LONG-TERM OUTCOME OF 28 CASES OF DRUG-RESISTANT MINIMAL CHANGE NEPHROTIC SYNDRIME TREATED WITH LDL APHERESIS -RESULT OF A RETROSPECTIVE MULTICENTER SURVEY-

Nephrotic syndrome in minimal change nephrotic syndrome（MCNS） is known to be highly responsive to steroid therapy. However, in substantial cases, it does not respond to drugs and sometimes progresses into focal segmental glomerulosclerosis(FSGS) with renal dysfunction. For fFSGS cases, previous studies reported that LDL apheresis treatment in combination with immunosuppressive drugs including steroids and cyclosporine A rapidly yielded a high rate of remission from refractory nephrotic syndrome with hypercholesterolemia. In these cases, improved response to steroids and cyclosporine A and consequent reduction of total dose of these drugs have also been suggested as the beneficial effects of LDL apheresis. As These effects were proved in FSGS, and this therapy was approved by ministry of health in 1992 in Japan,.However, approval fordrug-resistant MCNS was recently performed in 2024 and further investigation of the effectiveness is requested , In 2004, Japanese Society of Kidney and Lipids conducted a retrospective multicenter survey on the long-term outcome of refractory nephrotic syndrome patients treated with LDL apheresis in the last 5 years. The retrieved data showed a beneficial effect of LDL apheresis in 79 drug-resistant nephrotic syndrome patients. Within these cases, 41 FSGS and 28 MCNS patients were included. The results of FSGS was previously published (2007) however, those of MCNS was not yet performed as the late of official approval of indication.

Cases of refractory NS treated with LDL-A in Japan were searched for in reports published in 1999 to 2004. To clarify the outcome of each patient, a postal survey was conducted by mailing a questionnaire to each corresponding physician at 36 hospitals. The questionnaire was designed to clarify patient clinical profile, clinical history prior to the last onset of NS, values of parameters indicating renal function before, within a month, and at one to three months after a series of LDL-A (afterward, abbreviated as 0-1 months and 1-3 months), outcomes at 2 and 5 years after treatment (afterward, abbreviated as 2nd year and 5th year), procedures of LDL-A, and drugs used before and after treatment. Parameters of renal function included urinary protein (UP), total serum protein (TP), serum albumin (ALB), serum creatinine (Cr), creatinine clearance (Ccr), and serum total cholesterol (TC). Outcomes at the 2nd and 5th years were classified into four groups: complete remission (CR), type I incomplete remission (type I IR; UP: negative or < 1.0 g/day and ALB > 3.0 g/dl),  type II incomplete remission (type II IR; UP<3.5 g/day but ALB < 3.0 g/dl), and no improvement in NS (NS; UP> 3.5 g / day and ALB < 3.0 g/dl).  

LDL-A was performed using polysulphone hollow fibers (Sulflux; Kaneka Corp., Japan) for plasma separation and a dextran sulfate cellulose column (Liposorber LA-15; Kaneka Corp., Japan) as the LDL adsorber.

Patient profile and LDLA session:Age of patients ranged from 14 to 68 years, and two patients were younger than 16 years of age. The average duration of drug treatment without response before LDL-A after the last onset of NS in 25 patients was 2.7 months.. A total of two to thirteen (7.6 ± 3.5) sessions of LDL-A were combined with steroid (n=26) and/or CsA (n=11), other immunosuppressive drugs (n=4), or statins (n=10) as lipid-lowering agents.

Outcome:Mean levels of TC, UP, TP, and ALB were significantly improved at 0-1 and 1-3 months. TC and UP decreased to 219 mg/dL and 0.86 g/day at 1-3 months, respectively. In 16 patients (76%), UP was less than 1.0 g/day at 1-3 months. TP and ALB increased to 5.52 g/dL and 3.55 g/dL at 1-3 months, respectively. In 21 patients (88%), ALB was above 3.0 g/dL at 1-3 months. Cr and Ccr exhibited tendencies toward improvement at 0-1 and 1-3 months, though significant improvement was observed only in Cr at 0-1 months. At the 2nd year, 16 patients (84%), 2 patients (11%), 1 patient (5%) , and no patients were classified as in CR, Type I IR, Type II IR, and NS, respectively. At the 5th year, 8 patients (80%), 2 patients (20%), and no patients were classified as in CR, Type II IR, and NS, respectively. There was no patient diagnosed as chronic renal failure (CRF).  

The decrease in TC at 0-1 months was significantly correlated with the decrease in UP at 0-1 months (r=0.451, p=0.018) and the increase in ALB at 0-1 months (r=0.630, p<0.001)

 LDL apheresis treatment in combination with drug treatment is effective in achieving rapid remission and good long-term outcome in patients with refractory MCNS. Approval of this therapy for MCNS is highly expected to reduce the long term and high dose use of steroid  in drug resistant cases.