Hormones, Growth Factors, Cell Signaling, Cell Biology and Structure
Stimulation of Proximal Tubule Cell Apoptosis by Albumin Bound Fatty Acids Mediated by Peroxisome Proliferator Activated Receptor Tubulotoxic Effects of Proteinuria: The Lipid Connection Is Strengthened.
There is currently little doubt thatsustained high-grade proteinuria has damaging renal effects.While the mechanisms involved continue to unfold, a link betweenproteinuria-induced tubular responses and interstitial inflammationhas been documented. Several years ago, studies by Kees-Foltsand Schreiner implicated protein-bound fatty acids in this cascade.In the study reported by Arici et al., an important relationshipis documented between fatty acid-bearing albumin and tubularcell apoptosis. This effect appears to be mediated through activationof the peroxisome proliferator-activated receptor gamma (PPAR(),which is a nuclear receptor that initiates gene transcriptionfollowing ligand-dependent activation. Fatty acids are knownto be PPAR( ligands. Since the important structural connectionbetween tubulointerstitial disease and renal insufficiency istubular destruction, the ability of albumin-bound fatty acidsto activate PPAR( and initiate apoptosis in proximal tubularcells could represent an important pathophysiologic pathway.Furthermore, this study gives cause for some reflection aboutthe consequences of pharmacologic use of PPAR( agonists in thetreatment of type II diabetes. Much more clearly remains tobe learned about the effects of PPAR( and its activation byvarious ligands within the kidney.
Immunology and Pathology
Cloning of Rat Homologue of Podocin: Expression in Proteinuric States and in Developing Glomeruli Another Step Closer to Defining a Functional Role for Podocin in Diseases of the Podocyte.
Podocin is mutated in humans withautosomal recessive and sporadic forms of steroid-resistantnephrotic syndrome. Podocin is a membrane protein that has beenfound to be part of a large macromolecular complex that alsocontains nephrin, CD2AP, and other proteins important in podocytefunction. Kawachi et al. cloned rat podocin and studied itsexpression in animals with experimental glomerulonephritis.Rats are particularly useful for such studies because the administrationof puromycin or anti-nephrin antibodies produces a lesion resemblinghuman minimal change disease with proteinuria. In normal rats,podocin was located in the podocyte foot processes near theslit diaphragms, which are the major barrier to glomerular filtration.However, in rats with proteinuria, podocin was redistributedto the cytoplasm. These results suggest that the localizationof podocin near the slit diaphragms is important for maintainingthe integrity of the glomerular filtration barrier. Interestingly,podocin was also found in the brain, where it may be involvedin maintaining the blood-brain barrier.
Membrane Expression of Proteinase 3 Is Genetically Determined If ANCA Is Pathogenic, How Come Disease Activity Doesn’t Correlate Well with Antibody Levels?
Although the role of ANCA in renalvasculitides such as Wegener’s is still controversial(See editorial by Falk, J Am Soc Nephrol 13: 1977–1979,2002) ,the proposed mechanism for its pathogenicity involvesbinding to neutrophil membrane-expressed antigens such as PR3and MPO, inducing neutrophil localization and activation inthe microcirculation. However, disease expression is quite variableand not well correlated with ANCA antibody levels. In this issueof JASN, Kettridge et al. test the hypothesis that it is geneticallydetermined membrane expression of the ANCA antigens that accountsfor this variability rather than antibody levels. They reportsignificantly higher expression of PR3 on neutrophil membranesin patients with Wegener’s compared with normal patientsand good evidence that this expression is genetically determined.No attempt is made to correlate membrane antigen expressionwith disease activity, but the results do add another factorto our understanding of the role of ANCA in disease and mayprovide a useful clinical marker of disease activity or susceptibility.
Molecular Medicine, Genetics and Development
Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease New Mutations that Cause Polycystic Kidney Disease.
Autosomal recessive polycystic kidneydisease (ARPKD) is a genetic disorder that produces renal failurein infants and children. ARPKD is caused by mutations of thePKHD1 gene located on chromosome 6. The international ARPKDConsortium here reports 34 new mutations found by screening90 ARPKD patients. Their study effectively doubles the numberof known mutations of PKHD1 and permits some preliminary genotype-phenotypecorrelations. The rate of detection of mutations is only 61%,which is probably due to the enormous size of the gene and theinsensitivity of SSCP analysis. Mutations were found throughoutthe gene. However, a missense mutation in exon 3 that changesa threonine to a methionine was identified in multiple unrelatedindividuals, indicating that it represents a mutational hotspot.Individuals who carried two mutations that truncated the PKHD1protein died shortly after birth, whereas individuals with missensemutations had less severe disease. The results suggest thatcomplete loss of PKHD1 produces severe disease and that missensemutations may produce partially functional protein.
Pathophysiology of Renal Disease
Crystal Retention Capacity of Cells in the Human Nephron: Involvement of CD44 and its Ligands Hyaluronic Acid and Osteopontin in the Transition of Crystal-Binding into a Nonadherent Epithelium Once Calcium Crystals Form, Why Do They Stick to Cells to Make a Stone?
In medieval times, bladder stoneswere removed by a method called "Celsan," after Celsus’description in De Medicina. We are still, to some extent, inthe Dark Ages when it comes to the pathophysiology of idiopathiccalcium nephrolithiasis. We do know that hypercalciuria mayresult from genetic mutations altering tubular function andthat hyperoxaluria may cause supersaturation and oxidative stresson tubular cells. Natural inhibitors, such as bikunin and osteopontin,modulate crystallization and may also be involved in crystalattachment to cells. In this issue, Verhulst et al. use primarycultures of human proximal and collecting duct cells to examinethe factors responsible for attachment of calcium oxalate monohydrate(COM) crystals. Their results suggest that crystal retentionmay occur by calcium binding to CD44, osteopontin, and hyaluronidasethat would be preferentially expressed on the surface of damagedhuman proximal tubule cells, although other studies (see below)identify a role for osteopontin in protecting from calcium crystalformation. The implication is that tubular damage causes stones,and stones cause tubular damage.
Mineral Metabolism and Bone Disease
Osteopontin Is a Critical Inhibitor of Calcium Oxalate Crystal Formation and Retention in Renal Tubules A Natural Inhibitor of Calcium Stone Formation Lives up to Its Promise.
Osteopontin is a multifunctionalmacromolecule that is secreted by most cells and involved ina diversity of biologic processes. In the kidney, OPN from tubularcells has been implicated as a chemoadherent molecule in interstitialcellular infiltrates and progressive fibrosis in several renaldiseases. However, before it’s role in inflammation wasdiscovered, OPN was known to be a potent inhibitor of calciumcrystal formation in vitro. In this study, Wesson et al. makeuse of an OPN knockout mouse made hyperoxaluric with ethyleneglycol to document a clear and powerful role for OPN in protectingthe kidney tubules from calcium crystal formation in vivo. Thisis the first study to clearly establish the renoprotective roleof OPN in renal stone formation in intact animals and suggestspossible new approaches to stone disease involving modulationof OPN expression in the kidney.
Dialysis
Cardiac Valve Calcification as an Important Predictor for All-Cause Mortality and Cardiovascular Mortality in Long-Term Peritoneal Dialysis Patients: A Prospective Study Cardiac Calcification — A Predictor of High Mortality in Dialysis Patients.
Calcification of coronary arteriesand the aorta of ESRD patients, detected by electron beam computedtomography, has focused attention on the prevalence and consequencesof deposition of calcium in soft tissues and in cardiac valves.In this study, Wang et al. have reported on these phenomenain prevalent peritoneal dialysis patients in Hong Kong. Among192 patients (mean duration of peritoneal dialysis; 39 mo),62 patients (32%) had calcification of either the aortic ormitral valves or both. The one-year survival was 70% and 93%for those with and without calcification. The RR of all-causemortality and cardiac mortality were 2.50 and 5.39, respectively.Those with cardiac calcification also had a higher prevalenceof atherosclerotic disease than those without calcification(44% versus 29%). Those with both valvular calcification andatherosclerosis had a much higher mortality rate than did thosewith one complication only or with neither complication. Themechanism does not appear to be due to the direct effect ofvalve stenosis or insufficiency. The role of atheroscleroticdisease is probably not different than that in the general population,whereas that associated with valvular calcification may be associatedwith a more general process of vascular calcification, leadingto less compliant blood vessels, higher pulse wave velocity,and death due to the adverse cardiac effects of these hemodynamicfactors. On the other hand, both might be related to an unidentifiedconfounder. In any case, further research is required to addressthis prevalent condition, which is predictive of poor survival.
Epidemiology and Outcomes
Kidney Transplantation in the Elderly: A Decision Analysis More Cadaver Kidneys Are Going to Elderly Recipients — But Is This a Good Idea?
The rate of cadaveric and livingkidney donation increased over the past decade in the UnitedStates from 10,418 in 1990 to 13,590 in 1999. Despite the 30%increase in graft donation, this represents an overall declinein graft availability from one kidney for every five incidentpatients in 1990 to one for every seven patients in 1999. Furthermore,the allocation of donated kidneys to individuals aged 60 yearsand older increased from 9% to 23% of available kidneys. Thearticle by Jassal et al. in this issue of JASN is an importantcontribution to the evaluation of the appropriateness of thisincreased allocation of kidneys to older recipients. The authorsconducted a decision analysis to examine the cost-benefit tradeoffof allocation of cadaveric kidney transplantation for elderlyindividuals and found that the cost of extended life expectancy,measured by "quality-adjusted years" was favorable between 65and 80 years of age. As pointed out by the authors, this findingestablishes only one of the boundaries of an assessment of theappropriateness of organ allocation to elderly individuals
Cancers of the Kidney and Urinary Tract in Patients on Dialysis for ESRD: Analysis of Data from the United States The Risk of Urinary Tract Cancer Is Increased in ESRD Independent of Acquired Renal Cysts.
Stewart et al. have analyzed therisk of kidney and bladder cancer in over 800,000 ESRD patientsfollowed by the USRDS, EDTA, and ANZDATA renal registries. Theauthors report substantially increased risk for both cancerscompared with the general populations of the three regions.This report confirms previous observations, and it is an importantillustration of how data from the multiple population-basedregistries throughout the world can be used to identify importantassociations. For example, the authors report substantial heterogeneityof cancer risk across primary causes of renal disease, raisingthe possibility that disease-specific factors rather than factorscommon to ESRD, like acquired cystic disease of the kidney,may be responsible for the increased occurrence of kidney cancerin these patients.
Transplantation
Kidney Allograft and Patient Survival in Type I Diabetic Recipients of Cadaveric Kidney Alone Versus Simultaneous Pancreas/Kidney Transplants: A Multivariate Analysis of the UNOS Database Does Simultaneous Pancreas Transplantation Improve Renal Survival in Type I Diabetic Patients? Apparently Not.
The manuscript by Bunnapradist etal. reports data based on registry data analysis examining theoutcome of renal allografts in two groups of type I diabeticrecipients: recipients of kidneys alone or recipients of simultaneouspancreas transplantation (SPK). The results show that SPK wasassociated with better renal allograft survival as comparedwith kidney alone, despite a higher rate of renal allograftrejection in the SPK group. This observation was explained byfavorable donor and recipient factors in the SPK group. Aftercontrolling for these factors, SPK provided no protective ordetrimental effect on renal allograft or patient survival. Thestudy is important because it provides hard evidence that, whencircumstances of retrieval and distribution are taken into account,short-term renal allograft outcomes for type I diabetic recipientsare not different in kidney alone versus kidney-pancreas transplantrecipients. These data are helpful for nephrologists and transplantsurgeons because they help in planning the best strategy forrenal replacement in diabetic patients.
