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Tacrolimus TAC has been prescribed for maintaining remission of NS in patients who have developed treatment resistance or adverse effects with cyclosporin A CYA at our institution since Ten SDNS children eight males were reviewed quarterly from time of initial referral to the present day during 93 completed treatment patient years. Nine patients had minimal change disease and one had focal segmental glomerulosclerosis on their first biopsy.
The median age at diagnosis was 2. The median age at initial referral was 3. The reduction in GFR was 5. Three of the 10 patients showed histological evidence of mild CNI nephrotoxicity over the whole of the CNI treatment period despite achieving target therapeutic drug levels; no significant change in measured or calculated GFR over this prolonged CNI therapy was observed. Steroid dependency has been defined by the International Study for Kidney Diseases in Children [ 4 ] ISKDC as children with frequently relapsing nephrotic syndrome FRNS in whom two consecutive relapses, or two of four relapses in any 6 month period, occurred while still on a dose of steroids or within 14 days of discontinuing steroid therapy.
Although treatment with glucocorticoids remains the mainstay of therapy for these patients, significant morbidity is associated with prolonged glucocorticoid therapy. A retrospective longitudinal case study was performed on 10 patients who presented with SDNS to the paediatric renal unit at Guys Hospital, London. Data from case notes at our and other hospitals were analysed from the time of referral to 31 December, Patients with steroid-resistant nephrotic syndrome were excluded.
All patients after presentation were seen at least quarterly. At each clinic visit, patients had their height and weight recorded. Clinic review included recording of any relapses of NS, steroid regimen used, days to achieve remission and weaning regimen of steroid therapy. Blood pressure was recorded using an appropriately sized cuff and a mercury sphygmomanometer, and assessed using updated 2nd Task force blood pressure criteria [ 14 ].
Subsequent failure to maintain the patient in remission was then managed by prescribing TAC 0. Drug levels were measured at least 4 monthly. The CYA assay involved extraction of CYA from red blood cells as blood proteins are precipitated during the preparation steps.
Prior to analysis on the IMX system, a manual pre-treatment step is performed in which the whole blood sample is extracted with a precipitating reagent and centrifuged. The supernatant is decanted into a sample well and analysed on the IMX system. Renal biopsies were performed to detect histological evidence of CNI toxicity.
At the time of renal biopsy and GFR measurement, none of the patients were in clinical or biochemical relapse. GFR was also calculated by the method of Schwartz et al. A lack of response was noted if patients had failed to maintain a sustained remission after 1 year on CYA or if, while taking CYA therapy, they had frequent relapses requiring escalating doses of glucocorticoids to maintain remission. CYA was also stopped if adverse effects such as severe cushingoid appearances, hypertension and deterioration in GFR or histological evidence of CNI-induced nephrotoxicity were observed.
The clinical data obtained are analysed as comparisons of the two therapy periods on CYA and TAC with respect to efficacy and complications of drug therapy. Complications were analysed in terms of: Any significant side effects while on drug therapy were recorded.
Ten patients eight male were followed for 93 completed patient treatment years; nine patients had minimal change disease MCD at the time of presentation and one patient had FSGS. The median age range of the patients at initial referral was 3. The median age at start of CYA treatment was 4. The median interval after referral to initiation of CYA therapy was 0.
Four of the 10 patients had both a lack of response and adverse effects while on CYA therapy; three had reversible reductions of GFR and one had onset of new hypertension. The patient who became hypertensive on CYA had normal blood pressure while taking TAC and did not require any antihypertensive medication subsequently. Overall, six patients continued and four patients discontinued TAC therapy. In two patients there was poor disease control, one patient developed hypertension after 1 year of TAC therapy but became normotensive once TAC was discontinued and another patient developed insulin-dependent diabetes mellitus IDDM after 4.
This patient remains insulin dependent. The two patients with a poor response to TAC were subsequently treated with MMF; one of these patients went on to have bilateral nephrectomy and a renal transplant and the other remains stable on a second course of CYA treatment.
There were no observed differences in the efficacy of CNI therapy for the two treatment periods Table 1. No reduction in maintenance dose of glucocorticoid occurred with TAC. Seven calculated GFRs were below the normal limit in four patients; measured GFR was low on only one measurement at this time. No hyperfiltration was observed by calculated GFR methods. Box plot of formal GFR measurements.
The line through the box represents the median, and the whiskers represent the upper and lower ranges of the data set during the given 2 year treatment period. In a further analysis of measured GFR for the whole period spent on CNI therapy, the period has been arbitrarily divided into 2 year intervals.
Seven of the 10 patients required antihypertensives although none of the patients were on anyihypertensive medication before starting CNI therapy. Two further patients developed new onset hypertension as a result of CNI therapy.
These two patients became normotensive and have remained so once CNI therapy was stopped. Twenty-nine biopsies were performed in these 10 patients while taking CNI therapy. Evidence of CNI toxicity was observed on four biopsies in three patients; three biopsies affecting two patients while on CYA and one biopsy affecting one patient during TAC treatment, not previously known to have CNI nephrotoxicity.
One patient had two biopsies with CNI toxicity after 1. Both these patients had mild histological evidence of CNI toxicity with peritubular capillary thrombi with a well preserved interstitium. Neither had a change in calculated GFR. They both underwent subsequent biopsies that have shown no permanent damage due to CNI treatment. The patient with evidence of CNI toxicity while taking TAC for 5 years had intimal fibrosis involving small and medium arteries and tubular vacuolation.
This patient had previously taken CYA for 4 years with no histological evidence of CNI toxicity and has not as yet had another biopsy. The CNI drug levels were within the targeted therapeutic range around the time of the biopsies. We have reported a retrospective longitudinal clinical series of 10 children with severe SDNS who were treated with both CYA and TAC sequentially and were closely monitored for 91 patient years.
Although this study was non-randomized with respect to which CNI was prescribed first, our results demonstrate no significant difference in efficacy, cumulative steroid dosage, renal function or statural growth between CYA and TAC therapies in SDNS.
Their clinical management poses considerable problems—that of disease control, effects on growth and adverse effects of drugs, such as changes in appearance, renal function and blood pressure. In general, our patients were managed in a manner similar to that reported by Neuhaus et al. With the introduction of TAC, we hoped to produce lower annualized relapse rates, a reduced requirement for steroids while maintaining normal renal function and minimal nephrotoxicity, and improving the cosmetic side effects of CYA.
TAC achieved a superior anti-proteinuria profile but by a biological mechanism that remains unknown; investigators have associated this superior control of proteinuria with TAC's more potent effect on the release of cytokines such as interleukin-8 IL-8 [ 17 ], on its suppression of vascular permeability factor VPF production [ 18 ] or its action on intraglomerular haemodynamics [ 19 ].
We confirmed good control of SDNS with the low annualized relapse rate observed in our study. This difference may be explained by the fact that their patients were adult nephrotic patients with FSGS.
We observed no benefit in reduced glucocorticoid medication with TAC treatment either. Individual patients showed a varied response from one year to the next despite maintaining targeted blood drug levels.
CNI agents were able to control disease better when compared with other steroid-sparing agents that were used immediately before the initiation of CYA or TAC data not shown. Complications such as nephrotoxicity and hypertension from CNI medication raise important clinical considerations, as SDNS in children is not usually associated with permanent renal impairment or hypertension.
This is demonstrated in Figures 1 and 2. In our case series, patients who stopped CYA because of concerns of nephrotoxicity did not have a true GFR measured at the time, which is a shortcoming of this study. It is important to note that evidence for drug toxicity was seen histologically despite us achieving targeted drug levels and no significant change in calculated or measured GFR over prolonged periods of CNI therapy.
This may have been because the patients were older, peripubertal and in boys especially, had continued on steroid therapy. Reports in the literature have also expressed concerns on the long-term effect of CNI agents on renal function.
CYA was stopped because they had frequent relapses requiring increasing doses of glucocorticoids to maintain remission. These four patients had at the time of review been on TAC and prednisolone for a median of 5 years 1—7 and three of these four had associated adverse effects on CYA but not on TAC. The observation in the remaining six patients is consistent with the proposed superior anti-proteinuric effect of TAC [ 10 ]. The two patients in whom stopping CYA was indicated because of the onset of adverse effects had received CYA for 6 and 7 years.
Patients should be monitored for CNI nephrotoxicity by functional and histological investigations, but it is uncommon even after long-term CNI treatment. Nephrol Dial Transplant ; Oxford University Press is a department of the University of Oxford.
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Minimal change nephrotic syndrome, diffuse mesangial hypercellularity and focal glomerulosclerosis. Edelman CM Jr, ed. Ehrich JH, Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Long-term outcome for children with minimal-change nephrotic syndrome. International Study of Kidney Disease in Children.
Early identification of frequent relapsers among children with minimal change nephrotic syndrome. Remission of idiopathic nephrotic syndrome after treatment with cyclosporin A. Niaudet P, Habib R. Cyclosporine in the treatment of idiopathic nephrosis. J Am Soc Nephrol.