Nephropathy develops progressively in diabetic patients such that it becomes a major contributory risk factor for death from cardiovascular complications  . It is a common and disabilitating complication of diabetes mellitus with no effective therapy. The progression of nephropathy in diabetes from the reference time point of diagnosis of diabetes is:
- Incipient nephropathy (hyperfiltration and persistent microalbuminuria) - after ca. 18 years,
- Overt nephropathy (persistent proteinuria and decline in glomerular filtration rate (GFR) - after ca. 29 years,
- Endstage renal disease (ESRD) requiring renal replacement therapy - after ca. 39 years, and
- Median survival - ca. 45 years [1;3]
Diabetes is a common cause (30%) of chronic renal failure and is likely to be of increasing importance in the future as diabetes incidence increases - especially with early onset  . Glycemic control is a risk factor for the development of incipient nephropathy and progression from incipient to overt nephropathy in type 1 and type 2 diabetes [4;5] . Health care services have now prioritized the decreasing the risk of nephropathy by tight control of blood glucose and blood pressure and aggressive intervention to counter dyslipidaemia - as reflected in position statement reports [6;7] . This is not always achievable - particularly because of limitations of current drug therapy. Hence, diabetic nephropathy is still a significant clinical problem that needs new effective therapy urgently and preferably therapies working independent of existing strategies. One such therapy emerging is high dose thiamine supplements.
The link of hyperglycemia to renal dysfunction and development of nephropathy
High plasma glucose concentration leads to high cytosolic glucose concentration in renal endothelial cells and pericytes with consequent biochemical dysfunction: activation of protein kinase Cβ, hexosamine and polyol pathways, metabolic pseudohypoxia, mitochondrial dysfunction and oxidative stress, and accumulation of advanced glycation endproducts (AGEs)  – Figure 1.
Figure 1 - Biochemical dysfunction in hyperglycemia linked to diabetic nephropathy
Increased concentrations of triosephosphate glycolytic intermediates, glyceraldehyde-3-phosphate (GA3P) and dihydroxyacetonephosphate (DHAP), is the trigger for these processes. A pharmacological strategy that counters triosephosphate accumulation in hyperglycemia would suppress multiple pathogenic pathways and prevent the development of diabetic nephropathy. Activation of the reductive pentosephosphate pathway (PPP) by high dose thiamine therapy may achieve this by increasing transketolase (TK) activity and stimulating the conversion of GA3P and fructose-6-phosphate (F6P) to ribose-5-phosphate (R5P) – Figure 2.
Figure 2 - Reversal of biochemical dysfunction in hyperglycemia by high dose thiamine
We first established this response in cell culture  and then investigated the effect of high dose thiamine and Benfotiamine therapy on the development of incipient nephropathy in the streptozotocin (STZ)-induced diabetic rat model of diabetes with moderate insulin therapy.
Incipient nephropathy developed over a 24-week period in the STZ diabetic rats, as judged by hyperfiltration and microalbuminuria, and both high dose thiamine and Benfotiamine therapy prevented it  .
Figure 3. Study design: induction of diabetes, study groups and thiamine/Benfotiamine dosing