Experience with tacrolimus in children with steroid-resistant nephrotic syndrome

Children with steroid-resistant nephrotic syndrome (SRNS) are at risk of developing renal failure. We report here the results of a single-center retrospective observational study of the remission rate in pediatric patients with SNRS receiving tacrolimus. Serial renal biopsies from children on tacrolimus therapy were evaluated for tubulointerstitial fibrosis and transforming growth factor-β immunostaining. Of the 16 children with SRNS, 15 went into complete remission after a median of 120 days of therapy. Nine children were able to stop steroids, while the others were on tapering doses. Forty-seven percent had relapses, most of which were steroid-responsive. Serial renal biopsies were obtained from seven children after a median treatment duration of 24 months; two of these children had increased tubulointerstitial fibrosis and four showed increased transforming growth factor-β tissue staining. Children with worsening histological findings were younger. There was no significant association between tacrolimus exposure and biopsy changes, although the average trough level was higher in those children with worsening histological findings. In conclusion, tacrolimus may be a safe and effective alternative agent for inducing remission in children with SRNS. However, caution needs to be taken when prescribing this agent due to its narrow therapeutic index. Serial renal biopsies are necessary to check for subclinical nephrotoxicity, especially in younger children and those with higher trough levels.     

Body growth of children with steroid-resistant nephrotic syndrome

Whilst it is assumed that body growth is retarded in children with steroid-resistant nephrotic syndrome (NS), the degree of growth failure and the pathomechanisms involved are poorly understood. We collected serial growth data in 45 children (24 males) with steroid-resistant NS usually from onset to end-stage renal disease (ESRD) during childhood (n=10) or until final height was attained (n=27). Mean follow-up time was 9 (2–19) years. Mean initial standardized height was –0.3±1.2 standard deviation scores (SDS). Mean final height was +0.4 SDS in males and –1.0 SDS in females (sex difference not significant). In 16 patients with serum creatinine levels consistently <1.2 mg/dl, mean final height SDS was 0.3 SDS higher than that obtained within 6 months of onset. In contrast, 9 children who entered ESRD lost an average of 1.3 SDS from the initial record to ESRD (P=0.017). In prepubertal patients without renal insufficiency, mean height SDS decreased during corticosteroid treatment by 0.3 SDS, followed by a partial catch-up after discontinuation of treatment; the change from initial to final height SDS was inversely correlated with the total prednisone dose given (r=–0.50, P=0.03). In 16 prepubertal children with serial height and serum protein measurements who were off steroids and maintained normal creatinine levels, mean individual albumin concentrations correlated with the change in height SDS per year (r=0.65, P=0.0006) and in boys with final height (r=0.73, P=0.03). In conclusion, growth in steroid-resistant NS depends on the preservation of renal function, the cumulative dose of steroids applied, and the severity of hypoproteinemia. Received: 15 July 1998 / Revised: 30 November 1998 / Accepted: 11 December 1998     

Cyclosporine and steroid therapy in children with steroid-resistant nephrotic syndrome

We conducted a prospective, multicenter trial to evaluate the efficacy and safety of a 12-month course of cyclosporine in children with steroid-resistant nephrotic syndrome (SRNS). Thirty-five patients were enrolled, of whom 28 had minimal change or diffuse mesangial proliferation (MC/DMP), and seven had focal segmental glomerulosclerosis (FSGS). All patients received cyclosporine and prednisolone; patients with FSGS additionally received methylprednisolone pulse therapy (MPT). The dose of cyclosporine was adjusted to maintain a trough level of 120–150 ng/ml during the initial 3 months of treatment, followed by 80–100 ng/ml during months 4–12. The primary end point was the remission rate at month 12. Remission was achieved in 23 of 28 (82.1%) patients in the MC/DMP group and in six of the seven (85.7%) patients in the FSGS group. Follow-up renal biopsies were performed in 26 patients (nine at month 12, 17 at month 24), and cyclosporine-related nephrotoxicity was detected in one (3.8%). Major adverse events comprised severe bacterial infections (two patients) and posterior reversible encephalopathy syndrome (one patient). In conclusion, a high remission rate was achieved in our patient cohort using a combined cyclosporine/prednisolone treatment regimen in children with SRNS who had MC/DMP and a combined cyclosporine/prednisolone plus MPT regimen in children who had FSGS.     

Mycophenolate mofetil therapy for children with steroid-resistant nephrotic syndrome

Treating children with steroid-resistant nephrotic syndrome (SRNS) has been a clinical challenge for pediatricians. We recruited 24 children (18 boys and six girls) with steroid-resistant idiopathic nephrotic syndrome (SRINS) who were <2 years. All patients were administered prednisone 2 mg/kg per day prior to mycophenolate mofetil (MMF). By the end of the eighth week, MMF was initiated at 25–30 mg/kg daily for 6??12 months. Prednisone dose was reduced stepwise. Biochemical assays were performed every 2 months. Complete remission was achieved in 15 patients, partial remission in six, and no response to MMF was noted in three. With MMF treatment, the levels of urinary protein and serum cholesterol decreased and that of serum albumin increased in a time-dependant manner. We demonstrated the MMF could reduce proteinuria in SRINS children <2 years. Our study suggests that MMF therapy might be an effective strategy for treating SRINS in children <2 years.     

Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome

We aimed to test if fosinopril reduces urinary protein excretion and alleviates renal tubular damage in normotensive children with steroid-resistant idiopathic nephrotic syndrome (SRINS). We also aimed to evaluate whether there are changes in steady-state blood pressure and serum concentrations of serum angiotensin-converting enzyme (ACE) and plasma renin activity or angiotensin II (AT-II) in children under this treatment. Forty-five normotensive patients with SRINS were randomly divided into two groups. Group I was treated with fosinopril and prednisone for 12 weeks, while group II was treated with prednisone alone for the same duration. The values of 24-h urinary protein excretion were 1.25±0.64 vs 2.52±0.56 g/24 h (P<0.05), 1.16±0.45 vs 2.42±0.24 g/24 h (P<0.05), and 1.10±0.41 vs 2.05±0.46 g/24 h (P<0.05) in group I and group II patients, respectively, at 4, 8, and 12 weeks. Patients in group I showed lower serum concentrations of urinary retinol-binding protein and β₂-microglobulin (P<0.01) at the end of the study, but the patients’ blood pressure and components of the renin-angiotensin system (RAS) had no change during treatment. The result suggested that fosinopril significantly reduced proteinuria and alleviated renal tubular damage, but did not influence blood pressure and components of systemic RAS in normotensive children with SRINS.     

Low expression of glucocorticoid receptors in children with steroid-resistant nephrotic syndrome

Background

About 10–20 % of children with idiopathic nephrotic syndrome (NS) are steroid-resistant (SR). Low expression of glucocorticoid receptors (GRs) has been associated with poor response to steroids in a variety of autoimmune diseases. This study was done to assess the expression of cytoplasmic GRs for CD3 and CD14 in children with NS.

Methods

Expression of cytoplasmic GRs in lymphocytes (CD3⁺/GR) and monocytes (CD14⁺/GR) in the peripheral blood were assessed in 51 children with NS before the start of therapy by flow cytometry. Patients were divided into two groups: 30 children who were steroid-sensitive (SSNS) and 21 children who had initial steroid resistance (SRNS). Twenty age- and sex-matched healthy children served as controls.

Results

Expression of CD3⁺/GR was significantly lower in SRNS in comparison to SSNS patients and controls (p?<?0.0001). Similarly, expression of CD14⁺/GR was significantly lower in SRNS in comparison to SSNS patients (p?<?0.0001) and controls (p?=?0.002). CD3⁺/GR and CD14⁺/GR expression were not significantly different in SSNS patients compared with controls (p?=?0.06 and 0.07 respectively).

Conclusions

Patients with initial SRNS showed decreased GR expression in peripheral blood mononuclear cells (PBMC) before starting therapy, and this low expression may be one of the pathophysiological mechanisms of steroid resistance in these children.     

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome in children

Background

Several recent studies have shown improved short-term outcome of steroid-resistant nephrotic syndrome (SRNS) in children; however, only a few studies have evaluated the long-term outcome. The aims of our study were to obtain detailed data and analyze the long-term outcome of children with SRNS.

Methods

Sixty-nine children with idiopathic SRNS were enrolled and divided into two groups based on initial histopathological patterns: focal segmental glomerulosclerosis (FSGS) and minimal change (MC)/diffuse mesangial proliferation (DMP). The effects of initial treatment with the immunosuppressant of choice (cyclosporine or cyclophosphamide) on renal survival, remission, and incidence of complications were analyzed in both groups (4 subgroups).

Results

The renal survival rate was significantly different among the four different subgroups based on different combinations of initial histopathological pattern (FSGS vs. MC/DMP) and initial immunosuppressant used for treating SRNS (cyclosporine vs. cyclophosphamide) (P?=?0.013), with renal survival in the FSGS (cyclophosphamide) subgroup being especially low (54.6 %). Disease- and/or treatment-associated complications were relatively low; however, hypertension at last examination was observed in a considerable number of patients (31.9 %).

Conclusions

Our results suggest that a recently developed therapeutic regimen with cyclosporine considerably improves both the initial remission rate and the long-term renal survival rate of children with idiopathic SRNS.

     

Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus

We report the outcome of our single-center, long-term follow-up study of tacrolimus therapy in children with steroid-resistant nephrotic syndrome (SRNS). All cases of nephrotic syndrome (NS) with kidney biopsies treated at our center between January 2000 and July 2008 were reviewed. Children with systemic lupus erythematosus and steroid-dependent NS were excluded. Nineteen children with SRNS received tacrolimus. Histopathological analysis of the biopsy revealed the underlying conditions of these 19 patients to be focal segmental glomerulosclerosis (ten patients), C1q nephropathy (four), membranous nephropathy (two), minimal change disease (one), membranoproliferative glomerulonephritis (one), and immunoglobulin A nephropathy (one). The mean follow-up was 55 months, and the median age of the patient cohort was 10 years. We observed complete remission in 11 (58%) patients, partial remission in six (32%), and failure to respond in two (9%). The median time to response was 8 weeks. Side effects were mild and transient (one case of acute kidney injury and three cases of hyperglycemia). The initial rate for combined partial and complete remission of the NS in children with SRNS was 81%, which was sustained in 58% of the patients on follow-up. Among children with FSGS, the sustained remission rate was 50%, while 40% progressed to end-stage renal disease (ESRD) (mean time 52 months). Based on the results of this study, we conclude that tacrolimus is an effective and well-tolerated therapeutic option for the treatment of SRNS in children. However, the occurrence of relapses of the NS with progression to ESRD during the long-term follow-up indicates the need for careful monitoring of such patients.     

Subclinical non-autoimmune hypothyroidism in children with steroid resistant nephrotic syndrome

Background

Thyroid status has not been studied well in children with steroid resistant nephrotic syndrome (SRNS).

Methods

In this cross sectional study we recruited 20 children aged 1–16 years with SRNS and similar number of controls. Serum levels of FT3, FT4 and TSH were measured in all the subjects. Overt hypothyroidism was defined as low FT4 (normal values: 0.7–2.0 ng/mL) and elevated serum TSH above reference values (0.45–4.5 mIU/L). Subclinical hypothyroidism (SH) was defined as an elevation in serum TSH with a normal serum FT4 concentration. The primary outcome measure was serum levels of FT3, FT4 and TSH in children with SRNS.

Results

Thirty per cent of the children (n = 6) with SRNS had non-autoimmune subclinical hypothyroidism (2 children each with grade I, II and III). Children with SRNS had a median TSH value [3.9 mIU/L (0.5–13)] within normal range, but levels were high as compared to controls. Out of 6 children with SH, 3 were in partial remission, 3 were in complete remission. The TSH levels normalized on thyroxine supplementation in grades II and III subclinical hypothyroidism.

Conclusion

Subclinical non-autoimmune hypothyroidism is present in a significant proportion of children with SRNS despite partial or complete remission. Thyroid profile should be evaluated routinely in this subset of patients.     

Vincristine in steroid-resistant nephrotic syndrome

The therapeutic response to vincristine was examined in seven children (aged 2–15 years) with corticosteroid-resistant (CR) nephrotic syndrome (NS) with focal and segmental glomerulosclerosis (FGS). Five were also resistant to cyclophosphamide. Vincristine was given weekly (1.5 mg/m² intravenously) for 8 weeks. Simultaneously, prednisone (60 mg/m² per day, orally) was given for 4 weeks and then gradually tapered. Two of these patients had a complete and stable remission; in five no benefit was observed. It was not possible to identify any characteristics to predict the response to vincristine. Although there is a case for trying vincristine therapy in CR NS with FGS, the results of this study are not encouraging and a better understanding of its action and indications is necessary.     

Novel mutations in steroid-resistant nephrotic syndrome diagnosed in Tunisian children

Steroid-resistant nephrotic syndrome (NS) remains one of the most intractable causes of end-stage renal disease in the first two decades of life. Several genes have been involved including NPHS1, NPHS2, WT1, PLCE1, and LAMB2. Our aim was to identify causative mutations in these genes, in 24 children belonging to 13 families with NS manifesting with various ages of onset. We performed haplotype analysis and direct exon sequencing of NPHS1, NPHS2, PLCE1, LAMB2, and the relevant exons 8 and 9 of WT1. Ten different pathogenic mutations were detected in seven families concerning four genes (NPHS1 (3/7), LAMB2 (2/7), NPHS2 (1/7), and WT1 (1/7)). Five of the detected mutations were novel; IVS9 + 2 T > C and p.D616G in NPHS1; p.E371fsX16 in NPHS2, and p.E705X and p.D1151fsX23 in LAMB2. Nine of 24 patients failed to be categorized by mutational analysis. Our study extends the spectrum of abnormalities underlying NS, by reporting novel mutations in the NPHS1 and NPHS2 genes and the first cases of LAMB2 mutations in Tunisia. Congenital and infantile NS can be explained by mutations in NPHS1, NPHS2, WT1, or LAMB2 genes. The identification of additional genes mutated in NS can be anticipated.     

Intravenous cyclophosphamide in steroid-resistant nephrotic syndrome

We prospectively examined the effect of treatment with intravenous cyclophosphamide in patients with steroid-resistant nephrotic syndrome. Twenty-four patients (minimal change disease in 11, focal segmental glomerulosclerosis in 9, and mesangioproliferative glomerulonephritis in 4), who did not show remission of proteinuria despite treatment with 8 weeks of oral prednisolone and six intravenous pulses of dexamethasone, were studied. Cyclophosphamide was administered intravenously, at a dose of 750 mg/m(2) once a month for 6 months; therapy with alternate-day prednisolone was continued. The mean (SD) age at treatment was 7.8 (4.0) years; 18 patients had initial resistance and 6 had late resistance. At the end of 6 months treatment, 7 (29.2%) patients each had complete remission (absent proteinuria, normal serum albumin) and partial remission (1-2+ proteinuria, normal serum albumin). Ten (41.6%) patients showed no response to therapy. The mean time to complete or partial remission, after initiation of treatment with cyclophosphamide, was 2.4+/-1.7 months and 2.7+/-1.8 months, respectively. Most responders (85.8% complete and 57.2% partial responders) achieved remission by the third dose of pulse cyclophosphamide. More patients with late resistance (50%) compared with initial resistance (22.2%) achieved complete remission. Partial remission was transient and lasted for a mean duration of 6.4+/-3.5 months. Serious infections were observed during therapy in 5 patients. On long-term follow-up, 5 (20.8%) patients were in remission, while nephrotic-range proteinuria or end-stage renal disease was seen in 17 (70.8%). Findings from the present study suggest that therapy with intravenous cyclophosphamide has limited efficacy in inducing sustained remission in patients with initial corticosteroid resistance. Sustained remission is likely to occur in a significant proportion of patients with late resistance and those with absence of significant tubulointerstitial changes on renal histology.     

New developments in steroid-resistant nephrotic syndrome

Nephrotic syndrome is a disorder of the glomerular filtration barrier, a highly specialised tri-layer structure with unique functional properties. Recent advances emanating from the field of molecular genetics have revealed the podocyte as probably the central player in the control of glomerular filtration. More specifically, the cell–cell junction between adjacent podocyte foot processes, namely, the slit diaphragm, has been revealed to be made up of a sophisticated multi-protein complex which dynamically controls foot process architecture via signalling to the actin cytoskeleton. Key genes that have been identified from the study of inherited nephrotic syndromes include those encoding nephrin, podocin, TRPC6 (transient receptor potential canonical channel-6) and α-actinin-4, and more remain to be found. It is now possible to identify genetic causes underlying a proportion of nephrotic syndromes presenting at any age. The next big challenge for clinicians and researchers is to translate the molecular information learnt into the understanding of acquired, non-inherited forms of the disease and to guide therapeutic options. In this regard several exciting advances have been made, both in understanding the molecular mechanisms of current therapies and in revealing circulating plasma factors and the molecular pathways they trigger in the podocyte, that could be targeted by novel therapies.     

Enalapril dosage in steroid-resistant nephrotic syndrome

We have examined, in a randomized crossover trial, the antiproteinuric effect of treatment with low- (0.2 mg/kg daily) and high-dose (0.6 mg/kg daily) enalapril in 25 consecutive patients with steroid-resistant nephrotic syndrome (SRNS). Patients in group A (n=11) received enalapril at low doses for 8 weeks, followed by 2 weeks of washout and then at high doses for 8 weeks. Those in group B (n=14) initially received enalapril at high and then low doses. Patients continued to receive treatment with tapering doses of prednisolone; none received concomitant therapy with daily oral or intravenous steroids, alkylating agents, cyclosporine, non-steroidal anti-inflammatory drugs, and other antihypertensive medications. The urine albumin-to-creatinine (Ua/Uc) ratio and the percentage reduction were determined for each phase of therapy. Baseline clinical, biochemical, and histological features were comparable in the two groups. In the first phase, treatment with low-dose enalapril (group A) resulted in median 34.8% Ua/Uc reduction compared with 62.9% with high doses (group B) (P<0.01). High-dose enalapril was associated with a significant reduction in Ua/Uc ratio in both groups. The combined median Ua/Uc (95% confidence interval) reduction in the low-dose phase was 33% (–10.3% to 72.4%) and in the high-dose 52% (15.4%–70.4%) (P<0.05). The median Ua/Uc ratio at the end of 20 weeks was 1.1 and 1.8 in groups A and B, respectively (P>0.05). Systolic and diastolic blood pressure reductions were similar in both groups. No period or carry-over effect was found. Prolonged treatment with enalapril thus resulted in a dose-related reduction in nephrotic-range proteinuria. Titration of the dose of enalapril may be a useful strategy for achieving substantial reduction of proteinuria in children with SRNS.     

Tacrolimus in steroid-resistant and steroid-dependent nephrotic syndrome

BACKGROUND: Steroid resistance and steroid dependence constitute a major problem in the treatment of minimal-change disease and focal segmental glomerulosclerosis (FSGS). Cyclophosphamide and cyclosporine are well-established alternative immunomodulating agents, whereas data on FK 506 (tacrolimus) are rare. METHODS: The present work provides data from 10 patients of an open, monocentric, non-randomized, prospective trial. Five patients with steroid-dependent minimal-change nephrotic syndrome, 1 patient with steroid-refractory minimal-change disease and 4 patients with steroid-refractory FSGS were started on tacrolimus at trough levels of 5 10 microg/l. In case of steroid-dependence, prednisolone was tapered off in presence oftacrolimus within one month. RESULTS: Within 6 months, complete remission was achieved in 5 patients (50%) and partial remission in 4 patients (40%), yielding a final response rate of 90%. One patient was primarily resistent to tacrolimus (steroid-refractory minimal-change), another patient became secondarily resistant to tacrolimus after an initial remission (steroid-refractory FSGS). Average proteinuria significantly decreased by 77% from 9.5 +/- 1.4 - 2.2 +/- 1.1 g/day (p < 0.01). Serum protein significantly raised from 55.0 +/- 1.9 - 64.6 +/- 1.9 g/l (p < 0.01). Tacrolimus induced non-significant increases of blood glucose (4.9 +/- 0.1 - 5.1 +/- 0.2 mmol/l), systolic blood pressure (131.4 +/- 7.1 - 139.0 +/- 7.6 mmHg) and creatinine (93.2 +/- 13.9 103.2 +/- 15.3 mmol/l). Five patients have been tapered off tacrolimus so far, nephrotic syndrome relapsed in 4 of them (80%). Relapse occurred at tacrolimus levels between 2.6 and 6.9 ng/ml. CONCLUSIONS: Our data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant and steroid-dependent nephrotic syndrome.