Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome.

Glucocorticoids are the primary therapy for nephrotic syndrome (NS), but have serious side effects and are ineffective in ~20-50% of patients. Thiazolidinediones have recently been suggested to be renoprotective, and to modulate podocyte glucocorticoid-mediated nuclear receptor signaling. We hypothesized that thiazolidinediones could enhance glucocorticoid efficacy in NS. We found that puromycin aminonucleoside-induced proteinuria in rats was significantly reduced by both high-dose glucocorticoids (79%) and pioglitazone (61%), but not low-dose glucocorticoids (25%). Remarkably, pioglitazone + low-dose glucocorticoids also reduced proteinuria (63%) comparably to high-dose glucocorticoids, whereas pioglitazone + high-dose glucocorticoids reduced proteinuria to almost control levels (97%). Molecular analysis revealed that both glucocorticoids and pioglitazone enhanced glomerular synaptopodin and nephrin expression, and reduced COX-2 expression, after injury. Furthermore, the glomerular phosphorylation of glucocorticoid receptor and Akt, but not PPARγ, correlated with treatment-induced reductions in proteinuria. Notably, clinical translation of these findings to a child with refractory NS by the addition of pioglitazone to the treatment correlated with marked reductions in both proteinuria (80%) and overall immunosuppression (64%). These findings together suggest that repurposing pioglitazone could potentially enhance the proteinuria-reducing effects of glucocorticoids during NS treatment.

Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy.

The challenges of appropriate drug dosing in patients with renal failure requiring renal replacement therapy (RRT) have been exacerbated by recent trends in both RRT technology and practices. Nearly all these changes have resulted in augmented drug clearance, making most existing RRT drug dosing recommendations obsolete. Many barriers exist to conducting research to update our knowledge of appropriate drug dosing in the context of contemporary RRT. Recommendations on how this research could be conducted, including the use of in vitro techniques, are offered here.

Peritoneal dialysis for management of pediatric acute renal failure.

BACKGROUND: While the use of continuous renal replacement therapies in the management of children with acute renal failure (ARF) has increased, the role of peritoneal dialysis (PD) in the treatment of pediatric ARF has received less attention. DESIGN: Retrospective database review of children requiring PD for ARF over a 10-year period. SETTING: Pediatric intensive care unit at a tertiary-care referral center. PATIENTS: Sixty-three children without previously known underlying renal disease who required PD for treatment of ARF. RESULTS: Causes of ARF were congestive heart failure (27), hemolytic-uremic syndrome (13), sepsis (10), nonrenal organ transplant (7), malignancy (3), and other (3). Mean duration of PD was 11 +/- 13 days. Children with ARF were younger (30 +/- 48 months vs 88 +/- 68 months old, p < 0.0001) and smaller (11.9 +/- 15.9 kg vs 28 +/- 22 kg, p < 0.0001) than children with known underlying renal disease who began PD during the same time period. Percutaneously placed PD catheters were used in 62% of children with ARF, compared to 4% of children with known renal disease (p < 0.0001). Hypotension was common in patients with ARF (46%), which correlated with a high frequency of vasopressor use (78%) at the time of initiation of PD. Complications of PD occurred in 25% of patients, the most common being catheter malfunction. Recovery of renal function occurred in 38% of patients; patient survival was 51%. CONCLUSIONS: Peritoneal dialysis remains an appropriate therapy for pediatric ARF from many causes, even in severely ill children requiring vasopressor support. Such children can be cared for without the use of more expensive and technology-dependent forms of renal replacement therapies.

Identification and characterization of hic-5/ARA55 as an hsp27 binding protein.

hsp27 has been reported to participate in a wide variety of activities, including resistance to thermal and metabolic stress, regulation of growth and differentiation, and acting as a molecular chaperone or a regulator of actin polymerization. We hypothesized that these diverse functions are regulated in a cell- or tissue-specific manner via interaction with various binding proteins. To investigate this hypothesis, we used hsp27 as a "bait" to screen a yeast two-hybrid cDNA library from rat kidney glomeruli and identified a novel hsp27 binding protein, hic-5 (also known as ARA55), a focal adhesion protein and steroid receptor co-activator. Biochemical interaction between hsp27 and hic-5 was confirmed by co-immunoprecipitation, and critical protein.protein interaction regions were mapped to the hic-5 LIM domains and the hsp27 C-terminal domain. Initial analysis of the functional role of hsp27.hic-5 interaction revealed that hic-5 significantly inhibited the protection against heat-induced cell death conferred by hsp27 overexpression in co-transfected 293T cells. In contrast, when a non-hsp27-interacting hic-5 truncation mutant (hic-5/DeltaLIM4) was co-expressed with hsp27, the hic-5 inhibition of hsp27 protection was absent. We conclude that hic-5 is a true hsp27 binding protein and inhibits the ability of hsp27 to provide protection against heat shock in an interaction-dependent manner.

Intravenous nicardipine for treatment of severe hypertension in children.

OBJECTIVE: To examine the effect of intravenous nicardipine in the treatment of children with severe hypertension. METHODS: The medical records of 29 children (mean age 94 months) treated with intravenous nicardipine were retrospectively reviewed. The mean duration of severe hypertension before nicardipine use was 12.5 hours. Most (74%) patients were receiving other antihypertensive agents before nicardipine. RESULTS: The initial nicardipine dose was 0.8 +/- 0.3 microg/kg/min (mean +/- SD). The mean effective dose was 1.8 +/- 1.0 microg/kg/min (range, 0.3 to 4.0). Blood pressure control was achieved within 2.7 +/- 2.1 hours after nicardipine was started. Nicardipine treatment produced a 16% reduction in systolic blood pressure, a 23% reduction in diastolic blood pressure, and a 7% increase in heart rate. Nicardipine was effective as a single agent on 26 (84%) of 31 occasions. Adverse effects included tachycardia, flushing, palpitations, and hypotension. CONCLUSIONS: When administered in the intensive care unit setting with close patient monitoring, intravenous nicardipine effectively lowered blood pressure in children with severe hypertension. Larger prospective studies should be conducted to confirm these findings.

Treatment of Henoch-Schönlein Purpura glomerulonephritis in children with high-dose corticosteroids plus oral cyclophosphamide.

BACKGROUND: Henoch-Schönlein Purpura (HSP) is a common childhood vasculitis with manifestations in numerous organ systems, including glomerulonephritis. Patients with more severe HSP-associated glomerulonephritis may develop chronic renal failure. Currently, no widely accepted treatment protocols exist for patients with significant renal involvement. METHODS: We retrospectively reviewed the clinical courses of 12 children (mean age 9 years) with HSP glomerulonephritis treated with high-dose corticosteroids plus oral cyclophosphamide. All patients had nephrotic-range proteinuria, and all had significant histopathologic changes on biopsy, including crescentic nephritis in 10 patients. Treatment consisted of either intravenous pulse methylprednisolone or oral prednisone followed by oral cyclophosphamide (2 mg/kg/day) for 12 weeks, along with either daily or alternate-day oral prednisone. Prednisone was tapered following completion of cyclophsophamide. RESULTS: Serum albumin rose significantly after treatment from 2.8 +/- (SD) 0.5 to 3.7 +/- 0.4 g/dl (p < 0.001), and there was a concurrent reduction in proteinuria, as reflected by decreasing serial protein-to-creatinine ratios: from 6.3 +/- 4.4 to 0.8 +/- 0.8 (p = 0.002). Renal function remained normal in all patients. Hypertension developed during treatment in 10 patients, all but 1 of whom were normotensive at last follow-up, 35 +/- 17 months following biopsy. CONCLUSIONS: We conclude that treatment of children with HSP nephritis with high-dose corticosteroids plus oral cyclophosphamide is safe and, as in nephrotic syndrome, appears to significantly reduce proteinuria which is a known risk factor for the development of renal insufficiency in HSP. Further studies with larger numbers of patients should be conducted to confirm this finding.

Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children.

Hemodialysis is the usual recommended treatment for severe lithium intoxication; however, rebound of lithium levels may require repeated hemodialysis treatments. We proposed that the addition of continuous hemofiltration after hemodialysis would prevent rebound by providing ongoing clearance of lithium. We report two pediatric patients with lithium intoxication treated by hemodialysis followed by continuous venovenous hemofiltration with dialysis (CVVHD). Both patients were symptomatic at presentation and had initial lithium levels more than three times the usual therapeutic range. Hemodialysis followed by CVVHD resulted in rapid resolution of symptoms, followed by continuous clearance of lithium without requiring repeated hemodialysis sessions. Both patients had return of normal mental status during CVVHD treatment, and neither patient experienced complications of hemodialysis or CVVHD. Total duration of treatment with hemodialysis followed by CVVHD was 34.5 hours for the first patient and 26 hours for the second patient. We conclude that hemodialysis followed by CVVHD is a safe and effective approach to the management of lithium intoxication in children.

Treatment of hypertensive children with amlodipine.

Amlodipine, a long-acting dihydropyridine calcium channel blocking agent, was administered to 55 children (age: 11.5 +/- 5.4 years) with hypertension, 49 of whom (89%) had secondary hypertension. Efficacy was assessed by comparing pretreatment blood pressure (BP) to follow-up BP obtained in our outpatient Pediatric Nephrology clinic. Thirty-two (58%) patients achieved BP control with amlodipine alone, and 31 (55%) patients received amlodipine twice daily. Eleven patients received amlodipine as a suspension. Mean amlodipine dose was 0.16 +/- 0.12 mg/kg/day; there was an inverse relationship between patient age and amlodipine dose. Follow-up BP were significantly lower than pretreatment BP: systolic BP fell from 129 +/- 12 to 122 +/- 12 mm Hg (P = .004), and diastolic BP fell from 78 +/- 13 to 70 +/- 19 mm Hg (P = .003). A small, clinically insignificant increase in heart rate (from 91 +/- 19 beats/min to 99 +/- 26 beats/min; P = .02) occurred during amlodipine treatment. Adverse effects reported included dizziness (three patients), fatigue (two patients), flushing (two patients), and leg edema (one patient). All improved with dose reduction. We conclude that amlodipine provides effective BP control without significant adverse effects in children with hypertension, and can be used as monotherapy in most children. Young children appear to require significantly higher doses per kilogram of body weight than older children. Twice-daily dosing may be required in many children to achieve BP control. Detailed pharmacokinetic studies are needed to confirm these observations.

Regulation of mouse podocyte process dynamics by protein tyrosine phosphatases rapid communication.

BACKGROUND: Effacement of podocyte foot processes occurs early in many glomerular diseases associated with proteinuria and is accompanied by a reorganization of the actin cytoskeleton. The molecular mechanisms regulating these structural changes are poorly understood. METHODS: To address these questions, we analyzed the effect of the polycation, protamine sulfate (PS), and puromycin aminonucleoside (PA) on the morphology, cytoskeleton, and tyrosine phosphorylation of differentiated process-bearing cultured podocytes. RESULTS: PS and PA induced similar profound morphological alterations, including retraction and detachment of podocyte processes from the extracellular matrix (ECM). The effects of PS occurred within six hours, whereas PA showed its most severe effects after 72 hours. Structural changes included reorganization of the actin cytoskeleton and focal contacts and were accompanied by an increase in tyrosine phosphorylation. The same effects were induced by application of vanadate, an inhibitor of protein tyrosine phosphatases (PTPs), suggesting that PTPs regulate podocyte process structure. Since disruption of the actin cytoskeleton with cytochalasin B protected the cells from PS-induced effacement and detachment, cytoplasmic PTPs were implicated in these events. Using reverse transcription-polymerase chain reaction (RT-PCR), we demonstrated the expression of four cytoplasmic PTPs in podocytes: SHP-2, PTP-PEST, PTP-1B, and PTP-36. CONCLUSIONS: These studies indicate an important role for cytoplasmic PTPs as regulators of podocyte process dynamics. Future studies will aim at restoring the normal foot process architecture of podocytes in glomerular diseases associated with proteinuria by modulating the activity of cytoplasmic PTPs.

Childhood diethylene glycol poisoning treated with alcohol dehydrogenase inhibitor fomepizole and hemodialysis.

Diethylene glycol (DEG), a commonly used solvent, has been implicated in multiple poisoning deaths, the most recent being the Haitian acetaminophen tragedy. Unlike the more commonly seen ethylene glycol ingestion, little is understood of DEG metabolism or kinetics in humans. This has made the clinical presentation, biochemical correlates, and treatment options unclear. Patients presenting less than 12 hours after DEG ingestion may not show metabolic acidosis, whereas those presenting later may show florid metabolic acidosis. Kinetic data lend support to these observations. We report a case of DEG ingestion in a 17-month-old girl who was managed with activated charcoal, fomepizole (a recently available alcohol dehydrogenase inhibitor), and hemodialysis (HD). Pre-HD and post-HD DEG levels support clearance of DEG with HD.

Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis.

HYPOTHESIS: Amino acid (AA) loss is not equivalent on continuous venovenous hemofiltration (CVVH) compared with continuous venovenous hemodiafiltration (CVVHD). Amino acid supplementation may be necessary to adjust for a greater clearance on CVVH to maintain nitrogen balance similar to that of CVVHD. OBJECTIVE: To compare AA losses and nitrogen balance between CVVH and CVVHD in children with acute renal failure. SETTING: Pediatric patients in the pediatric intensive care unit of a tertiary referral center. DESIGN: Prospective randomized crossover study in consecutive children who required hemofiltration. PATIENTS: A total of 12 plasma clearance studies for AA and urea, consisting of 24-hr collections of ultrafiltrate and urine for nitrogen balance, was performed on six patients during CVVH and CVVHD. Patients received total parenteral nutrition (TPN) with caloric intake 20% to 30% above their resting energy expenditure measured by indirect calorimetry and 1.5 g/kg/day protein of TPN. Study conditions were comprised of 2 L/hr/1.73 m2 of dialysate or prefiltered replacement fluid and hemofilter flow rates of 4 mL/kg/min were maintained for all patients. METHODS AND MAIN RESULTS: Amino acid clearances were greater on CVVH than CWHD, except for glutamic acid, where clearance was 6.73+/-2.31 (SEM) mL/min/1.73 m2 on CVVH and 7.59+/-2.79 mL/min/1.73 m2 for CVVHD (NS). The clearance difference between the two modalities was 30%. Urea clearance was equivalent (30.1+/-1.74 mL/min/1.73 m2 and 29.0+/-.97 mL/min/1.73 m2) for CVVH and CVVHD, respectively. Amino acid loss on CVVH and CVVHD was similar (12.50+/-1.29 g/day/1.73 m2 vs. 11.61+/-1.86 g/day/1.73 m2, respectively), representing 12% and 11%, respectively, of the daily protein intake. The catabolic state, as measured by urea nitrogen appearance, was high for all patients during the 48-hr study period with a mean of 291 mg/kg/day during CVVH, and 245 mg/kg/day for CVVHD. Nitrogen balance varied from a negative 12.95 g/day/1.73 m2 to a positive 4.93 g/day/1.73 m2 on CVVH and a negative 7.69 g/day/1.73 m2 to a positive 5.50 g/day/1.73 m2 on CVVHD. CONCLUSIONS: Clearance of AA is greater on CVVH than on CVVHD, but no significant difference in AA loss was present between the two therapies. Nitrogen balance often is not met on either therapy when a standard 1.5 g/kg/day protein and a resting energy expenditure of 120% to 130% of calories is delivered by TPN.

Regulation of podocyte structure during the development of nephrotic syndrome.

Nephrotic syndrome is a common kidney disease seen in both children and adults. The clinical syndrome includes massive proteinuria, hypoalbuminemia, edema, and usually hypercholesterolemia. Development of these clinical changes is closely correlated with profound structural changes in glomerular epithelial cells, or podocytes, which together with the glomerular basement membrane and endothelium comprise the kidney's blood filtration barrier. Although relatively little is known about the cellular or molecular changes which occur within podocytes during the development of nephrotic syndrome, cytoskeletal proteins very likely play a central role in these changes since they are primarily responsible for the maintenance of cell structure in almost all cells. This review focuses on: (a) the structure and function of podocytes in both the normal state and during nephrotic syndrome and (b) the potential roles of several cytoskeleton-associated proteins identified in podocytes in the development of and/or recovery from the pathophysiological cytoskeletal changes which occur in podocytes during nephrotic syndrome.

Neoral induction in pediatric renal transplantation.

Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4-6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 +/- 1.1 months' followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly.

Outcome of antineutrophil cytoplasmic autoantibodies-positive glomerulonephritis and vasculitis in children: a single-center experience.

Vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCA) can be accompanied by a focal and necrotizing glomerulonephritis that carries a high morbidity. As many as 60% of reported children with ANCA-associated glomerulonephritis progress to end-stage renal disease. Seven children (13.0+/-0.89 years, mean age +/- SEM) with both a focal and necrotizing glomerulonephritis and a positive ANCA titer are described. Presenting symptoms were constitutional (100%) and sinopulmonary (71%); additional renal features included microscopic hematuria (100%), proteinuria (71%), and renal insufficiency (71%). Acute therapy (0 to 2 weeks from diagnosis) included intravenous corticosteroids and intravenous cyclophosphamide for all patients. Induction therapy (2 weeks to 6 months from diagnosis) consisted of cyclophosphamide (100%) and daily corticosteroids (86%) for a minimum of 6 months. Maintenance therapy that followed 6 months of induction therapy consisted of alternate day steroids (100%) combined with either oral azathioprine (50%) or oral cyclophosphamide (50%). Long-term follow-up for 48+/-12 months in all seven patients revealed that only one (14%) patient had end-stage renal disease, whereas the remaining patients had microscopic hematuria (100%), proteinuria (50%), and renal insufficiency (33%). These findings suggest that early recognition and aggressive treatment of children with ANCA-associated glomerulonephritis and vasculitis may result in an improved renal outcome compared with previous reports.

Quantitative morphometry of renal biopsies prior to cyclosporine in nephrotic syndrome.

Use of cyclosporine (CsA) in the management of children with steroid-resistant (SRNS) and steroid-dependent (SDNS) nephrotic syndrome has become increasingly popular in recent years. Although most children receive a renal biopsy prior to initiation of CsA, the relationship between initial renal histology and the subsequent clinical response to CsA is not known. We analyzed the correlation between pre-CsA segmental and global glomerular scarring and interstitial fibrosis and the subsequent response to CsA in 23 children (5.6+/-1.0 years, Mean+/-SEM) with SDNS (n=8) and SRNS (n=15) treated with CsA for 24.2+/-3.8 months and followed for 28.0+/-4.1 months. Complete remission was obtained in 78% of patients within 67.6+/-16 days, while 18% had a partial response and 4% no response. Quantitative histological analysis revealed a trend toward partial rather than complete response with increasing segmental glomerular (P=0.13), global glomerular (P=0.05), and interstitial (P=0.08) scarring, and among patients with minimal change nephrotic syndrome versus IgM nephropathy versus focal segmental glomerulosclerosis. Among complete responders, linear regression analyses revealed no correlation between time to response and pre-CsA glomerular or interstitial scarring. We conclude that increased glomerular or interstitial scarring on a pre-CsA renal biopsy tends to correlate with a partial, rather than complete, response to CsA in childhood nephrotic syndrome.

Improvement of glycemic control by CAPD with intraperitoneal insulin in a child with IDDM and ESRD.

Use of intraperitoneal insulin in diabetic end-stage renal disease (ESRD) patients receiving continuous ambulatory peritoneal dialysis (CAPD) is known to result in improved glycemic control. This route of insulin administration, although standard in adult diabetic CAPD patients, has not previously been reported in children. A 12-year old boy with ESRD from renal dysplasia who also had insulin-dependent diabetes mellitus (IDDM) was treated with CAPD and intraperitoneal insulin prior to renal transplantation. Diabetes and renal dysplasia were both diagnosed at 11 weeks of age. When he reached end-stage he was initially started on hemodialysis via a central line but was switched to CAPD because of recurrent line sepsis. His IDDM had been poorly controlled up to that time. CAPD was performed using 4 exchanges per day of 1.5% dialysate with a fixed dose of insulin added to each bag and with adjustments made based on blood glucose. His glycemic control markedly improved, with a fall in his glycosylated hemoglobin from 13.6% to 6%. CAPD was continued for 7 months until a living-related renal transplant was performed. Two episodes of peritonitis occurred while the patient received CAPD (1 episode/3.5 patient-months). We conclude that the use of intraperitoneal insulin in children with IDDM and ESRD leads to improved glycemic control. The rate of peritonitis, however, may be increased in these children.

Beneficial effect of Sandoglobulin upon allograft survival in the pediatric renal transplant recipient.

The use of pooled immunoglobulin (IgG) has been shown to decrease panel reactive antibodies (PRA) in highly sensitized patients awaiting transplantation. IgG infusions have also been found effective for CMV prophylaxis. Analysis of 52 non-highly sensitized children (ages 1-18) who received kidney transplants from May 1991 through January 1995 was undertaken to determine if the immunoglobulin administered for CMV prophylaxis effected allograft survival. Comparison of the "Sando Pos" group (those who received Sandoglobulin for CMV prophylaxis) to the "Sando Neg" group demonstrates a significantly improved allograft survival at 1, 2, and 3 yr post-transplantation. Despite the Sando Pos group being younger [7.3 +/- 1.3 yr vs. 10.7 +/- 0.9 yr; (mean +/- SEM) p < 0.05] allograft survival was 95%, 95% and 88% in the Sando Pos group vs. 88%, 79% and 79% in the Sando Neg group at 1, 2 and 3 yr, respectively (p < 0.01 at all three time points). It is concluded that the potential mechanism of the immunosuppressive benefit of Sandoglobulin is speculative but presumed to be upon inhibition of anti-HLA class I antibodies. We conclude that Sandoglobulin may not only be useful for CMV prophylaxis but also as an adjunct to routine immunosuppression.

Management of acute renal failure in the pediatric patient: hemofiltration versus hemodialysis.

Although outcome data for acute renal failure (ARF) in the adult population (analyzed by etiology of ARF, severity of illness, and modality of treatment) are readily available, few similar data exist for the pediatric population. Pediatric survival rate data vary widely, based upon era of analysis, age and size of child, and cause of ARF. Few comparative data are available that address impact by modality chosen to treat ARF. Comparison of 122 children who were treated by hemodialysis (HD; n = 58) versus hemofiltration (HF; n = 64) reveals a combined survival rate of 65%. Survival by modality was higher for HD (83%) than for HF (48%). The major diagnosis treated with HF was sepsis (29/64; 45%), with a survival rate of 31%, whereas the major diagnosis treated with HD (27/58; 46%) was primary renal failure, with a survival rate of 96%. Seventy-one percent of children undergoing HF required pressor support for hypotension, whereas only 24% of those receiving HD needed pressor support (P < 0.01). We conclude that the choice of renal replacement therapy (RRT) modality needs to be determined by the best treatment available. To adequately evaluate therapy measures, further analyses of outcome need to consider those factors that determine choice of RRT and those that affect survival independent of ARF.

Oral feeding of renal tubular antigen abrogates interstitial nephritis and renal failure in Brown Norway rats.

We have examined whether oral feeding of antigen can regulate the expression of autoimmune interstitial nephritis induced by antigen-in-adjuvant (RTA/CFA) immunization of Brown Norway rats. Male rats were divided into six experimental groups: Group I, RTA/CFA immunization alone; Groups II, III, and IV were pretreated with 1 mg (Group II), 5 mg (Group III), and 25 mg (Group IV) of oral tubular antigen every other day for ten days, followed by RTA/CFA immunization; Group V was pretreated with a control antigen, followed by RTA/CFA immunization; and Group VI was immunized with CFA alone. Renal histology, inulin clearance, DTH responses to RTA, and IgG antibody responses to RTA were monitored as endpoints of the study. Our results demonstrated that Group III and IV animals had significantly less severe renal injury, as assessed by inulin clearance and extent of renal cortical involvement by mononuclear cells. Group II and IV animals had suppressed DTH responses, and only Group IV animals had significantly depressed antigen-specific IgG serum titers. Group III animals had neither suppressed DTH responses or IgG titers. We conclude that oral administration of tubular antigen can modulate the intensity of interstitial nephritis produced by immunization, but that the regulatory mechanism is not dependent (at all doses of fed antigen) on suppressed DTH reactivity to RTA or suppressed antigen-specific IgG.