Cell and Transport Physiology Phosphate-Induced Vascular Calcification: Role of Pyrophosphate and Osteopontin The Heartbreak of Vascular Calcification?
Calcium phosphate deposition isrecognized as a serious issue in patients with stage V chronickidney disease. Vascular calcification can cause dermal andperineural deposits, calciphylaxis, anastomosis failures fortransplantation, and vascular access, and it may contributeto adverse cardiovascular outcomes. Current approaches focuson reducing the calcium x phosphate product and controllingparathyroid secretion. The in vitro model of vascular calcificationdescribed by Lomashvili et al. provides a novel approach tounderstanding the factors that may regulate mineral depositionin the vasculature. If this model is relevant to the processesthat occur in vivo in dialysis patients, then unique approachesto controlling vascular calcification may be developed. Thecritical roles of pyrophosphate and alkaline phosphatase mustbe examined. Since the bisphosphonates have impressive safetymargins and are essentially pyrophosphate congeners, their utilityin treating calciphylaxis and vasculature calcification maybe well worth considering. Page 1392
Cell Biology Reduction in Connective Tissue Growth Tissue Factor by Antisense Treatment Ameliorates Renal Tubulointerstitial Fibrosis Blockade of Connective Tissue Growth Factor Ameliorates Renal Tubulointerstitial Fibrosis.
Based on data from in vitro studies,connective tissue growth factor (CTGF/CCN2) is proposed as oneof the downstream mediators of TGF-–induced fibrosis.In this study, a cleaver approach of retrograde delivery ofCTGF antisense oligonucleotides via the renal vein was usedto inhibit CTGF production by renal interstitial cells. Associatedwith a remarkable reduction in renal CTGF expression, the degreeof interstitial fibrosis was reduced 50 to 60% in rats withureteral obstruction of 7-d duration compared with rats treatedwith vehicle alone or with reverse oligonucleotides. An importantfinding in the CTGF antisense treatment group was a 60% reductionin the number of interstitial myofibroblasts. These beneficialoutcomes were not mediated via effects on TGF- expression, asthese were similar in all three groups with obstructive nephropathy.Exactly how CTGF regulates myofibroblast recruitment and matrixprotein synthesis remains to be determined. Three differentreceptors (v3 integrin, IIb3 integrin, and low-density lipoproteinreceptor-related proteinz), but not TGF- receptors, can bindCTGF. This in vivo study establishes a profibrotic role forCTGF in kidney fibrosis. Page 1430
Genetics and Development Mouse Model of X-Linked ALPORT Syndrome A Mouse with PKD—At Last!
X-linked Alport syndrome (XLAS)is caused by mutations of the Col4a5 gene encoding the 5 chainof type IV collagen. Rheault et al. have produced the firstmouse model of XLAS. Using a knock-in approach, they produceda mutation of Col4a5 identical to a naturally occurring mutationin humans. Mutant mice displayed proteinuria and died prematurelyfrom renal failure. Similar to humans with XLAS, males had moresevere disease than female carriers. Histological examinationof the kidneys revealed focal glomerulosclerosis, absence ofboth the 5 and 3 chains of type IV collagen, and characteristicsplitting and lamellation of the glomerular basement membrane.The phenotype of the mutant mice faithfully recapitulates theclinical and pathological features of human XLAS. These miceshould be a useful experimental model for studies of pathogenesisand treatment Page 1466
Basic Immunology and Pathology Late Onset of Treatment with a Chemokine Receptor CCR1 Antagonist Prevents Progression of Lupus Nephritis in MRL-Fas(lpr) Mice It’s Never Too Late to Protect the Interstitium.
Inflammatory cells are present inthe interstitium of all chronically damaged kidneys, where theyeither contribute to ongoing injury or help to reverse it dependingon phenotypic and functional features that remain poorly defined.Several recent studies have documented an impressive role forcertain chemokines in interstitial mononuclear cell recruitment,and chemokine-dependent pathways have generally led to detrimentalkidney effects. The present study strengthens this pathogeneticparadigm. The kidneys of MRLlpr/lprmice with lupus nephritisexpress the CCL3/MIP-1 chemokine, whereas its receptor (CCR1)is detected on interstitial macrophages and T cells. Mice withestablished nephritis were treated with a soluble CCR1 antagonist(BX471) from 20 to 24 wk of age with both impressive and surprisingeffects. In the BX471-treated group, interstitial inflammationand fibrosis were significantly attenuated, renal TGF- mRNAlevels were significantly lower, and serum BUN concentrationswere significantly better than in the vehicle-treated group;however, anti-CCR1 therapy had no effect on serum autoantibdytiters, glomerular immune deposits, glomerular pathology, andthe degree of proteinuria. Together with prior studies of nephrotoxicserum nephritis in CCR1 null mice and CCR1 antagonism in obstructivenephropathy and transplant rejection, it appears that targetingchemokine-dependent leukocyte recruitment is therapeuticallybeneficial even in established kidney disease. Page 1504
CLINICAL SCIENCE
Clinical Nephrology Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis A New Look at Renal Ammoniagenesis.
In this issue, Garibotto et al.examine the intrarenal fate of amino acids in an important attemptto better define the catabolic processes that are importantfeatures of chronic kidney disease. Recent work has focusedthe factors that regulate catabolism and the important roleplayed by acidosis in this process. Unraveling the mysteriesof the proteosome in experimental models has been an importantstep forward, and the work by Garibotto et al. brings theseefforts into focus in human subjects. A practical aspect ofthese studies relates to the generation of ammonia by the kidney,and the effects that ammonia can have to collapse intralysosomalpH gradients, thereby slowing the rate of protein degradation.Although the number of subjects is limited, the implicationsof these findings are important for our understanding of themultifactorial processes that contribute to the clinical conditionsassociated with chronic kidney disease. Page 1606
Development of Chronic Kidney Disease and Cardiovascular Prognosis in Essential Hypertensive Patients Blood Pressure and CKD: A Risk Factor for Initiation as well as Progression.
The role of elevated BP in the initiationof renal injury remains controversial. In this issue of JASN,Segura et al. report that nearly 15% of hypertensive patientswith normal renal function developed CKD during an average of13 years of follow-up. Characteristics associated with developingCKD included age, systolic BP, and elevated serum cholesterollevels. These risk factors, along with smoking, male gender,diabetes mellitus, and left ventricular hypertrophy by electrocardiogramare the Framingham risk factors associated with increased riskof coronary artery disease. Not surprisingly, the risk of cardiovasculardisease (CVD) among the patients who developed CKD was threefoldthat of those who maintained their renal function. Another wayto view these results is that 35% of those patients who developedCVD also developed CKD, underscoring the importance of viewingpatients with CVD as individuals who are at high risk of CKD.Page 1616
Epidemiology and Outcomes Development, Prevention, and Potential Reversal of Left Ventricular Hypertrophy in Chronic Kidney Disease Prevention and Reversal of Left Ventricular Hypertrophy in CKD – A Pipe Dream?
In this issue of JASN, McMahon etal. report a randomized controlled trial designed to test thehypothesis that correction of anemia corrects left ventricularmass (LVM). The outcome was negative by intention-to-treat analysis.Does this indicate that correction of anemia is irrelevant?Certainly not, since hemoglobin (Hb) values failed to decreasesubstantially and the working hypothesis could not be properlytested. Why is the information interesting regardless? The studyprovides a unique opportunity for assessing the prevalence ofand change in left ventricular hypertension (LVH) in a well-definedgroup of patients exposed to standardized treatment protocolsand followed using standardized serial echocardiography. LVHis a potent risk factor for cardiac death; therefore, the findingsare of undoubted interest. First the prevalence of LVH, 30%in patients with CKD stage 3 and 4, was lower than suggestedby past reports, and LVM did not change in 63%, possibly reflectingthe high quality of management. In a small proportion (10%),LV indices regressed primarily in younger patients with better-preservedrenal function. A lower pulse pressure was the sole factor predictingnormalization. The good news is that reduction of volume andpressure overload seem to be effective to control LVH in thisobservational analysis. The bad news is that we still don’tknow whether prevention of anemia is helpful in this respect.Page 1640
Clinical Transplantation Incorporating Recipient Choice in Kidney Transplantation Should Recipients Choose the Kidney Transplant they Want?
In this interesting article, Chertow’sgroup used a sophisticated modeling system to analyze the impactof incorporating recipient choice on the type of donor kidneyto be transplanted on equity, efficiency, and quality-adjustedlife expectancy of patients. The results show that, comparedwith the UNOS allocation system, an algorithm that incorporatedrecipient choice predicted a 5% increase in quality-adjustedlife expectancy, a 17% decrease in median waiting time, a 27%increase in the likelihood of transplantation, and an 80% reductionin the number of discarded kidneys. Benefits were observed acrosscategories of age, gender, and race. This is important informationfor the transplant community, which should consider a regionaldemonstration project o prove the utility of such an approach.Page 1656
–induced fibrosis. In this study, a cleaver approach of retrograde delivery of CTGF antisense oligonucleotides via the renal vein was used to inhibit CTGF production by renal interstitial cells. Associated with a remarkable reduction in renal CTGF expression, the degree of interstitial fibrosis was reduced 50 to 60% in rats with ureteral obstruction of 7-d duration compared with rats treated with vehicle alone or with reverse oligonucleotides. An important finding in the CTGF antisense treatment group was a 60% reduction in the number of interstitial myofibroblasts. These beneficial outcomes were not mediated via effects on TGF-
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