The Human Cortical Distal Nephron: Distribution of Electrolyte and Water Transport Pathways Basic Research on Human Kidneys Provides a New Insight into Renal Calcium Handling.
Although Alexander Pope proposed that ‘The proper studyof Mankind is Man,‘ in renal physiology we have primarilystudied rat, rabbit, mouse, and dog kidneys to try to bettertreat our human patients. Sometimes the resulting extrapolationshave failed. For example, in the 1980s Pak’s group foundthat either thiazides or amiloride would lower urinary calciumexcretion in human subjects. Subsequent animal data offereda ready explanation for the thiazide part of the story: coexpressionof the apical NaCl cotransporter, and the basolateral calcium-extrudingtransporters (Na/Ca exchanger and Ca-ATPase) suggested thatthiazides block apical sodium entry, hyperpolarize the cell,and thus enhance apical calcium entry via channels. The amiloridedata were, however, a puzzle because lower organisms do notsignificantly coexpress amiloride-sensitive sodium channelsin the same cells as calcium transporters. In a careful studyin this issue, Biner et al. immunolocalized seven transportersand a calcium-binding protein along the human distal nephron.It turns out that when you take a look under the hood in humans,the Na/Ca exchanger and the Ca-ATPase are, indeed, coexpressedwith ENaC along the cortical collecting duct. Thus, the hyperpolarizationmodel readily explains amiloride-induced hypocalciuria in humans.Interestingly, ENaC in all four kidneys was internalized incytoplasmic vesicles, consistent with our high-sodium Westerndiet. These and other insights from this important article willsurely help us take better care of our all-too-human patients.
Cisplatin Induces Apoptosis in LLC-PK1 Cells via Activation of Mitochondrial Pathways A Step toward Preventing Nephrotoxicity from Chemotherapeutic Drugs.
The chemotherapeutic agent, cisplatin, is commonly used to treata variety of human cancers, but its use is limited by nephrotoxicity.Cisplatin accumulates in renal proximal tubules and causes celldeath via apoptosis, but the mechanism has been poorly understood.In this issue of the Journal, Park et al. show that cisplatininduces apoptosis of cultured renal epithelial cells via a signalingpathway that involves members of the Bcl-2 family. In this pathway,activation of pro-apoptotic Bcl-2 family members leads to alterationsin mitochondrial permeability, release of cytochrome c intothe cytosol, and activation of an intracellular protease calledcaspase-9. Activation of caspase-9 then triggers a cascade thatresults in DNA fragmentation and other characteristic featuresof apoptosis. In addition to elucidating the molecular mechanismof cisplatin-induced apoptosis, these studies suggest possibletherapeutic targets for mitigating nephrotoxicity.
Differential Expression Patterns of Claudins, Tight Junction Membrane Proteins, in Mouse Nephron Segments Beyond Transporters—Another Reason Why Different Parts of the Tubule Do Different Things.
The claudins are a family of cell-adhesion proteins that arelocated in tight junctions that form the seals between epithelialcells. Claudins are thought to regulate the diffusion of waterand solutes between cells, and mutations of one member of thefamily, claudin-16 (paracellin), have been shown to cause renalmagnesium wasting. In the most comprehensive survey completedto date, Kiuchi-Saishin et al. describe the localization of12 claudins in the mouse kidney. The claudins exhibit a complexpattern of segment-specific expression. For example, claudins-2,-10, and -11 are expressed in the proximal tubule, which isa relatively "leaky" epithelium, whereas claudins-3, -10, -11,and -16 are expressed in the water-impermeant thick ascendinglimb of the loop of Henle. These studies suggest that the molecularcomposition of tight junctions may be an important determinantof the permeability of different nephron segments to both saltand water.
Hormones, Growth Factors, Cell Signaling, Cell Biology and Structure
Expression of a Novel PDGF Isoform, PDGF-C, in Normal and Diseased Rat Kidney Another Potential Therapeutic Target in Diseases of Mesangial Cell Proliferation.
For well over a decade it was considered established that dimericcombinations of two known isoforms of platelet-derived growthfactor (PDGF A and B) constituted all of the relevant ligandsfor the two known PDGF receptors, and ß, both ofwhich can be expressed by mesangial cells and other renal celltypes. This ligand-receptor family has been shown to mediateglomerular and interstitial cell proliferation during injury,proliferative changes in injured blood vessels, and glomerulogenesisduring development. A paradigm has developed, based largelyon experimental studies in the anti-Thy 1 rat model of mesangiolysisand repair, that mesangial cell proliferation during injurycan be mediated largely, but not entirely, by interactions ofoverexpressed PDGF-B chain with concurrently upregulated PDGFreceptor ß. Recently, two additional isoforms of PDGF(C and D) have been identified. These isoforms bind to the knownPDGF receptors, but their function is largely unknown. Eitneret al. surveyed PDGF-C expression in a variety of rat modelsof renal injury and, in conjunction with in vitro studies, provideevidence that PDGF-C may function as a mesangial mitogen. Thedimer PDGF-CC preferentially binds the PDGF receptor; therefore,this introduces a new ligand-receptor system for regulationof mesangial cell behavior and increases the complexity of theparadigm of regulation of mesangial cell proliferation by PDGFduring injury. These studies are an important first step inidentifying potential functions for PDGF-C, but the extent towhich PDGF-C mediates renal injury and cell proliferation remainsan open question.
C6 Mediates Progressive Interstitial Disease in Rats with Remnant Kidneys Is C5b-9 the Principal Mediator of All Progressive Proteinuric Diseases?
There is abundant clinical data suggesting that progressionof glomerular diseases is related to the amount and durationof nonselective proteinuria. Several mechanisms have been suggested.This study explores the role of complement, via C5b-9 membraneattack complex formation and attack on tubular cells, in mediatingprogression in the remnant kidney model in rats, a standardmodel of progression attributed largely to glomerular hypertensionand sclerosis. The results suggest two phases of progressiveinjury after renal ablation: an early one presumably hemodynamicallymediated and a later phase attributable to effects of proteinuriaon the interstitium. This later phase is largely prevented whenC5b-9 formation cannot take place. The results not only establisha role for C5b-9 in proteinuric renal injury in a nonimmunesetting, but they also suggest the possibility that complement-inhibitortherapy may benefit progressive glomerular diseases throughmechanisms unrelated to effects on the glomerulus.
Nephrin Dissociates from Actin, and Its Expression Is Reduced in Early Experimental Membranous Nephropathy Is Nephrin a Player in Aquired as well as Congenital Nephrotic Syndrome?
Nephrin, a recently discovered consituent of the slit diaphragmbetween glomerular epithelial cells, is mutated in congenitalnephrotic syndrome, leading to a massive increase in proteinfiltration. Is nephrin also a player in the more common acquiredforms of nephrotic syndrome? The hunt is on to demonstrate thatit is. In this issue, Yuan et al. add to a growing understandingof the role of nephrin in the organization of the subepithelialsurface of the glomerular capillary filter and its alterationsin disease. Using the passive Heymann nephritis model of membranousnephropathy, the authors demonstrate displacement or loss offiltration slit diaphragms concurrent with formation of subepithelialimmune deposits. This article goes on to demonstrate that patternsof nephrin distribution become altered as part of this processand that this is characterized by detachment of nephrin fromthe podocyte actin cytoskeleton. The findings link changes innephrin attachment to the podocyte cytoskeleton to alterationsin slit diaphragm structure to the onset of proteinuria. Thefindings suggest that damage to slit diaphragms occurs withthe onset of proteinuria prior to widespread effacement of podocytefoot processes and that nephrin may be involved. In what appearsto be the decade of the podocyte, this is another step forwardin understanding the molecular basis of proteinuria.
Albumin/Creatinine Ratio to Detect Microalbuminuria: Implications of Sex and Race Is Kidney Disease More Common than We Thought? A New Approach to Early Detection.
Examining the use of the albumin/creatinine ratio (ACR) to detectmicroalbuminuria, which is a strong risk factor for cardiovasculardisease and progressive renal disease among individuals withdiabetes mellitus, Mattix et al. used NHANES III data to determinethe prevalence of microalbuminuria within the US population.These analyses are possible because this national data set andsoftware that allows the analyst to account for the survey sampledesign have become widely available, and contemporary computerscan handle the formidable task of analysis of this data set.Research like that of Mattix et al. is providing detailed informationabout the distribution of renal disease within the population.Of note, these investigators found that a substantial proportionof the US population has evidence of microalbuminuria as measuredby a single albumin-to-creatinine ratio. The distribution ofthe ACR differed for men and women and among non-Hispanic blackswhen compared with other races. The authors use gender-specificACR levels that eliminate the increased risk among women formicroalbuminuria but do not account for that observed amongnon-Hispanic blacks. The reasons why black Americans are atincreased risk for microalbuminuria and the relationship ofthis to the increased rates of chronic kidney disease have yetto be determined.
Matching Older Kidneys with Older Patients Does Not Improve Allograft Survival Matching for Age: Common Practice with Little Impact on Kidney Graft Outcome!
In this issue, Kasiske et al. use results reported to the USRDSfrom 1988 to 1998 to examine the practice of matching olderkidney recipients with older kidney donors and define the impacton outcome. Based on examination of the results reported on>74,000 patients, the authors report two interesting andimportant results. First, the practice of matching kidneys forage of older recipient and donor is not uncommon, and second,there was no beneficial impact of such matching on graft outcome.The results also confirm previously published data of pooreroutcome of older recipients and kidneys from older donors, withthe latter being even worse. The results in this article areparticularly helpful at a time when transplanting older recipientsand utilizing older donors for transplantation is common practice(see Figure 1), although it seems that transplanting older kidneysinto older recipients for the purpose of improving outcome isnot necessarily justified. One could argue however that sinceolder kidneys do not do as well as younger kidneys it is perhapsjustifiable to transplant older kidneys into older donors whomay not live as long as younger recipients even through graftoutcome may not be significantly improved!
Congestive Heart Failure in Renal Transplant Recipients: Risk Factors, Outcomes, and Relationship to Ischemic Heart Disease Another Posttransplant Risk and Another Connection between the Kidney and Cardiovascular Disease.
This is the first study to examine the occurrence and consequencesof incident heart failure among posttransplant patients. Aftera one-year lag to ensure that new cases were not the delayedconsequence of risk factors associated with dialysis therapy;Rigatto et al. identified all new episodes of heart failureand ischemic heart disease in 638 consecutive transplant patientswho were free of heart disease prior to transplantation. Aftertransplantation, the ten-year cumulative risk of developingheart failure was 12% and 11% for ischemic heart disease, ratessubstantially higher than reported for the general population.Both heart failure and ischemic heart disease increased therisk of subsequent mortality. Diabetes mellitus, elevated systolicblood pressure, and anemia were also associated with increasedrisk of death in these patients. These observations underscorethe importance of cardiovascular disease during posttransplantfollow-up and suggest that appropriate management of anemia,high blood pressure, and elevated blood glucose have considerablepromise for improving posttransplant survival.
and ß, both of which can be expressed by mesangial cells and other renal cell types. This ligand-receptor family has been shown to mediate glomerular and interstitial cell proliferation during injury, proliferative changes in injured blood vessels, and glomerulogenesis during development. A paradigm has developed, based largely on experimental studies in the anti-Thy 1 rat model of mesangiolysis and repair, that mesangial cell proliferation during injury can be mediated largely, but not entirely, by interactions of overexpressed PDGF-B chain with concurrently upregulated PDGF receptor ß. Recently, two additional isoforms of PDGF (C and D) have been identified. These isoforms bind to the known PDGF receptors, but their function is largely unknown. Eitner et al. surveyed PDGF-C expression in a variety of rat models of renal injury and, in conjunction with in vitro studies, provide evidence that PDGF-C may function as a mesangial mitogen. The dimer PDGF-CC preferentially binds the PDGF
