Enzyme Therapy in Diabetic Nephropathy – Experimental and First
Clinical Data
*Stauder G., *Wood G., **Paczek
L. Enzyme Therapy in Diabetic Nephropathy – Experimental and First
Clinical Data. Czech summary. 6th Taormina Course of Nephrology.
October 20th - 22th, 2000, pp. 227-232, Editoriale Bios 2000 PZ 22
(5-14-3)-(19-11-3). * Mucos Pharma, Geretsried, Germany. **
Transplantation Institute, University Warsaw, Poland
English summary of
lecture: Diabetic nephropathy is characterized by cell hypertrophy,
thickening of the basement membranes and accumulation of
extracellular matrix (ECM), that is attributed to an elevated
protein synthesis and an inhibition of protein degradation, the
latter due to reduced proteolytic activity.
The main trigger for this
process is over expression of transforming growth factor beta-1
(TGF-b1). This is induced by numerous factors such as hyperglycemia,
stimulation of the RAS, formation of advanced glycation endproducts
(AGE), elevated IL-6 levels, and increased mesangial stretch. A
reduction of TGF-b1 levels was documented to be associated with a
retardation of disease progression. Based on the findings in
endothelial cells that the receptor for AGEs (RAGE) is trypsin-sensitive,
the modulatory action of this serine protease was investigated in
tubule cells. The distinct overexpression of TGF-b1 as well as the
hypertrophy of the cells, induced by AGE-BSA, were normalized after
coincubation with trypsin. In addition, the cellular accumulation of
AGEs was markedly reduced. The enzyme therapy (12 mg/day of a
mixture of the active ingredients of Phlogenzym®) was able to reduce
the increased intraglomerular TGF-b content in rats. In a
second study in uninephrectomized, STZ induced diabetes in rats the
combination of Phlogenzym® with the ACE inhibitor enalapril showed
an almost 67% reduction of glomerular sclerosis, while single
treatment with either enalapril or Phlogenzym® led to a 20-30%
reduction only, indicating clear additive effect.
In human studies (patients
with rheumatoid arthritis or myelofibrosis), elevated serum levels
of TGF-b were diminished by oral enzyme therapy. A clinical
pilot study in patients with diabetic nephropathy demonstrated that
oral enzyme therapy (2 tablets t.i.d.) is able to reduce enhanced
levels of IL-6 both in serum and urine.
A clinical double-blind
placebo controlled pilot study on 24 patients with diabetic
nephropathy, stages III or IV, was performed in 4 centers in Germany
and Poland. Either the enzyme preparation Phlogenzym® or placebo was
administered double-blinded for 16 weeks. 21 patients, mean age
51.3, and 53.5 years, respectively, were evaluated. Five patients in
the enzyme group were suffering from diabetes type I, 5 patients
from type II; in the placebo group 5 patients were suffering from
the type I and 6 patients from type II. Five patients (enzyme group)
had stage III nephropathy (microalbuminuria), 5 patients stage IV (macroalbuminuria);
in the placebo group 4 patients had stage III, and 7 patients stage
IV. At baseline, 7 patients in the enzyme group had proteinuria <1
g/day, 3 patients >1 g/day; in the placebo group 7 patients had
proteinuria <1 g/day, and 4 patients >1 g/day. The groups were
comparable. Blood glucose and mean blood pressure were controlled
effectively.
At baseline, a proteinuria
(median) of 0.4 g/day was measured in the enzyme group, 0.8 g/day in
the placebo group. After 16 weeks the value was unchanged in the
enzyme group (0.36 g/day), whereas it slightly deteriorated to 1.08
g/day in the placebo group (p > 0.05).
The albuminuria tended to
lower levels (from 242.5 mg/day to 200.0 mg/day) in the enzyme
group; in the placebo group, a slight increase from 508.0 mg/day to
562.0 mg/day was observed (p > 0.05). Creatinine clearance did not
change in either group during the 16-week treatment period (which
was not at all expected in this short time), while serum creatinine
tended to decline in the enzyme group (from 1.05 mg/dl at baseline
to 0.95 mg/dl), and remained unchanged (at 1.2 mg/dl) in the placebo
group (p = 0.0279).
There were recorded only 2
drug related side effects, 1 under placebo (mild diarrhea) and 1
(mild constipation) under enzyme therapy. Thus, the enzyme therapy
proved to be safe.
Another double-blind, placebo controlled clinical trial with
Phlogenzym® will be performed in 16 centers in Europe.