Distal Delivery Research Articles

Use of the Proxis embolic protection device for guide anchoring and stent delivery during complex saphenous vein graft interventions

Optimal guide catheter engagement and an embolic protection strategy are crucial for successful saphenous vein graft (SVG) percutaneous coronary interventions. We describe three SVG cases during which the use of Proxis device not only provided embolic protection, but also served as a guide catheter anchor allowing distal stent delivery, after failed attempts using conventional techniques.

Thiazide Effects and Adverse Effects

One of the longest-running debates in clinical medicine shows no sign of disappearing; just when it seems that thiazides have reassumed their role as front-line drugs to treat hypertension,1 new concerns emerge,2–4 leading some to question their role once again.5 Thiazides are effective antihypertensives with long track records and low cost. The major concerns about their use arise from their tendency to cause hypokalemia, impair glucose tolerance, increase serum cholesterol, and increase serum uric acid. Few medical controversies have generated as much heat, with well-established camps staking out positions that appear resistant to change.6–9 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest study of antihypertensive monotherapy ever performed,10 was intended to identify the best first-line treatment for high-risk hypertensive individuals; however, despite its size and the numerous resulting publications, its implications and authority continue to be disputed. The goal of this review is not take sides in this debate but rather to inject a distinct, and sometimes neglected, perspective; during the past 15 years, remarkable developments in molecular biology and human genetics have provided substantial insights into the pathogenesis of hypertension and mechanisms and adverse effects of diuretics. Diuretic proponents and antagonists alike often neglect these developments when addressing the topic; it is the purpose of this Brief Review to integrate these developments into the debate with the goal of generating questions that can be addressed scientifically. Thiazide diuretics were developed during the 1950s, when chemists and physiologists at Merck Sharpe and Dohme tested derivatives of sulfonamide-based carbonic anhydrase inhibitors, with the goal of discovering drugs that enhance the excretion of sodium with chloride rather than sodium bicarbonate.* Although these drugs lower arterial pressure effectively, the mechanisms have long perplexed investigators.11 Thiazides reduce cardiac output acutely by reducing extracellular …

Use of the Heartrail II catheter as a distal stent delivery device; an extended case series

The Terumo Heartrail catheter (Terumo Corp., Tokyo, Japan) allows extra deep catheter intubation of coronary vessels and has been shown to be useful in CTO lesions. The aim of this study is to assess the safety and efficacy of using the Heartrail II catheter as a distal stent delivery system in PCI following failure of conventional techniques. We prospectively identified cases performed over a 15-month period in which a Heartrail catheter was used to facilitate stent delivery following failure of conventional techniques. Stent delivery using the Heartrail catheter was performed in 35 cases and was successful in 31 cases. Success rates of 100% in grafts, 95% in RCA, 80% in LAD and 60% in circumflex cases were recorded respectively. Successful stent delivery was associated with intubation depth, with 29/29 succeeding when the intubation depth was > 2 cm and failure in 4/5 cases when the intubation depth <or= 2 cm. There were no complications related to deep intubation of the catheter. Use of the Heartrail catheter is safe and highly effective for aiding stent delivery across proximal obstructions in both left and right coronary systems. The small number of unsuccessful cases were related to inability of the catheter to traverse stenotic proximal obstructions within 2 cm of the RCA and LCA origins.

Enhanced Distal Nephron Sodium Reabsorption in Chronic Angiotensin II–Infused Mice

Chronic angiotensin II (Ang II) infusions enhance urinary excretion of angiotensinogen, suggesting augmentation of distal nephron sodium reabsorption. To assess whether chronic Ang II infusions (15 ng/min for 2 weeks) enhance distal nephron sodium reabsorption, we compared sodium excretion before and after blockade of the 2 main distal nephron sodium transporters by IV amiloride (5 mg/kg of body weight) plus bendroflumethiazide (12 mg/kg of body weight) in male C57/BL6 anesthetized control mice (n=10) and in chronic Ang II-infused mice (n=8). Chronic Ang II infusions increased systolic blood pressure to 141+/-6 mm Hg compared with 106+/-4 mm Hg in control mice. After anesthesia, mean arterial pressure averaged 97+/-4 mm Hg in chronic Ang II-infused mice compared with 94+/-3 mm Hg in control mice, allowing comparison of renal function at similar arterial pressures. Ang II-infused mice had lower urinary sodium excretion (0.16+/-0.04 versus 0.30+/-0.05 microEq/min; P<0.05), higher distal sodium reabsorption (1.74+/-0.18 versus 1.12+/-0.18 microEq/min; P<0.05), and higher fractional reabsorption of distal sodium delivery (91.1+/-1.8% versus 77.9+/-4.3%; P<0.05) than control mice. Urinary Ang II concentrations, measured during distal blockade, were greater in Ang II-infused mice (1235.0+/-277.2 versus 468.9+/-146.9 fmol/mL; P<0.05). In chronic Ang II-infused mice treated with spironolactone (n=5), fractional reabsorption of distal sodium delivery was similarly augmented as in chronic Ang II-infused mice (94.6+/-1.7%; P<0.01). These data provide in vivo evidence that there is enhanced distal sodium reabsorption dependent on sodium channel and Na(+)-Cl(-) cotransporter activity and increased urinary Ang II concentrations in mice infused chronically with Ang II.

Unexpected effect of angiotensin AT1receptor blockade on tubuloglomerular feedback in early subtotal nephrectomy

After subtotal nephrectomy (STN), the remaining nephrons engage in hyperfiltration, which may be facilitated by a reduced sensitivity of the tubuloglomerular feedback (TGF) response to increased distal delivery. However, a muted TGF response would contradict the notion of remnant kidney as a prototype of angiotensin II (ANG II) excess, since ANG II normally sensitizes the TGF response and stimulates proximal reabsorption. We examined the role of ANG II as a modulator of TGF and proximal reabsorption in 7 days after STN in male rats. Single-nephron glomerular filtration rate (SNGFR) and proximal reabsorption (J(prox)) were measured in late proximal collections while perfusing Henle's loop for minimal and maximal TGF stimulation in rats treated with the angiotensin type 1 (AT(1)) receptor blocker losartan or placebo in drinking water for 7 days. Perfusion of Henle's loop yielded a robust TGF response in sham-operated rats. In STN, the feedback responses were highly variable and nil, on average. Paradoxical TGF responses to augmented late proximal flow were confirmed in SNGFR measurements from the early distal nephron. Chronic losartan treatment normalized the average TGF response without reducing the variability. J(prox) was subtly affected by chronic losartan in sham surgery or STN, after controlling for differences in SNGFR. However, when administered acutely into the early S1 segment, losartan potently suppressed J(prox) in STN and sham-operated rats alike. Chronic losartan stabilizes the TGF system in remnant kidneys. This cannot be explained by currently known actions of AT(1) receptors but is commensurate with a salutary effect of an intact TGF system on dynamic autoregulation of intraglomerular flow and pressure.

High-resolution mapping of anxiety-related traits using consomic mouse strains

Endogenous renal dopamine is a major physiological regulator of renal ion transport; however its intracellular signaling pathways are not thoroughly understood. The present study examined the role of 20-hydroxyeicosatetraenoic acid (20-HETE), the major cytochrome P450 (CYP4A) metabolite of arachidonic acid formed in the renal cortex, on the natriuretic response to dopamine in Sprague Dawley rats. Infusion of dopamine (1.5 μg/kg/min, i.v.) increased urine flow (1.9 fold over basal), sodium excretion (UNaV, 2.7 fold), fractional sodium excretion (FENa, 3.3 fold) and proximal and distal delivery of sodium by 1.5‐ and 2-fold respectively. Administration of two inhibitors of the synthesis of 20-HETE, 1-aminobenzotriazole (ABT) and N-hydroxy-N′-(‐4-butyl-2-methylphenyl)formamidine (HET0016) reduced the response to dopamine by 65%. Induction of the renal expression of CYP4A enzymes with clofibrate did not alter the response to dopamine. The natriuretic response to dopamine was lower in Dahl salt-sensitive rats in comparison to an SS.BN5 consomic strain in which transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats upregulates the renal expression of CYP4A protein and the production of 20-HETE. Treatment with HET0016 blocked the renal effects of dopamine in SS.BN5 rats. We also examined the influence of 20-HETE in the natriuretic response to acute volume expansion that is in part mediated via the release of endogenous dopamine. The increase in urine flow, UNaV, FENa and distal FENa following volume expansion was markedly reduced in rats treated with ABT. These results suggest that 20-HETE plays at least a permissive role in the natriuretic response to dopamine.

Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients

A main mechanism of idiopathic hypercalciuria (IH) in calcium stone-forming patients (IHSF) is postprandial reduction of renal tubule calcium reabsorption that cannot be explained by selective reduction of serum parathyroid hormone levels; the nephron site(s) responsible are not as yet defined. Using fourteen 1-h measurements of the clearances of sodium, calcium, and endogenous lithium during a three-meal day in the University of Chicago General Clinical Research Center, we found reduced postprandial proximal tubule reabsorption of sodium and calcium in IHSF vs. normal subjects. The increased distal sodium delivery is matched by increased distal reabsorption so that urine sodium excretions do not differ, but distal calcium reabsorption does not increase enough to match increased calcium delivery, so hypercalciuria results. In fact, urine calcium excretion and overall renal fractional calcium reabsorption both are high in IHSF vs. normal when adjusted for distal calcium delivery, strongly suggesting a distal as well as proximal reduction of calcium reabsorption. The combination of reduced proximal tubule and distal nephron calcium reabsorption in IHSF is a new finding and indicates that IH involves a complex, presumably genetic, variation of nephron function. The increased calcium delivery into the later nephron may play a role in stone formation via deposition of papillary interstitial apatite plaque.

Leptospiral Nephropathy

Leptospirosis is recognized as a globally re-emerging zoonosis. Interstitial nephritis is the principal feature of the disease. Leptospirosis-induced acute kidney injury typically is nonoliguric and includes hypokalemia. Tubular function alterations precede a decrease in the glomerular filtration rate, which could explain the high frequency of hypokalemia. Studies in human beings and animals have shown increased urinary fractional excretion of potassium and sodium, as well as an increased potassium/sodium ratio, suggesting increased distal potassium secretion caused by increased distal sodium delivery consequent to functional impairment of proximal sodium reabsorption. Confirming these findings, Western blot studies have shown lower renal expression of the sodium/hydrogen exchanger isoform 3 and of aquaporin 2, together with higher renal expression of the Na-K-2Cl cotransporter NKCC2, in infected animals. The severe form (Weil's disease) manifests as diffuse alveolar hemorrhage, pulmonary edema, acute respiratory distress syndrome, or a combination of these features, accompanied by acute kidney injury and can be highly lethal. Antibiotic treatment is efficient in the early and late/severe phases. For critically ill leptospirosis patients, the following are recommended: daily hemodialysis, low daily net fluid intake (because of the risk for pulmonary hemorrhage), and lung-protective strategies (low tidal volumes and high positive end-expiratory pressures after recruitment maneuvers).

Acute Angiotensin II Infusions Elicit Pressure Natriuresis in Mice and Reduce Distal Fractional Sodium Reabsorption

Acute angiotensin II (Ang II) infusions into mice increase arterial pressure (AP) and elicit pressure natriuresis. We used this model of pressure natriuresis to delineate the distal nephron responses to AP-mediated increases in distal sodium delivery. In the first group, we measured changes in urinary sodium excretion (U(Na)V) in male C57/BL6 anesthetized mice (n=9) before and during acute Ang II infusions (5 ng/g of body weight per minute). Acute Ang II infusions increased AP (98+/-3 to 126+/-5 mm Hg; P<0.001), urine flow (2.7+/-0.5 to 6.0+/-0.8 microL/min; P<0.01), and U(Na)V (0.6+/-0.2 to 1.3+/-0.2 microEq/min; P<0.05). There were significant relationships between U(Na)V and urine flow (y=0.207x+0.030; P<0.0001) and between U(Na)V and AP (y=0.027x-2.100). In a separate series, distal sodium delivery and fractional reabsorption of distal sodium delivery were determined in control (n=12) and Ang II-infused mice (n=8) by comparing U(Na)V before and after blockade of the 2 major distal nephron sodium transporters with amiloride (5 mg/kg of body weight) plus bendroflumethiazide (12 mg/kg of body weight). A positive relationship was found between U(Na)V (y=0.015x-1.100; P<0.0001) or distal sodium delivery (y=0.027x-0.900; P<0.0001) and AP. An inverse relationship was found between fractional reabsorption of distal sodium delivery and AP (y=-0.511x+128.300; P<0.01). These data indicate that Ang II-mediated pressure natriuresis involves an increase in distal sodium delivery combined with a reduced distal nephron fractional sodium reabsorption, suggesting that increased AP prevents the distal nephron transport mechanisms from accommodating the increased distal delivery.

Segmental Regulation of Sodium and Water Excretion by TRPV1 Activation in the Kidney

Our previous studies show that activation of the transient receptor potential vanilloid type 1 (TRPV1) channels by a selective agonist, capsaicin (CAP), given unilaterally into the renal pelvis leads to increases in urine flow rate (Uflow) and urinary sodium excretion (UNa) bilaterally, although the mechanisms underlying enhanced renal excretory function are unknown. The present study was designed to determine the contribution of each of the renal segments to enhanced renal excretory function when TRPV1 expressed in sensory nerve fibers innervating the renal pelvis is activated. To accomplish the goal, LiCl was given intravenously to male Wistar rats while the left renal pelvis (LRP) was perfused with vehicle or CAP with or without a selective TRPV1 antagonist, capsazepine (CAPZ). Uflow and clearance of creatinine, lithium, sodium, and water, either filtered or fractionally, were determined in both kidneys. LRP perfusion of CAP at 2.4 nmol increased Uflow (microL.ming; ipsilaterally from 6.6 +/- 0.6 to 14.6 +/- 2.2 and contralaterally from 7.4 +/- 0.7 to 13.9 +/- 1.8, P < 0.05) and UNa (micromol.ming; ipsilaterally from 0.6 +/- 0.2 to 1.8 +/- 0.3 and contralaterally from 0.7 +/- 0.2 to 1.9 +/- 0.4, P < 0.05). Ipsilateral blockade of the TRPV1 with CAPZ at 24 nmol prevented CAP-induced increases in Uflow and UNa bilaterally. Creatinine, lithium, sodium, and free water clearance (ml.min) were increased in CAP (1.47 +/- 0.27, 0.44 +/- 0.05, 0.026 +/- 0.004, 0.41 +/- 0.05, respectively) compared to vehicle (0.72 +/- 0.12, 0.25 +/- 0.05, 0.010 +/- 0.001, 0.24 +/- 0.05), CAPZ+CAP (0.83 +/- 0.13, 0.24 +/- 0.03, 0.014 +/- 0.002, 0.23 +/- 0.03), and CAPZ (0.88 +/- 0.05, 0.21 +/- 0.01, 0.010 +/- 0.001, 0.20 +/- 0.01) groups (P <or= 0.01). Filtered sodium load, distal delivery of sodium, and distal sodium reabsorption (muEq.min) were also increased in CAP (202.2 +/- 33.3, 61.3 +/- 7.4, 57.6 +/- 7.4, respectively) compared to vehicle (97.7 +/- 16.6, 33.6 +/- 5.8, 32.2 +/- 5.9), CAPZ+CAP (110.5 +/- 16.3, 32.5 +/- 4.5, 30.7 +/- 4.3), and CAPZ (118.0 +/- 4.5, 27.9 +/- 1.2, 26.8 +/- 1.2) groups (P <or= 0.01). In contrast, fractional lithium and sodium excretion, absolute proximal reabsorption, fractional proximal reabsorption, fractional distal sodium, and water reabsorption were not different among groups. Therefore, activation of the TRPV1 expressed in primary afferent nerves innervating the renal pelvis leads to diuresis and natriuresis in both kidneys. The TRPV1-induced sodium and water excretion appears to be mediated by increases in glomerular filtration rate and distal tubular delivery of sodium but not by suppression of renal proximal and distal tubular reabsorption, suggesting a key role of segmental regulation of renal function by TRPV1-positive primary sensory nerves in the maintenance of sodium and water homeostasis.

Adaptive Changes of Sodium and Potassium Transporters in CRF Rat Kidneys

In chronic renal failure (CRF), residual nephrons can magnify their excretion of sodium and potassium. However, long‐term adaptive mechanism of renal tubular transporters in CRF has not been fully evaluated. We performed immunoblotting and immunocytochemistry, thus investigating the sequential changes of expression of major renal sodium and potassium transporters in rats from 4 weeks to 12 weeks after 5/6 nephrectomy (Nx). At 4 weeks, the density of NKCC2, NCC, ENaC‐α, and ENaC‐γ in CRF rats significantly increased (477%, 222%, 451%, and 435% of control, respectively) although the expression of NHE3 and SGLT1 did not altered. In contrast, expression of NKCC2 and NCC markedly decreased at 12 weeks (55.4% and 30.8%, respectively), and NHE3 and SGLT1 also decreased at 12 weeks (48.4% and 24.6%, respectively). The protein abundance of ENaC‐α significantly increased during the whole period. Urinary potassium excretion rate was well‐correlated with urinary urea or sodium excretion rate, although immunoblotting of ROMK and Na‐K‐ATPase showed a gradual decrease in the late stages of CRF. We suggest that this sequential decrease of major renal sodium transporters may be a main mechanism for increased urinary sodium excretion, and that increased urea excretion rates or distal sodium delivery may be a major explanation for increased urinary potassium excretion in CRF rats.

Successful use of the Heartrail III catheter as a stent delivery catheter following failure of conventional techniques

The Terumo "five in six" system involves insertion of an extra length, 5 Fr Terumo guide catheter (Heartrail, Terumo) into a standard 6 Fr guide catheter so that the tip protrudes beyond the 6 Fr guide. This system increases backup support and has been used successfully to advance balloon catheters across chronic total occlusions. We describe the use of this system to facilitate extra deep intubation, enabling distal stent delivery beyond proximal points of obstruction that had been unsuccessful using more conventional techniques.

Papel del túbulo en la vasoconstricción renal inducida por ciclosporina

Introduction:Cyclosporine (CyA) has proved to induce cell apoptosis on cultured proximal tubule cells. However, there is no much data about the in vivo functional consequences of this injury or the long time observed CyA-induced renal vasoconstriction. Material and Methods:In a swine model of subacute CyA nephrotoxicity (10 mg/ Kg. d x 15 days), we performed a right nephrectomy, followed by left renal artery, vein and ureter catheterisation. After inducing water diuresis, three clearance periods of 15 minutes were performed before and after a furosemide 1 mg/kg infusion. Plasma and urine electrolytes, blood gas, acid excretion, plasma renin activity and aldosterone concentration, GFR, RPF, RBF, intra-renal vascular resistances, glomerular filtration pressure, distal Cl- delivery, water clearance and TTKG were measured or estimated on 7 control and 7 treated animals. Right kidney was processed for NaKATPase activity and immunostaining. Results:Treated animals presented detaching proximal cells, luminal blebbing and loss of tight junctions. Cortical but not medullar sodium pump was internalised and partially inactive. Treated animals showed much lower fractional excretions of Na+, with significantly higher distal fractional reabsorption of Cl-. Distal shift in fluid load resulted in a significant rise in renal O2 consumption, and modifications in the global renal estequiometry of Na+ transport/O2 uptake. Several consequences followed this situation: preglomerular resistances increased 3 times with only minor changes in postglomerular resistances and renal blood and plasma flow were significantly reduced. Furosemide partially reversed these effects. A slight increase in fractional filtration prevented GFR differences to become statistically significant. Conclusión:subacute CyA treatment even al doses not modifying GFR, may cause proximal tubule Na+ transport impairment, resulting in increased rates of distal delivery and absorption of fluid load. Renal uptake of O2 may be increased and tubule glomerular feedback should be expected to be activated. Absence of changes of GFR with furosemide is an early sign of CyA renal damage.

Mouse Models and the Urinary Concentrating Mechanism in the New Millennium

Our understanding of urinary concentrating and diluting mechanisms at the end of the 20th century was based largely on data from renal micropuncture studies, isolated perfused tubule studies, tissue analysis studies and anatomical studies, combined with mathematical modeling. Despite extensive data, several key questions remained to be answered. With the advent of the 21st century, a new approach, transgenic and knockout mouse technology, is providing critical new information about urinary concentrating processes. The central goal of this review is to summarize findings in transgenic and knockout mice pertinent to our understanding of the urinary concentrating mechanism, focusing chiefly on mice in which expression of specific renal transporters or receptors has been deleted. These include the major renal water channels (aquaporins), urea transporters, ion transporters and channels (NHE3, NKCC2, NCC, ENaC, ROMK, ClC-K1), G protein-coupled receptors (type 2 vasopressin receptor, prostaglandin receptors, endothelin receptors, angiotensin II receptors), and signaling molecules. These studies shed new light on several key questions concerning the urinary concentrating mechanism including: 1) elucidation of the role of water absorption from the descending limb of Henle in countercurrent multiplication, 2) an evaluation of the feasibility of the passive model of Kokko-Rector and Stephenson, 3) explication of the role of inner medullary collecting duct urea transport in water conservation, 4) an evaluation of the role of tubuloglomerular feedback in maintenance of appropriate distal delivery rates for effective regulation of urinary water excretion, and 5) elucidation of the importance of water reabsorption in the connecting tubule versus the collecting duct for maintenance of water balance.

Mechanism of Hypokalemia in Magnesium Deficiency

Magnesium deficiency is frequently associated with hypokalemia. Concomitant magnesium deficiency aggravates hypokalemia and renders it refractory to treatment by potassium. Herein is reviewed literature suggesting that magnesium deficiency exacerbates potassium wasting by increasing distal potassium secretion. A decrease in intracellular magnesium, caused by magnesium deficiency, releases the magnesium-mediated inhibition of ROMK channels and increases potassium secretion. Magnesium deficiency alone, however, does not necessarily cause hypokalemia. An increase in distal sodium delivery or elevated aldosterone levels may be required for exacerbating potassium wasting in magnesium deficiency.

Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride

Distal renal tubular acidosis (RTA) can lead to rickets in children or osteomalacia in adults if undetected. This disorder is normally diagnosed by means of an oral ammonium chloride-loading test; however, the procedure often leads to vomiting and abandonment of the test. In this study, we assess an alternative, more palatable approach to test urinary acidification. This was achieved by the simultaneous oral administration of the diuretic furosemide and the mineralocorticoid fludrocortisone to increase distal tubular sodium delivery, principal cell sodium reabsorption, and alpha-intercalated cell proton secretion. We evaluated 11 control subjects and 10 patients with known distal RTA by giving oral ammonium chloride or furosemide/fludrocortisone in random order on separate days. One control and two patients were unable to complete the study owing to vomiting after NH4Cl; however, there were no adverse effects with the furosemide/fludrocortisone treatment. The urine pH decreased to less than 5.3 in the controls with both tests, whereas none of the patients was able to lower the urine pH below 5.3 with either test. We conclude that the simultaneous administration of furosemide and fludrocortisone provides an easy, effective, and well-tolerated alternative to the standard ammonium chloride urinary acidification test for the diagnosis of distal RTA.

Renal response to an acute protein challenge in pregnant women with borderline hypertension

The renal reserve (RR), assessed after an oral protein challenge or the intravenous administration of amino acids, is still present in healthy pregnant women (NP), although resting glomerular filtration rate (GFR) and renal plasma flow (RPF) increase progressively throughout normal gestation. No studies have addressed this issue in hypertensive gravidas; the aim of this trial was to evaluate renal response to an acute protein load (PL) in NP and pregnant women with borderline hypertension (HP). Five NP, eight HP and eight healthy non-pregnant women (CG) were evaluated. After fasting overnight, all subjects received an oral water load (20 mL/kg of body weight), the urinary output was then replaced orally with equal volumes of water. After two 30 min periods, an 80 g PL was provided. Creatinine clearance (CCr) was measured every 30 min from 1 h before and for 4 h following PL. Participants remained recumbent during the study, bladder emptiness was assessed by ultrasound immediately after each micturition. Baseline CCr was taken as the average of two 30 min periods before PL and peak Ccr as the maximal CCr recorded thereafter. The groups were similar with regard to age, weight or gestation age. Baseline CCr (NP: 118.5+/-6.0, HP: 127.4+/-6.7 and CG: 99.8+/-2.9 mL/min, P=0.004 (CG vs NP and HP), increased after PL to NP: 223.5+/-9.8 to HP: 178.5+/-13 and to CG: 149.1+/-4.0 mL/min, P<0.0004 (CG vs HP, CG vs NP and NP vs HP)). Peak minus baseline CCr was 97.3+/-10.1; 46.3+/-12.7 and 48.3+/-4.8 for NP, HP and CG, respectively (P<0.006 HP vs CG and NP). The peak CCr was obtained significantly earlier in both pregnant groups (Period 3) compared with the healthy non-pregnant women (Period 5) (P=0.02). The fractional proximal reabsorption of sodium (FPRNa+) at peak CCr was similar in the groups (NP: 0.74+/-0.01 HP: 0.78+/-0.02 and CG: 0.74+/-0.03, P=not significant (NS)) as was the distal delivery of sodium (DDNa+) (NP: 5.8+/-0.5; HP: 4.1+/-0.5 and CG: 4.3+/-0.4 meq/min, P=NS). Fractional excretion of urea (%) increased from 91.4+/-5.5 to 105.5+/-9.8%; 80.7+/-8.0 to 97.3+/-9.8; and 44.4+/-7.8 to 86.0+/-7.1 in NP, HP and CG, respectively (P=NS). There was a trend towards a poorer maternal and fetal outcome in the HP group. Mid-term borderline HP failed to increase CCr as much as NP did after a protein challenge, suggesting altered functional response of the nephron or lessened sensitivity of renal vasculature to additional vasodilator stimuli. These results support the interest of additional prospective studies with a larger number of patients to confirm these findings and evaluate the value of RR tests as predictors of outcome of pregnancies at risk.

Tubuloglomerular Feedback ‐ A System For Nephron Self‐Regulation

The large amounts of filtered NaCl represent a latent threat to body salt homeostasis by potentially overwhelming the tubular reabsorptive capacity. Tubuloglomerular feedback (TGF) is an autonomous, single nephron-based mechanism designed to contain this risk by regulating salt delivery into the collecting duct system where the transport capacity for NaCl is intrinsically limited. Deviations of NaCl concentration at the macula densa (MD) cells, whether caused by changes of GFR or proximal reabsorption, are translated into changes of afferent arteriolar resistance and inverse changes of GFR, thus preventing inappropriate late nephron overloading. The regulatory process in the juxtaglomerular control region begins with a change in NaCl uptake by MD cells that is mediated by the furosemide-sensitive Na,K,2Cl-cotransporter. Changes in NaCl transport then initiate events that lead to the release of ATP and to the generation of adenosine by a cascade of ecto-ATPases and ectonucleotidases. Afferent arteriolar vasomotor responses are mostly the result of activation of A1 adenosine receptors. The TGF response magnitude is variable with increases in sensitivity resulting mainly from high ambient angiotensin II levels, and decreases of sensitivity caused by nitric oxide generated locally by macula densa bNOS. TGF as a minute-to-minute stabilizer of distal salt delivery is critical in determining NaCl excretion during fast and random perturbations of filtration forces that are unrelated to body salt balance. Because renin secretion is partly under the control of NaCl at the MD, stability of distal NaCl concentration has the secondary consequence of supporting stability of plasma renin activity. Changes of TGF sensitivity secure the regulatory capacity of nephron self-regulation during prolonged alterations of MD NaCl that exceed the ambient regulatory range.

Rapid Correction of Severe Hyponatremia After Computed Tomography With Intravenous Contrast

To the Editor: Overly rapid correction of hyponatremia is a major concern in severely hyponatremic patients because of the potential development of osmotic demyelination. Numerous factors can contribute to overly rapid correction of hyponatremia (Table 1).1Pham P-CT Pham P-MT Miller J et al.Treatment of chronic hyponatremia.Proc UCLA Healthcare. Fall 2002; 6: 32-36Google Scholar We report a case in which a patient developed osmotic diuresis after contrast dye injection that rapidly self-corrected the severe hyponatremia.TABLE 1Potential Causes of Overly Rapid Correction of HyponatremiaAdapted from Proceedings of UCLA HealthCare,1Pham P-CT Pham P-MT Miller J et al.Treatment of chronic hyponatremia.Proc UCLA Healthcare. Fall 2002; 6: 32-36Google Scholar with permission. Unawareness of the recommended rate of correction for hyponatremiaMiscalculationsUnrecognized sources of sodium Exogenous Sodium administration at another site before transfer to the current unitAddition of excess salt to patient's diet by patient's family or facility staff membersEndogenous Potassium supplementation with resultant extracellular sodium shiftExcess free water loss Water deprivation in primary polydipsiaWithdrawal of thiazide diuretics during treatment of hyponatremiaGlucocorticoid replacement in a cortisol-deficient patientRecovery from acute respiratory failureExcessive gastrointestinal, pulmonary, or skin hypotonic fluid lossSevere hyponatremia with subsequent cerebral edema and pituitary infarctionNonelectrolyte osmotic diuresis: urea, glucose, mannitol, contrast dye, total parenteral nutritionIntracellular free water shift SeizuresRhabdomyolysisCorrection of hyperglycemiaPotassium supplementation Open table in a new tab Report of a Case. A 59-year-old woman with diabetes mellitus and hypertension presented with a 1-week history of slow mentation, fatigue, nausea, vomiting, abdominal pain, and subjective left hemiparesthesia. A dietary history revealed that she routinely ate only fruits and cereals and drank only water. Her medications included hydrochlorothiazide, fosinopril, atenolol, metformin, and aspirin. Physical examination revealed dry oral mucosa, slow mentation, and generalized sluggish deep tendon reflexes. On initial evaluation, the serum sodium concentration was 115 mEq/L, and urinary studies revealed an osmolality of 526 mosm/kg, a sodium level of 130 mEq/L, and a chloride level of less than 10 mEq/L. The patient was given two 500-mL boluses of normal saline during the first 12 hours of hospitalization. In the interim, she underwentcomputed tomography of the head and abdomen with intravenous contrast (iohexol). Despite correction of the hypovolemia, the patient had no improvement in her symptoms or serum sodium concentration during the first 24 hours. However, approximately 24 to 26 hours after presentation, she developed progressive polyuria (up to 150-175 mL/h). During the polyuric phase, the urine osmolality ranged from 217 to 393 mosm/kg. During the subsequent few hours, the patient's mentation noticeably improved in association with a spontaneous rapid increase in serum sodium concentration (8 mEq/L over 6 hours). In fact, hypotonic saline had to be administered to halt the rapid self-correction of the hyponatremia. Given the patient's history of poor dietary nutrition, use of hydrochlorothiazide, and current pain and vomiting, we suspected that the hyponatremia resulted from ongoing water intake concurrent with the patient's inability to excrete free water maximally because of a reduced dietary solute load and syndrome of inappropriate secretion of antidiuretic hormone-induced enhanced free water reabsorption.2Fichman MP Vorherr H Kleeman CR Telfer N Diuretic-induced hyponatremia.Ann Intern Med. 1971; 75: 853-863Crossref PubMed Scopus (239) Google Scholar, 3Thaler SM Teitelbaum I Berl T “Beer potomania” in non-beer drinkers: effect of low dietary solute intake.Am J Kidney Dis. 1998; 31: 1028-1031Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Despite saline infusion, the patient's serum sodium concentration remained at 115 mEq/L 12 to 18 hours after presentation, presumably a reflection of the sustained syndrome of inappropriate secretion of antidiuretic hormone caused by her nausea and pain. However, by 24 hours after presentation, the patient had a rapid increase in urinary output as well as serum sodium concentration despite the discontinuation of all intravenous fluids at least 6 hours previously. At that point, the patient possibly had adequate volume reexpansion, reduced proximal tubular reabsorption of salt and water, and resultant increased distal delivery for excretion. In addition, the control of nausea and pain and the volume reexpansion may have inhibited antidiuretic hormone secretion sufficiently to result in the aquaretic phase. However, subsequent urinary electrolyte studies revealed high osmolality (217-393 mosm/kg) relative to serum osmolality (240-264 mosm/kg), which suggested that she had osmotic diuresis, not aquaresis. Further analysis of her urine by ultraviolet spectrophotometry revealed that the predominant source of the urine osmolality during the polyuric phase was the contrast dye iohexol. The findings in this case are important because computed tomography with intravenous contrast is performed routinely for the evaluation of nonspecific complaints in severely hyponatremic patients.

Acid-Base and Potassium Disorders in Liver Disease

Acid-base and potassium disorders occur frequently in the setting of liver disease. As the liver's metabolic function worsens, particularly in the setting of renal dysfunction, hemodynamic compromise, and hepatic encephalopathy, acid-base disorders ensue. The most common acid-base disorder is respiratory alkalosis. Metabolic acidosis alone or in combination with respiratory alkalosis also is common. Acid-base disorders in patients with liver disease are complex. The urine anion gap may help to distinguish between chronic respiratory alkalosis and hyperchloremic metabolic acidosis when a blood gas is not available. A negative urine anion gap helps to rule out chronic respiratory alkalosis. In this disorder a positive urine anion gap is expected owing to suppressed urinary acidification. Distal renal tubular acidosis occurs in autoimmune liver disease such as primary biliary cirrhosis, but often is a functional defect from impaired distal sodium delivery. Potassium disorders are often the result of the therapies used to treat advanced liver disease.