Diabetic glomerulopathy-natural history, intervention and prediction of complications

Diabetes mellitus is one of the most common chronic diseases in childhood. Diabetic nephropathy (DN) is one of the threatening complications of diabetes that occurs in 30-40% of patients after 20 years duration of disease. Before the introduction of antihypertensive treatment, patients with DN progressed to renal insufficiency within 5-7 years and had very high overall mortality.

The aim of this thesis was to study the natural history of the renal morphology and the effect of intervention with antihypertensive treatment in a well defined, unselected group of normoalbuminuric and normotensive adolescents with type 1 diabetes. Forty-six patients underwent their first renal biopsy between 1992 and 1994 when they were 17 years old and had diabetes for 10 years. Six years after the first renal biopsy, 29 patients underwent a second renal biopsy. During the follow-up period ten of the 29 patients developed microalbuminuria and/or hypertension and 6 of the patients had received antihypertensive treatment for at least two years.

In the 19 patients who were still normoalbuminuric and normotensive at the time of the second renal biopsy, progression of the diabetic glomerulopathy from the first renal biopsy was observed with further increases in mesangial matrix and mesangial volume fraction. The females had higher values of mesangial matrix, mesangial volume fraction and glomerular volume at the time of the first renal biopsy compared to the males. In males the mesangial matrix and mesangial volume fraction, but not glomerular volume, increased to the time of the second renal biopsy reaching values similar to the females.

The six patients who had received antihypertensive treatment during the follow-up period showed higher values in basement membrane thickness, mesangial matrix and mesangial volume fraction at the first renal biopsy but with antihypertensive treatment and better metabolic control the morphologicalparameters remained stable or even regressed. The basement membrane thickness and mesangial matrix volume fraction at the time of the second renal biopsy correlated well with the degree of long-term metabolic control since onset and with male gender.

When predicting the outcome of microalbuminuria and hypertension after 17 years duration in the 46 patients who had a first renal biopsy, the basement membrane thickness, the day systolic blood pressure and the metabolic control, especially from puberty, were risk-factors. GFR or hyperfiltration could not be identified as a risk factor.

Following the second renal biopsy, thirteen normoalbuminuric and normotensive patients participated in a placebo controlled treatment study with an angiotensin II receptor blocker, Candesartan. After 5 years of treatment, the Candesartan group had a lower blood pressure compared to the placebo group as well as a significant regression in morphology on a third renal biopsy performed after 6 years. The placebo group showed a tendency (not significant) to regression in morphology. Two patients in the placebo group developed hypertension and/or microalbuminuria and needed antihypertensive treatment but no patient in the Candesartan group did.

It is concluded that it is possible to favorably affect renal morphological changes in as much as the previously observed deterioration in renal morphology was attenuated. The importance of regular follow-up and good metabolic control cannot be overestimated.

List of scientific papers

I. Perrin NE, Torbjörnsdotter TB, Jaremko GA, Berg UB (2004). Follow-up of kidney biopsies in normoalbuminuric patients with type 1 diabetes. Pediatr Nephrol. 19(9): 1004-13. Epub 2004 Jun 23
https://pubmed.ncbi.nlm.nih.gov/15221426

II. Perrin NE, Torbjörnsdotter TB, Jaremko GA, Berg UB (2006). The course of diabetic glomerulopathy in patients with type I diabetes: a 6-year follow-up with serial biopsies. Kidney Int. 69(4): 699-705.
https://pubmed.ncbi.nlm.nih.gov/16518327

III. Perrin N, Torbjörnsdotter TB, Jaremko GA and Berg UB (2008). Predicting the risk for future microalbuminuria and hypertension from clinical and morpological parameters in young adolescents with type 1 diabetes. [Submitted]

IV. Perrin NE, Jaremko GA, Berg UB (2008). The effects of candesartan on diabetes glomerulopathy: a double-blind, placebo-controlled trial. Pediatr Nephrol. Feb 13: Epub ahead of print.
https://pubmed.ncbi.nlm.nih.gov/18270751