Various aberrations of cell biology have been reported in polycystic kidney diseases and in cystic renal dysplasias. A common theme in these disorders is failure of maturation of renal cells which superficially resemble embryonic tissue. Apoptosis is a feature of normal murine nephrogenesis, where it has been implicated in morphogenesis, and fulminant apoptosis occurs in the small, cystic kidneys which develop in mice with null mutations of bcl-2. Therefore, we examined the location and extent of apoptosis in pre- and postnatal samples of human polycystic and dysplastic kidney diseases using propidium iodide staining, in situ end-labeling and electron microscopy. In dysplastic kidneys cell death was prominent in undifferentiated cells around dysplastic tubules and was occasionally found in cystic epithelia. The incidence of apoptosis was significantly greater than in normal controls of comparable age both pre- and postnatally. In the polycystic kidneys there was widespread apoptosis in the interstitium around undilated tubules distant from cysts, in undilated tubules between cysts and in cystic epithelia. The level of apoptosis compared to controls was significantly increased postnatally. A similar increase of cell death was also noted in the early and late stages of renal disease in the polycystic cpk/cpk mouse model. We speculate that deregulation of cell survival in these kidneys may reflect incomplete tissue maturation, and may contribute to the progressive destruction of functional kidney tissue in polycystic kidneys and the spontaneous involution reported in cystic dysplastic kidneys.

The early institution of peritoneal dialysis in acute renal failure and low cardiac output after cardiac operations not only removes fluid, thus easing fluid restriction, but may also improve cardiopulmonary function.

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0-12) of 27.2 microg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

A number of clinical laboratory and biopsy-derived parameters were assessed for their prognostic significance in the short (24 months), intermediate (60 months) and long terms in 45 patients (43 female, 2 male) with diffuse proliferative lupus glomerulonephritis (DPGN). The factors evaluated were serum creatinine (SCr) and urinary protein at time of biopsy, initial dose of prednisone and immunosuppressive after biopsy, activity index (AI), chronicity index (CI), their individual components, extent of extraglomerular (tubulo-interstitial) immune deposits (EGD) and mean number of intraglomerular monocytes per glomerulus (NSE index). Using proportional hazards analysis to evaluate the parameters, SCr (P = 0.003), AI (P = 0.005) and NSE index (P = 0.038) were shown to be significant predictors of outcome when all variables except the components of AI and CI were considered. When AI and CI were omitted but their components included, SCr (P = 0.0005), NSE index (P = 0.024), extent of karyorrhexis (P = 0.035) and glomerulosclerosis (P = 0.033) were then demonstrated to be significant prognostic factors of DPGN. The results suggest that intraglomerular monocyte infiltration has a protective effect and confirm that AI index is a relatively powerful predictor of outcome. Histologic and nonhistologic biopsy factors contribute significant additional prognostic information to that provided by SCr.

Renal-coloboma syndrome includes abnormalities in the urogenital and ocular systems as its primary manifestations, although it can be associated with abnormalities in other systems as well. This syndrome is caused by mutations in the PAX2 gene and is transmitted as an autosomal dominant trait. We report a family in which at least 7 members have manifestations of renal-coloboma syndrome, including two in whom renal disease was diagnosed prenatally by ultrasound examination. A pathogenic frame-shift mutation (619insG) was found in the PAX2 gene in affected family members, who show remarkable variability in both the ocular and renal manifestations of the syndrome.

PBL was as effective in knowledge uptake and retention as lecture-based continuing medical education (CME) programs. Further study is warranted to investigate whether the assessment of higher educational value or an increase in response rate to delayed testing is replicable in other RCTs addressing common confounders and if these factors influence future CME participation, changes in physician clinical behavior, or patient health outcomes.

The distinctiveness of IgM nephropathy (IgMN) as a clinicopathologic entity is controversial. Twenty-seven children (16 males, 11 females) with IgMN as defined immunohistochemically by diffuse mesangial staining of glomeruli for IgM were compared to a group of 63 children (40 males, 23 females) with minimal change disease (MCD). While mesangial expansion was significantly greater in IgMN than in MCD (p = 0.0014), there were no significant differences between the two groups with respect to the other biopsy factors. IgMN showed a significantly higher incidence of hypertension at presentation. More than 90% of patients in both groups presented with the nephrotic syndrome which in most initially responded to prednisone. Frequently relapsing/steroid-dependent nephrotic syndrome was the most common indication for biopsy in both groups. Approximately 60% of patients from both groups received cytotoxic therapy. Eight percent of IgMN and 7% of MCD patients failed to respond to therapy. Relapse rates and mean dose of prednisone at relapse were very similar in both groups prior to biopsy. Relapse rates diminished significantly after treatment in the postbiopsy interval, but mean dose of prednisone at relapse did not change appreciably over time. None of the patients developed renal failure or hypertension in the follow-up period. At last visit 23% of IgMN and 27% of MCD had proteinuria. The results indicate that IgMN and MCD are indistinguishable clinically in children who are biopsied for the nephrotic syndrome.

We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C max ), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m 2 , and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r 2 = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI. Keywords Patients and methodsAll PK profiles were performed as part of an ongoing multi-center randomized clinical trial to evaluate steroid withdrawal protocols in pediatric renal transplant recipients. All study subjects received induction therapy with basiliximab preoperatively and on postoperative day 4. SRL was administered beginning on postoperative day 1 at a dose of 6 mg/m 2 , and was thereafter adjusted to achieve target trough levels in the range of 10-20 ng/mL. SRL was administered q.d. when given in combination with CsA (25 subjects), and q.d. (10 subjects) or b.i.d. (14 subjects) when given in combination with TCL. CsA doses were initiated at 400 mg/m 2 /day for children younger than six yr of age, and at 10 mg/kg/day for children six yr of age and over. CsA doses were adjusted to whole blood trough TDX monoclonal levels within the range of 175-400 ng/mL for the first two wk, then 175-300 ng/mL for three wk to three months, then 50-250 ng/mL after three months. The study protocol allows for the use of TCL as an alternative to CsA. TCL was given b.i.d. at 0.1 mg/kg/dose, and was adjusted to maintain whole blood trough levels between 10 and 15 ng/mL for the first four postoperative wk, and between 5 and 10 ng/mL thereafter. Methylprednisolone was administered peri-operatively and on postoperative day 1. Full dose prednisone (2 mg/kg/day, maximum of 60 mg/day) was initiated on postoperative day 2, and prednisone tapering began on postoperative day 4. At posttransplant month 7, all patients who had no evidence of sub-clinical rejection as determined by protocol biopsy underwent blinded randomization to undergo either steroid withdrawal via placebo or remain on steroid therapy.SRL PK was performed at post-transplant...