Acute post-streptococcal glomerulonephritis in a 14-month-old boy: why is this uncommon?

Acute post-streptococcal glomerulonephritis (APSGN) is rare in children under 2 years of age. This is related in part to the disease patterns of group A streptococcus (GAS) and in part to impaired immunogenicity in infants. We report the case of a 14-month-old child with APSGN following GAS pharyngitis. This case illustrates that APSGN needs to be considered in the evaluation of both gross and microscopic hematuria in this age group. We review the literature of both GAS and APSGN and discuss the pathogenesis and epidemiologic reasons for this association.     

Should hyperlipidemia in children with the nephrotic syndrome be treated?

 The pathogenesis, clinical significance, and treatment options of the disturbances in lipid metabolism in children with persistent nephrotic syndrome are reviewed. The lipoprotein profile is characterized by elevations of total plasma cholesterol and often triglycerides, elevated very low-density lipoprotein and low-density lipoprotein cholesterol, whereas high-density lipoprotein-cholesterol levels are variable; plasma levels of the atherogenic and thrombogenic lipoprotein(a) are also elevated. The pathophysiology of nephrotic dyslipoproteinemia is multifactorial, including both an increased hepatic synthesis and a diminished plasma catabolism of lipoproteins. There is a rationale for treatment, since dyslipidemia may contribute to the development of atherosclerosis and the progression of chronic renal failure. However, the benefits of treatment with lipid-lowering drugs have not been proven. Short-term studies in adults with nephrotic syndrome have documented safety and efficacy of lipid-lowering drugs, including hydroxymethylglutaryl-CoA reductase inhibitors (”statins”), bile acid sequestrants, fibric acids, fish oil, and probucol. Statins are the most-effective medication, resulting in a decrease of total cholesterol levels by about 30%–40%. Prospective controlled studies in children evaluating efficacy and safety of lipid-lowering drugs are needed. Received: 23 March 1998 / Revised: 15 June 1998 / Accepted: 15 June 1998     

Node-positive transcranial recurrent melanoma: is an aggressive resection warranted?

Locally advanced, node-positive recurrence of malignant melanoma is a harbinger of distant metastases and signifies poor prognosis. However, the clinical course may vary due to the unpredictable biology of malignant melanoma. The presented patient developed a recurrent melanoma of the scalp that eroded through the skull and involved regional lymph nodes with extracapsular extension. He was treated with wide local excision of the recurrence, bilateral posterolateral neck dissection, and immediate microvascular reconstruction followed by adjuvant radiation therapy. The patient remains free of disease at 12 years. This case illustrates that an aggressive resection should be considered for the operable patients with locally advanced recurrent melanoma to render them disease free surgically.     

Is single-daily low-dose cyclosporine therapy really effective in children with idiopathic frequent-relapsing nephrotic syndrome?

BACKGROUND: A recent study on renal transplant patients has shown that a single dose of cyclosporine (CsA) has added the advantage of decreasing dosages and adverse effects, while maintaining graft function. However, the efficacy of this regimen in children with idiopathic frequent-relapsing nephrotic syndrome (NS) remains controversial. METHODS: 20 children with steroid-dependent NS or CsA-dependent NS (18 with minimal change disease, MCD and 2 with focal segmental glomerulosclerosis, FSGS) were enrolled in this prospective study. CsA was commenced at 1.5 a 2 mg/kg, given as a single daily dose before breakfast, and the dose was adjusted to reach 2 hours post-dose CsA levels (C2) of 600 - 800 ng/ml. RESULTS: In 9 out of 18 patients with MCD, treatment with single-daily CsA for a median of 13 months (range 7 - 21) resulted in a reduction of mean minimum prednisolone (PSL) dose from 1.1 A+/- 0.55 to 0.04 A+/- 0.09 mg/kg on alternate days (p < 0.01), and the median relapse rate from 1.3 (1.1 - 2.5) to 0 (0 - 0.2) episodes/6 months (p < 0.01). Of them, PSL could be weaned off in 7 patients (4 of 6 with steroid-dependent NS, only 3 of 14 with CsA-dependent NS) without relapse of NS while on this therapy. However, 11 out of 20 were considered to have treatment failure: 1 with steroid-dependent NS and 10 with CsA-dependent NS. In 2 patients having FSGS, this method showed no beneficial effects. In 18 patients with MCD, relapse free ratio on single-daily CsA therapy was significantly higher in patients whose average C2 levels were greater than 700 ng/ml (p < 0.05). CONCLUSIONS: Our experience demonstrates that single-daily low-dose CsA therapy maintaining C2 levels greater than 700 ng/ml may be effective in children with steroid-dependent NS or MCD, with no relapse. In contrast, the usefulness of this regimen in children with CsA-dependent NS appears to be limited.     

Intravenous pulse cyclophosphamide—is it effective in children with steroid-resistant nephrotic syndrome?

Treatment of steroid-resistant nephrotic syndrome (SRNS) remains a challenge to pediatric nephrologists. Recently, intravenous cyclophosphamide (IV-CPM) infusion was shown to be effective, safe, and economical for the treatment of SRNS, particularly minimal change disease (MCD), as it results in more sustained remissions, longer periods without proteinuria, and fewer significant side effects at a lower cumulative dose. A prospective study was conducted to evaluate IV-CPM infusions in the management of children with SRNS secondary to MCD or IgM nephropathy. Five patients with SRNS (4 IgM nephropathy and 1 MCD) received six monthly IV-CPM infusions at a dose of 500 mg/m². No patient achieved complete or sustained remission. Three patients attained partial remission, which was not sustained for more than 1 month post therapy. One patient progressed rapidly to end-stage renal disease during treatment. Side effects included vomiting in four patients and alopecia in one patient. Conclusion: IV-CPM pulse therapy at a dose of 500 mg/m² is unsuccessful in obtaining complete or sustained remission in children with SRNS secondary to IGM nephropathy or MCD. Further randomized controlled studies with higher doses are required.     

Uncertainty in management of childhood-onset idiopathic nephrotic syndrome: is the long-term prognosis really favorable?

Despite the recent establishment of clinical practice guidelines, many areas in the management of childhood idiopathic nephrotic syndrome (INS) remain uncertain. In this edition of Pediatric Nephrology Samuel et al. report significant differences between Canadian pediatric nephrologists’ practice and guideline recommendations, including initial duration of glucocorticoid treatment, choice of glucocorticoid-sparing agents in cases of frequently relapsing or steroid-dependent INS, and biopsy timing. Although evidence is emerging that the incidence of subsequent relapse can be reduced with longer initial glucocorticoid therapy, even with this new regimen relapse occurs in more than half of the children with steroid-sensitive INS. Cyclosporine (CsA) as a glucocorticoid-sparing agent for children with frequently relapsing or steroid-dependent INS is believed to provide protection from steroid toxicity and significantly improve the quality of life. However, recent follow-up studies of the post-CsA era have revealed a high incidence of INS relapse in adulthood in patients treated with CsA in childhood, and CsA use itself is a significant predictor of recurrent relapses. Therefore, pediatric nephrologists must recognize the potential of adverse effects that may appear later in life because of prolonged immunosuppressive therapy in childhood.     

The heart of children with steroid-resistant nephrotic syndrome: is it all podocin?

Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.     

Levamisole in steroid-sensitive nephrotic syndrome of childhood: the lost paradise?

Among the different drugs used for sparing steroids in steroid-sensitive nephrotic syndrome (SSNS) with frequent relapses and steroid dependency, levamisole is the least toxic and the least expensive. However, it is neither approved for this indication nor widely used in Europe. This may be explained by the difficulty in obtaining levamisole in some countries and the lack of good quality evidence for its effectiveness. Evidence is limited to three clinical trials that all suffered from methodological limitations. Statistical synthesis of these trials showed that levamisole reduces the risk of a relapse during treatment (relative risk 0.60, 95% confidence interval 0.45–0.79). From the available information, no conclusions can be drawn on the steroid-sparing effect, the long-term efficacy, and safety, as well as possible differences in efficacy in different subgroups of SSNS patients. The confirmation of a favorable effect of levamisole on the reduction of the frequency of relapses and on sparing steroids in an adequately powered, double-blind, placebo-controlled, randomized, multi-center clinical trial will promote consensus on the place of levamisole in the treatment of SSNS of childhood. Follow-up should be at least 1 year to evaluate long-term efficacy and side effects. If the results of such a clinical trial confirm the beneficial effects of levamisole in nephrotic syndrome, this may allow registration for this indication and interest companies other than Jansen-Cilag, which only recently has decided to stop its production.     

Is an aggressive surgical approach to the patient with gastric lymphoma warranted?

At the Mayo Clinic, from 1970 through 1979, 84 patients (52 males and 32 females) had abdominal exploration for primary gastric lymphoma. All patients were observed a minimum of 5 years or until death. The histologic findings for all 84 patients were reviewed. Forty-four patients had "curative resection," and 40 patients had either biopsy alone or a palliative procedure. The probability of surviving 5 years was 75% for patients after potentially curative resection and 32% for patients after biopsy and palliation (p less than 0.001). The operative mortality rate was 5% overall and 2% after potentially curative resection. Increased tumor size (p less than 0.02), increased tumor penetration (p less than 0.01), and lymph node involvement (p less than 0.02) decreased the probability of survival, whereas histologic classification did not affect survival. Radiation therapy after surgery did not significantly affect the survival rate for the entire group or the survival rate for patients who had potentially curative resection. Resectability was associated with increased patient survival--independent of other prognostic factors--when our experience was analyzed by the Cox proportional-hazards model (p less than 0.005). It was concluded that an aggressive surgical attitude in the treatment of primary gastric lymphoma is warranted. The role of radiotherapy remains in question.     

Acute epiglottitis in the adult: is intubation mandatory?

Acute epiglottitis (AE) in the adult results in inflammation of the supraglottic structures and carries the potential for complete airway obstruction. There is disagreement in the medical literature as to the appropriate management of the airway in the adult with AE. Some authors advocate intubation in all patients while others propose more selective intervention, intubating the trachea only in those patients presenting with airway compromise. We reviewed our institutional experience with 21 patients over the last seven years admitted with a proven diagnosis of AE. Six patients presented with respiratory distress, three in severe distress with symptoms and signs of upper airway obstruction. The three patients in severe distress were taken to the operating room, in two the tracheas were intubated and one underwent tracheostomy after failed intubation. All other patients were monitored but their tracheas were not intubated. The majority of the patients were monitored for 24 hr in the ICU before transfer to wards. No patient initially monitored required tracheal intubation for progression of disease. There were no deaths. Recommendations for the care of the airway in the adult with AE based on our experience and a review of approximately 1000 cases reported in the last ten years are presented. It is our opinion that adults presenting without respiratory symptoms may be safely monitored in an intensive care setting given that provision is made for tracheal intubation or tracheostomy should respiratory distress become evident.     

Is focal segmental glomerulosclerosis increasing in patients with nephrotic syndrome?

Idiopathic nephrotic syndrome in children has conventionally been associated with minimal change disease. However, recent reports have conflictingly suggested that the frequency of focal segmental glomerulosclerosis (FSGS) in children might be on the increase, as has occurred in adults. The aim of the present work was to review the medical literature to ascertain whether an increase in the frequency of FSGS is occurring and, if so, to quantify such increase. We reviewed the studies comparing the frequency of FSGS in two consecutive periods over the past three decades (period 1 versus period 2). We pooled the data of the studies and then estimated FSGS frequency in two ways: (a) including in the denominator all patients with nephrotic syndrome and (b) including only patients who had undergone kidney biopsy. Both analyses were aimed to determine the odds ratio of FSGS occurrence in the second period. Six studies fulfilled the inclusion criteria, involving 1,149 patients with nephrotic syndrome. Four studies were used to calculate FSGS frequency, including in the denominator all nephrotic patients (n = 885), yielding an odds ratio of 2.22 (95% CI = 1.18–4.18). The analysis combining five studies with the number of biopsies in the denominator (n = 603) produced an odds ratio of 1.98 (95% CI = 1.12–3.50). These results suggest that a shift in the pathological pattern of nephrotic syndrome in children might be occurring, resulting in an increase in FSGS frequency. This hypothesis has major clinical significance due to the poorer prognosis associated with FSGS.     

Urinary annexin V in children with nephrotic syndrome: a new prognostic marker?

Annexin V has a molecular weight of 32–35 kDa and has been reported to possess anticoagulant activity, inhibition of phospholipase A₂, regulation of membrane transport, proliferation and signal transduction. It is reported that urinary annexin V concentration may be an indicator of apoptosis and acute renal injury related to the urinary protein level. The aim of this study was to define the role of urinary annexin V excretion and serum annexin V concentrations as new prognostic tools and follow-up criteria in children with steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS). Annexin V concentrations were measured in serum and 24-h urine samples in 23 SSNS patients in both relapse and remission periods of each patient and in 22 SRNS patients and 22 healthy controls. Total protein, albumin, blood urea nitrogen (BUN), creatinine, total cholesterol concentrations, and 24-h urinary excretion of protein and creatinine were also measured in each patient. In the SRNS group, median 24-h urinary annexin V levels were significantly higher than for all other groups (5,048.8 ng/g creatinine vs. 2,839.5 ng/g creatinine in SSNS relapse group; 2,500.0 ng/g creatinine in SSNS remission group, and 2,018.3 ng/g creatinine in healthy control group). No significant correlation was found between urinary protein excretion and 24-h urinary annexin V levels in all subjects. Twenty-four-hour urinary annexin V excretion may be a predictor in children with SRNS, and it may be a prognostic marker in children with NS.     

Rituximab: is replacement of cyclophosphamide and calcineurin inhibitors in steroid-dependent nephrotic syndrome possible?

The anti-CD20 antibody rituximab has been used successfully as a rescue therapy in some patients with therapy-refractory steroid-dependent nephrotic syndrome (SDNS), including both primary SDNS with minimal changes on biopsy and recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation. All patients showed remission from steroid dependency for at least 9 months concurring with the reappearance of B lymphocytes that had been eliminated by rituximab. The doses used so far vary between 375 mg/m² per dose at weekly intervals for 6 weeks and a single dose of 375 mg/m². Until now, with the limited information available, no substantial adverse effects have been reported. However, a recommendation to use rituximab instead of any other established treatment, such as cyclophosphamide, in SDNS cannot be given before clinical studies have been conducted, especially as publication bias cannot be excluded.     

Esophagectomy in the state of Florida: is regionalization of care warranted?

Centralization of cancer care needs to be based on evidence that regionalization will improve outcomes in a given region. We analyzed outcomes for esophagectomy performed in Florida using the Agency for Health Care Administration database. We determined the risk-adjusted mortality rate for the procedure in low-volume and high-volume centers. From 1997 to 2006, 991 esophagectomies were performed in Florida. The incidence of esophagectomy significantly increased from 1997 to 2001 compared with 2002 to 2006, and the postoperative mortality decreased in the latter time period (odds ratio [OR], 1.87; confidence interval [CI], 1.16-3.03). The risk-adjusted postoperative mortality was significantly lower (OR, 0.54; CI, 0.32-0.92) in high-volume centers (5.1 vs 10.4%). The anastomotic leak rates were 8.2 per cent in both high- and low-volume centers. In the largest population-based study for esophagectomy in Florida, outcomes are better in high-volume centers. These data support the regionalization of esophagectomy to high-volume locations in Florida to reduce procedure-related mortality.     

Does rituximab induce hypogammaglobulinemia in patients with pediatric idiopathic nephrotic syndrome?

Background

Rituximab (RTX) is a promising strategy for treating steroid-dependent idiopathic nephrotic syndrome (SDNS). RTX induces profound B-cell depletion, suggesting hypogammaglobulinemia as a potential side effect after long-term treatment.

Patients and methods

We analyzed immunoglobulin G (IgG) levels in 12 pediatric patients on RTX with a B-cell depletion of a minimum of 3 months and compared the results to 16 patients on orally administered immunosuppressive drugs, such as mycophenolate mofetil (MMF) and/or cyclosporine A (CyA). All patients were in stable remission of SDNS at the time of IgG analysis.

Results

IgG levels in the RTX group before RTX introduction were 6.2?±?1.0 g/L and were not significantly different from the MMF/CyA group (8.2?±?2.5 g/L). In the MMF/CyA group, five patients had at least one episode of hypogammaglobulinemia. In two of them, this episode was prolonged (>3 months), and only one required IgG supplementation. In the RTX group, eight patients had decreased IgG levels before RTX infusion. After RTX, hypogammaglobulinemia persisted in seven among those eight patients. No decreased IgG plasma levels were noted in patients with normal baseline IgG levels before RTX treatment.

Conclusion

RTX does not seem to directly induce decreased IgG levels in patients with SDNS, but it seems to prolong a preexisting low IgG levels.     

Axillary recurrence in DCIs: is axillary lymphadenectomy warranted?

Widespread use of screening mammography has resulted in a remarkable increase in the incidence (or detection rate) of ductal carcinoma in situ (DCIS). Axillary lymph node involvement in DCIS is reported to occur at a frequency of 1-12 per cent. Over the past few years, however, there has been increasing emphasis on axillary sampling, limited axillary dissection, and the potential role of sentinel lymph node biopsy. The clinical relevance of axillary lymph node biopsy or dissection remains unanswered. This retrospective analysis was performed on 171 patients who underwent treatment for DCIS at a tertiary care center over a period of 14 years. Clinical and tumor factors were evaluated, and the local, axillary, and systemic recurrence rates were noted. No axillary recurrences from the primary DCIS diagnosis were noted in the entire group of 171 patients. During a mean follow-up of 70 months, 10 patients (6%) developed recurrence in the ipsilateral breast. Six of these recurrences were in the form of DCIS, whereas, four recurred as invasive cancers. Nine patients developed a new primary (seven DCIS and two invasive) in the same breast but in a different quadrant. Two patients with ipsilateral invasive disease also developed systemic disease and eventually died of disease. During the same period, 10 patients (6%) developed DCIS, and seven patients (4%) developed invasive cancer in the contralateral breast. The data show that the risk of axillary recurrence in pure DCIS is, at most, extremely low and support the position that nodal sampling or dissection is unwarranted.     

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active inside-out signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.     

Cyclosporin A therapy for severe Henoch-Schönlein nephritis with nephrotic syndrome

To evaluate the efficacy of cyclosporin A (CyA) for treating severe Henoch-Schönlein nephritis (HSN), seven patients with nephrotic syndrome, aged 3.9–13.8 years (mean 6.5 years), were analyzed retrospectively. Mean follow-up times were 5.5 years (range 2–9 years). All underwent renal biopsy before treatment, and follow-up renal biopsy was performed in six of the seven patients. All patients improved, with 24-h protein declining from a mean of 9.2 g/m²/day (range 1.5–16 g/m²/day) to 0.3 g/m²/day (range 0.03–1.2 g/m²/day) (p=0.016) and serum albumin increasing from a mean of 2.1 g/dl (range 1.5–2.4 g/dl) to 4.6 g/dl (range 3.5–5.3 g/dl) (p=0.016) after CyA therapy. The activity index decreased significantly at the second renal biopsies obtained at a mean interval of 11.7 months after the first (6.4±3.3 vs 3.5±1.2, p=0.042, respectively), while the chronicity index and the tubulointerstitial scores did not change. On the immunofluorescent findings at the second biopsies, the degree of deposits of immunoglobulins such as IgA, IgM, C3, and fibrinogen decreased in five of the six patients. Although this case series is without controls, our study suggests that CyA may be beneficial to a subset of HSN patients with nephrotic syndrome.