In this report of our 3-yr protocol biopsy program, we describe the evolution of acute rejection (AR) and chronic renal allograft nephropathy (CAN) in a cohort of 21 children treated with antibody induction, tacrolimus, mycophenolate mofetil, and prednisone. The aims of this study were to compare the pathogenicity of clinical acute rejection (CAR) and subclinical acute rejection (SAR), and to determine whether functional studies accurately represent acute and chronic renal allograft pathology in pediatric recipients with disproportionately large grafts. Using concurrent biopsies, we evaluated: (i) the utility of changes in the baseline sCr (DeltasCr) to predict both the onset of AR and the response to immunosuppressive therapy; and (ii) the relationship of the calculated creatinine clearance and the presence of pathologic proteinuria to the severity of CAN. We performed 112 biopsies: 11 donor, 73 protocol, 16 acute graft dysfunction and 12 1-month follow-up AR therapy. CAR and SAR were similar in incidence, timing and histologic severity. Progression of CAN was associated with the first episode of CAR (p < 0.02) and the cumulative number of episodes of CAR (p < 0.01), SAR (p < 0.05), CAR plus SAR (p < 0.002) and borderline SAR (B-SAR) (p < 0.006). One-month post-treatment DeltasCrs could not distinguish 1-month follow-up biopsies with histologically confirmed worsened or unchanged AR from those with improved histology (35.2 +/- 74.8% vs. 23.8 +/- 24.9%, p = NS). These findings led to the addition of anti-lymphocyte antibody therapy in five of 10 (50%) cases. Despite 100% 3-yr actuarial graft survival and excellent function (GFR = 111 +/- 36 mL/min/1.73 m(2)), 18 of 21 (86%) patients had grade I CAN or greater chronic histology at a mean +/- sd follow-up period of 18.2 +/- 13.1 months. Thirteen of 21 (62%) patients progressed to grade I CAN at 5.2 +/- 3.6 months and five (38%) of these patients progressed to grade II CAN at 17.8 +/- 11.3 months. Schwartz GFR did not differ between patients with or without CAN (108 +/- 38 mL/min/1.73 m(2) vs. 127 +/- 8 mL/min/1.73 m(2), p = NS). In biopsies with CAN and no associated AR, neither the Banff chronic tubulointerstitial (Banff ci) score nor the Banff chronic grade correlated with the GFR. Proteinuria was not associated with CAN. Clinical AR and SAR are similar histologic lesions with a capacity for CAN progression. In pediatric renal transplant recipients, longitudinal protocol biopsies are superior to functional studies for the diagnosis and post-therapeutic monitoring of AR and for the surveillance of CAN.

Isocaloric soy protein feeding ameliorates both epithelial and interstitial changes in the Han:SPRD-cy rat independent of a hypocholesterolemic effect. The histologic benefit is associated with changes in polyunsaturated fatty acid metabolism that may influence both inflammatory and proliferative pathways.

Low-fat diets and diets containing n-3 fatty acids (FA) slow the progression of renal injury in the male Han:Sprague-Dawley (SPRD)-cy rat model of polycystic kidney disease. To determine whether these dietary fat effects are similar in females and in another model of renal cystic disease, in this study we used both male and female pcy mice to examine the effects of fat level and type on disease progression. Adult pcy mice were fed 4, 10, or 20 g soybean oil/100 g diet for 130 d in study 1. In study 2, weanling pcy mice were fed high or low levels of fat rich in 18:2n-6 (corn oil, CO), 18:3n-3 (flaxseed oil/CO 4:1 g/g, FO), or 22:6n-3 (algal oil/CO 4:1 g/g, DO) for 8 wk. In adult pcy mice, low- compared with high-fat diets lowered kidney weights (2.4 +/- 0.2 vs. 3.1 +/- 0.2 g/100 g body weight, P = 0.006) and serum urea nitrogen (SUN) (9.6 +/- 0.6 vs. 11.9 +/- 0.6 mmol/L, P = 0.009), whereas in young pcy mice it reduced renal fibrosis volumes (0.44 +/- 0.04 vs. 0.62 +/- 0.04 mL/kg body weight, P < 0.0001). FO feeding in young pcy mice mitigated the detrimental effects of high fat on fibrosis while not altering kidney size, function, and oxidative damage when compared with the CO-fed mice. In contrast, DO- compared with CO-fed mice had higher kidney weights (2.64 +/- 0.07 vs. 2.24 +/- 0.08 g/100 g body weight, P = 0.005), SUN (9.4 +/- 0.57 vs. 7.0 +/- 0.62 mmol/L, P < 0.0001), and cyst volumes (7.9 +/- 0.28 vs. 6.2 +/- 0.30 mL/kg body weight, P < 0.0001) and similar levels of oxidative damage and fibrosis. The FA compositions of the diets were reflected in the kidneys: 18:2n-6, 18:3n-3, and 22:6n-3 were the highest in the CO, FO, and DO diets, respectively. Dietary effects on kidney disease progression were similar in males and females. A low-fat diet slows progression of renal injury in male and female pcy mice, consistent with findings in the male Han:SPRD-cy rat. Dietary fat type also influenced renal injury, with flaxseed oil diets rich in 18:3n-3 slowing early fibrosis progression compared with diets rich in 18:2n-6 or in 22:6n-3.

Flaxseed ameliorates Han:SPRD-cy rat polycystic kidney disease through moderation of the associated chronic interstitial nephritis. The diet alters renal content of polyunsaturated fatty acids in a manner that may promote the formation of less inflammatory classes of renal prostanoids.

As whole flaxseed is beneficial in the treatment of experimental renal disease, we undertook a study to determine whether previously documented benefits of whole flaxseed could be reproduced with dietary low-lignan flax oil (FO), a rich source of alpha-linolenic acid, in experimental polycystic kidney disease. Male offspring of Han:SPRD-cy heterozygous rats were fed a synthetic diet containing FO or corn oil (CO) for 8 wk from the time of weaning. Renal inflammation, fibrosis, proliferation, cystic change, and oxidized-LDL were assessed morphometrically. Hepatic and renal lipid composition was assessed using GC. FO feeding produced hepatic and renal enrichment of n-3 PUFA and an increase in C18:>C18 PUFA ratios (18-carbon PUFA compared to longer-chain PUFA), with a reduction in proportion of hepatic long-chain PUFA. The FO-based diet was associated with lower mean cystic change by 29.7% (P = 0.018), fibrosis by 21.7% (P = 0.017), macrophage infiltration by 31.5% (P < 0.0001), epithelial proliferation by 18.7% (P = 0.0035), and ox-LDL detection by 31.4% (P < 0.0001) in Han:SPRD-cy heterozygotes. Serum creatinine was significantly lower in FO-fed diseased animals. A small hypocholesterolemic effect was noted in all animals fed FO. FO feeding moderates renal injury, modifies the profile of substrates available for elongation to eicosanoid precursors, and inhibits the elongation of C18 PUFA in this model. The consumption of FO-based products may prove a more practical way of obtaining health benefit than attempts to increase dietary content of unrefined seed.