Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome: The ATLANTIS Randomized Trial.

BACKGROUND AND OBJECTIVES: There is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants aged 2-20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects. RESULTS: The trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9-32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14-51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P>0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P=0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids. CONCLUSIONS: ACTH at 80 U/1.73 m2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome.

Ambulatory hypertension in a pediatric cohort of sickle cell disease.

Hypertension is an established risk factor for subsequent cardiovascular and renal disease in children as well as adults. Sickle cell disease (SCD) is a genetic disorder associated with chronic hemolytic anemia with the major manifestation of vaso-occlusive crises. Although this disease entity involves most organ systems causing vascular and pulmonary injury, little is known about blood pressure (BP) levels or prevalence of hypertension in children with SCD. A cross-sectional study was conducted on 56 children with SCD (54 with hemoglobin SS disease; 2 with hemoglobin Sß0 thalassemia; 29 females). Study participants underwent 24-hour ambulatory BP monitoring (ABPM). Serum creatinine and cystatin C were obtained to assess estimated glomerular filtration rate with age-based formulas. A random urine sample was obtained to estimate urine osmolality and urine albumin to creatinine ratio. Mean age range was 11.9 (±4.5) years. Seventeen participants (30%) met criteria for hypertension based on ABPM. Of the 17 participants classified with hypertension, three had office hypertension with ambulatory hypertension, and 14 had masked hypertension detected on ABPM. Another 28 participants (50%) had some abnormal ABPM parameters in the form of either prehypertension and/or lack of normal nocturnal dipping status. The prevalence of confirmed hypertension, largely manifest by masked hypertension, is high in children, as young as 6 years of age with SCD. Early identification of hypertension in SCD children can confer benefit as it is an important modifiable risk factor for progression of cardiovascular and renal disease.

Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes.

BACKGROUND: Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children and is associated with the expression of CD80 in podocytes and the increased excretion of CD80 in urine. We hypothesized that serum from patients with MCD might stimulate CD80 expression in cultured podocytes. METHODS: Sera and peripheral blood mononuclear cells (PBMCs) were collected from subjects with MCD in relapse and remission and from normal controls. Immortalized human podocytes were incubated with culture media containing patient sera or supernatants from patient and control PBMC cultures. CD80 expression was measured by quantitative PCR and western blot analysis. RESULTS: Sera collected from patients with MCD in relapse, but not in remission, significantly increased CD80 expression (mean ± standard deviation: 1.8 ± 0.7 vs. 0.8 ± 0.2; p < 0.004) and CD80 protein secretion by podocytes (p < 0.05 between relapse and normal controls). No such CD80 increase was observed when podocytes were incubated with supernatants of PBMC cultures from patients in relapse. CONCLUSIONS: Sera from MCD patients in relapse, but not in remission, stimulated CD80 expression in cultured podocytes. Identifying this factor in sera could provide insights into the pathogenesis of this disorder. No role in CD80 expression by podocytes was found for cytokines released by PBMCs.

Missed viral surveillance testing visits associate with full blown viral diseases in children receiving kidney transplants.

Surveillance testing for major viral infections such as CMV, EBV, and BKV early in their natural history course may allow for early intervention and prevention of FBVD, but the testing is expensive and optimal interval/frequency are uncertain. At our center we initiated routine monthly viral surveillance for CMV, EBV, and BKV in July 2008 for the first 12 months post-transplant. Here, we retrospectively analyzed for outcome of the patients who missed three or more surveillance tests in the first 12 months post-transplant vs. those who did not. Of 21 patients, five missed three or more surveillance tests. Two of those five developed FBVD (one BKV nephropathy and one EBV-PTLD). None of the 16 patients with more regular surveillance testing developed FBVD. The incidence of viral replication was similar in both groups. The odds ratio for FBVD if viral surveillance tests were missed was 23.57 (p-value of 0.047). In this small group of contemporaneous patients on identical immunosuppression, those patients who missed regular viral surveillance were more likely to develop FBVD. Prospective randomized trials to confirm the benefit of regular viral testing are recommended.

The factors that may predict response to rituximab therapy in recurrent focal segmental glomerulosclerosis: a systematic review.

Recurrence of FSGS occurs in 30-40% of allografts. Therapies for recurrence are not well established. We retrieved all published reports depicting kidney transplant recipients with focal segmental glomerulosclerosis (FSGS) recurrence, treated with rituximab, to determine factors associated with treatment response. We found 18 reports of 39 transplant recipients who received rituximab. By univariate analysis for two outcomes (no response versus any response), fewer rituximab infusions and normal serum albumin at recurrence were associated with treatment response. For 3 outcomes (no response, partial and complete remission), male gender, fewer rituximab infusions, shorter time to rituximab treatment, and normal serum albumin were associated with remission. Multivariate analysis for both models revealed that normal serum albumin at FSGS recurrence and lower age at transplant were associated with response. Rituximab for recurrence of FSGS may be beneficial for only some patients. A younger age at transplant and normal serum albumin level at recurrence diagnosis may predict response.

Minimal change disease: a CD80 podocytopathy?

Minimal change disease is the most common nephrotic syndrome in children. Although the etiology of minimal change disease remains to be elucidated, it has been postulated that it is the result of a circulating T-cell factor that causes podocyte cytoskeleton disorganization leading to increased glomerular capillary permeability and/or changes in glomerular basement membrane heparan sulfate glycosaminoglycans resulting in proteinuria. Minimal change disease has been associated with allergies and Hodgkin disease. Consistent with these associations, a role for interleukin-13 with minimal change disease has been proposed. Furthermore, studies evaluating podocytes also have evolved. Recently, increased expression of CD80 (also termed B7-1) on podocytes was identified as a mechanism for proteinuria. CD80 is inhibited by binding to CTLA-4, which is expressed on regulatory T cells. Recently, we showed that urinary CD80 is increased in minimal change disease patients and limited studies have suggested that it is not commonly present in the urine of patients with other glomerular diseases. Interleukin-13 or microbial products via Toll-like receptors could be factors that induce CD80 expression on podocytes. CTLA-4 appears to regulate CD80 expression in podocytes, and to be altered in minimal change disease patients. These findings lead us to suggest that proteinuria in minimal change disease is caused by persistent CD80 expression in podocytes, possibly initiated by stimulation of these cells by antigens or cytokines.

The BK virus in renal transplant recipients-review of pathogenesis, diagnosis, and treatment.

The BK virus, a DNA virus from the Polyomavirus group, represents an opportunistic infection of immunosuppressed transplant recipients. Though the virus was discovered approximately 40 years ago, the emergence of BK virus nephropathy since 1995 onwards, with associated high graft loss rates, has revolutionized renal transplantation medicine. Kidney transplant professionals realized that the consequences of over-immunosuppression were as severe as the consequences of under-immunosuppression and we entered the era of immunosuppressive minimization. Despite this recognition, the optimal testing type for BK virus infections and frequency of testing are hotly debated. Similarly, optimal treatment strategies remain sources of intense controversy. The authors review the current strategies of screening, diagnosis, and possible treatment, and also review the amount and quality of evidence in favor or against. Similarities and differences between cytomegalovirus, Epstein-Barr virus, and BV virus, the three major viral infections in kidney transplantation, are highlighted.

Comparison of generic tacrolimus and Prograf drug levels in a pediatric kidney transplant program: brief communication.

A generic version of tacrolimus was approved for use in the USA in August 2009. These narrow therapeutic index generics are tested for bioequivalence only in adults. No data are available on generic tacrolimus levels in children with allografts. Four patients with stable renal allografts in our pediatric program were inadvertently switched to generic tacrolimus. We retrospectively analyzed pre- and post-switch trough tacrolimus and serum creatinine levels. Twelve-h trough tacrolimus levels (mean ± s.e.) were (i) patient 1 (12-yr-old girl): 7.0 ± 0.69 and 9.7 ± 3.5 (p =NS); (ii) patient 2 (eight-yr-old boy): 4.7 ± 0.68 and 3.4 ± 0.84 (p = 0.04); (iii) patient 3 (22-yr-old woman): 6.8 ± 0.17 and 6.6 ± 0.4 (p = NS); (iv) patient 4 (20-yr-old woman): 5.4 ± 0.25 and 4.9 ± 1.4 (p = NS). Creatinine levels were similar pre- and post-switch (eGFR > 75 mL/min/1.73 m²) in the first three. Patient 4 experienced a biopsy proven acute rejection immediately after switching. Mean creatinine rose from 1.15 ± 0.05 to 2.168 ± 0.07 after switch (p < 0.001). Given our mixed picture with the early data, we suggest careful monitoring of pediatric patients who get switched to generic tacrolimus.

Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis.

Controversy exists as to whether minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) represent different diseases or are manifestations within the same disease spectrum. Urinary excretion of CD80 (also known as B7.1) is elevated in patients with MCD and hence we tested whether urinary CD80 excretion might distinguish between patients with MCD from those with FSGS. Urinary CD80 was measured in 17 patients with biopsy-proven MCD and 22 with proven FSGS using a commercially available enzyme-linked immunosorbent assay and its molecular size determined by western blot analysis. A significant increase in urinary CD80, normalized to urinary creatinine, was found in patients with MCD in relapse compared to those in remission or those with FSGS. No significant differences were seen when CD80 urinary excretion from MCD patients in remission were compared to those with FSGS. In seven of eight MCD patients in relapse, CD80 was found in glomeruli by immunohistochemical analysis of their biopsy specimen. No CD80 was found in glomeruli of two patients with FSGS and another MCD patient in remission. Thus, our study supports the hypothesis that MCD and FSGS represent two different diseases rather than a continuum of one disease. Urinary CD80 excretion may be a useful marker to differentiate between MCD and FSGS.

Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients.

BKVAN affects about 5% of kidney transplant recipients and may lead to graft failure. Treatment for BKVAN is challenging. Leflunomide, an immunosuppressant with antiviral activity in vitro was used successfully in some adult patients but there are no reports of its use in pediatric patients. We present our experience with three kidney transplant recipients with BKVAN who received leflunomide. Three male patients aged 9, 12, and 20 yr developed BKVAN at 9, 12, and 2 months after a kidney transplant. Immunosuppression was reduced and cidofovir was administered in all patients 2-3 wk apart. Due to inability to travel to receive cidofovir in one, lack of reduction in BK viral load in the second, and rising serum creatinine despite cidofovir in the third patient, we discontinued cidofovir and initiated leflunomide. Teriflunomide target trough levels were 30-60 microg/mL. The patients received leflunomide for 27, 26, and 24 months, respectively. BK viral load decreased below 1000 DNA copies/mL in one and was undetectable in two patients after beginning leflunomide. All patients tolerated leflunomide without side effects. Leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients.

Xanthogranulomatous pyelonephritis in pediatric patients: case report and review of literature.

Xanthogranulomatous pyelonephritis (XPN) is an unusual and rare form of chronic renal suppuration. XPN is often mistaken for renal malignancy; hence nephrectomy is commonly performed and the diagnosis confirmed by histopathology. Recent advances in imaging have allowed the radiological features to be characterized, such that routine nephrectomy is avoided. Approximately 240 cases of XPN have been reported in children. We report a 17-year-old female who presented with a 2-month history of increasing abdominal pain and intermittent episodes of increased frequency and dysuria. Plain antero-posterior radiograph of the abdomen revealed a left staghorn calculus. Computed tomography scan with intravenous contrast revealed a low-density inflammatory area and reduced cortical dye uptake on the left renal parenchyma as compared to the opposite side. A dimercapto-succinic acid renal scan revealed that the affected kidney contributed 18% of differential function. A diagnosis of XPN was made. The patient underwent percutaneous nephrostomy tube placement in an attempt to salvage the kidney. The patient eventually failed conservative management. Our review of the literature suggests that medical management has worked in some focal XPN cases, but has not been sufficiently tested in diffuse XPN.

Treatment of systemic hypertension in children and adolescents.

PURPOSE OF REVIEW: This review aims to update the practitioner in recent developments in the treatment of hypertension in children and adolescents. RECENT FINDINGS: In the last years, the treatment of hypertension in children and adolescents has been characterized by an improvement in the definition of hypertension and the more widespread use of the 24-h blood pressure monitor to define the hypertension pattern and assess efficacy of the therapy. A few studies on the use of converting enzyme inhibitors and angiotensin II receptor blocker emphasizing doses, efficacy, and side effects have been published. Of special interest is the tantalizing hypothesis on the role of uric acid in essential hypertension and the practical application of the use of allopurinol as monotherapy for this condition. SUMMARY: The authors aim to convey the need to define the blood pressure pattern in these patients before any type of therapy is started and the titration of medications according to the pathophysiologic mechanisms involved.

A patient with an unusual cause right lower quadrant pain and vomiting: pyelonephritis of an ectopic right kidney masquerading as acute appendicitis.

An adolescent female presented with one day of abdominal pain and clinical findings of acute appendicitis. CT scan revealed an ectopic right kidney with changes of acute pyelonephritis. This paper underscores the importance of imaging the right pelvis prior to surgical intervention in suspected cases of acute appendicitis in children.

Native kidney post-transplant lymphoproliferative disorder in a non-renal transplant patient.

PTLD is an important post-transplant complication. Although PTLD affects kidney allografts after renal transplantation, it has not been reported in native kidneys of other solid organ recipients. Herein, we report a child who underwent an orthotropic liver transplant for cryptogenic cholestatic hepatitis and developed fever, generalized lymphadenopathy, chronic EBV viremia, and lymphatic PTLD. Subsequently, she also developed gross hematuria and nephrotic range proteinuria. Kidney histology revealed EBV-positive mononuclear infiltrates within the renal parenchyma consistent with PTLD. Electron microscopy examination demonstrated subepithelial electron-dense deposits consistent with a membranous glomerulopathy pattern. The PTLD was successfully treated with reduced immunosuppression and cyclic cyclophosphamide, rituximab, and prednisone, but the renal disease progressed to end-stage renal failure within two yr. Repeat kidney histology showed chronic nephropathy and membranous glomerulopathy without PTLD infiltrates or detectable EBV staining, although chronic viremia persisted. To our knowledge, this is the first such child to be reported and highlights the importance of remaining vigilant for renal PTLD even in non-kidney organ recipients.

Post-transplant lymphoproliferative disease.

Post-transplant lymphoproliferative disease (PTLD) emerged in the mid-1990s as a major graft- and life-threatening complication of pediatric kidney transplantation. This condition, usually involving uncontrolled B lymphocyte proliferation, straddles the border between infection and malignancy, since Epstein-Barr virus (EBV) is intimately associated with the pathogenesis. PTLD is seen more in younger children (more likely to be EBV seronegative), Caucasian race, and in association with the more potent immunosuppression drugs. The clinical presentation typically involves multiple enlarged lymph nodes but varies based on localization of the lymphadenopathy. The diagnosis is based primarily on histopathological features. Treatment strategies include reduction of immunosuppression, use of anti-B cell antibodies, infusion of EBV-specific cytotoxic T lymphocytes, and chemotherapy. Many different strategies have been tried to prevent PTLD, ranging from serial EBV viral load monitoring and pre-emptive immunosuppression reduction to anti-viral prophylaxis. None of the major treatment or prevention strategies has been subject to randomized clinical trials, so their relative efficacy is still unknown. PTLD remains a risk factor for graft loss, though re-transplants have not, to date, been associated with repeat PTLD.

Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy.

BKVAN has emerged as a major morbidity in kidney transplant recipients. Among treatment options is cidofovir, which can be nephrotoxic. We previously reported that intermediate dose cidofovir could be used without significant nephrotoxicity. We present extended results of the same treatment protocol in a larger cohort and with longer follow up. Diagnosis of BKVAN was based on detection of BK viral DNA from plasma and renal allograft biopsy tissue. All patients received cidofovir (0.25-1 mg/kg/dose) every 2-3 wk. Total number of cidofovir doses ranged from 1 to 18 (mean 8). This report includes eight patients, aged 5-21 yr, treated with intermediate dose cidofovir. Median follow-up was 11 months (range 4-32). Mean fall in reciprocal of serum creatinine (1/sCr) from baseline at BKVAN diagnosis was 64% (range 28-120%). A time-series plot of plasma BK virus PCR and 1/sCr showed marked reduction in viral loads without significant deterioration in 1/sCr from the initial value at BKVAN diagnosis. In this larger series with extended follow up, intermediate dose cidofovir without probenecid for the treatment of BKVAN continues to show stabilization of renal function without progression to renal failure.

Assessing the value of ureteral stent placement in pediatric kidney transplant recipients.

BACKGROUND: Ureteral stent placement at kidney transplantation may reduce stenosis or leakage (S/L) complication rates. However, stent placement may also increase risk for early urinary tract infection (early UTI; <3 months after transplant) and BK virus allograft nephropathy (BKVAN). In children, the usefulness of stent placement is not well defined. METHODS: We analyzed retrospective data from children transplanted at our center for the three above outcomes in relation to stents. At our center, stent placement decision is driven by surgeon preference. RESULTS: Among 129 transplants from 1996 to 2006, early UTI was seen in 9.3% and S/L in 4.6%. By univariate analyses, stent placement was a significant risk factor for early UTI (P=0.0399) but not protective for S/L (P=0.23). In multivariate analyses, stent placement, human leukocyte antigen match, and bladder augmentation increased the odds ratio for early UTI. Only deceased donor source increased the odds ratio for S/L. In a truncated data set from 1999 to 2006, BKVAN occurred in 9 of 93 (9.6%). Per minute increase in warm ischemia time was the only significant risk factor for BKVAN by both univariate and Cox regression analyses. Stent placement did not improve graft survival (P=0.5726) but required general anesthesia for removal in the operating room, leading to additional cost and potential risk. CONCLUSION: Routine stent placement in children in this era of low urological complication rates and BKVAN needs reevaluation.

Hemodialysis catheter-related bacteremia in children: increasing antibiotic resistance and changing bacteriological profile.

BACKGROUND: Catheter-related infections limit catheter survival. The success of antimicrobial therapy for the treatment of patients with hemodialysis catheter-related bacteremia (HD-CRB) depends on the infectious organisms. We determined whether the rate of positive blood culture results per tunneled catheter-days, the spectrum of bacterial isolates, and their antibiotic susceptibility changed over time in our pediatric dialysis unit. METHODS: Data were collected retrospectively for all positive blood culture results from long-term hemodialysis patients in our pediatric unit from July 1990 to July 1995 (period A) and July 2000 to July 2005 (period B). RESULTS: Rates of HD-CRB were similar between periods A and B (2.1 versus 2.2/1,000 catheter-days). In period A, 33% of isolates were coagulase-positive staphylococci, with Staphylococcus aureus accounting for 72% of these. In period B, the most common organism was Staphylococcus epidermidis (28%), whereas coagulase-positive staphylococci were identified in only 17%. There was a larger number of gram-positive bacilli in period B (20%) compared with period A (4%). A significant decrease in susceptibility to penicillins (40% to 5%; P = 0.007) and cephalosporins (58% to 21%; P = 0.04), but not aminoglycosides, was noted for gram-positive bacteria. There was no significant change in susceptibility of gram-negative bacteria to cephalosporins and aminoglycosides in either period. CONCLUSION: Both types of organism and antibiotic sensitivity patterns have changed over time. Based on these data, we changed our empiric antibiotic combination for HD-CRB to vancomycin plus an aminoglycoside.

A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome.

Idiopathic minimal lesion nephrotic syndrome (IMLNS) was proposed to be a disorder of T-cell dysfunction by Shalhoub in 1974. The mechanisms by which T-cells increase glomerular permeability have remained elusive (and unproven). There is evidence that IMLNS may be due to a circulating factor released from activated T-cells. In recent years, efforts have been made to identify this pathogenetic cytokine as well as to understand the mechanism(s) for the increased release of this factor. This review attempts to critically analyze the available published data. Using different methodologies, investigators have focused on the production of cytokines in patients with IMLNS during relapse and remission. This has resulted in a plethora of data without definitive conclusions. The pathogenetic cytokine has not been identified, and it is questionable whether there is a Th2 dominance in IMLNS. The review of the available data illustrates the difficulties encountered when one is studying the cytokine secretory pattern in patients with IMLNS. Differences in patient population, type of cells studies, sample preservation, and methodology used to measure cytokines are some of the factors that could account for the disparity of observed results.