with moderate to severe hypertension. Description of their management, usage of nifedipine, and pregnancy outcome. RESULTS: Sublingual nifedipine resulted in significant lowering of blood pressure without hypotension. Pregnancy outcome was satisfactory in all patients. CONCLUSIONS: Sublingual nifedipine was effective, easy to administer, and without serious complications in this retrospective study.

A thermodynamic equilibrium model for calcium salt urolithiasis: clinical application.

It is proposed that urine is better modelled as a true equilibrium rather than in a supersaturated/metastable state and that the free citrate3- ion plays a major role in maintaining dispersion of the solid particles (reduced agglomeration). Published urinary chemistries, in conjunction with the computer programme SEQUIL, have been used to formulate a novel risk index for calcium stone formation independent of the traditional clinical classification of the stone former. Applying the risk index to three consecutive 24-hour urine samples of 39 untreated Ca stone formers showed that 35 (90%) patients produced at least one abnormal urine. Traditional single urinary parameter assessment, Ca/Cr, oxalate/Cr or citrate/Cr ratios, showed that only 17, 14, and 18% of the patients, respectively, had an abnormality, while taking all three together 24 (70%) had some abnormality and thus 30% were 'idiopathic' stone formers. Treatment regimens have been devised using the computer programme to return an abnormal urine to the normal according to the proposed risk index. In most urines two or more factors had to be changed simultaneously. Clinically there has been only one recurrence in 36 months, whereas before they had 4.4/3 years.

Insulin-like growth factor I stimulates apical sodium/hydrogen exchange in human proximal tubule cells.

To determine whether insulin-like growth factor I (IGF-I) stimulated apical sodium/hydrogen exchange (NHE), confluent primary human proximal tubule cells (PTC) were incubated for 48 h in serum-free media in the presence or absence of 100 ng/ml IGF-I. Cells incubated in IGF-I demonstrated significant increases in thymidine incorporation (181.2 +/- 30.3% of control values; n = 12, P = 0.01) and in resting intracellular pH (pHi) (7.52 +/- 0.08 vs. 7.30 +/- 0.06; n = 20, P < 0.05), as determined by 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein quantitative microspectrofluorometry. Following intracellular acid loading, ethylisopropylamiloride (EIPA)-inhibitable H+ efflux and 22Na+ influx after 1 min were both significantly enhanced in IGF-I-treated cells compared with controls (8.78 +/- 1.69 vs. 3.03 +/- 0.72 mM/min and 3.47 +/- 0.49 vs. 1.55 +/- 0.35 nmol x mg protein(-1) x min(-1), respectively). 22Na+ uptake studies in PTC grown on permeable supports demonstrated preferential stimulation of apical vs. basolateral NHE. The 50% inhibitory concentrations (IC50) in IGF-I-treated and control cells for EIPA (0.5 and 1.1 microM, respectively) and for HOE-694 (4.0 and 10.0 microM, respectively) were also consistent with predominant activation of apical, rather than basolateral, NHE activity. Kinetic analysis revealed an increase in maximal transport velocity (Vmax, 15.50 +/- 1.50 vs. 7.26 +/- 3.07 mM/min; n = 10, P < 0.05), without a significant change in antiporter affinity for extracellular Na+. Incubation of PTC with 100 ng/ml IGF-I produced an acute, reversible, and EIPA-inhibitable pHi increase of 0.05 +/- 0.01 pH units (n = 5, P < 0.05). The results suggest that IGF-I may contribute to the metachronous stimulation of apical NHE and PTC growth observed in many physiological and pathological conditions involving the human kidney.

Human renal fibroblasts modulate proximal tubule cell growth and transport via the IGF-I axis.

To determine the paracrine interactions involved in the tubulointerstitial response to progressive renal disease, the role of insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBPs) in in vitro interactions between human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were studied in primary cell culture. PTC growth and transport were increased in the presence of CF-conditioned media (CF-CM), as shown by increased thymidine incorporation, cellular protein content and sodium-hydrogen exchange (NHE) activity, to 185 +/- 31% (P < 0.01), 150 +/- 18% (P < 0.05) and 195 +/- 27% (P < 0.01) of the control values, respectively. IGF-I was produced by cultured CF at a rate of 64.6 +/- 7.5 ng/mg protein/day. Exogenous IGF-I applied to PTC provoked similar enhancement of growth and NHE activity as CF-CM and the stimulatory effect of CF-CM was blocked by specific immunoneutralization of IGF-I receptors. These receptors were threefold more abundant on PTC basolateral versus apical membranes. IGF binding proteins (IGFBP)-2 and IGFBP-3 were secreted by CF at rates of 694 +/- 88 and 1769 +/- 45 ng/mg/day, with the release of IGFBP-3 being enhanced in the presence of PTC-CM (120.0 +/- 9.7% of control, P < 0.01). Moreover, the addition of CF-CM to PTC increased cell-associated IGFBP-3 on PTC surfaces, without changes in IGF-I receptor numbers or affinity and without changes in PTC mRNA for IGFBP-3. Des(1-3)IGF-I, an analog that binds to the IGF-I receptor but not to IGFBPs, provided a less potent stimulus for PTC growth compared with IGF-I, indicating that cell-associated IGFBP-3 facilitates the action of IGF-I on PTC. The results support important paracrine roles for both IGF-I and IGFBPs in the interstitial regulation of proximal tubule growth and transport.

Chronic volume expansion in the rat: proximal tubular Na+ transport and Na+ pump inhibition.

1. The lesser natriuresis of chronic volume expansion (ChVE) compared with that of acute volume expansion (AcVE) implies different homeostatic mechanisms. Because little information is available in the literature on proximal tubular (PT) Na+ transport and intracellular electrolyte concentrations, these were investigated in a rat model of ChVE. 2. Haematocrit was significantly lower and urine volume and Na+ excretion were significantly higher in ChVE rats compared with control rats. 3. Proximal tubular Na+ transport with artificial PT fluid was normal (3.67 +/- 0.09 x 10(-4) mm3 mm-2 s-1; mean+/-S.E.M.), while with endogenously harvested tubular fluid it was reduced to 2.78 +/- 0.07 x 10(-4) mm3 mm-2 s-1 in ChVE rats (P < 0.0001). 4. Intracellular Na+ was significantly elevated from 18.0 +/- 0.7 mmol (kg wet wt)-1 in control rats to 20.2 +/- 0.8 mmol (kg wet wt)-1 in ChVE rats (P = 0.044). The cells showed residual swelling, with dry weight and phosphorus values decreasing significantly compared with controls (19.5 +/- 0.4 to 18.5 +/- 0.03% and 130.4 +/- 3.7 to 117.8 +/- 2.8 mmol (kg wet wt)-1, P = 0.04 and 0.006, respectively). 5. The results demonstrate that in ChVE a tubular factor inhibits PT Na+ transport associated with an inhibition of the Na+ pump and this resembles one mechanism defined in AcVE.

X-ray microanalysis of cell elements in normal and cystic fibrosis jejunum: evidence for chloride secretion in villi.

BACKGROUND & AIMS: Cystic fibrosis transmembrane conductance regulator (CFTR) is an adenosine 3',5'-cyclic monophosphate-dependent chloride channel that is defective in cystic fibrosis. The aims of this study were to determine if defective apical chloride secretion in the intestine of patients with cystic fibrosis alters the intracellular electrolyte milieu and to examine the geographical localization of CFTR in the normal intestine. METHODS: The content of intracellular elements was assessed in cryosections using energy-dispersive x-ray microanalysis, and CFTR was identified by immunocytochemistry using commercially available antibodies. RESULTS: Cystic fibrosis jejunum had a significantly lower Na+ content, higher K+ and Cl- content, and higher potassium/phosphorus ratio in both villus and crypt regions. Incubation of normal jejunum with the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (300 mumol/L) resulted in decreased K+ and Cl- content in both crypt and villus regions, indicative of Cl- secretion. CFTR was identified on the surface of normal villus and crypt enterocytes but not in cystic fibrosis samples. CONCLUSIONS: Defective apical chloride channels in cystic fibrosis result in alterations in the intracellular electrolyte milieu. The microanalysis observations and immunocytochemical studies imply a role for villus enterocytes in human intestinal chloride secretion.

Transferable circulating factors and epithelial sodium transport after unilateral nephrectomy in the rat.

1. In order to investigate the role of circulating serum factors in the altered renal haemodynamics and enhanced renal tubular transport observed in renal growth, micropuncture experiments were performed on normal animals infused with 20% plasma derived from animals in whom unilateral nephrectomy had been performed 3 days previously. 2. When animals infused with plasma from uninephrectomized animals (NxP) were compared with those infused with control plasma, the former had a higher tubular fluid flow rate measured at both the late proximal (LP; 26.7 +/- 1.6 vs. 18.4 +/- 1.4 nl min-1; P < 0.001) and early distal (ED; 14.9 +/- 1.0 vs. 7.8 +/- 1.0 nl min-1; P < 0.0001) sites, which was reflected in the final urine flow rate (16.1 +/- 3.4 vs. 5.1 +/- 0.8 microliter min-1; P < 0.005). 3. The single nephron glomerular filtration rate (SNGFR) was higher in animals infused with NxP as determined from samples taken at the LP (45.8 +/- 2.8 vs. 35.7 +/- 2.3 nl min-1; P < 0.01) and at the ED (34.5 +/- 2.5 vs. 28.1 +/- 1.8 nl min-1; P = 0.05) sites. However, this increase was not reflected in the whole kidney GFR (1.04 +/- 0.06 vs. 0.89 +/- 0.06; P = 0.07), suggestive of a preferential increase in filtration in the outer cortical nephrons. 4. Tubular Na+ transport was higher in the animals infused with NxP as evidenced by a decrease in the fractional delivery of Na+ at the ED site (4.5 +/- 0.4 vs. 6.5 +/- 0.6% of the filtered load; P < 0.05). However, in the final urine there was a significant increase in the urinary sodium excretion in animals infused with NxP (0.67 +/- 0.14 vs. 0.29 +/- 0.09%; P < 0.05) indicating that natriuresis and probably diuresis was a result of inhibition of Na+ and water transport in the late distal tubule and collecting duct. 5. In conclusion, these experiments demonstrate that circulating factors induced by a reduction in renal mass significantly alter glomerular filtration and tubular Na+ transport.

Neonatal outcome in a randomized, controlled trial of low-dose aspirin in high-risk pregnancies.

OBJECTIVE: To determine the value of low-dose aspirin in high-risk pregnancies, and assess its impact on fetal growth, as well as on perinatal mortality and morbidity. METHODOLOGY: One hundred and eight women with singleton pregnancies were enrolled in a randomized, double-blind, placebo-controlled trial of 100 mg/day aspirin from 17 to 19 week gestation. Enrolment criteria included pre-existing chronic essential hypertension or renal disease, or a history of previous early, severe pre-eclampsia. RESULTS: There were four stillbirths (all aspirin) and two neonatal deaths (both placebo), to yield respective perinatal mortality rates of 69/1000 and 40/1000 (P = 0.499). Liveborn infants in the aspirin group were significantly more mature (P = 0.017) and of heavier birthweight (P = 0.034) but had similar length (P = 0.091) and head circumference (P = 0.257). Fewer infants in the aspirin group were liveborn prematurely (5/54 vs 14/50; P = 0.016) or were of low birthweight (3/54 vs 9/50; P = 0.052). There were no significant between-group differences for standard deviation (Z) scores for weight, length or head circumference, or for skinfold thickness measurements. There was no significant difference in occurrence of low Apgar scores or in neonatal intensive care unit use between the groups. CONCLUSIONS: Low-dose aspirin does not appear to have a significant effect on perinatal morbidity. The increase in weight at birth associated with low-dose aspirin therapy is due to prolongation of pregnancy rather than prevention of intra-uterine growth retardation.

Comparison of simultaneous renal clearances of true endogenous creatinine and subcutaneously administered iothalamate in man.

125I-iothalamate and true endogenous creatinine clearances, measured over two short collections periods of 1 and 2 h, were compared simultaneously in 70 patients with a variety of renal diseases and a wide range of renal function. Reproducibility of the iothalamate clearance was 18.5% and that of the creatinine clearance 12.2%. The slope of the regression was not significantly different from 1 (95% confidence interval, CI, 0.964-1.155) for the whole group, nor in any subgroup chosen. The intercept at 12.6 ml/min (CI = 5.0-20.2) indicates that there is some creatinine secretion, but this was constant at all levels of GFR. It is concluded that although the clearance of true creatinine obtained during short collection periods consistently overestimates GFR by a constant proportion, it is a reproducible and accurate measure of GFR suitable for use in the clinical setting.