Journal of the American Society of Nephrology current issue

This Month's Highlights

Fri, 30 Oct 2009 10:04:36 PDT

Slow-Cycling Cells in Renal Papilla: Stem Cells Awaken?

Humphreys, B. D. — Fri, 30 Oct 2009 10:04:30 PDT

Cell Therapy for Alport Syndrome

Wong, C. J., Rogers, I. — Fri, 30 Oct 2009 10:04:30 PDT

Critical Care Nephrology: It's Not Just Acute Kidney Injury

Palevsky, P. M., Weisbord, S. D. — Fri, 30 Oct 2009 10:04:31 PDT

Allograft Biopsies: Studying Them for All They're Worth

Stillman, I. E., Pavlakis, M. — Fri, 30 Oct 2009 10:04:31 PDT

Is Calcitriol Life-Protective for Patients with Chronic Kidney Disease?

Thadhani, R. — Fri, 30 Oct 2009 10:04:31 PDT

Clinical Consequences and Management of Hypomagnesemia

Martin, K. J., Gonzalez, E. A., Slatopolsky, E. — Fri, 30 Oct 2009 10:04:31 PDT

Magnesium deficiency and hypomagnesemia remain quite prevalent, particularly in patients in intensive care units, and may have important clinical consequences. Magnesium should be measured directly in clinical circumstances in which a risk for magnesium deficiency exists and appropriately corrected when found. This commentary reviews the current knowledge of magnesium homeostasis and the risk factors and clinical consequences of magnesium deficiency and outlines approaches to therapy.

Transgenic and Infectious Animal Models of HIV-Associated Nephropathy

Rosenstiel, P., Gharavi, A., D'Agati, V., Klotman, P. — Fri, 30 Oct 2009 10:04:31 PDT

HIV-associated nephropathy (HIVAN) is a major cause of HIV-related morbidity and mortality. Transgenic and infectious models of HIVAN faithfully recapitulate the human disease and are important tools in advancing our understanding of disease pathogenesis, genetic susceptibility, and therapeutic intervention beyond the inhibition of viral replication. This review discusses the available transgenic murine models and infectious models of HIVAN in mice, rats, nonhuman primates, and felines. Particular emphasis is given to cell type–specific HIV expression as well as partial HIV genome expression used to map HIV-1 Nef and Vpr as pathologic determinants.

Measured GFR as a Confirmatory Test for Estimated GFR

Stevens, L. A., Levey, A. S. — Fri, 30 Oct 2009 10:04:32 PDT

Clinical assessment of kidney function is central to the practice of medicine. GFR is widely accepted as the best index of kidney function in health and disease, and accurate values are required for optimal decision making. Estimated GFR based on serum creatinine is now widely reported by clinical laboratories, and in most circumstances, estimated GFR is sufficient for clinical decision making. GFR estimates may be inaccurate in the non–steady state and in people in whom non-GFR determinants differ greatly from those in whom the estimating equation was developed. If GFR estimates are likely inaccurate or if decisions based on inaccurate estimates may have adverse consequences, a measured GFR is an important confirmatory test. Endogenous creatinine clearance is the most common method used to measure GFR in clinical practice but may be difficult to obtain or fraught with error. We review methods for GFR measurement using urinary and plasma clearance of exogenous filtration markers and focus on urinary clearance of iothalamate and plasma clearance of iohexol compared with inulin clearance. We suggest plasma clearance of nonradioactive markers be more widely implemented in clinical settings. Further research is necessary on the impact of the use of measured GFR as a confirmatory test.

Proliferation and Migration of Label-Retaining Cells of the Kidney Papilla

Fri, 30 Oct 2009 10:04:32 PDT

The kidney papilla contains a population of cells with several characteristics of adult stem cells, including the retention of proliferation markers during long chase periods (i.e., they are label-retaining cells [LRCs]). To determine whether the papillary LRCs generate new cells in the normal adult kidney, we examined cell proliferation throughout the kidney and found that the upper papilla is a site of enhanced cell cycling. Using genetically modified mice that conditionally expressed green fluorescence protein fused to histone 2B, we observed that the LRCs of the papilla proliferated only in its upper part, where they associate with "chains" of cycling cells. The papillary LRCs decreased in number with age, suggesting that the cells migrated to the upper papilla before entering the cell cycle. To test this directly, we marked papillary cells with vital dyes in vivo and found that some cells in the kidney papilla, including LRCs, migrated toward other parts of the kidney. Acute kidney injury enhanced both cell migration and proliferation. These results suggest that during normal homeostasis, LRCs of the kidney papilla (or their immediate progeny) migrate to the upper papilla and form a compartment of rapidly proliferating cells, which may play a role in repair after ischemic injury.

p53 Regulates Metanephric Development

Saifudeen, Z., Dipp, S., Stefkova, J., Yao, X., Lookabaugh, S., El-Dahr, S. S. — Fri, 30 Oct 2009 10:04:32 PDT

p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53^–/– embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53^–/– embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line–derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53^–/– WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD.

Embryonic Stem Cells Proliferate and Differentiate when Seeded into Kidney Scaffolds

Fri, 30 Oct 2009 10:04:32 PDT

The scarcity of transplant allografts for diseased organs has prompted efforts at tissue regeneration using seeded scaffolds, an approach hampered by the enormity of cell types and complex architectures. Our goal was to decellularize intact organs in a manner that retained the matrix signal for differentiating pluripotent cells. We decellularized intact rat kidneys in a manner that preserved the intricate architecture and seeded them with pluripotent murine embryonic stem cells antegrade through the artery or retrograde through the ureter. Primitive precursor cells populated and proliferated within the glomerular, vascular, and tubular structures. Cells lost their embryonic appearance and expressed immunohistochemical markers for differentiation. Cells not in contact with the basement membrane matrix became apoptotic, thereby forming lumens. These observations suggest that the extracellular matrix can direct regeneration of the kidney, and studies using seeded scaffolds may help define differentiation pathways.

Intestinal Npt2b Plays a Major Role in Phosphate Absorption and Homeostasis

Fri, 30 Oct 2009 10:04:33 PDT

Intestinal phosphate absorption occurs through both a paracellular mechanism involving tight junctions and an active transcellular mechanism involving the type II sodium-dependent phosphate cotransporter NPT2b (SLC34a2). To define the contribution of NPT2b to total intestinal phosphate absorption, we generated an inducible conditional knockout mouse, Npt2b^–/– (Npt2b^fl/fl:Cre^+/–). Npt2b^–/– animals had increased fecal phosphate excretion and hypophosphaturia, but serum phosphate remained unchanged. Decreased urinary phosphate excretion correlated with reduced serum levels of the phosphaturic hormone FGF23 and increased protein expression of the renal phosphate transporter Npt2a. These results demonstrate that the absence of Npt2b triggers compensatory renal mechanisms to maintain phosphate homeostasis. In animals fed a low phosphate diet followed by acute administration of a phosphate bolus, Npt2b^–/– animals absorbed approximately 50% less phosphate than wild-type animals, confirming a major role of this transporter in phosphate regulation. In vitro analysis of active phosphate transport in ileum segments isolated from wild-type or Npt2b^–/– mice demonstrated that Npt2b contributes to >90% of total active phosphate absorption. In summary, Npt2b is largely responsible for intestinal phosphate absorption and contributes to the maintenance of systemic phosphate homeostasis.

Stem Cell Therapies Benefit Alport Syndrome

Fri, 30 Oct 2009 10:04:33 PDT

Patients with Alport syndrome progressively lose renal function as a result of defective type IV collagen in their glomerular basement membrane. In mice lacking the 3 chain of type IV collagen (Col4A3 knockout mice), a model for Alport syndrome, transplantation of wild-type bone marrow repairs the renal disease. It is unknown whether cell-based therapies that do not require transplantation have similar potential. Here, infusion of wild-type bone marrow-derived cells into unconditioned, nonirradiated Col4A3 knockout mice during the late stage of disease significantly improved renal histology and function. Furthermore, transfusion of unfractionated wild-type blood into unconditioned, nonirradiated Col4A3 knockout mice improved the renal phenotype and significantly improved survival. Injection of mouse and human embryonic stem cells into Col4A3 knockout mice produced similar results. Regardless of treatment modality, the improvement in the architecture of the glomerular basement membrane is associated with de novo expression of the 3(IV) chain. These data provide further support for testing cell-based therapies for Alport syndrome.

Klotho Prevents Renal Calcium Loss

Fri, 30 Oct 2009 10:04:33 PDT

Disturbed calcium (Ca²⁺) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin D metabolism, but alternative possibilities exist. We hypothesized that failed tubular Ca²⁺ absorption is primary, which causes increased urinary Ca²⁺ excretion, leading to elevated 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and its sequelae. Here, we assessed intestinal Ca²⁺ absorption, bone densitometry, renal Ca²⁺ excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho^–/– mice. We observed elevated serum Ca²⁺ and fractional excretion of Ca²⁺ (FE_Ca) in klotho^–/– mice. Klotho^–/– mice also showed intestinal Ca²⁺ hyperabsorption, osteopenia, and renal precipitation of calcium-phosphate. Duodenal mRNA levels of transient receptor potential vanilloid 6 (TRPV6) and calbindin-D_9K increased. In the kidney, klotho^–/– mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D_28K, implying a failure to absorb Ca²⁺ through the distal convoluted tubule/connecting tubule (DCT/CNT) via TRPV5. Gene and protein expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D-1--hydroxylase (1OHase), and calbindin-D_9K excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca²⁺ wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca²⁺ handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca²⁺ loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis.

The PPAR{gamma} Agonist Pioglitazone Ameliorates Aging-Related Progressive Renal Injury

Yang, H.-C., Deleuze, S., Zuo, Y., Potthoff, S. A., Ma, L.-J., Fogo, A. B. — Fri, 30 Oct 2009 10:04:33 PDT

Peroxisome proliferator-activated receptor- (PPAR-) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against nondiabetic chronic kidney disease in experimental models. Here, we found that the PPAR- agonist pioglitazone protected against renal injury in aging; it reduced proteinuria, improved GFR, decreased sclerosis, and alleviated cell senescence. Increased local expression of PPAR- paralleled these changes. Underlying mechanisms included increased expression of klotho, decreased systemic and renal oxidative stress, and decreased mitochondrial injury. Pioglitazone also regulated p66^Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C-β. These results suggest that PPAR- agonists may benefit aging-related renal injury by improving mitochondrial function.

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Fri, 30 Oct 2009 10:04:34 PDT

Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10- to 12-wk-old male noncystic Pkd1^+/– and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.

Trps1 Functions Downstream of Bmp7 in Kidney Development

Fri, 30 Oct 2009 10:04:34 PDT

During embryonic development, the mesenchyme of the lungs, gut, kidneys, and other tissues expresses Trps1, an atypical member of the GATA-type family of transcription factors. Our previous work suggested the possibility that Trps1 acts downstream of bone morphogenic protein 7 (Bmp7), which is essential for normal renal development. To examine the role of Trps1 during early renal development, we generated Trps1-deficient mice and examined their renal histology. Compared with wild-type mice, Trps1-deficient newborn mice had fewer tubules and glomeruli, an expanded renal interstitium, and numerous uninduced metanephric mesenchymal cells, which resulted in fewer nephrons. In wild-type kidneys, Trps1 expression was present in ureteric buds, cap mesenchyme, and renal vesicles, whereas Trps1 was virtually absent in Bmp7-deficient kidneys. Furthermore, Trps1-deficient kidneys had low levels of Pax2 and Wt1, which are markers of condensed mesenchymal cells, suggesting that a lack of Trps1 affects the differentiation of cap mesenchyme to renal vesicles. In cultured metanephric mesenchymal cells, Bmp7 induced Trps1 and E-cadherin and downregulated vimentin. Knockdown of Trps1 with small interference RNA inhibited this Bmp7-induced mesenchymal-to-epithelial transition. Last, whole-mount in situ hybridization of Wnt9b and Wnt4 demonstrated prolonged branching of ureteric buds and sparse cap mesenchyme in the kidneys of Trps1-deficient mice. Taken together, these findings suggest that normal formation of nephrons requires Trps1, which mediates mesenchymal-to-epithelial transition and ureteric bud branching during early renal development.

Dexamethasone Ameliorates Renal Ischemia-Reperfusion Injury

Fri, 30 Oct 2009 10:04:34 PDT

In the setting of renal ischemia-reperfusion injury (IRI), the effect and mechanism of action of glucocorticoids are not well understood. In rat renal IRI, a single dose of dexamethasone administered before ischemia, or at the onset of reperfusion, ameliorated biochemical and histologic acute kidney injury after 24 h. Dexamethasone upregulated Bcl-xL, downregulated ischemia-induced Bax, inhibited caspase-9 and caspase-3 activation, and reduced apoptosis and necrosis of proximal tubular cells. In addition, dexamethasone decreased the number of infiltrating neutrophils and ICAM-1. We observed the protective effect of dexamethasone in neutrophil-depleted mice, suggesting a neutrophil-independent mechanism. In vitro, dexamethasone protected human kidney proximal tubular (HK-2) cells during serum starvation and IRI-induced apoptosis, but inhibition of MEK 1/2 abolished its anti-apoptotic effects in these conditions. Dexamethasone stimulated rapid and transient phosphorylation of ERK 1/2, which required the presence of the glucocorticoid receptor and was independent of transcriptional activity. In summary, in the setting of renal ischemia-reperfusion injury, dexamethasone directly protects against kidney injury by a receptor-dependent, nongenomic mechanism.

CKD Associates with Cognitive Decline

Fri, 30 Oct 2009 10:04:35 PDT

Cognitive impairment and chronic kidney disease (CKD) will become increasingly prevalent in the aging US population. Although evidence exists that CKD is a risk factor for cognitive decline, longitudinal studies are limited and largely have excluded ethnically diverse populations. The Northern Manhattan Study includes a population-based, prospective, stroke-free cohort. We assessed global cognitive function annually using the modified Telephone Interview for Cognitive Status (TICS-m) and estimated kidney function using Cockcroft–Gault creatinine clearance (CCl), Modification of Diet in Renal Disease estimated GFR (eGFR), and serum creatinine (sCr). We examined the association between CKD and change in TICS-m scores over time, adjusting for sociodemographic and vascular risk factors. Of 2172 subjects (mean age 71.5 yr, mean follow-up 2.9 yr), 59% were Hispanic, 20% were black, and 63% were women. Participants with a CCl <60 ml/min and those with a CCl between 60 and 90 ml/min performed significantly worse on the TICS-m over time than those with a CCl >90 ml/min, adjusting for potential confounders. Our results were similar when we used eGFR or sCr to estimate kidney function. In conclusion, decreased kidney function associates with greater cognitive decline, even in those with mild CKD. Kidney disease may represent a novel mechanism leading to cognitive impairment and a target for early intervention.

Pregnancy and Maternal Outcomes Among Kidney Transplant Recipients

Levidiotis, V., Chang, S., McDonald, S. — Fri, 30 Oct 2009 10:04:35 PDT

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 ± 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation ±5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.

Outcomes of Chronic Dialysis Patients Admitted to the Intensive Care Unit

Fri, 30 Oct 2009 10:04:35 PDT

Admission rates and outcomes of patients who have ESRD and are admitted to an intensive care unit (ICU) are not well defined. We conducted a historical cohort study using a prospective regional ICU database that captured all 11 adult ICUs in Winnipeg, Canada. Between 2000 and 2006, there were 34,965 total admissions to the ICU, 1173 (3.4%) of which were patients with ESRD. The main admission diagnoses among patients with ESRD were cardiac disease (31%), sepsis (15%), and arrest (10%). Compared with other patients in the ICU, those with ESRD were significantly younger but had more diabetes, peripheral arterial disease, and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) scores; mean length of stay in the ICU was similar, however, between these two groups. Restricting the analysis to first admissions to the ICU, unadjusted in-hospital mortality was higher for patients with ESRD (16 versus 11%; P < 0.0001), but this difference did not persist after adjustment for baseline illness severity. In conclusion, although ESRD associates with increased mortality among patients who are admitted to the ICU, this effect is mostly a result of comorbidity.

Six-Month Prophylaxis Is Cost Effective in Transplant Patients at High Risk for Cytomegalovirus Infection

Luan, F. L., Stuckey, L. J., Park, J. M., Kaul, D., Cibrik, D., Ojo, A. — Fri, 30 Oct 2009 10:04:35 PDT

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of $34,362 and $16,215 per case of infection and disease avoided, respectively, and $8,304 per one quality adjusted life-year gained. Sensitivity analyses supported the cost effectiveness of 6-mo prophylaxis over a wide range of valganciclovir and hospital costs, as well as variation in the incidence of CMV disease. In summary, 6-mo prophylaxis with valganciclovir combined with a one-time determination of viremia is cost effective in reducing CMV infection and disease in seronegative recipients of seropositive kidney and/or pancreas transplants.

TCF7L2 Polymorphism Associates with New-Onset Diabetes after Transplantation

Fri, 30 Oct 2009 10:04:36 PDT

New-onset diabetes after transplantation (NODAT) is a serious and frequent complication in transplant recipients. Whether NODAT shares the same susceptibility genes as type 2 diabetes is unknown. In this multicenter study, we genotyped 1076 white patients without diabetes at transplantation for 11 polymorphisms that associate with type 2 diabetes. We defined NODAT as a fasting plasma glucose ≥126 mg/dl on at least two occasions or de novo hypoglycemic therapy. We compared clinical and genetic factors between patients who developed NODAT within 6 mo of transplantation (n = 118; incidence 11%) and patients without diabetes (n = 958). In multivariate analysis, NODAT significantly associated with the following characteristics: TCF7L2 polymorphism (odds ratio [OR] 1.60 per each T allele; P = 0.002), age (OR 1.03 per year; P < 0.001), body mass index at transplantation (OR 1.09 per unit; P < 0.001), tacrolimus use (OR 2.26; P < 0.001), and the occurrence of a corticoid-treated acute rejection episode (OR 2.78; P < 0.001). In summary, our data show that the TCF7L2 rs7903146 polymorphism, a known risk factor for type 2 diabetes in the general population, also associates with NODAT.

Donor Age and Renal P-Glycoprotein Expression Associate with Chronic Histological Damage in Renal Allografts

Fri, 30 Oct 2009 10:04:36 PDT

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr. We assessed determinants of histologic evolution, including tacrolimus exposure, renal P-glycoprotein (ABCB1) expression, and polymorphisms in the CYP3A4, CYP3A5, and ABCB1 genes. Within the first 3 yr after transplantation, we noted a progressive increase in interstitial fibrosis, tubular atrophy, glomerulosclerosis, and vascular intimal thickening. Older donor age, absence of P-glycoprotein expression at the apical membrane of tubular epithelial cells, and combined donor–recipient homozygosity for the C3435T variant in ABCB1 significantly associated with increased susceptibility to chronic allograft damage independent of graft quality at implantation. Changes in graft function over time reflected these associations with donor age and ABCB1 polymorphisms, but it was acute T cell-mediated and antibody-mediated rejection that determined early graft survival. In conclusion, the effects of older donor age reach beyond the quality of the allograft at implantation and continue to be important for histologic evolution in the posttransplantation period. In addition, ABCB1 genotype and expression of P-glycoprotein in renal tubular epithelial cells determine susceptibility to chronic tubulointerstitial damage of transplanted kidneys.