Immunosuppressive agents for treating IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a world-wide disease and the cause of end-stage renal failure (ESRF) in 15 to 20% of patients within 10 years and in 30 to 40% of individuals within 20 years from the apparent onset of disease. No specific treatment has yet been established but many approaches have been investigated. OBJECTIVES: To assess the benefits and harms of immunosuppressive treatment for IgAN. SEARCH STRATEGY: We searched The Cochrane Renal Group's specialized register (May 2003), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2002) MEDLINE (1966 - September 2002), EMBASE (1988 - September 2002) and handsearched reference lists of retrieved articles and conference proceedings. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs comparing treatment of IgAN with immunosuppressive agents against placebo, no treatment, other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes, with 95% confidence intervals (CI). MAIN RESULTS: Thirteen eligible RCTs involving 623 patients were identified. All identified RCTs had a placebo, no treatment or warfarin/dipyridamole control group. Seven trials used steroids, three used alkylating agents/cyclosporin and three used combinations of steroids and alkylating agents/cyclosporin. No trial directly compared steroids versus alkylating agents/cyclosporin. Quality was sub-optimal. Steroids were associated with a lower risk of progression to ESRF (RR 0.44, 95% CI 0.25 to 0.80) and lower urinary protein excretion (WMD -0.49 g/24h, 95% CI -0.72 to -0.12). Urinary protein excretion was lower for patients treated with alkylating agents/cyclosporin compared to placebo/no treatment (WMD -0.94 g/24h, 95% CI -1.43 to -0.46). There was no significant reduction of urinary protein excretion with combination treatment of steroids and alkylating agents compared with placebo/no treatment. REVIEWER'S CONCLUSIONS: The optimal management of IgAN remains uncertain. The RCTs identified were small, of sub-optimal methodological quality and tended to only report favorable and surrogate outcomes without a thorough reporting of treatment harms. All outcomes favor the use of immunosuppressive interventions, with steroids appearing to be the most promising. Further study, in the form of RCTs, is necessary to ascertain which patients would benefit from these interventions, whether they are the ones with early signs of renal dysfunction or those with more advanced renal impairment.

Effective clearance of methotrexate using high-flux hemodialysis membranes.

We report the first series demonstrating effective clearance of methotrexate using acute intermittent hemodialysis with a high-flux dialyzer. The study was performed on six patients, two females and four males aged 13 to 72 years. All were patients at M.D. Anderson Cancer Center. Patients were dialyzed for 4 to 6 hours daily using a Fresenius F-80 membrane (Fresenius Inc, Walnut Creek, CA). Following the initiation of dialysis, there was a reduction in arterial and venous serum concentration of methotrexate with time. Mean plasma clearance of methotrexate during dialysis in these six patients was 92.1 +/- 10.3 mL/min. One patient who was nearly functionally anephric was studied in detail. In this patient, following a high dose of methotrexate (7.2 g/m2), approximately 63% of this dose was cleared with 6 hours of hemodialysis. With subsequent dialysis performed daily for 6 hours, the drug was cleared completely in 5.6 +/- 0.3 days (n = 7 separate methotrexate treatments). A reduction in plasma methotrexate concentration from 1,733 +/- 40 micromol/L 1 hour postinfusion to less than 0.3 micromol/L in 5 to 6 days was observed for these seven separate treatments. We conclude that significant clearance of methotrexate can be achieved with high-flux dialyzers, making methotrexate therapy a viable treatment option in patients with responsive malignancies despite the presence of renal failure.

Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography.

OBJECTIVE: To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period. DESIGN: Randomized double-blind, placebo-controlled trial. SETTING: Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg(systolic) and 95 and 120 mm Hg (diastolic). INTERVENTION: Placebo (n = 6), nicardipine hydrochloride (20 mg [n = 5]), captopril (12.5 mg [n = 3]), or clonidine hydrochloride (0.1 mg [n = 2]) given every 8 hours for 3 days. MAIN OUTCOME MEASURES: Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale. RESULTS: Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo (P < .001). There was no difference in blood pressure levels between these two groups throughout the study period. Patients receiving nicardipine had a consistently lower pressure than the other groups. A significant negative relationship was noted between the maximum blood pressure fall and improvement in cerebral blood flow. There were four patients whose blood pressure dropped by more than 16% of the baseline value on any 24 hours in the first 3 days. All either failed to increase or actually decreased their cerebral blood flow to the affected area. Three of these patients were treated with nicardipine. There was no significant difference in clinical course between the placebo-and drug-treated groups as a whole. CONCLUSIONS: Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution.

Diluting power of thick limbs of Henle. III. Modulation of in vitro diluting power.

This paper considers the quantitative interplay of various factors in modulating diluting power of in vitro medullary and cortical thick ascending limbs of Henle (MTAL and CTAL, respectively) segments from mouse and rabbit. Experimentally, the measured diluting power of the in vitro rabbit CTAL is greater than that of the rabbit MTAL, although the inherent rate of net Cl- absorption at high perfusion rates is considerably greater in the rabbit MTAL than in the rabbit CTAL. Similar results apply when comparing the rabbit CTAL to the mouse MTAL exposed to antidiuretic hormone (ADH). Our calculations show that, in the rabbit CTAL, the measured static head luminal salt concentration can be accounted for quantitatively by the measured rate of net salt absorption at a high perfusion rate together with the passive permeability coefficients for Na+ and Cl-. Moreover, with perfusion rates of 10% of single-nephron glomerular filtration rate, the transport properties of the CTAL predict that, at the end of the CTAL, the static head luminal Cl- concentration occurs if the initial perfusate contains either 50 or 150 mM Cl-. Thus one can argue that, in vivo the CTAL may be the cardinal determinant of the TAL contribution to diluting power and to external salt balance. The relatively blunted diluting power of in vitro MTAL segments can be accounted for quantitatively by assuming that luminal dilution, and the attendant osmotic gradient from lumen to cell, suppresses the inherent rate of transcellular Cl- transport. Our calculations also show that prostaglandin E2 and peritubular osmolality increases blunt tubular diluting power. Thus in vivo, the MTAL segment may be the cardinal determinant of TAL contribution to concentrating power and to intrarenal salt balance.

Diluting power of thick limbs of Henle. I. Peritubular hypertonicity blocks basolateral Cl- channels.

This paper provides the results of experiments intended to assess the mechanism responsible for the suppression of net salt absorption and the attendant spontaneous voltage (Ve, mV) that occurs when isolated thick ascending limbs of Henle (TAL) are exposed to a hypertonic environment. In isolated mouse medullary (MTAL) and cortical (CTAL) segments, as well as in rabbit MTAL segments, increases in peritubular osmolality with urea produced a graded suppression of Ve. This effect was evaluated in further detail in isolated mouse MTAL segments, where 600 mM peritubular urea produced a reversible reduction in Ve and a reversible reduction in the transcellular electrical conductance (Gc; mS.cm-2). There was no detectable effect on the paracellular conductance (Gs; mS.cm-2). Simultaneously, 600 mM peritubular urea also produced hyperpolarization of the voltage across basolateral membranes (mV). Moreover, 600 mM peritubular urea produced virtually the same magnitude reduction in Gc either in the absence or presence of 10(-4) M luminal furosemide. Thus we conclude that peritubular urea hypertonicity directly suppresses the Cl- conductance of basolateral membranes (mS.cm-2).

ADH increases apical Na+, K+, 2Cl- entry in mouse medullary thick ascending limbs of Henle.

These studies were designed to evaluate the mechanism for the ADH-dependent increase in transcellular conductance (Gc, mS X cm-2), which accompanies hormone-dependent increases in the spontaneous transepithelial voltage (Ve, mV) and in the net rate of Cl- absorption in single medullary thick ascending limbs of Henle (mTALH) isolated from mouse kidney. The total transepithelial conductance (Ge, mS X cm-2) was measured with perfusing solutions containing 5 mM K+, zero Ba2+; Gc was that component of Ge blocked by luminal 20 mM Ba2+, zero K+. In paired experiments, antidiuretic hormone (ADH) increased Gc from 44.5 +/- 5.6 to 58.9 +/- 8.9 mS X cm-2 (delta = 14.3 +/- 5.5; P less than 0.02); however, in the presence of 10(-4) M luminal furosemide, ADH had no significant effect on Gc (delta = 5.0 +/- 4.3; NS). A set of similarly paired measurements together with paired observations on the effects of bath Cl- deletion, permitted an assessment of the effect of ADH on the magnitude of the fall in Gc on bath Cl- removal (delta GClc, mS X cm-2). delta GClc was clearly larger with ADH, 29.6 +/- 4.3, than without ADH, 19.2 +/- 1.0 (delta = 10.4 +/- 4.9; P less than 0.05). However, with luminal furosemide, ADH had no significant effect on delta GClc (delta = 1.7 +/- 4.5; NS). These results indicate that the ADH-dependent increase in Gc is secondary to increased salt entry across the apical membrane. We computed apical (ga, mS X cm-2) and basolateral (gb, mS X cm-2) membrane conductances from the Gc measurements and apical-to-basolateral membrane resistance ratios (Ra/Rb) obtained from cell impalement: the ADH-dependent Gc increase was due to an increase in gb, which was blocked entirely by luminal furosemide. We propose that ADH increases the number of functioning apical membrane Na+,K+,2Cl- transport units, and that gb increases because cell Cl- activity rises and depolarizes the basolateral membrane. Thus the calculated cellular Cl- activity was 16.3 mM without ADH, and 25 mM with ADH.

Some transport characteristics of mammalian renal diluting segments.

As a consequence of its ability to absorb salt in excess of water, the thick ascending limb of the mammalian kidney dilutes the urine and supplies the energy for counter current multiplication. This latter effect follows directly from the ability of the medullary thick ascending limb (mTALH) to enrich medullary osmolality. In this review, we consider certain selected aspects of mTALH function that determine its ability to dilute the urine and to contribute to overall renal concentrating power. Specifically, we shall review the mechanisms for salt absorption in the mTALH and the modulation of salt absorption in the mTALH and hence urinary concentrating power, by antidiuretic hormone (ADH), prostaglandin E2 (PGE2) and peritubular hypertonicity. Furthermore, we shall advance an explanation of how these latter three agents modulate mTALH function without affecting external salt balance.

Prostaglandins: physiological and clinical correlations.

This review has necessarily been incomplete. We have not considered the potentially important interplay between PGs and male and female reproductive functions or the well-documented relationships between PGs and inflammation. We have examined the evidence for the influence of PGs on the pulmonary and peripheral vascular circulations and the interaction between PGs and the kidney and the autonomic nervous system. Emphasis has been placed on the role of PGs in the control of the circulation of the ductus arteriosus, and our recent experiences with indomethacin in sick, preterm infants with large left-to-right ductal shunting have been outlined. Existing information has been reviewed concerning PGs and the fetal-placental and fetal-maternal units. It should be clear that a host of proposed functions exists for PGs; many remain tentative in light of the conflicting and often bewildering results of animal experimentation.