Membranous glomerulopathy in an adult patient with X-linked agammaglobulinemia receiving intravenous gammaglobulin.

BACKGROUND: Immune complex deposition in the subepithelial zone of glomerular capillaries can lead to membranous glomerulopathy. OBJECTIVE: To present the case of a 23-year-old man with X-linked agammaglobulinemia (XLA) who developed idiopathic membranous glomerulopathy while receiving intravenous immunoglobulin (IVIG). METHODS: We performed an immunological workup, genetic testing, and a renal biopsy. RESULTS: XLA was confirmed with less than 0.02% CD19+ cells in the blood after sequence analysis revealed a nonfunctional BTK gene. The patient presented with microhematuria, which persisted for 3 years and spanned treatment with 5 different preparations of intravenous gammaglobulin. Immunohistochemistry revealed membranous glomerulopathy. CONCLUSION: Although endogenous serum immunoglobulin (Ig) production is severely impaired in XLA, rare B lymphocytes that have managed to mature can produce functional IgG antibodies. The pathogenic immune complexes could reflect IVIG reacting with polymorphic autoantigens, an endogenous IgG-producing clone reacting with a common idiotype present in the IVIG, or both.

Improving outcomes from acute kidney injury (AKI): Report on an initiative.

Acute Kidney Injury (AKI) is a complex disorder for which currently there is no accepted definition. We describe an initiative to develop uniform standards for defining and classifying AKI and establish a forum for multidisciplinary interaction to improve care for patients with, or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a 2-day conference in Amsterdam in September 2005 to draft consensus recommendations for diagnosing and staging AKI. This report describes the proposed diagnostic and staging criteria for AKI and the formation of a multidisciplinary collaborative network.

Prevention, protection, and the intrarenal renin-angiotensin systems.

The use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, or aldosterone antagonists can have important beneficial effects on the progression of renal disease associated with glomerular and interstitial fibrosis, especially if the adverse side effects (eg, hyperkalemia) can be minimized. Because it appears that chronic renal insufficiency and proteinuria may well be cardiovascular risk factors, it is exciting to note that recent large scale epidemiologic studies (Heart Outcomes and Prevention Evaluation [HOPE]) have shown both cardioprotective and renoprotective effects of ACE inhibition. It appears paradoxic that such renoprotective effects are clearly evident in diabetes mellitus in which the plasma renin activity may be suppressed. Even in this setting, it appears that there is activation of the renal angiotensin system(s), and inhibitions of these intrarenal systems are involved in the renoprotective effects of these agents. Recent studies have identified nearly all of the components needed to generate angiotensin II in the renal luminal compartment, and suggest that there may be a direct effect through AT(1) receptors on NaCl transport in the distal nephron. The possibility that the components of this intraluminal renin-angiotensin system may be acutely regulated by variations in dietary salt intake provides an opportunity to better understand the normal maintenance of salt balance. Whether or not inhibition of these pathways is involved in the renoprotective effects of ACE inhibitors and angiotensin receptor antagonists is an important issue to be addressed.

Localization and functional characterization of Na+/H+ exchanger isoform NHE4 in rat thick ascending limbs.

The Na+/H+ exchanger NHE4 was cloned from a rat stomach cDNA library and shown to be expressed predominantly in the stomach and less dramatically in the kidney. The role and precise localization of NHE4 in the kidney are still unknown. A polyclonal antibody against a unique NHE4 decapeptide was used for immunohistochemistry in rat kidney. Simultaneous use of antibodies to Tamm-Horsfall glycoprotein and aquaporin-2 or -3 permitted identification of thick ascending limbs and collecting ducts, respectively. The results indicate that NHE4 is highly expressed in basolateral membranes of thick ascending limb and distal convoluted tubule, whereas collecting ducts from cortex to inner medulla and proximal tubules showed weaker basolateral NHE4 expression. Western blot analysis of NHE4 in membrane fractions prepared from the inner stripe of the outer medulla revealed the presence of a 95-kDa protein that was enriched in basolateral membrane vesicles isolated from medullary thick ascending limbs. The inhibition curve of H+-activated (22)Na uptake by 5-(N-ethyl-N-isopropyl)amiloride (EIPA) was consistent with the presence, beyond the EIPA high-affinity NHE1 isoform, of an EIPA low-affinity NHE with apparent half-maximal inhibition of 2.5 microM. Kinetic analyses showed that the extracellular Na+ dependence of NHE4 activity followed a simple hyperbolic relationship, with an apparent affinity constant of 12 mM. Intravesicular H+ activated NHE4 by a positive cooperative mechanism. NHE4 had an unusual low affinity for intravesicular H+ with a half-maximal activation value of pK 6.21. We conclude that NHE4, like NHE1, is expressed on the basolateral membrane of multiple nephron segments. Nevertheless, these two proteins exhibited dramatically different affinities for intracellular H+, suggesting that they may play distinct physiological roles in the kidney.

Genetic forms of human hypertension.

Our basic understanding of sodium mechanisms provides unique insights into epithelial transport processes, and unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect sodium balance, with both sodium-retaining and sodium-wasting conditions being the consequence. A major focus of such studies has been the epithelial sodium channel, which can be activated by mutations in the channel subunits or mineralocorticoid receptor, and changes in the response to or production of mineralocorticoids. As a result, there are now clearly defined Mendelian syndromes in which epithelial sodium channel activity is 'dysregulated', with the subsequent development of systemic hypertension with suppressed plasma renin activity that can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension, and more clearly define the interactions of dietary constituents such as sodium and potassium in the regulation of blood pressure.

An Alu cassette in the human epithelial sodium channel.

Here, we report the presence of two splice variants of the human epithelial sodium channel alpha subunit (h alpha ENaC) containing Alu cassette, namely h alpha ENaC+22 and h alpha ENaC+Alu, in various tissues. Functional expression of these splice variants with hENaC beta and gamma subunits produced loss-of-channel activity in the Xenopus oocyte expression system. Interestingly, coexpression of h alpha ENaC+22 or h alpha ENaC+Alu, respectively, with wild type hENaC alpha, beta, and gamma subunits enhanced the expression of amiloride-sensitive current in oocytes. The presence of Alu sequences in the 3'-untranslated region of h gamma ENaC was also identified.

Simplified citrate anticoagulation for continuous renal replacement therapy.

BACKGROUND: Regional anticoagulation with trisodium citrate is an effective form of anticoagulation for continuous renal replacement therapy (CRRT) for patients with contraindications to heparin. However, because of the metabolic complications of trisodium citrate, it is a complicated technique requiring specialized dialysis solutions. We have designed a simplified protocol for citrate regional anticoagulation for CRRT. METHODS: Two percent trisodium citrate was delivered at 250 mL/h via the prefilter port of a COBE PRISMA device, with the rate adjusted to maintain a postfilter ionized calcium (iCa++) <0.5 mmol/L. A central calcium gluconate infusion was used to maintain a systemic iCa++ at 1.1 mmol/L. A standard dialysate solution consisting of 0.9% saline, KCl 3 mmol/L, and MgSO4 1 mmol/L was delivered at 1000 mL/h. We retrospectively reviewed the outcomes and complications associated with this protoco1 in 29 patients treated from July 1999 to October 1999, evaluating the frequency of clotting of the dialyzer, bleeding complications, citrate toxicity, and patient mortality. RESULTS: The Kaplan-Meier curve for dialyzer survival demonstrated a 61% survival rate at 48 hours. There were no episodes of significant bleeding or citrate toxicity. Seventy-two percent of patients died for reasons unrelated to CRRT. CONCLUSIONS: A CRRT protocol using regional 2% trisodium citrate anticoagulation is not associated with significant bleeding complications or citrate toxicity, and represents a simplified approach compared with previous applications using 4% trisodium citrate.

Genetic renal tubular disorders of renal ion channels and transporters.

This perspective on genetic renal tubular transport disorders selectively reviews the pathophysiology of renal apical Na(+) transport systems. These transporters play an essential role in the control of extracellular fluid volume and blood pressure. Significant advancements in the understanding of the role of these genes in Mendelian forms of extracellular volume homeostatic disorders have been achieved in the recent years. Of even greater importance will be the ongoing definition of the various factors that regulate the expression and activity of the Na(+) transport systems. These regulatory pathways, and the responses to environmental factors such as dietary salt, stress, and so on, may determine the appearance, severity and complexity of the clinical phenotypes that result from genetic disorders of the renal apical Na(+) transporters.

Liddle syndrome: genetics and mechanisms of Na+ channel defects.

Our current understanding of Na+ transport defects has been greatly expanded over the last several years and has provided new insights into unusual clinical syndromes resulting from mutations of specific ion transporters. These genetic disorders affect Na+ balance, with both Na+ retaining and Na+ wasting conditions being the consequence. A major focus of these studies has been the epithelial sodium channel (ENaC), which can be directly affected by mutations (eg, Liddle syndrome, autosomal recessive pseudohypoaldosteronism, type I) or by changes in the response to (autosomal recessive pseudohypoaldosteronism, type I), or production of mineralocorticoids (apparent mineralocorticoid excess syndrome, glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined syndromes in which ENaC activity is "dysregulated" with subsequent development of disorders of systemic blood pressure that can be attributed to a primary renal mechanisms. The focus of the current review is on Liddle syndrome ("pseudoaldosteronism").

Disorders of the epithelial Na(+) channel in Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1.

The epithelial Na(+) channel (ENaC) is the key step in many Na(+)-absorptive epithelia, such as kidney and distal colon, that controls the overall rate of transepithelial Na(+) transport. ENaC is composed of three homologous subunits, alpha, beta, and gamma. The alpha subunit is the key subunit for the formation of a functional ion channel, while the beta and gamma subunits can greatly potentiate the level of expressed Na(+) currents. ENaCs belong to the recently identified DEG/ENaC supergene family, sharing the same basic structure with cytoplasmic amino and carboxy termini, two transmembrane regions, and a large extracellular loop. The human ENaC genes have been cloned, and using genetic linkage analysis the involvement of ENaC gene mutations in two distinct human diseases, Liddle's syndrome and autosomal recessive pseudohypoaldosteronism type 1 (PHA-1), has been demonstrated. In Liddle's syndrome, gain-of-function mutations in the beta or gamma ENaC subunits have been found; all identified mutations so far reside in the carboxy terminus of the protein, either deleting or modifying the functionally important PY motif. In PHA-1, loss-of-function mutations in the alpha, beta, or gamma subunits have been found; these mutations either truncate a significant portion of the structure or modify an amino acid that plays an important role in channel function. In this review, our current understanding about ENaC and the pathophysiology of Liddle's syndrome and PHA-1 caused by ENaC mutations will be discussed.

Interaction of syntaxins with epithelial ion channels.

Recent evidence suggests that some of the syntaxin isoforms may physically interact with and regulate the transport activity of a defined set of membrane transport proteins. This review examines recent studies of the cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel which define distinct roles of syntaxin 1A and syntaxin 3 in the regulation of surface expression as well as intrinsic properties of these epithelial ion transporters.

Aldosterone-related genetic effects in hypertension.

Our basic understanding of Na(+) transport mechanisms provides unique insights into epithelial transport processes. Unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect Na(+) balance, resulting in both N(a+) retaining and Na(+) wasting conditions. A major focus has been the epithelial sodium channel (ENaC), which can be activated by mutations (eg, Liddle's syndrome), changes in the response to mineralocorticoids (apparent mineralocorticoid excess syndrome), or production of mineralocorticoids (glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined Mendelian syndromes in which ENaC activity is "dysregulated." This dysregulation leads to systemic hypertension associated with suppressed plasma renin activity, which can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low-renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension.

Macula densa Na(+)/H(+) exchange activities mediated by apical NHE2 and basolateral NHE4 isoforms.

Functional and immunohistochemical studies were performed to localize and identify Na(+)/H(+) exchanger (NHE) isoforms in macula densa cells. By using the isolated perfused thick ascending limb with attached glomerulus preparation dissected from rabbit kidney, intracellular pH (pH(i)) was measured with fluorescence microscopy by using 2',7'-bis-(2-carboxyethyl)-5-(and -6) carboxyfluorescein. NHE activity was assayed by measuring the initial rate of Na(+)-dependent pH(i) recovery from an acid load imposed by prior lumen and bath Na(+) removal. Removal of Na(+) from the bath resulted in a significant, DIDS-insensitive, ethylisopropyl amiloride (EIPA)-inhibitable decrease in pH(i). This basolateral transporter showed very low affinity for EIPA and Hoechst 694 (IC(50) = 9.0 and 247 microM, respectively, consistent with NHE4). The recently reported apical NHE was more sensitive to inhibition by these drugs (IC(50) = 0.86 and 7.6 microM, respectively, consistent with NHE2). Increasing osmolality, a known activator of NHE4, greatly stimulated basolateral NHE. Immunohistochemical studies using antibodies against NHE1-4 peptides demonstrated expression of NHE2 along the apical and NHE4 along the basolateral, membrane, whereas NHE1 and NHE3 were not detected. These results suggest that macula densa cells functionally and immunologically express NHE2 at the apical membrane and NHE4 at the basolateral membrane. These two isoforms likely participate in Na(+) transport, pH(i), and cell volume regulation and may be involved in tubuloglomerular feedback signaling by these cells.

Low renin hypertension in the next millennium.

With the expression cloning of the subunits of the epithelial sodium channel, a new era has evolved in our basic understanding of the low-renin forms of human hypertension. The monogenic hypertensive syndromes manifest dysregulation of the epithelial sodium channel in the cortical collecting tubule. These rare syndromes provide a schema for organizing our thinking about the more common form(s) of low renin hypertension, and raise the possibility that dysregulation of sodium channel activity and consequent salt retention and volume expansion provide a basic pathophysiological mechanism for low-renin hypertension. What are needed are more specific agents to interrupt the mineralocorticoid response pathways, and clinically relevant approaches to measuring sodium channel activity at the level of the collecting tubule in the individual patient. The combined use of aldosterone antagonists and angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists could have a beneficial effect on "progression" of renal disease associated with glomerular and interstitial fibrosis, especially if the effects of hyperkalemia on the heart and aldosterone secretion can be minimized.

Regulation by PKC isoforms of Na(+)/H(+) exchanger in luminal membrane vesicles isolated from cortical tubules.

The present study was designed to determine the Na/H exchanger isoforms present in luminal membrane vesicles (LMV) isolated from rat kidney cortical tubule suspensions, as well as the effects of acute phorbol ester (phorbol myristate acetate, PMA) and angiotensin II (ANG II) pretreatment of suspensions on NHE activity and protein kinase C (PKC) isoform abundance. In LMV, both NHE3 and NHE2 proteins were found by Western blot analysis, but only ethylisopropylamiloride-sensitive and almost completely Hoe-694-resistant Na/H exchange activity was observed from (22)Na uptake and thus attributed to NHE3. PMA pretreatment increased Na/H exchange activity and PKC isoforms alpha, delta, and epsilon abundance in LMV, and these effects were prevented by PKC inhibition. Low-dose ANG II (10(-11) M) pretreatment increased Na/H exchange activity and only PKC-zeta abundance in LMV, and these effects were also prevented by PKC inhibition. After high-dose ANG II (10(-7) M), Na/H exchange activity was decreased in LMV. PKC inhibition did not prevent this effect. In conclusion, the stimulating effects of PMA and low-dose ANG II are explained by the translocation of different isoforms of PKC in LMV, whereas the inhibitory effect of high-dose ANG II is not PKC dependent.