Ciprofloxacin activity in cyst fluid from polycystic kidneys.

Renal cyst infection in patients with polycystic kidney disease (PKD) is often unresponsive to standard antimicrobial therapy, in part because of the failure of most antibiotics to adequately penetrate cyst fluid. Ciprofloxacin, a new quinolone antibiotic, possesses in vitro activity against most pathogens likely to be encountered in renal cyst infection. To study the potential usefulness of ciprofloxacin for the treatment of cyst infection, fluid from 70 cysts was obtained from seven patients with polycystic kidney disease who were receiving the drug. Cysts were categorized as nongradient or gradient by the sodium concentration in the fluid. The ciprofloxacin concentration within cysts was measured, and the cyst fluid bactericidal activity against likely cyst fluid pathogens was determined. The mean (+/- standard error) ciprofloxacin concentration was 12.7 +/- 2.9 micrograms/ml. Preferential accumulation of ciprofloxacin occurred in gradient cysts; these levels exceeded levels in serum by more than fourfold. Cyst fluid bactericidal activity titers were uniformly high against Escherichia coli and Proteus mirabilis, while less activity was observed against Streptococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis.     

Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation

Autosomal dominant polycystic kidney disease (ADPKD) is the most common human monogenic genetic disorder and is characterized by progressive bilateral renal cysts and the development of renal insufficiency. The cystogenesis of ADPKD is believed to be a monoclonal proliferation of PKD-deficient (PKD(-/-)) renal tubular epithelial cells. To define the function of Pkd1, we generated chimeric mice by aggregation of Pkd1(-/-) ES cells and Pkd1(+/+) morulae from ROSA26 mice. As occurs in humans with ADPKD, these mice developed cysts in the kidney, liver, and pancreas. Surprisingly, the cyst epithelia of the kidney were composed of both Pkd1(-/-) and Pkd1(+/+) renal tubular epithelial cells in the early stages of cystogenesis. Pkd1(-/-) cyst epithelial cells changed in shape from cuboidal to flat and replaced Pkd1(+/+) cyst epithelial cells lost by JNK-mediated apoptosis in intermediate stages. In late-stage cysts, Pkd1(-/-) cells continued immortalized proliferation with downregulation of p53. These results provide a novel understanding of the cystogenesis of ADPKD patients. Furthermore, immortalized proliferation without induction of p53 was frequently observed in 3T3-type culture of mouse embryonic fibroblasts from Pkd1(-/-) mice. Thus, Pkd1 plays a role in preventing immortalized proliferation of renal tubular epithelial cells through the induction of p53 and activation of JNK.     

The acute effect of acetazolamide on glomerular filtration rate and proximal tubular reabsorption of sodium and water in normal man

The acute effects on kidney function of acetazolamide (250 mg) given intravenously were evaluated in seven healthy subjects. Glomerular filtration rate was measured as the renal clearance of 51Cr-EDTA, and fluid flow rate out of the proximal tubules was assessed by measurement of the renal lithium clearance. An 18% decline in glomerular filtration rate (ml/min) was observed after acetazolamide administration (109 +/- 16 vs 89 +/- 14, p less than 0.02), while lithium clearance (ml/min) increased by 35% (30 +/- 5 vs 38 +/- 8, p less than 0.02). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one third (79 +/- 12 vs 51 +/- 9, p less than 0.02), and fractional proximal reabsorption of water and sodium (%) declined (73 +/- 2 vs 58 +/- 6, p less than 0.02). Renal sodium clearance and absolute distal reabsorption of sodium increased, while fractional distal reabsorption of sodium declined. Acetazolamide reduces absolute and fractional proximal tubular reabsorption of sodium and water, and glomerular filtration rate. Primarily, this induces an increase in the output of fluid from the proximal tubules accounting for the diuretic effect of the drug. The acute fall in glomerular filtration rate is probably mediated by a temporary increase in proximal intratubular pressure and activation of the tubuloglomerular feedback mechanism.     

In vitro function of cyst epithelium from human polycystic kidney

It is thought that cysts in polycystic kidneys originate from nephron segments and function in a manner similar to the segment or origin. The indirect evidence for this derives from studies of microanatomy and cyst fluid composition. Cysts with low Na+ have been classified as distal, whereas cysts with high Na+ have been classified as proximal. In order to directly determine the transport characteristics of cyst epithelium, cysts from a human polycystic kidney were studied in vitro using Ussing chamber techniques. Composition of cyst fluid was determined in parallel with these studies. Cysts with low Na+ (gradient cysts) demonstrate characteristics consistent with distal nephron origin including elevated potential difference (PD), short-circuit current (Isc), and low conductance. PD and Isc of gradient cysts were amiloride sensitive. Nongradient cysts, however, require additional characterization. At least two types of nongradient cysts were identified, one with characteristics consistent with proximal nephron origin and another apparently without function. These studies are the first direct evidence for active transport of cysts from human polycystic kidney and provide strong evidence to support the concept that cysts function in the same manner as the nephron segment of origin.     

Abdominal sonographic study of autosomal dominant polycystic kidney disease

PURPOSE: The purpose of this study was to determine whether kidney size in patients who have autosomal dominant polycystic kidney disease (ADPKD) is related to renal function, hypertension, or extrarenal manifestations of the disease and to sonographically evaluate the abdominal manifestations of ADPKD. METHODS: Between 1994 and 1998, 400 individuals from 85 families with a history of ADPKD were examined. There were 213 persons with ADPKD and 187 unaffected family members; there were 182 males and 218 females, 1-82 years old (mean, 39.3 years). We obtained a complete medical history, performed a physical examination, measured the arterial blood pressure and serum creatinine levels, and performed abdominal sonography on each subject. The sonographic features that were studied were renal length and the presence and number of cysts on the kidneys, liver, and pancreas. RESULTS: There was a relationship between kidney size and age (p < 0.05), kidney size and renal function (p < 0.001), and kidney size and hypertension (p < 0.001). The overall prevalence of hepatic cysts in patients with ADPKD was 67%, and the prevalence increased with age. The presence of hepatic cysts was related to the severity of renal disease. Females had more severe polycystic liver disease, and massive polycystic liver disease (ie, hepatomegaly with innumerable cysts) was seen only in females. The prevalence of pancreatic cysts in the 187 persons in whom the pancreas was well evaluated sonographically was 5%. CONCLUSIONS: Kidney size in patients with ADPKD is related to renal function, hypertension, and extrarenal involvement and can be used to predict the outcome of the disease. Hepatic cysts are very common in patients with ADPKD and are related to age and renal function; pancreatic cysts are infrequent in these patients.     

Distal tubular feedback in the autoregulation of single nephron glomerular filtration rate

Renal clearance and recollection micro-puncture experiments were conducted to evaluate the possible role of a distal tubular feedback mechanism in the phenomenon of renal autoregulation in dogs. Single nephron glomerular filtration rate (SNGFR) was measured from collection sites in both the proximal (proximal SNGFR) and distal tubules (distal SNGFR). Single nephron autoregulatory behavior was assessed by evaluating the response of SNGFR to a reduction in renal arterial pressure imposed by means of an aortic constrictor. Whole kidney function was evaluated by parallel measurements of renal blood flow and inulin clearance. Whole kidney autoregulation was observed when renal arterial pressure was decreased from 141 +/- 3 (SE) mm Hg to 101 +/- 2 mm Hg; renal blood flow and GFR were not significantly altered from control values of 3.76 +/- 0.2 ml/min.g and 0.69 +/- 0.04 ml/min.g kidney weight, respectively. In 11 autoregulating preparations, proximal transit time was likewise unchanged from the control value of 26 +/- 2 s, indirectly suggesting that the superficial nephrons also participated in the autoregulatory response. However, proximal SNGFR decreased significantly from 88 +/- 7 nl/min to 66 +/- 6 nl/min, a reduction which was proportional to the decrease in arterial pressure. In 14 dogs in which both proximal SNGFR and distal SNGFR were measured at control blood pressure (136 +/- 5 mm Hg), distal SNGFR was 47 +/- 4 nl/min, a value significantly lower than that for proximal SNGFR (79 +/- 6 nl/min). In contrast to the results based upon proximal collections, distal SNGFR was not significantly altered following aortic constriction (44 +/- 5 nl/min vs. 47 +/- 5 nl/min) therefore exhibiting autoregulation in association with that observed for the whole kidney. These experiments indicate that though superficial nephrons do possess autoregulatory capability, interruption of distal delivery due to complete collection from the proximal tubule interferes with that nephron's ability to manifest an autoregulatory response. They support the concept that a feedback mechanism, related to some function of distal delivery, is of significance in the intrinsic regulation of SNGFR. The data further suggest that quantitative estimates of SNGFR based on complete proximal collections may not be representative of those throughout the superficial cortex of the dog, at least in certain experimental circumstances.     

High-resolution ultrasonography in the differential diagnosis of cystic diseases of the kidney in infancy and childhood: preliminary experience

Autosomal recessive polycystic kidney disease, autosomal dominant polycystic disease, and glomerulocystic disease may all appear in the perinatal period as bilaterally enlarged echogenic kidneys. Current ultrasonographic equipment can better demonstrate the underlying pathologic state and assist in the differentiation of these conditions. The primary abnormality in autosomal recessive polycystic kidney disease is at the level of the collecting ducts, which are dilated and saccular. The nephrons remain normal. These dilated ectatic tubules are seen in their usual distribution as a radial array, with major ducts being perpendicular to the renal capsule, in both the renal cortex and the medulla. The peripheral renal cortex does not normally contain collecting ducts and remains unaffected in patients with mild disease. Autosomal dominant polycystic disease is characterized by cystic changes involving both the nephron and the collecting ducts. The nephron may become cystic at any point. Multiple discrete cysts of varying sizes are seen in both the renal cortex and the medulla in the severely affected infant. Subcapsular cysts are seen regularly. Glomerulocystic disease is an unusual sporadic condition characterized by the cystic dilation of the space of Bowman and the proximal convoluted tubule. On ultrasonographic examination tiny, isolated cysts, usually smaller than those occurring in autosomal dominant polycystic kidney disease, are seen in the echogenic renal cortex and may extend to the periphery of the kidney. No cysts are seen in the renal medulla. Correlation between pathologic findings and sonographic images is of value in correctly diagnosing these conditions.     

Hypertension and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

Hypertension is a common problem in patients with autosomal dominant polycystic kidney disease affecting both renal and patient survival. Activation of the renin-angiotensin-aldosterone system due to cyst expansion and local renal ischemia has been proposed to play an important role in the development of hypertension in autosomal dominant polycystic kidney disease. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with autosomal dominant polycystic kidney disease. Both hypertension and the activation of the renin-angiotensin-aldosterone system play a role in the development of left ventricular hypertrophy in these patients. Prospective randomized results indicate that aggressive control of blood pressure is important for the optimal reversal of left ventricular hypertrophy, thereby diminishing a major risk factor for cardiovascular morbidity and mortality of patients with autosomal dominant polycystic kidney disease. There is also substantial epidemiological support for aggressive control of blood pressure in slowing renal disease progression in autosomal dominant polycystic kidney disease patients. Blockade of the renin-angiotensin-aldosterone system should be the initial approach in the treatment of hypertension in these patients.     

Hypertension and left ventricular hypertrophy in autosomal dominant polycystic kidney disease

Hypertension is a common problem in patients with autosomal dominant polycystic kidney disease affecting both renal and patient survival. Activation of the renin–angiotensin–aldosterone system due to cyst expansion and local renal ischemia has been proposed to play an important role in the development of hypertension in autosomal dominant polycystic kidney disease. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with autosomal dominant polycystic kidney disease. Both hypertension and the activation of the renin–angiotensin–aldosterone system play a role in the development of left ventricular hypertrophy in these patients. Prospective randomized results indicate that aggressive control of blood pressure is important for the optimal reversal of left ventricular hypertrophy, thereby diminishing a major risk factor for cardiovascular morbidity and mortality of patients with autosomal dominant polycystic kidney disease. There is also substantial epidemiological support for aggressive control of blood pressure in slowing renal disease progression in autosomal dominant polycystic kidney disease patients. Blockade of the renin–angiotensin–aldosterone system should be the initial approach in the treatment of hypertension in these patients.     

Effects of lithium chloride and ethacrynic acid on experimental polycystic kidney disease

Hydrocortisone acetate is known to produce polycystic kidney disease when administered to susceptible animals in the perinatal period. To assess whether sodium and water transport mechanisms are involved in cyst pathogenesis, we administered lithium, an inhibitor of such transport in the distal nephron, and ethacrynic acid, an inhibitor of sodium transport in the Loop of Henle, to hydrocortisone acetate treated newborn rats. Hydrocortisone acetate alone resulted in significant polycystic kidney disease with the development of uremia, hypokalemia, and shortened life span. Co-administration of lithium and hydrocortisone acetate increased the severity of cystic tubular change and further compromised renal function. Ethacrynic acid reduced the degree of cyst formation induced by the combination of lithium chloride and hydrocortisone acetate but otherwise had no effect. We conclude that fluid and electrolyte disturbance plays a significant role in cyst formation, but we are unable to ascribe that effect to a single ion. We also conclude that the antinatriuretic effect of glucocorticoids is not the principal factor in glucocorticoid induced polycystic kidney disease.     

Antagonist capacities of nifedipine, captopril, phenoxybenzamine, prostacyclin and indomethacin on cyclosporin A induced impairment of rat renal function

Experimental evidence indicates that cyclosporin A (CyA) nephrotoxicity is due to renal arteriolar constriction, reducing renal blood flow, glomerular filtration rate (GFR), and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle. The proximal tubular fractional reabsorption (PFR) is increased. Therefore, the impact on renal function of vasodilating agents was studied in rats given CyA. Conscious catheterized rats and clearance techniques were used. In acute experiments a preexisting CyA-nephrotoxicity was resistant to infusion of phenoxybenzamine, prostacyclin, captopril, nifedipine and indomethacin. Concomitant treatment with captopril and CyA did not improve renal function, while concomitant treatment with CyA and nifedipine improved GFR to 1.13 +/- 0.34 ml min-1 g-1 kidney weight (gKW) (n = 19, P less than 0.05), as compared to CyA and placebo treated controls (n = 12, 0.83 +/- 0.32 ml min-1 g-1 KW). Nifedipine also reduced FPR (88.6 +/- 5.1% vs. 83.2 +/- 5.6%. P less than 0.01), and increased lithium clearance from 99 +/- 54 to 184 +/- 64 microliters min-1 g-1 KW (P less than 0.001). The results are further evidence that CyA nephrotoxicity includes renal vasoconstriction, and indicates that calcium entry blockade is nephroprotective in the case of CyA toxicity.     

经后腹腔镜肾囊肿去顶减压术治疗常染色体显性遗传性多囊肾

目的：观察经后腹腔镜肾囊肿去顶减压术治疗常染色体显性遗传性多囊肾病的临床效果。方法：2004～2007年经后腹腔镜囊肿去顶减压术治疗成人型多囊肾20例,术后随访6～36月,观察手术前后肾功能指标变化术后。结果：20例手术均获成功。平均手术时间71．0±5．28分钟,术后平均住院天数5±0．38天。结论：经后腹腔镜囊肿去顶减压术治疗多囊肾具有创伤小、出血少、恢复快等优点,是外科治疗成人型多囊肾安全有效的方法。     

On the site of decreased fluid reabsorption after release of ureteral obstruction in the rat.

Fluid reabsorption in surface nephrons was studied by micropuncture 3 hours after release of complete left ureteral ligation (LUL) or after unilateral release of bilateral ureteral ligation (BUL). In 11 rats with LUL, glomerular filtration rate (GFR) averaged 0.23 +/- 0.04 ml. per minute in the experimental vs. 1.25 +/- 0.11 ml. per minute in the control kidney. GFR averaged 0.18 +/- 0.02 ml. per minute in BUL. Single nephron glomerular filtration rate (SNGFR) was decreased in the experimental kidney of LUL or BUL when determined at proximal or distal sites as compared to the SNGFR determined in shams or the left kidney following right ureteral ligation (RUL). Fractional water excretion was increased after release of obstruction. LUL 2.72 +/- 0.66 per cent; BUL 12.3 +/- 2.82 per cent when compared to sham-operated rats (0.48 +/- 0.07 per cent) or to the untouched kidneys of the RUL group (0.60 +/- 0.09 per cent). Despite increased water and sodium excretion after release of unilateral ureteral ligation and BUL there were marked differences in tubular fluid reabsorption between these two groups. Following release of LUL there was increased fractional water reabsorption along the accessible length of surface nephrons of the experimental kidney. At 55 per cent of proximal tubular length TF/Pin averaged 4.02 +/- 0.02 in LUL vs. 2.18 +/- 0.06 in shams. The mean TF/Pin at 90 per cent of distal tubular length was 31.0 +/- 1.37 in LUL vs. 10.6 +/- 0.08 in sham-operated rats. In contrast, water reabsorption after BUL was slightly but significantly suppressed proximally (TF/Pin 1.95 +/- 0.02) and markedly depressed distally (TF/Pin 3.35 +/- 0.29). These results suggest that the change in fluid reabsorption observed after relief of LUL is located at a site beyond the accessible length of surface nephrons, most likely in the collecting duct. However, the data could also be explained by alterations in fluid reabsorption in deep nephrons. The changes in fluid reabsorption seen following release of BUL reflect the additive effects of release of obstruction and a marked reduction in functioning nephron mass.     

Effects of Felodipine on the dog kidney: a lithium clearance study.

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorption rate increased significantly from 2.1 +/- 0.3 to 2.7 +/- 0.4 mmol min-1. Sodium clearance (C-Na) increased from 0.22 +/- 0.08 to 0.40 +/- 0.07 ml min-1. The alpha-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After alpha-adrenergic blockade felodipine caused an increase in C-Na from 0.28 +/- 0.06 ml min-1 to 0.63 +/- 0.04 ml min-1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after alpha-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local alpha-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.     

The excretion of carbonic anhydrase isozymes CA I and CA II in the urine of apparently healthy subjects and in patients with kidney disease

Carbonic anhydrase isozymes CA I and CA II were assayed by a radio-immunosorbent technique in the plasma and urine of apparently healthy subjects and of patients with renal disease. The concentrations (mean +/- SD, n = 8) of CA I and CA II in the plasma of healthy subjects were 2.3 +/- 2.3 and 0.8 +/- 0.5 mg/l, respectively. The urinary excretion values were 3.8 +/- 2.0 and 3.5 +/- 1.9 micrograms/24 h, and the apparent renal clearances were 21 +/- 17 and 52 +/- 44 microliters/min, respectively, values that are similar to those of other low molecular weight proteins. CA I and CA II have mol. wt of 28,850 and 29,300, respectively, they are globular in shape and have a Stoke-Einstein radius of 25 A. They could, therefore, be expected to be filtered at the glomeruli and thereafter reabsorbed by the proximal tubules. CA II is also present in the cytoplasm of renal proximal and distal tubular cells. A study of the pattern of urinary excretion of CA I and CA II could permit detection of damage to renal tubular cells in two ways--either from defective reabsorption of filtered CA I and CA II by the proximal tubular cells, or from leakage of CA II from the proximal or distal tubules into the urine. Some patients with hypercalcuria and renal tubular acidosis showed increased excretion of these enzyme proteins and of beta 2-microglobulin (BMG) into the urine, but the prevalence was rather low (27%). Further studies of patients with more severely damaged kidneys are required.     

The increased proximal tubular reabsorption of sodium and water is maintained in long-term insulin-dependent diabetics with early nephropathy

Proximal tubular reabsorption of sodium and water was investigated in long-term insulin-dependent diabetic patients with normoalbuminuria (group I, n = 19), microalbuminuria (group II, n = 39), diabetic nephropathy (group III, n = 12) and in 13 healthy age-matched subjects. Glomerular filtration rate was measured with the single injection, 51Cr-EDTA technique. The fluid flow rate out of the proximal tubules was assessed by the renal lithium clearance. Although glomerular filtration rate was significantly elevated in the diabetic patients (Group I: 122 +/- 16, Group II: 121 +/- 18, Group III: 110 +/- 17, Controls: 105 +/- 13 ml/min X 1.73 m2), lithium clearance was similar in the four groups (Group I: 19 +/- 6, Group II: 22 +/- 7, Group III: 19 +/- 5, Controls: 23 +/- 4 ml/min X 1.73 m2). Both absolute and fractional proximal reabsorption of sodium and water was enhanced in diabetes. Indices of distal tubular function did not differ between controls and patients with insulin-dependent diabetes. Sodium clearance was about the same in the four groups. Our study suggests that the enhanced proximal reabsorption of sodium and water in insulin-dependent diabetic patients is still observed despite the presence of incipient or overt diabetic nephropathy.     

Expression and cellular localisation of renal endothelin-1 and endothelin receptor subtypes in autosomal-dominant polycystic kidney disease

The major factors influencing the rate of progression of chronic renal disease in autosomal-dominant polycystic kidney disease (ADPKD) are unknown and there are currently no effective treatments for slowing the progression of chronic renal failure in ADPKD patients. As a first step in investigating the potential role of endothelin-1 (ET1) and its receptors (ETA and ETB) in the pathophysiology of progression in ADPKD, we have studied their expression and cellular localisation in ADPKD kidney. Immunoreactive ET1 was detected in cyst epithelia, mesangial cells and vascular smooth muscle cells suggesting continuing ET1 synthesis in the cystic kidney. Compared to healthy controls, ETA mRNA was 5-10-fold higher in ADPKD cystic kidney. In cystic kidney, neo-expression of ETA receptors was found overlying glomeruli and cysts and markedly increased in medium-sized renal arteries by microautoradiography. This is the first study to demonstrate a specific upregulation of ETA receptors in human renal disease. Future studies should address whether ETA selective antagonists may be effective in slowing renal disease progression in ADPKD.     

Renal tubular effects of chronic phosphate depletion.

The effects of chronic phosphate depletion on renal tubular function were evaluated by micropuncture and free water clearance studies in the dog. Proximal tubular punctures demonstrated that chronic hypophosphatemia led to a reduction in ratio of tubular fluid to plasma inulin in late superficial tubular from 1.59+/-0.08 in control animals to 1.29+/-0.06 in phosphate-depleted dogs, with proportional inhibition of calcium and sodium reabsorption. The chronic decrease in proximal tubular fluid reabsorption was confirmed by the analysis of sustained water diuresis in conscious, phosphate-depleted dogs, before and after repletion of body PO4 stores, and in control animals. Urine flow rate/100 ml glomerular filtration rate (V/GFR) was significantly higher in PO4 DEPLETION THAN CONTROL (15.8+/-1.1 VS. 10.7+/-0.82). In addition, acetazolamide infusion did not increase V/GFR in phosphate-depleted dogs (15.8+/-1.1 vs. 17.16+/-0.9), supporting the conclusion that inhibition of proximal tubular fluid reabsorption was responsible for the elevated urine flow rate. PO4 repletion over 5 days reduced V/GFR to 9.2+/-0.7 despite no change in urine osmolality and no change in GFR, further suggesting a specific reversible alteration in proximal tubular reabsorption in phosphate depletion. Although hypercalciuria was a constant finding in phosphate depletion (fractional excretion of calcium of 2.04+/-0.4% vs. 0.47+/-0.13% in controls), the enhanced distal delivery of calcium was not a crucial factor; acute phosphate infusion reduced urinary calcium excretion to control values without affecting the reduced proximal tubular reabsorption in either intact or thyroparathyroidectomized phosphate-depleted dogs the change in distal nephron calcium reabsorption was independent of parathyroid hormone (PTH) levels since infusion of PTH failed to alter urinary calcium excretion. We conclude that chronic phosphate depletion leads to a reversible, sustained inhibition in proximal tubular reabsorptive fuction as well as a specific decrease in distal nephron calcium reabsorption. This latter reabsorptive defect is sensitive to phosplate infusion but not corrected by PTH.     

Epidermal growth factor receptor activity mediates renal cyst formation in polycystic kidney disease.

A consistent phenotype observed in both human patients and several different mouse models of autosomal recessive polycystic kidney disease (ARPKD) is an increased activity of the epidermal growth factor receptor (EGFR) in the affected kidneys. To determine whether this increased activity of the EGFR is a functional event that is directly part of the disease pathway of renal cyst formation, we used a genetic approach to introduce a mutant EGFR with decreased tyrosine kinase activity into a murine model of ARPKD. We found that the modified form of the EGFR could block the increase in EGFR-specific tyrosine kinase activity that normally accompanies the development of renal cysts, and this correlated with an improvement in kidney function and a substantial decrease in cyst formation in the collecting ducts. These results suggest that changes in the expression of the EGFR contribute to the formation of cysts in the collecting ducts, and that drugs that target the tyrosine kinase activity of the EGFR may potentially be therapeutic in ARPKD.     

Stereoselective inhibition of pindolol renal clearance by cimetidine in humans.

There are few data on whether differences exist in the renal tubular secretion of enantiomers and no data on whether inhibition of renal secretion of individual enantiomers is stereoselective. Pindolol was used as a probe drug because it is used clinically as a racemic mixture of R-(+) and S-(-) enantiomeric forms and is highly secreted by the proximal tubules of the kidney. Eight young healthy subjects received a single 15 mg oral dose of racemic pindolol with and without 400 mg cimetidine twice daily. The area under the plasma concentration-time curve of both R-(+)- and S-(-)-pindolol were significantly (p less than 0.01) increased by cimetidine from 234 +/- 90 (mean +/- SD) to 344 +/- 78 ng/ml.hr for R-(+)-pindolol and from 209 +/- 73 to 288 +/- 69 ng/ml.hr for S-(-)-pindolol. The renal clearance of R-(+)-pindolol (170 +/- 55 ml/min) was significantly (p less than 0.05) less than that for S-(-)-pindolol (222 +/- 66 ml/min). Cimetidine significantly (p less than 0.01) reduced the renal clearances of R-(+)-pindolol to 104 +/- 18 ml/min and for S-(-)-pindolol to 155 +/- 38 ml/min. The enantiomer with the higher renal clearance [S-(-)-pindolol] had its renal clearance reduced less by cimetidine (26% versus 34%, p less than 0.05). Cimetidine appears to have a stereoselective action on the active transport system for organic cations in the proximal tubule.