Enzyme Therapy in Diabetic Nephropathy – Experimental and First Clinical
Gerhard Stauder*, Gavin Wood*, Leczek Paczek**
* Mucos Pharma, Geretsried, Germany
** Transplantation Institute, University Warsaw, Poland
In: Consolo F, Bellinghieri G, Savica V. (eds.): 6th Taormina
Course of Nephrology. Editoriale Bios, Cosenza, (2000); 227-232.
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 overexpression 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.