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Patients are often advised to reduce sodium and potassium intake, but supporting evidence is limited. To help provide such evidence we estimated 24 h urinary sodium and potassium excretion in 28,879 participants at high cardiovascular risk who were followed for a mean of 4.5 years in the ONTARGET and TRANSCEND trials. The primary outcome was eGFR decline of 30% or more or chronic dialysis. Secondary outcomes were eGFR decline of 40% or more or chronic dialysis, doubling of serum creatinine or chronic dialysis, an over 5%/year loss of eGFR, progression of albuminuria, and hyperkalemia. Multinomial logit regression with multivariable fractional polynomials, adjusted for confounders, determined the association between urinary sodium and potassium excretion and renal outcomes, with death as a competing risk. The primary outcome occurred in 2,052 (7.6%) patients. There was no significant association between sodium and any renal outcome (primary outcome odds ratio 0.99; 95% CI 0.89-1.09 for highest [median 6.2 g/day] vs. lowest third [median 3.3 g/day]). Higher potassium was associated with lower odds of all renal outcomes (primary outcome odds ratio 0.74; 95% CI 0.67-0.82 for highest [median 2.7 g/day] vs. lowest third [median 1.7 g/day], except hyperkalemia nonsignificant. Thus, urinary potassium, but not sodium, excretion predicted clinically important renal outcomes. Our findings do not support routine low sodium and potassium diets for prevention of renal outcomes in people with vascular disease with or without chronic kidney disease. [ABSTRACT FROM AUTHOR]

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m2 or more versus the normal of 18.5-25 kg/m2) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m2, height 1.76 m, and BMI 22 or 45 kg/m2 had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research. [ABSTRACT FROM AUTHOR]

Current guidelines recommend under 2 g/day sodium intake in chronic kidney disease, but there are a few studies relating sodium intake to long-term outcomes. Here we evaluated the association of mean baseline 24-h urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality using Cox regression in 840 participants enrolled in the Modification of Diet in Renal Disease Study. Mean 24-h urinary sodium excretion was 3.46 g/day. Kidney failure developed in 617 participants, and the composite outcome was reached in 723. In the primary analyses, there was no association between 24-h urine sodium and kidney failure (HR 0.99 (95% CI 0.91-1.08)) nor on the composite outcome (HR 1.01 (95% CI 0.93-1.09)), each per 1 g/day higher urine sodium. In exploratory analyses, there was a significant interaction of baseline proteinuria and sodium excretion with kidney failure. Using a two-slope model, when urine sodium was under 3 g/day, higher urine sodium was associated with increased risk of kidney failure in those with baseline proteinuria under 1 g/day and with lower risk of kidney failure in those with baseline proteinuria of ⩾1 g/day. There was no association between urine sodium and kidney failure when urine sodium was⩾3 g/day. Results were consistent using first baseline and time-dependent urinary sodium excretion. Thus, we noted no association of urine sodium with kidney failure. Results of the exploratory analyses need to be verified in additional studies and the mechanism explored. [ABSTRACT FROM AUTHOR]

Current teaching states that when sodium intake is increased from low to high levels, total-body sodium (TBNa) and water increase until daily sodium excretion again equals intake. When sodium intake is reduced, sodium excretion briefly exceeds intake until the excess TBNa and water are eliminated, at which point sodium excretion again equals intake. However, careful balance studies oftentimes conflict with this view and long-term studies suggest that TBNa fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for several weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly to cortisol. TBNa was not dependent on sodium intake but instead exhibited far longer (monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. The findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing 23Na-magnetic resonance imaging (MRI) to pursue open questions on sodium balance in patients. Our findings could be relevant to therapeutic strategies for hypertension and target-organ damage. [ABSTRACT FROM AUTHOR]

Increased serum urate predicts chronic kidney disease independent of other risk factors. The use of xanthine oxidase inhibitors coincides with improved renal function. Whether this is due to reduced serum urate or reduced production of oxidants by xanthine oxidase or another physiological mechanism remains unresolved. Here we applied Mendelian randomization, a statistical genetics approach allowing disentangling of cause and effect in the presence of potential confounding, to determine whether lowering of serum urate by genetic modulation of renal excretion benefits renal function using data from 7979 patients of the Atherosclerosis Risk in Communities and Framingham Heart studies. Mendelian randomization by the two-stage least squares method was done with serum urate as the exposure, a uric acid transporter genetic risk score as instrumental variable, and estimated glomerular filtration rate and serum creatinine as the outcomes. Increased genetic risk score was associated with significantly improved renal function in men but not in women. Analysis of individual genetic variants showed the effect size associated with serum urate did not correlate with that associated with renal function in the Mendelian randomization model. This is consistent with the possibility that the physiological action of these genetic variants in raising serum urate correlates directly with improved renal function. Further studies are required to understand the mechanism of the potential renal function protection mediated by xanthine oxidase inhibitors. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that in end-stage renal disease is markedly increased in serum; however, the mechanisms responsible for this increase are unclear. Here, we tested whether phosphate retention in chronic kidney disease (CKD) is responsible for the elevation of FGF23 in serum using Col4α3 knockout mice, a murine model of Alport disease exhibiting CKD. We found a significant elevation in serum FGF23 in progressively azotemic 8- and 12-week-old CKD mice along with an increased fractional excretion of phosphorus. Both moderate and severe phosphate restriction reduced fractional excretion of phosphorus by 8 weeks, yet serum FGF23 levels remained strikingly elevated. By 12 weeks, FGF23 levels were further increased with moderate phosphate restriction, while severe phosphate restriction led to severe bone mineralization defects and decreased FGF23 production in bone. CKD mice on a control diet had low serum 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and 3-fold higher renal Cyp24α1 gene expression compared to wild-type mice. Severe phosphate restriction increased 1,25(OH)2D levels in CKD mice by 8 weeks and lowered renal Cyp24α1 gene expression despite persistently elevated serum FGF23. Renal klotho gene expression declined in CKD mice on a control diet, but improved with severe phosphate restriction. Thus, dietary phosphate restriction reduces the fractional excretion of phosphorus independent of serum FGF23 levels in mice with CKD. [ABSTRACT FROM AUTHOR]

Renal K+ excretion is increased rapidly following dietary K+ intake, but the underlying molecular mechanisms are largely unknown. Sorensen and colleagues show that K+ intake in mice provoked rapid and near-complete dephosphorylation of the renal distal convoluted tubule NaCl cotransporter, temporally associated with increases in both Na+ and K+ excretion. This response was independent of aldosterone and may be a crucial component of the acute homeostatic adaptation of the kidney to K+ intake. [ABSTRACT FROM AUTHOR]

Many biological functions follow circadian rhythms driven by internal and external cues that synchronize and coordinate organ physiology to diurnal changes in the environment and behavior. Urinary acid-base parameters follow diurnal patterns and it is thought these changes are due to periodic surges in gastric acid secretion. Abnormal urine pH is a risk factor for specific types of nephrolithiasis and uric acid stones result from excessively low urine pH. Here we placed 9 healthy volunteers and 10 uric acid stone formers on fixed metabolic diets to study the diurnal pattern of urinary acidification. All showed clear diurnal trends in urinary acidification, but none of the patterns were affected by inhibitors of the gastric proton pump. Uric acid stone formers had similar patterns of change throughout the day but their urine pH was always lower compared to healthy volunteers. Uric acid stone formers excreted more acid (normalized to acid ingestion), with the excess excreted primarily as titratable acid rather than ammonium. Urine base excretion was also lower in uric acid stone formers (normalized to base ingestion), along with lower plasma bicarbonate concentrations during part of the day. Thus, increased net acid presentation to the kidney and the preferential use of buffers, other than ammonium, result in much higher concentrations of undissociated uric acid throughout the day and consequently an increased risk of uric acid stones. [ABSTRACT FROM AUTHOR]

Noncommunicable diseases (NCDs) are the most common causes of premature death and morbidity and have a major impact on health-care costs, productivity, and growth. Cardiovascular disease, cancer, diabetes, and chronic respiratory disease have been prioritized in the Global NCD Action Plan endorsed by the World Health Assembly, because they share behavioral risk factors amenable to public-health action and represent a major portion of the global NCD burden. Chronic kidney disease (CKD) is a key determinant of the poor health outcomes of major NCDs. CKD is associated with an eight- to tenfold increase in cardiovascular mortality and is a risk multiplier in patients with diabetes and hypertension. Milder CKD (often due to diabetes and hypertension) affects 5-7% of the world population and is more common in developing countries and disadvantaged and minority populations. Early detection and treatment of CKD using readily available, inexpensive therapies can slow or prevent progression to end-stage renal disease (ESRD). Interventions targeting CKD, particularly to reduce urine protein excretion, are efficacious, cost-effective methods of improving cardiovascular and renal outcomes, especially when applied to high-risk groups. Integration of these approaches within NCD programs could minimize the need for renal replacement therapy. Early detection and treatment of CKD can be implemented at minimal cost and will reduce the burden of ESRD, improve outcomes of diabetes and cardiovascular disease (including hypertension), and substantially reduce morbidity and mortality from NCDs. Prevention of CKD should be considered in planning and implementation of national NCD policy in the developed and developing world. [ABSTRACT FROM AUTHOR]

The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid. [ABSTRACT FROM AUTHOR]

Elevated urinary albumin excretion in patients with type 1 diabetes reverts to normoalbuminuria in a majority of patients but advances toward proteinuria in some. In order to gain valuable insights into the early pathophysiology of diabetic nephropathy we evaluated the association of kidney tubular injury biomarkers with changes in albuminuria in patients with type 1 diabetes mellitus. Urine levels of kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and some inflammatory markers were determined in 38 healthy individuals and 659 patients with type 1 diabetes mellitus having varying degrees of albuminuria. Urinary interleukin-6, CXCL10/IP-10, NAG, and KIM-1 levels were very low in healthy individuals, increased in type 1 patients with normoalbuminuria, and were highest in diabetic patients that had microalbuminuria. Low baseline concentrations of urinary KIM-1 and NAG both individually and collectively were significantly associated with the regression of microalbuminuria over the subsequent 2 years; an effect independent of clinical characteristics. Progression and regression of microalbuminuria were unrelated to urinary levels of interleukins 6 and 8, CXCL10/IP-10, and monocyte chemoattractant protein-1. Thus our results show that lower urinary KIM-1 and NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus. Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

We present here the anatomy and histopathology of kidneys from 11 patients with renal stones following small bowel resection, including 10 with Crohn's disease and 1 resection in infancy for unknown cause. They presented predominantly with calcium oxalate stones. Risks of formation included hyperoxaluria (urine oxalate excretion greater than 45 mg per day) in half of the cases, and acidic urine of reduced volume. As was found with ileostomy and obesity bypass, inner medullary collecting ducts (IMCDs) contained crystal deposits associated with cell injury, interstitial inflammation, and papillary deformity. Cortical changes included modest glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Randall's plaque (interstitial papillary apatite) was abundant, with calcium oxalate stone overgrowth similar to that seen in ileostomy, idiopathic calcium oxalate stone formers, and primary hyperparathyroidism. Abundant plaque was compatible with the low urine volume and pH. The IMCD deposits all contained apatite, with calcium oxalate present in three cases, similar to findings in patients with obesity bypass but not an ileostomy. The mechanisms for calcium oxalate stone formation in IMCDs include elevated urine and presumably tubule fluid calcium oxalate supersaturation, but a low calcium to oxalate ratio. However, the mechanisms for the presence of IMCD apatite remain unknown. [ABSTRACT FROM AUTHOR]

Controversy exists as to whether minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) represent different diseases or are manifestations within the same disease spectrum. Urinary excretion of CD80 (also known as B7.1) is elevated in patients with MCD and hence we tested whether urinary CD80 excretion might distinguish between patients with MCD from those with FSGS. Urinary CD80 was measured in 17 patients with biopsy-proven MCD and 22 with proven FSGS using a commercially available enzyme-linked immunosorbent assay and its molecular size determined by western blot analysis. A significant increase in urinary CD80, normalized to urinary creatinine, was found in patients with MCD in relapse compared to those in remission or those with FSGS. No significant differences were seen when CD80 urinary excretion from MCD patients in remission were compared to those with FSGS. In seven of eight MCD patients in relapse, CD80 was found in glomeruli by immunohistochemical analysis of their biopsy specimen. No CD80 was found in glomeruli of two patients with FSGS and another MCD patient in remission. Thus, our study supports the hypothesis that MCD and FSGS represent two different diseases rather than a continuum of one disease. Urinary CD80 excretion may be a useful marker to differentiate between MCD and FSGS. [ABSTRACT FROM AUTHOR]

Urinary exosomes or microvesicles are being studied intensively to identify potential new biomarkers for renal disease. We sought to identify whether these microvesicles contain nucleic acids. We isolated microvesicles from human urine in the same density range as that previously described for urinary exosomes and found them to have an RNA integrity profile similar to that of kidney tissue, including 18S and 28S rRNA. This profile was better preserved in urinary microvesicles compared with whole cells isolated from urine, suggesting that microvesicles may protect RNA during urine passage. We were able to detect mRNA in the human urinary microvesicles encoding proteins from all regions of the nephron and the collecting duct. Further, to provide a proof of principle, we found that microvesicles isolated from the urine of the V-ATPase B1 subunit knockout mice lacked mRNA of this subunit while containing a normal amount of the B2 subunit and aquaporin 2. The microvesicles were found to be contaminated with extraneous DNA potentially on their surface; therefore, we developed a rapid and reliable means to isolate nucleic acids from within urine microvesicles devoid of this extraneous contamination. Our study provides an experimental strategy for the routine isolation and use of urinary microvesicles as a novel and non-invasive source of nucleic acids to further renal disease biomarker discovery. [ABSTRACT FROM AUTHOR]

There is increasing evidence that urinary albumin excretion, even when below the accepted threshold values for normal excretion, may have significant impact on future cardiovascular risks. To further define this, a total of 1086 patients, aged 45 years and older from the population-based, longitudinal ‘Study of Health in Pomerania’ were evaluated. Patients had echocardiographic analysis at baseline and 5-year follow-up, and were grouped into quartiles according to their baseline urinary albumin-to-creatinine ratio. At baseline, left ventricular mass in the first three quartiles was similar; however, the fourth quartile was significantly elevated and further increased over the 5-year follow-up. In the first quartile, the albumin-to-creatinine ratio and left ventricular mass did not significantly change over 5 years. In the second and third quartiles, the left ventricular mass progressively increased and was significantly correlated with the albumin-to-creatinine ratio. In multivariable analysis, this association was independent of other common cardiovascular risk factors and applicable to both genders. Our study found that the urinary albumin-to-creatinine ratio, even below the current threshold for definition of microalbuminuria, is significantly associated with increased left ventricular mass. [ABSTRACT FROM AUTHOR]

Cerebral salt-wasting (CSW), or renal salt-wasting (RSW), has evolved from a misrepresentation of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) to acceptance as a distinct entity. Challenges still confront us as we attempt to differentiate RSW from SIADH, ascertain the prevalence of RSW, and address reports of RSW occurring without cerebral disease. RSW is redefined as ‘extracellular volume depletion due to a renal sodium transport abnormality with or without high urinary sodium concentration, presence of hyponatremia or cerebral disease with normal adrenal and thyroid function.’ Our inability to differentiate RSW from SIADH lies in the clinical and laboratory similarities between the two syndromes and the difficulty of accurate assessment of extracellular volume. Radioisotopic determinations of extracellular volume in neurosurgical patients reveal renal that RSW is more common than SIADH. We review the persistence of hypouricemia and increased fractional excretion of urate in RSW as compared to correction of both in SIADH, the appropriateness of ADH secretion in RSW, and the importance of differentiating renal RSW from SIADH because of disparate treatment goals: fluid repletion in RSW and fluid restriction in SIADH. Patients with RSW are being incorrectly treated by fluid restriction, with clinical consequences. We conclude that RSW is common and occurs without cerebral disease, and propose changing CSW to RSW. [ABSTRACT FROM AUTHOR]

On a typical Western diet, the body is faced with the generation of a metabolically derived acid load that must be excreted to maintain systemic acid–base balance. The kidney is responsible for this task and matches daily acid excretion with daily acid production. Multiple nephron segments are involved in the process, including the proximal tubule cell. This review discusses the acid-activated signaling pathway in the proximal tubule that senses a decrease in cell pH and then mediates stimulation of the apical membrane Na/H antiporter, isoform NHE3. NHE3 mediates secretion of the majority of protons involved in bicarbonate reclamation, is involved in ammonium secretion, and provides a source of luminal protons for titrating filtered titratable acids and secreted ammonia to ammonium.Kidney International (2007) 72, 1324–1329; doi:10.1038/sj.ki.5002543; published online 19 September 2007 [ABSTRACT FROM AUTHOR]

A 35-year-old African-American woman with sickle cell trait presented to our medical center with severe gross hematuria. The patient reported having had dark urine for at least 2 months, but after a recent 2 h and 30 min air travel, her urine became bright red and she began passing dark clots. In addition, she started experiencing generalized fatigue, weakness, and mild dizziness. The patient had experienced several episodes of gross hematuria in the past. One such episode, 15 years ago, resulted in a prolonged hospitalization and transfusion of 5U of blood. Another episode took place 11 years ago lasting for approximately 2 weeks, but symptoms resolved spontaneously. The etiology of her hematuria had never been established. Other medical problems included chronic right knee osteoarthritis and degenerative lumbar disk disease. She denied chronic use of non-steroidal anti-inflammatory agents, but admitted to frequent use of acetaminophen for arthritic pain. Upon presentation, the patient appeared comfortable. Her blood pressure was 130/60, and heart rate was 80/min. Head, neck, lung, and heart examinations were unremarkable. The abdomen was soft and non-tender and liver span was normal. The tip of the spleen was palpable. There was no pedal edema. Her laboratory values were significant for mild anemia with hematocrit of 33% (normal 34-44%). The platelet count was 313 × 109/l (normal 165-415 ×109/l) and white blood cell count was 6.5 ×109/l (normal 3.5-9.0 × 109/l). Her coagulation parameters were normal. The serum electrolytes were also within normal range. Her renal function was preserved with a creatinine of 0.9 mg/dl (normal 0.5-0.9 mg/dl) and a blood urea nitrogen of 7 mg/dl (normal 7-20 mg/dl). Urine analysis revealed 3 + hemoglobin and no protein. Urine microscopy showed 182 red blood cells per high powerfield. Urine cultures were negative. Renal ultrasound measured the right kidney length at 11.7 cm; the left kidney was 11.9 cm in length; there was no hydronephrosis or calculus in either kidney. The urinary bladder was unremarkable. Magnetic resonance imaging confirmed that both kidneys were of normal size and signal, and no solid enhancing lesion was identified. Diagnostic cystoscopy and ureteroscopy were performed. Blood was visualized effluxing from the right ureteral orifice. Upon inspection of the collecting system, the posterior middle pole calyx was found to have a stenotic infundibulum. Endoinfundibulotomy was performed to enter the calyx, where there appeared to be a sloughed ischemic papilla with an accompanying hemorrhage (Figure 1). The papilla was fully fulgurated in an attempt to stop the bleeding. The remaining calyces and the renal pelvis were also inspected and found to be free of disease. Although the bleeding ceased in the immediate post-procedure period, it reappeared later that day. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) is hardly controlled in chronic kidney disease (CKD). We compared the effect of very low protein diet (VLPD) supplemented with ketoanalogs of essential amino acids (0.35 g/kg/day), low protein diet (LPD, 0.60 g/kg/day), and free diet (FD) on BP in patients with CKD stages 4 and 5. Vegetable proteins were higher in VLPD (66%) than in LPD (48%). LPD was prescribed to 110 consecutive patients; after run-in, they were invited to start VLPD. Thirty subjects accepted; 57 decided to continue LPD; 23 refused either diet (FD group). At baseline, protein intake (g/kg/day) was 0.79±0.09 in VLPD, 0.78±0.11 in LPD, and 1.11±0.18 in FD (P<0.0001). After 6 months, protein intake was lower in VLPD than LPD and FD (0.54±0.11, 0.78±0.10, and 1.04±0.21 g/kg/day, respectively; P<0.0001). BP diminished only in VLPD, from 143±19/84±10 to 128±16/78±7 mm Hg (P<0.0001), despite reduction of antihypertensive drugs (from 2.6±1.1 to 1.8±1.2; P<0.001). Urinary urea excretion directly correlated with urinary sodium excretion, which diminished in VLPD (from 181±32 to 131±36 mEq/day; P<0.001). At multiple regression analysis (R2=0.270, P<0.0001), BP results independently related to urinary sodium excretion (P=0.023) and VLPD prescription (P=0.003), but not to the level of protein intake. Thus, in moderate to advanced CKD, VLPD has an antihypertensive effect likely due to reduction of salt intake, type of proteins, and ketoanalogs supplementation, independent of actual protein intake.Kidney International (2007) 71, 245–251. doi:10.1038/sj.ki.5001955; published online 11 October 2006 [ABSTRACT FROM AUTHOR]

Dietary protein as casein (CAS) augments intrinsic acid production, induces endothelin-mediated kidney acidification, and promotes kidney injury. We tested the hypothesis that dietary CAS induces endothelin-mediated kidney injury through augmented intrinsic acid production. Munich–Wistar rats ate minimum electrolyte diets from age 8 to 96 weeks with 50 or 20% protein as either acid-inducing CAS or non-acid-inducing SOY. Urine net acid excretion and distal nephron net HCO3 reabsorption by in vivo microperfusion (Net JHCO3) were higher in 50 than 20% CAS but not 50 and 20% SOY. At 96 weeks, 50% compared the 20% CAS had higher urine endothelin-1 excretion (UET-1V) and a higher index of tubulo-interstitial injury (TII) at pathology (2.25±0.21 vs 1.25±0.13 U, P<0.03), but each parameter was similar in 50 and 20% SOY. CAS (50%) eating NaHCO3 to reduce intrinsic acid production had lower Net JHCO3, lower UET-1V, and less TII. By contrast, 50% SOY eating dietary acid as (NH4)2SO4 had higher Net JHCO3, higher UET-1V, and more TII. Endothelin A/B but not A receptor antagonism reduced Net JHCO3 in 50% CAS and 50% SOY+(NH4)2SO4 animals. By contrast, endothelin A but not A/B receptor antagonism reduced TII in each group. The data support that increased intake of acid-inducing dietary protein induces endothelin B-receptor-mediated increased Net JHCO3 and endothelin A-receptor-mediated TII through augmented intrinsic acid production.Kidney International (2007) 71, 210–217. doi:10.1038/sj.ki.5002036; published online 13 December 2006 [ABSTRACT FROM AUTHOR]

A body mass index (BMI)25 kg/m2 increases the risk for long-term renal damage, possibly by renal hemodynamic factors. As epidemiological studies suggest interaction of BMI and sodium intake, we studied the combined effects of sodium intake and BMI on renal hemodynamics. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in 95 healthy men (median age 23 years (95% confidence interval: 22–24), BMI: 23.0±2.5 kg/m2) on low (50 mmol Na+, LS) and high (200 mmol Na+, HS) sodium intake. Mean GFR and ERPF significantly increased by the change to HS (both P<0.001). During HS but not LS, GFR and filtration fraction (FF) positively correlated with BMI (R=0.32 and R=0.28, respectively, both P<0.01). Consequently, BMI correlated with the sodium-induced changes in GFR (R=0.30; P<0.01) and FF (R=0,23; P<0.05). The effects of HS on GFR and FF were significantly different for BMI25 versus <25 kg/m2, namely 7.8±12.3 versus 16.1±13.1 ml/min (P<0.05) and −0.1±2.2 and 1.1±2.3% (P<0.05). FF was significantly higher in BMI25 versus <25 kg/m2, (22.6±2.9 versus 24.6±2.4%, P<0.05) only during HS. ERPF was not related to BMI. Urinary albumin excretion was increased by HS from 6.0 (5.4–6.7) to 7.6 (6.9–8.9). Results were essentially similar after excluding the only two subjects with BMI>30 kg/m2. BMI is a determinant of the renal hemodynamic response to HS in healthy men, and of GFR and FF during HS, but not during LS. Consequently, HS elicited a hyperfiltration pattern in subjects with a BMI25 kg/m2 that was absent during LS. Future studies should elucidate whether LS or diuretics can ameliorate the long-term renal risks of weight excess.Kidney International (2007) 71, 260–265. doi:10.1038/sj.ki.5002011; published online 8 November 2006 [ABSTRACT FROM AUTHOR]

Type II Bartter's syndrome is a hereditary hypokalemic renal salt-wasting disorder caused by mutations in the ROMK channel (Kir1.1; Kcnj1), mediating potassium recycling in the thick ascending limb of Henle's loop (TAL) and potassium secretion in the distal tubule and cortical collecting duct (CCT). Newborns with Type II Bartter are transiently hyperkalemic, consistent with loss of ROMK channel function in potassium secretion in distal convoluted tubule and CCT. Yet, these infants rapidly develop persistent hypokalemia owing to increased renal potassium excretion mediated by unknown mechanisms. Here, we used free-flow micropuncture and stationary microperfusion of the late distal tubule to explore the mechanism of renal potassium wasting in the Romk-deficient, Type II Bartter's mouse. We show that potassium absorption in the loop of Henle is reduced in Romk-deficient mice and can account for a significant fraction of renal potassium loss. In addition, we show that iberiotoxin (IBTX)-sensitive, flow-stimulated maxi-K channels account for sustained potassium secretion in the late distal tubule, despite loss of ROMK function. IBTX-sensitive potassium secretion is also increased in high-potassium-adapted wild-type mice. Thus, renal potassium wasting in Type II Bartter is due to both reduced reabsorption in the TAL and K secretion by max-K channels in the late distal tubule.Kidney International (2006) 70, 51–59. doi:10.1038/sj.ki.5000388; published online 17 May 2006 [ABSTRACT FROM AUTHOR]

The primary goal of this study was to test the hypothesis that Oxalobacter colonization alters colonic oxalate transport thereby reducing urinary oxalate excretion. In addition, we examined the effects of intraluminal calcium on Oxalobacter colonization and tested the hypothesis that endogenously derived colonic oxalate could be degraded by lyophilized Oxalobacter enzymes targeted to this segment of the alimentary tract. Oxalate fluxes were measured across short-circuited, in vitro preparations of proximal and distal colon removed from Sprague–Dawley rats and placed in Ussing chambers. For these studies, rats were colonized with Oxalobacter either artificially or naturally, and urinary oxalate, creatinine and calcium excretions were determined. Colonized rats placed on various dietary treatment regimens were used to evaluate the impact of calcium on Oxalobacter colonization and whether exogenous or endogenous oxalate influenced colonization. Hyperoxaluric rats with some degree of renal insufficiency were also used to determine the effects of administering encapsulated Oxalobacter lysate on colonic oxalate transport and urinary oxalate excretion. We conclude that in addition to its intraluminal oxalate-degrading capacity, Oxalobacter interacts physiologically with colonic mucosa by inducing enteric oxalate secretion/excretion leading to reduced urinary excretion. Whether Oxalobacter, or products of Oxalobacter, can therapeutically reduce urinary oxalate excretion and influence stone disease warrants further investigation in long-term studies in various patient populations.Kidney International (2006) 69, 691–698. doi:10.1038/sj.ki.5000162; published online 11 January 2006 [ABSTRACT FROM AUTHOR]

Background. Phenylalanine is converted to para- and ortho-tyrosine by hydroxyl free radical, or to para-tyrosine by the phenylalanine hydroxylase enzyme. The aim of this study was to measure para- and ortho-tyrosine in the urine and plasma of patients with chronic renal disease and/or diabetes, to obtain information on the renal handling of the different tyrosine isomers and, furthermore, to measure urinary levels of 8-epi-prostaglandin-F2α, a marker of lipid peroxidation. Methods. In our cross-sectional study we measured para-, ortho-tyrosine, and phenylalanine levels, using high performance liquid chromatography and 8-epi-prostaglandin-F2α with enzyme-linked immunosorbent assay (ELISA). We compared 4 groups: ( 1) controls (CONTR, N= 14), ( 2) patients with chronic kidney disease (CKD, N= 12), ( 3) patients with type 2 diabetes mellitus (DIAB, N= 17), ( 4) patients with chronic kidney disease and type 2 diabetes (DIAB-CKD, N= 19). Results. We found a decreased plasma para-tyrosine level and decreased urinary para-tyrosine excretion in CKD patients, while the fractional excretion of para-tyrosine was similar in all 4 groups, approximately 1%. There was no difference in the plasma ortho-tyrosine levels between the groups. However, urinary ortho-tyrosine excretion was higher in all 3 groups of patients than in the CONTR group, and higher in DIAB and in DIAB-CKD patients than in CKD patients. The fractional excretion of ortho-tyrosine was significantly higher in DIAB and in DIAB-CKD patients than in the CONTR group. The fractional excretion of ortho-tyrosine exceeded 100% in the 2 diabetic groups. Urinary 8-epi-prostaglandin-F2α/creatinine ratio did not correlate with urinary ortho-tyrosine excretion. Conclusion. The difference between para-tyrosine levels of the groups is probably due to renal impairment, while there is indirect evidence for an increased tubular secretion or production of ortho-tyrosine in the kidney in diabetic patients with or without CKD. [ABSTRACT FROM AUTHOR]

Increased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes.Background.The tubular excretion of creatinine significantly contributes to its clearance. Administration of an angtiotensin-converting enzyme (ACE) inhibitor is associated with increased organic ion clearance in experimental diabetes. This study examines the effect and implications of chronic ACE inhibition on renal organic ion excretion in patients with type 1 diabetes.Methods.Samples were obtained from the Melbourne Diabetic Nephropathy Study Group (MDNSG) that randomized patients to receive perindopril (N= 11), nifedipine (N= 11), or placebo (N= 8). Albumin excretion rate, creatinine clearance, and isotopic glomerular filtration rate (GFR) were assessed at baseline and after 24 months. In addition, the clearance of the endogenous cations N-methylynicotinamide (NMN), creatinine, and the anion hippurate were determined by high-performance liquid chromatography (HPLC).Results.Following treatment with the ACE inhibitor, perindopril, renal clearance of NMN was increased (+96%) (P<0.05). There was no difference in patients treated with nifedipine (P= 0.25) and NMN clearance fell in the placebo-treated patients (−26%) (P<0.05). Changes in NMN clearance were unaffected after adjusting for the effects of perindopril on GFR. However, they were attenuated after adjusting for hippurate clearance, a marker of renal blood flow. This effect of perindopril on NMN clearance was seen in both men and women, regardless of baseline clearance and was correlated with reduced albuminuria following perindopril treatment.Conclusion.Organic ion clearance is increased in patients with diabetes following chronic ACE inhibition. This is consistent with experimental models showing increased ion transporter expression and improved tubular blood flow, following blockade of the renin-angiotensin system (RAS). These findings may have implications for the interpretation of creatinine-based indices in patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: It is generally acknowledged that calcium excretion is a determinant of bone mineral density. Since data confirming this hypothesis are not conclusive, the present study evaluates the relationship between calcium excretion and volumetric bone mineral density (vBMD) in a sample of general population mostly composed of elderly subjects. Methods: This relationship was studied in 595 subjects in good health (M/F 302/293), selected from the InCHIANTI population, an epidemiologic survey on aging in Tuscany (Italy). Of these subjects, 432 (72.6%) were 65 years old or older. Trabecular and cortical apparent vBMDs were measured by peripheral quantitative computed tomography at right tibia and standardized to age and body mass index (BMI) in each gender (z-score). Results: Men in the highest tertile of calcium excretion had significantly lower trabecular vBMD, and were more likely to have a trabecular z-score of -1 or less. These results were confirmed in men older than 64 years, but not in women and younger men. Sodium excretion and 25-hydroxycolecalciferol (25(OH)D) were greater in men and women in the highest tertile. No differences among tertiles were observed for cortical vBMD, circulating levels of interleukin-1beta and interleukin-6, and intake of principal nutrients and calcium. The lower levels of vBMD z-score were confirmed in men in the highest tertile of calcium excretion, standardized to creatinine clearance, sodium excretion, plasma calcium, and logarithm of circulating 25(OH)D, and resulted to be associated with calcium excretion at multiple regression analysis in men. Conclusion: High calcium excretion is associated with a decreased trabecular BMD in elderly men and may predispose men to trabecular bone loss. [ABSTRACT FROM AUTHOR]

Down-regulation of urinary AQP2 and unaffected response to hypertonic saline after 24 hours of fasting in humans.Background.In rats, 24 hours of fasting impairs urinary concentrating ability by down-regulation of aquaporin-2 (AQP2). We tested the hypothesis that 24 hours of fasting in humans reduces the capability to form AQP2 and impairs the antidiuretic response to hypertonic saline infusion.Methods.In a crossover study of 14 healthy subjects, the effect of 24 hours of fasting was compared to a nonfasting control experiment on urinary excretion of AQP2 (u-AQP2), free water clearance (CH2O), plasma arginine vasopressin (AVP), urinary cyclic AMP (u-cAMP), and natriuretic peptides. The following response to 3% sodium infusion was measured using the same effect variables. U-AQP2, AVP, and u-cAMP were determined by radioimmunoassays.Results.Fasting during 24 hours reduced u-AQP2 (14%), increased AVP (30%) despite a reduction in serum osmolality (P<0.05), and depleted volume. CH2O and urine volume were not reduced, thus relatively increased after fasting. u-cAMP was not significantly different between the two procedures. Three percent saline resulted in the same relative increases in AVP, serum osmolality, u-AQP2, and u-cAMP and decreases in CH2O and urine volume independently of fasting. The reduced u-AQP2 and increased AVP after fasting were maintained during and after saline infusion.Conclusion.Twenty-four hours of fasting decreased u-AQP2 and reduced urine osmolality likely as a result of decreased sensitivity of collecting duct cells to AVP. Fasting-related insensitivity of collecting duct cells to AVP was restored by 3% saline infusion. Finallly, after saline infusion, other factors such as the increased plasma atrial natriuretic peptide (p-ANP) levels could contribute to the u-AQP2 regulation. [ABSTRACT FROM AUTHOR]

Quantitative amino acid and proteomic analysis: Very low excretion of polypeptides>750 Da in normal urine.Background.Quantitative data on protein and polypeptide excretion in normal urine are lacking. In Fanconi syndrome, failure of proximal tubular protein reabsorption leads to‘tubular’ proteinuria, but little is known about peptide excretion.Methods.Urine from normal (N= 5) and Fanconi patients (Dent's disease,N= 2; Lowe syndrome,N= 3) was fractionated by size-exclusion chromatography into proteins (>10 kD) and smaller polypeptides. Each fraction was subjected to amino acid analysis after acid hydrolysis. In complementary proteomic approaches, urinary polypeptides were each subjected to reversed-phase high-performance liquid chromatography (HPLC) followed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and nano-flow liquid chromatography directly coupled to electrospray ionization/tandem mass spectrometry (NanoLC-ESI-MS/MS) before and after tryptic digestion.Results.Based on amino acid composition, normal human urine, excluding Tamm-Horsfall protein, contains 33.7± 10.7 mg protein per 24 hr (mean± SEM) protein defined as polypeptide>10 kD; peptide content in range 750 Da to 10 kD is 22.0± 9.6 mg. Fanconi patients excrete greatly increased amounts of protein, 1740± 660 mg/24 hr, and peptide, 446± 145 mg/24 hr. Peptides 2 to 5 kD were present in 12.9-± 3.9-fold excess in Fanconi compared with normal urine. In contrast, free amino acid excretion in Fanconi was elevated only 2.14-± 0.73-fold. Mass spectrometric techniques determined that the major form of albumin in both normal and Fanconi urine was the full-length protein, and did not detect significant peptides of nonrenal origin.Conclusion.There is only very low excretion of polypeptides>750 Da in normal human urine. In Fanconi syndrome, excretion of unknown peptides of mass 2 to 5 kD, possibly relevant to the development of renal failure, is greatly increased. [ABSTRACT FROM AUTHOR]

Relation of urinary albumin excretion to coronary heart disease and low renal function: Role of blood pressure. Background. Previous studies report that urinary albumin excretion is associated with coronary heart disease (CHD). The present epidemiologic study investigated if ( 1) blood pressure status affects the association of urinary albumin excretion with CHD; and ( 2) urinary albumin excretion is associated with low renal function also. Methods. The cross-sectional association was analyzed of overnight urinary albumin excretion with prevalence of CHD (myocardial infarction and/or ischemia as defined by standard electrocardiogram) and low renal function (overnight creatinine clearance <60 mL/min) in a population sample of 1632 men and women with ages 45 to 64 years. Hypertension, hypercholesterolemia, smoking habit, and diabetes mellitus were included in analyses. Results. CHD prevalence was in the whole sample 8.2% ( N= 134), in the hypertensive subgroup 11.9% ( N= 79), and in the nonhypertensive subgroup 5.7% ( N= 55). For the association between urinary albumin excretion (logarithm-transformed due to skewed distribution) and CHD, the multivariate logistic coefficient with 95% CI was significant in the whole sample (+0.79, 95% CI =+0.32/+1.26, P < 0.001) and in the hypertensive subgroup (+0.97, 95% CI =+0.70/+1.24, P < 0.001), not in the nonhypertensive subgroup (−0.06, 95% CI =−0.80/+0.68, P= 0.997). Prevalence of low creatinine clearance was in the whole sample 4.0% ( N= 66), in the hypertensive subgroup 4.8% ( N= 32), and in the nonhypertensive subgroup 3.5% ( N= 34). [ABSTRACT FROM AUTHOR]

Schedule of taking calcium supplement and the risk of nephrolithiasis. Background. Variation in the timing of calcium supplement may affect gastrointestinal absorption of both calcium and oxalate differently and may associate with variable risk of calcium oxalate nephrolithiasis. There are few human studies addressing specifically the appropriate time for taking calcium supplement. Therefore, this study was performed to compare calcium bioavailability and the risk of calcium oxalate stone formation for calcium supplement taken with meal vs. taken at bedtime. Methods. Thirty-two healthy male navy privates, 22.7 ± 1.9 years old (mean ± SD), who had normal renal function (serum creatinine less than 150 umol/L) and no history of renal stone, participated in the study. The subjects were randomly allocated into two groups of 16 each. Group A took 1 g of calcium carbonate with meal, 3 times/day; and group B took 3 g/day of calcium carbonate at bedtime. After taking the regimens for 1 week, followed by 1 month of washout period, crossover between both groups was done. The diet was controlled throughout the study. Twenty-four–hour urine collections for the determination of urinary constituents were obtained at baseline and after taking both regimens of calcium supplement. Activity product for calcium oxalate was determined to assess the risk of calcium oxalate stone formation. Results. Urinary excretions of calcium were significantly elevated above the baseline values when taking calcium supplement both with meal (3.48 ± 2.13 mmol/day vs. 5.17 ± 2.61 mmol/day, P < 0.05) and at bedtime (3.09 ± 1.70 mmol/day vs. 5.08 ± 2.34 mmol/day, P < 0.05). There was no difference between the two regimens in the urinary calcium excretions. The urinary oxalate was decreased significantly when the subjects took calcium supplement with meal compared with the corresponding baseline value (0.13 ± 0.05 vs. 0.17 ± 0.07 mmol/d, P= 0.01). In contrast, there was no alteration in urinary oxalate when calcium supplement was taken at bedtime compared to the baseline values (0.15 ± 0.05 mmol/day vs. 0.15 ± 0.06 mmol/day, P= 0.9). Compared with the corresponding baseline values, there was no significant increase in the activity product for calcium oxalate when taking calcium with meal (0.54 ± 0.25 vs. 0.57 ± 0.22, P= 0.54), but it was increased significantly when calcium supplement was taken at bedtime (0.47 ± 0.21 vs. 0.72 ± 0.27, P < 0.01). Conclusion. Calcium supplement should be taken with meal in order to avoid increasing the risk of calcium oxalate nephrolithiasis. [ABSTRACT FROM AUTHOR]

The phosphatonin pathway: New insights in phosphate homeostasis. Serum phosphate concentrations are maintained within a defined range by processes that regulate the intestinal absorption and renal excretion of inorganic phosphate. The hormones currently believed to influence these processes are parathyroid hormone (PTH) and the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1α,25(OH)2D). A new class of phosphate-regulating factors, collectively known as the phosphatonins, have been shown to be associated with the hypophosphatemic diseases, tumor-induced osteomalacia (TIO), X-linked hypophosphatemic rickets (XLH), and autosomal-dominant hypophosphatemic rickets (ADHR). These factors, which include fibroblast growth factor 23 (FGF23) and secreted frizzled-related protein 4 (FRP4), decrease extracellular fluid phosphate concentrations by directly reducing renal phosphate reabsorption and by suppressing 1α,25(OH)2D formation through the inhibition of 25-hydroxyvitamin D 1α-hydroxylase. The role of these substances under normal or pathologic conditions is not yet clear. For example, it is unknown whether any of the phosphatonins are directly responsible for the decreased concentrations of 1α,25(OH)2D observed in chronic and end-stage kidney disease or whether they are induced in an attempt to correct the hyperphosphatemia seen in late stages of chronic renal failure. Future experiments should clarify their physiologic and pathologic roles in phosphate metabolism. [ABSTRACT FROM AUTHOR]

Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. Background. Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation. Methods. To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2% calcium diet alone or with 1%, 3% or 5% trans-4-hydroxy-l-proline (hydroxyproline). Results. The addition of 1% hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter calcium excretion while the provision of 5% hydroxyproline led to a decrease in urine calcium excretion. The addition of 1% hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5% hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3% hydroxyproline diet the addition of 5% hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1% hydroxyproline group, all of the stones were composed of calcium and... [ABSTRACT FROM AUTHOR]

Urea and nitrogen excretion in pediatric peritoneal dialysis patients. Background. Adequate nutrition is critical to the care of children with end-stage renal disease, and failure to reach the target dietary intake is associated with growth failure. Prospective studies of urea and nitrogen output in adults have led to the derivation of quantitative relationships, which allow assessment of dietary protein intake when only urea appearance is known. Such a clinically useful relationship has not been defined in children receiving chronic peritoneal dialysis (PD). Methods. We studied 18 pediatric PD patients (ages 0.8 to 14.3 years) on 132 occasions and determined norms of urea nitrogen appearance (UNA), total nitrogen appearance (TNA), and nonurea nitrogen appearance (NUNA). We stratified data on UNA, TNA, NUNA, nonprotein nitrogen appearance, and the protein equivalent of nitrogen appearance by age groups (0 to 5, 6 to 10, and 11 to 15 years of age) and demonstrated significant differences. In addition, dietary protein and energy intake were measured in the outpatient setting with food scales and dietitian interviews, and the results were stratified by age, presence of residual renal function, and recombinant human growth hormone (rhGH) therapy. Results. UNA (3.05 ± 1.38 g/day, 103 ± 42 mg/kg/day) and TNA (4.67 ± 1.86 g/day, 159 ± 52 mg/kg/day) varied significantly between different age groups. NUNA in pediatric subjects (56 ± 24 mg/kg/day) was significantly greater than previously published adult norms. A linear relationship was defined between UNA and TNA that was specific to pediatric PD patients [TNA (g/day) = 1.26(UNA) + 0.83]. When the relationship was scaled to body mass, the y intercept was significantly different in the youngest subjects [TNA = 1.03 (UNA) + 0.02 (weight in kg) + 0.56 (for subjects age 0 to 5) or 0.98 (for subjects age 11 to 15 or 6 to 10), r 2 = 0.91]. Dietary protein intake was significantly greater in... [ABSTRACT FROM AUTHOR]

Massive reduction of urea transporters in remnant kidney and brain of uremic rats. Background. The facilitated urea transporters (UT), UT-A1, UT-A2, and UT-B1, are involved in intrarenal recycling of urea, an essential feature of the urinary concentrating mechanism, which is impaired in chronic renal failure (CRF). In this study, the expression of these UTs was examined in experimentally induced CRF. Methods. The abundance of mRNA was measured by Northern analysis and that of corresponding proteins by Western blotting in rats one and five weeks after 5/6 nephrectomy (Nx). Results. At five weeks, urine output was enhanced threefold with a concomitant decrease in urine osmolality. The marked rise in plasma urea concentration and fall in urinary urea concentration resulted in a 30-fold decrease in the urine/plasma (U/P) urea concentration ratio, while the U/P osmoles ratio fell only fourfold. A dramatic decrease in mRNA abundance for the three UTs was observed, bringing their level at five weeks to 1/10th or less of control values. Immunoblotting showed complete disappearance of the 97 and 117 kD bands of UT-A1, and considerable reduction of UT-A2 and UT-B1 in the renal medulla. Similar, but less intense, changes were observed at one-week post-Nx. In addition to the kidney, UT-B1 is also normally expressed in brain and testis. In the brain, its mRNA expression remained normal one-week post-Nx, but decreased to about 30% of normal at five-weeks post-Nx, whereas no change was seen in testis. Conclusions. (1) The decline in urinary concentrating ability seen in CRF is largely due to a major reduction of UTs involved in the process of urea concentration in the urine, while factors enabling the concentration of other solutes are less intensely affected. (2) The marked reduction of brain UT expression in CRF may be responsible for brain edema of dialysis disequilibrium syndrome observed in some patients after fast dialysis. [ABSTRACT FROM AUTHOR]

Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Background. The objectives of this study were to compare the effects of the angiotensin II receptor blocker, losartan, to those of the angiotensin-converting enzyme inhibitor, enalapril, on albuminuria and renal function in relationship to clinic and ambulatory blood pressure (ABP) in hypertensive type 2 diabetic subjects with early nephropathy. The tolerability of these agents and their effect on the metabolic profile were also evaluated. Methods. The study was a one-year prospective, double-blind trial with losartan and enalapril administered alone or in combination with hydrochlorothiazide and other antihypertensive agents. ABP and renal and biochemical parameters were measured at baseline and after 12, 28, and 52 weeks of active treatment. Ninety-two hypertensive type 2 diabetics with early nephropathy completed the study. Results. Both losartan and enalapril administered alone or in combination with other agents induced significant reductions in sitting clinic (P < 0.05) and ABP (P < 0.002) without a statistical difference between groups. Geometric means for urinary albumin excretion (UAE) decreased significantly (P < 0.001) in patients treated with losartan from 64.1 to 41.5 μg/min and in those treated with enalapril from 73.9 to 33.5 μg/min after 52 weeks of therapy. A significant relationship (P < 0.05) between changes in systolic and diastolic ABP and the decrease in UAE at 52 weeks was seen in both groups. The decline in glomerular filtration rate (GFR) was stabilized at the end of therapy and was identical in both treatment groups. Treatment with enalapril was associated with a significantly higher incidence of cough (P = 0.006) and a rise in serum uric acid (P = 0.002) compared with losartan. Conclusions. Our results indicate that a one-year course of antihypertensive therapy with either losartan or enalapril... [ABSTRACT FROM AUTHOR]

Comparative effects of potassium chloride and bicarbonate on thiazide-induced reduction in urinary calcium excretion. Background. The chronic low-grade metabolic acidosis that occurs in various renal disorders and in normal people, and that is related both to dietary net acid load and age-related renal functional decline, may contribute to osteoporosis by increasing urine calcium excretion. Administration of potassium (K) alkali salts neutralizes acid and lowers urine calcium excretion. Urine calcium excretion also can be reduced by the administration of thiazide diuretics, which are often given with supplemental K to avoid hypokalemia. We determined whether the K alkali salt potassium bicarbonate (KHCO3 ) and the thiazide diuretic hydrochlorothiazide (HCTZ) combined is more effective in reducing urinary calcium than KHCO3 alone or HCTZ combined with the conventionally coadministered nonalkalinizing K salt potassium chloride (KCl). Methods. Thirty-one healthy men and women aged 50 or greater were recruited for a four-week, double-blind, randomized study. After a baseline period of 10 days with three 24-hour urine and arterialized blood collections, subjects were randomized to receive either HCTZ (50 mg) plus potassium (60 mmol daily) as either the chloride or bicarbonate salt. Another 19 women received potassium bicarbonate (60 mmol) alone. After two weeks, triplicate collections of 24-hour urines and arterialized bloods were repeated. Results. Urinary calcium excretion decreased significantly in all groups. KHCO3 alone and HCTZ + KCl induced similar decreases (-0.70 ± 0.60 vs. -0.80 ± 1.0 mmol/day, respectively). Compared with those treatments, the combination of HCTZ + KHCO3 induced more than a twofold greater decrease in urinary calcium excretion (-1.8 ± 1.2 mmol/day, P < 0.05). Both HCTZ + KHCO3 and KHCO3 alone reduced net acid excretion significantly (P < 0.05) to values of... [ABSTRACT FROM AUTHOR]

Renal function in the AT1A receptor knockout mouse during normal and volume-expanded conditions. Background. Genetically altered mice lacking the AT1A angiotensin II (Ang II) receptor were used to examine the role of AT1A receptors in regulating renal hemodynamics, sodium excretion, glomerulotubular balance, and Ang II levels in plasma and kidney during normal and volume-expanded conditions. Methods. AT1A receptor-deficient mice and their wild-type controls were anesthetized with inactin and ketamine, and were prepared to allow intravenous infusions of solutions and measurements of aortic pressure and urine collections. Inulin and para-aminohippurate (PAH) solutions were infused intravenously for clearance determinations under conditions of euvolemia (2.5 μl/min infusion of isotonic saline) or volume-expansion conditions (12.5 μl/min). After three 30-minute urine collections, blood samples were collected, and kidneys were harvested. Plasma and kidney Ang II measurements were made by radioimmunoassay. Results. In the euvolemic state, mean arterial pressures (MAPs) were significantly lower in the AT1A receptor-deficient mice (68 ± 4 mm Hg) compared with wild-type controls (89 ± 3 mm Hg). Despite the lower MAP, the glomerular filtration rate (GFR), renal plasma flow (RPF), absolute sodium excretion, and fractional sodium excretion were not significantly different between wild-type and AT1A -/- mice. Volume expansion did not alter MAP in wild-type mice, but significantly increased MAP in the AT1A -/- mice (68 ± 4 to 83 ± 5 mm Hg). Similar increases in GFR, RPF, absolute sodium excretion, and fractional sodium excretion in AT1A +/+ and AT1A -/- mice were observed. Glomerulotubular balance was not disrupted by the absence of AT1A receptors. During euvolemia, plasma Ang II concentrations were significantly higher in the... [ABSTRACT FROM AUTHOR]

Detects alpha-Adducin polymorphism and renal sodium handling in patients with essential hypertension. Relationship between blood pressure and sodium excretion; Importance of alpha-Adducin locus in human hypertension; Detection of plasma renin activity and fractional excretion of sodium.