Nephrotoxicity of once-daily cyclosporine A in minimal change nephrotic syndrome

Background  

Although once-daily cyclosporine (CsA) therapy may have greater nephrotoxic-sparing effects than standard twice-daily therapy, little information is available in children with steroid-dependent minimal change nephrotic syndrome (MCNS) regarding histological analysis after long-term once-daily administration.     

Foot process fusion and glomerular filtration rate in minimal change nephrotic syndrome

Reduced glomerular filtration rate (GFR), not due to hypovolemia, has been reported in patients in the proteinuric phase of the minimal change nephrotic syndrome (MCNS). A group of children with MCNS was studied to investigate the possible relationship between the fusion of glomerular epithelial foot processes and the reduction in GFR. The degree of foot process fusion was estimated as the harmonic true mean of foot process width and the length density of epithelial slit pores as determined by quantitative electron microscopic stereology. In the patients investigated GFR ranged between 40 and 127 ml/min/1.73 m2 body surface area, the filtration fraction between 6.9 and 22.5%, and the serum albumin concentration between 14 and 46 g/liter. The mean foot process width, which varied between 330 and 870 nm, showed a close correlation with GFR (r = -0.859) and the filtration fraction (r = -0.812), as well as with the serum albumin concentration (r = -0.756). As expected, a reduction of epithelial slit pore length occurred concomitant with the broadening of the foot processes. These results agree with the hypothesis that the reduction in the total length of glomerular epithelial slit pores, due to the fusion of foot processes, results in a reduced glomerular capillary permeability to water and small solutes.     

Fc-receptor function in minimal change nephrotic syndrome of childhood

This study was undertaken to establish whether the Fc-receptor function of circulating monocytes (CM) and/or of splenic macrophages (SM) is modified during the course of minimal change nephrotic syndrome (MCNS) of childhood. The Fc-receptor function of SM was ascertained by measuring the spleen to liver uptake ratio 40 min after IV injection of heat-damaged autologous erythrocytes labeled with 99Tc, whereas the Fc-receptor function of CM was determined by a "rosetting" test. The Fc-receptor function was followed in six girls presenting with a MCNS and receiving no therapy at the time of testing. The Fc-receptor function of SM was decreased in five patients during an acute phase of MCNS. In four of these five patients, the Fc-receptor function of CM was also altered. No significant correlations were observed between the Fc-receptor blockade and the C3, C3d, C4, C3PA or immune complex-plasma levels. The Fc-receptor blockade was persistent in three girls during remission. A prior incubation of CM with trypsin did not completely reverse the Fc-receptor blockade. Further studies are now being pursued in order to determine whether this persisting abnormality is inherited and mainly observed in relapsing nephrotic syndrome.     

Effect of cyclosporin A on glomerular filtration rate in children with minimal change nephrotic syndrome

Cyclosporin A (CyA) is now commonly used in the management of children with steroid-dependent nephrotic syndrome. In order to assess nephrotoxicity related to CyA therapy, we measured glomerular filtration rate (GFR) on 123 occasions in 24 children with minimal change nephrotic syndrome receiving CyA. GFR was estimated from the plasma clearance of⁵¹chromium-EDTA every 3 months during CyA therapy of up to 27 months duration. There was a significant reduction in GFR after 3 months of CyA therapy [118±33 (SD) to 93±24 ml/min per 1.73 m²] but no further fall thereafter, although the reduction in GFR was sustained for the duration of CyA therapy. This reduction in GFR appeared to be reversible upon cessation of CyA, but careful monitoring of renal function is necessary in such patients to prevent the development of longer term nephrotoxic sequelae.     

A case of high-age minimal change nephrotic syndrome relapse after 18-year remission and effective treatment with steroid and cyclosporin combined therapy

We describe the clinical course of a 69-year-old woman, who suffered from minimal change nephrotic syndrome(MCNS) after long-term remission. In 1979, she was admitted to Kanazawa University Hospital due to MCNS verified by renal biopsy and was treated with oral prednisolone(initially 40 mg/day) for two years. She suffered from edema again in 1999 with massive proteinuria. Renal biopsy revealed minor glomerular abnormality without any deposition of immunoglobulins or complements. Electron microscopic findings showed extensive foot process effacement. Therefore, we diagnosed this case as a recurrence of MCNS. She was treated with the combination of methylprednisolone pulse therapy(500 mg, 3 days), oral prednisolone(20 mg/day) and cyclosporin(CyA, 3 mg/kg/day), which could induce earlier complete remission. These results suggest that recurrence after long-term remission could occur in adult-onset MCNS and that the combination therapy of prednisolone and CyA may be effective for the induction of early remission in MCNS.     

Combined effect of cyclosporin and prednisolone for minimal change nephrotic syndrome: comparison with prednisolone therapy

BACKGROUND: Minimal change nephrotic syndrome (MCNS) is the most common type of glomerular disease and treated mainly with corticosteroids, usually prednisolone(PSL). The recurrence rate during PSL treatment is approximately 20-30 %. In addition, the adverse effects of long term PSL treatment include diabetes, osteoporosis, infection etc, most of which are serious. We treated MCNS with PSL and cyclosporin (CyA) as an initial therapy to reduce PSL dosage and its side effects, and compared various clinical parameters in MCNS treated with the conventional PSL therapy. SUBJECTS AND METHODS: MCNS patients were divided to two groups. Group A consisted of 10 patients, average age 40 years old, treated initially with PSL 20 mg and CyA (2 mg/kg B.W.). Group B consisted 15 patients, average age 43 years old, treated PSL, initial dose 34.7+/-11.9 mg. Data evaluated included whole admission term, reduction of body weight at the discharge, total PSL dosage, period of urinary protein excretion more than 1.0 g/day and side effects. RESULTS: Average admission term was significantly shorter in Group A(19.3+/-8.8 days) than in Group B (56.5+/-22.3 days) (p= 0.0008). Reduction of body weight at discharge from admission was comparable in both Groups (A: 8.3+/-4.8 kg, B: 7.8+/-5.8 kg, p=0.8388). Total PSL dosage in Group A in hospital (386+/-173 mg) was smaller than in Group B (1,884+/-1,573 mg) (p=0.0067). PSL dosage out hospital for 6 months showed the same results A: 1,926+/-776 mg, B: 15,474+/-3,863 mg (p<0.0001). Periods with urinary protein excretion more than 1.0 g/day was slightly shorter in Group A (12.9+/-8.4 days) than Group B (23.7+/-18.3 days) (p= 0.0963). SIDE EFFECTS: One patient in Group B had steroid induced diabetes. Other patients did not show significant side effects. RECURRENCE: Two patients in Group A had recurrence after CyA stopped, but were improved by treatment. CONCLUSION: Initial therapy with PSL and CyA for MCNS is effective for the resolution of nephrotic syndrome, the reduction of PSL amount and whole admission term.     

Rapid deterioration of renal function in minimal change nephrotic syndrome

This report concerns two boys with minimal change nephrotic syndrome progressed to renal failure. The first case aged 17 being a steroid sensitive infrequent relapse developed acute renal failure at his third relapse and recovered soon after the treatment with diuretics and corticosteroids. The second case aged 15 being a steroid dependent frequent relapse became steroid resistant at his 11th relapse and progressed to renal failure seven months later. As the causes of renal failure, acute tubular necrosis and tubular obstruction by casts were suspected in the former. Renal vein thrombosis, morphological transition of renal histology, hemodynamic change and change in glomerular permeability might be occurred in the latter. Renal failure is a rare complication of minimal change nephrotic syndrome and the cause is variable. Precise diagnosis and prompt treatment should be needed to improve the prognosis.     

Use of tacrolimus in steroid- and cyclophosphamide-resistant minimal change nephrotic syndrome

The authors report a case of adult-onset minimal change nephrotic syndrome (MCNS) that was resistant to steroid and cyclophosphamide therapy. Introduction of cyclosporin induced an usual cutaneous reaction of severe flushing attacks. Tacrolimus successfully alleviated both the nephrotic syndrome and the cutaneous side effect associated with cyclosporin use. The antiproteinuric mechanisms of tacrolimus and its potential in treating refractory MCNS and other forms of primary glomerulonephritides are discussed.     

Adrenomedullin and nitrite levels in children with minimal change nephrotic syndrome

Nitric oxide (NO) serves many functions within the kidney, and recent evidence suggests that NO contributes to glomerular injury. Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from human pheochromocytoma. Recent studies showed that plasma AM concentrations correlated with the extent of proteinuria. We have examined the possible role of these two agents by studying plasma and urinary total nitrite (NO⁻ ₂ + NO⁻ ₃) and AM levels in children with minimal change nephrotic syndrome (MCNS). In comparison with healthy controls, children with MCNS had increased urinary nitrite excretion (μmol/mg urinary creatinine), irrespective of whether the disease was in relapse or remission (3.2±0.2 in relapse, n=13; 1.9±0.3 in remission, n=12; 1.0±0.2 in controls, n=10, P<0.05). Plasma nitrite levels (μmol/l) were high in relapse compared with controls (53.2±8.7 vs. 32±4.0, P<0.05). Plasma AM levels (pmol/ml) were decreased in relapse (27.6±1.4 in relapse, 43.3±1.2 in remission, 41.5±1.6 in controls, P<0.05). Urinary AM levels (pmol/mg urinary creatinine) were significantly higher in relapse than in remission and in controls (156±43 in relapse, 56±18 in remission, 36±16 in controls, P<0.05). Our data indicate that NO may play a role in mediating the clinical manifestations of MCNS in children. However, changes in AM levels may be the result of heavy proteinuria. Received: 20 December 1999 / Revised: 12 June 2000 / Accepted: 15 June 2000     

Frequently relapsing minimal change nephrotic syndrome with natural killer cell deficiency prior to the overt relapse of Hodgkin's disease

A 15-year-old boy developed minimal change nephrotic syndrome (MCNS) during remission of Hodgkin's disease. Natural killer (NK) cell activity was practically absent at the onset of MCNS, with a value of 3% compared with the normal value of 44.1%±7.8% (mean ± SD). Treatment with prednisolone resulted in transient remission of MCNs and partial improvement of NK cell activity. Extensive investigations for Hodgkin's disease were performed at 1- to 3-month intervals; a relapse finally became apparent 25 months after the diagnosis of MCNS. Successful treatment of Hodgkin's disease resulted in complete disappearance of proteinuria and normalisation of NK cell activity. Frequently relapsing MCNS with NK cells deficiency during remission of Hodgkin's disease appears to imply its subclinical relapse.     

Combined cyclosporine and prednisolone therapy using cyclosporine blood concentration monitoring for adult patients with new-onset minimal change nephrotic syndrome: a single-center pilot randomized trial

Background

Minimal change nephrotic syndrome (MCNS) responds well to steroids, but some patients show frequent relapses. Long-term steroid administration leads to various adverse effects. We previously reported the effectiveness in refractory nephrosis patients of administrating microemulsified CyA (ME-CyA) once before meals and setting the target value of the CyA blood concentration at 2 h after ME-CyA administration (C2) to 600–1200 ng/ml. On this trial we evaluate the effectiveness and safety of ME-CyA for suppressing relapse of adult new-onset MCNS patients using C2 monitoring.

Methods

Adult new-onset MCNS patients were randomly allocated to a ME-CyA + prednisolone group (“CyA + PSL”) (n = 11) and a PSL-alone group (“PSL-alone”) (n = 10). The drug administration period was 18 months followed by an observation period of 12 months.

Results

The duration of remission tended to be longer in CyA + PSL with C2 >600 ng/ml than in PSL-alone (P = 0.112). The relapse rate up to 18 months was significantly lower in CyA + PSL with C2 >600 ng/ml than in PSL-alone (P = 0.02). C2 was significantly higher in the patients with no relapse at 18 months than that in the patients with relapse (P = 0.048). In CyA + PSL, the total dose of PSL was significantly reduced compared with PSL-alone (P = 0.002). Cosmetic adverse effects tended to be fewer in CyA + PSL.

Conclusions

The combination treatment regimen of ME-CyA and PSL with C2 >600 ng/ml has potential to be an important treatment option for adult new-onset MCNS patients. However, after ME-CyA dosage reduction and discontinuation, the relapse rate increased. It is thus necessary to establish a better dose-reduction method.

     

Beneficial effect of second courses of cytotoxic therapy in children with minimal change nephrotic syndrome

Therapeutic guidelines are not available for children with minimal change nephrotic syndrome (MCNS) who experience frequent relapses or develop steroid resistance after a course of cytotoxic therapy. The records of nine children with biopsy-proven MCNS who received two courses of cytotoxic therapy with either chlorambucil or cyclophosphamide were reviewed to evaluate the length of remission, associated side-effects and long-term outcome. Initial cytotoxic therapy was given to five frequent-relapsing patients and four steroid-resistant patients 2–48 months (mean 16 months) following diagnosis of nephrotic syndrome. The second drug was given 4–85 months (mean 27 months) after the first. Steroid-resistant patients attained remissions of 0–81 months (mean 23 months) following the first agent and 13–67 months (mean 32 months) following the second. Frequent-relapsing patients experienced remissions of 0.5–24 months (mean 7.4 months) following the first cytotoxic drug and 3–72 months (mean 22 months) after the second. Remissions following the second agent were equal to or longer than those following the first in the seven patients who received both chlorambucil and cyclophosphamide. In the 19- to 128-month follow-up (mean 66 months), all four steroid-resistant patients experienced infrequent relapses which responded to prednisone. One frequent-relapsing patient remains in remission, three have chronic proteinuria and one still has a frequent-relapsing course. For the select group of patients who become frequent relapsing or steroid resistant after one course of cytotoxic therapy, a second course of cytotoxic therapy may allow time for catch-up growth, as well as improve steroid responsiveness once relapses occur.