Nephrol Dial Transplant (1992) 7: 642-646 © 1992 European Dialysis and Transplant Association-European Renal Association
Nephrology Dialysis Transplantation
Case Report
A. Innes1, P. N. Furness2, R. E. Cotton2, R. P. Burden1 and A. G. Morgan1 Departments of 'Renal Medicine and 2 Histopathology, City Hospital, Nottingham, UK
Abstract. The duration of diabetes mellitus and presence of hyperglycaemia appear to be important in the development of diabetic nephropathy. The presence of nodular glomerulosclerosis is thought to be pathognomonic of the condition. We report two patients with histological features of diabetic glomerulosclerosis who did not have diabetes mellitus. The discussion reviews the literature and concludes that diabetic glomerulosclerosis with normal glucose tolerance is very rare and that most cases are due to overt diabetes mellitus or a degree of glucose intolerance. However, cases with only minimal glucose intolerance suggest that factor(s) other than hyperglycaemia are responsible for diabetic renal damage. Key words: Kimmelstiel-Wilson nodules; without diabetes mellitus
Introduction Diabetic nephropathy is thought to affect over 20% of insulin-dependent diabetic patients who have had diabetes mellitus for 20-25 years [1]. The prevalence of clinical diabetic nephropathy has been found to correlate with the duration of insulin-dependent diabetes mellitus (IDDM) [1], and hyperglycaemia seems to be an important factor in its development [2]. The histological lesions of diabetic nephropathy
were initially described by Kimmelstiel and Wilson [3] but of the various changes, only the lesion of nodular glomerulosclerosis is thought to be pathognomonic [4]. This has been challenged by single case reports of patients with histological features of diabetic glomerulosclerosis in the absence of overt diabetes. In this study we present two patients with the renal pathology of diabetic glomerulosclerosis who did not have diabetes mellitus, and review the literature on the subject.
Subjects and methods Thirteen renal biopsies taken since 1977, which had been reported as suggestive of diabetic nephropathy when the patient was not known to be diabetic, were reviewed independently by two histopathologists. Mesangial sclerosis and hyaline changes in blood vessels consistent with diabetic nephropathy were present in 13 biopsies, but only two exhibited the classical changes of nodular glomerulosclerosis.
Case report (1)
A 52-year-old male presented with a 2-month history of anaemia and malaise. There was no relevant family or past medical history. His blood pressure was 180/90mmHg and he had a soft ejection systolic murmur. There was no evidence of diabetic retinopathy on fundoscopy or of neuropathy. Investigations showed a normochromic normocytic anaemia (haeCorrespondence and offprint requests to: Dr Andrew Innes, Department of Renal Medicine, City Hospital. Nottingham NG5 1PB, moglobin 8.1 g/dl) and uraemia (plasma urea UK. 37.1 mmol/l, plasma creatinine 972 umol/l). There was
Downloaded from https://academic.oup.com/ndt/article-abstract/7/7/642/1823025 by INSEAD user on 10 September 2018
Diabetic glomerulosclerosis without diabetes mellitus — two case reports and a review of the literature
Diabetic glomenilosclerosis without diabetes
were also undetectable, despite strong staining of appropriate control material. The appearances were therefore considered to be typical of nodular diabetic nephropathy, and amyloidosis and light-chain disease were excluded. An oral 75 g glucose tolerance test (OGTT), was normal (Table 1). Plasma fructosamine was 1.5 mmol 1. Renal function continued to deteriorate and he started CAPD 1 month later. Random blood glucose measurements since starting dialysis 18 months ago have never exceeded 5.4 mmol, 1.
Case report (2) A 74-year-old male presented with excessive tiredness, anaemia, weight loss, anorexia, and orthopnoea. Table I. Results of OGTT Time of sample (min)
Venous plasma glucose (mmol/1) Patient 1
Fasting 30 60 90 120
4.9 6.5 !
.
%
•
7.8 7.1
Patient 2 4.2 8.4 10.8
Fig. 1. Case 1. The glorr.mjlus shows early nodule formation (arrow) together uith more diffuse hyaline diabetic change in the remainder of the glomerulus and marked hyaline thickening of arterial walls. H & E x 100.
Downloaded from https://academic.oup.com/ndt/article-abstract/7/7/642/1823025 by INSEAD user on 10 September 2018
hypoalbuminaemia (serum albumin 27 g/1) and proteinuria (1.9g'24h). Serum immunoglobulins, TSH and plasma cortisols were normal and no paraprotein was found on electrophoresis of blood or urine. Both kidneys appeared to be of normal size on urography and a percutaneous renal biopsy was carried out. Thirty-two glomeruli were present and all showed a variable degree of segmental mesangial hyaline material. Three glomeruli contained typical Kimmelstiel-Wilson nodules (Figure 1). Sirius red stains for amyloid were negative. Electron-microscopy revealed basement membrane thickening (440 nm) with amorphous material showing no laminations and having an electron density similar to that of the normal lamina densa. Measurement of glomerular basement membranes was made between endothelial to epithelial cell cytoplasmic membranes at the thinnest points found after study of a whole glomerulus. By this method, normal basement membrane thickness is under 350 nm in our laboratory and although several of the other cases of histologically suspected diabetes had equivocally thickened basement membranes, none approached 440 nm. Amyloid fibrils were not present and the nodular material was amorphous, with no evidence of lamination. These appearances were not suggestive of light-chain disease; this was supported by the absence of immunoperoxidase staining for kappa and lambda light chains; a, u and y heavy chains and complement components
643
A. Innes el al.
644
fasting blood glucose estimations, on CAPD, never exceeded 10 mmol/1.
Discussion and review of the literature The differential diagnosis of nodular glomerulosclerosis includes diabetic nephropathy, amyloidosis, and light-chain disease [4]. Mesangiocapillary glomerulonephritis is sometimes included in the differential diagnosis, though this condition is usually obviously different on clinical and pathological grounds. When amyloidosis and light-chain disease have been excluded, as with the two cases we describe, nodular glomerulosclerosis is generally held to be pathognomonic of diabetic nephropathy. The other histological findings in these two cases, such as basement membrane thickening and hyaline thickening of blood vessels, are also considered to be characteristic features of diabetic nephropathy. The patients were not, however, demonstrably diabetic by the 1985 WHO criteria: the first case had normal glucose tolerance and the second patient had impaired glucose tolerance. It is possible that patient 2 had long-standing impaired glucose tolerance producing retinopathy and nephropathy. Also, chronic renal failure^/- se is associated with impaired glucose tolerance [5] irrespective of the cause of the renal
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Nephrology Dialysis Transplantation
Case Report
A. Innes1, P. N. Furness2, R. E. Cotton2, R. P. Burden1 and A. G. Morgan1 Departments of 'Renal Medicine and 2 Histopathology, City Hospital, Nottingham, UK
Abstract. The duration of diabetes mellitus and presence of hyperglycaemia appear to be important in the development of diabetic nephropathy. The presence of nodular glomerulosclerosis is thought to be pathognomonic of the condition. We report two patients with histological features of diabetic glomerulosclerosis who did not have diabetes mellitus. The discussion reviews the literature and concludes that diabetic glomerulosclerosis with normal glucose tolerance is very rare and that most cases are due to overt diabetes mellitus or a degree of glucose intolerance. However, cases with only minimal glucose intolerance suggest that factor(s) other than hyperglycaemia are responsible for diabetic renal damage. Key words: Kimmelstiel-Wilson nodules; without diabetes mellitus
Introduction Diabetic nephropathy is thought to affect over 20% of insulin-dependent diabetic patients who have had diabetes mellitus for 20-25 years [1]. The prevalence of clinical diabetic nephropathy has been found to correlate with the duration of insulin-dependent diabetes mellitus (IDDM) [1], and hyperglycaemia seems to be an important factor in its development [2]. The histological lesions of diabetic nephropathy
were initially described by Kimmelstiel and Wilson [3] but of the various changes, only the lesion of nodular glomerulosclerosis is thought to be pathognomonic [4]. This has been challenged by single case reports of patients with histological features of diabetic glomerulosclerosis in the absence of overt diabetes. In this study we present two patients with the renal pathology of diabetic glomerulosclerosis who did not have diabetes mellitus, and review the literature on the subject.
Subjects and methods Thirteen renal biopsies taken since 1977, which had been reported as suggestive of diabetic nephropathy when the patient was not known to be diabetic, were reviewed independently by two histopathologists. Mesangial sclerosis and hyaline changes in blood vessels consistent with diabetic nephropathy were present in 13 biopsies, but only two exhibited the classical changes of nodular glomerulosclerosis.
Case report (1)
A 52-year-old male presented with a 2-month history of anaemia and malaise. There was no relevant family or past medical history. His blood pressure was 180/90mmHg and he had a soft ejection systolic murmur. There was no evidence of diabetic retinopathy on fundoscopy or of neuropathy. Investigations showed a normochromic normocytic anaemia (haeCorrespondence and offprint requests to: Dr Andrew Innes, Department of Renal Medicine, City Hospital. Nottingham NG5 1PB, moglobin 8.1 g/dl) and uraemia (plasma urea UK. 37.1 mmol/l, plasma creatinine 972 umol/l). There was
Downloaded from https://academic.oup.com/ndt/article-abstract/7/7/642/1823025 by INSEAD user on 10 September 2018
Diabetic glomerulosclerosis without diabetes mellitus — two case reports and a review of the literature
Diabetic glomenilosclerosis without diabetes
were also undetectable, despite strong staining of appropriate control material. The appearances were therefore considered to be typical of nodular diabetic nephropathy, and amyloidosis and light-chain disease were excluded. An oral 75 g glucose tolerance test (OGTT), was normal (Table 1). Plasma fructosamine was 1.5 mmol 1. Renal function continued to deteriorate and he started CAPD 1 month later. Random blood glucose measurements since starting dialysis 18 months ago have never exceeded 5.4 mmol, 1.
Case report (2) A 74-year-old male presented with excessive tiredness, anaemia, weight loss, anorexia, and orthopnoea. Table I. Results of OGTT Time of sample (min)
Venous plasma glucose (mmol/1) Patient 1
Fasting 30 60 90 120
4.9 6.5 !
.
%
•
7.8 7.1
Patient 2 4.2 8.4 10.8
Fig. 1. Case 1. The glorr.mjlus shows early nodule formation (arrow) together uith more diffuse hyaline diabetic change in the remainder of the glomerulus and marked hyaline thickening of arterial walls. H & E x 100.
Downloaded from https://academic.oup.com/ndt/article-abstract/7/7/642/1823025 by INSEAD user on 10 September 2018
hypoalbuminaemia (serum albumin 27 g/1) and proteinuria (1.9g'24h). Serum immunoglobulins, TSH and plasma cortisols were normal and no paraprotein was found on electrophoresis of blood or urine. Both kidneys appeared to be of normal size on urography and a percutaneous renal biopsy was carried out. Thirty-two glomeruli were present and all showed a variable degree of segmental mesangial hyaline material. Three glomeruli contained typical Kimmelstiel-Wilson nodules (Figure 1). Sirius red stains for amyloid were negative. Electron-microscopy revealed basement membrane thickening (440 nm) with amorphous material showing no laminations and having an electron density similar to that of the normal lamina densa. Measurement of glomerular basement membranes was made between endothelial to epithelial cell cytoplasmic membranes at the thinnest points found after study of a whole glomerulus. By this method, normal basement membrane thickness is under 350 nm in our laboratory and although several of the other cases of histologically suspected diabetes had equivocally thickened basement membranes, none approached 440 nm. Amyloid fibrils were not present and the nodular material was amorphous, with no evidence of lamination. These appearances were not suggestive of light-chain disease; this was supported by the absence of immunoperoxidase staining for kappa and lambda light chains; a, u and y heavy chains and complement components
643
A. Innes el al.
644
fasting blood glucose estimations, on CAPD, never exceeded 10 mmol/1.
Discussion and review of the literature The differential diagnosis of nodular glomerulosclerosis includes diabetic nephropathy, amyloidosis, and light-chain disease [4]. Mesangiocapillary glomerulonephritis is sometimes included in the differential diagnosis, though this condition is usually obviously different on clinical and pathological grounds. When amyloidosis and light-chain disease have been excluded, as with the two cases we describe, nodular glomerulosclerosis is generally held to be pathognomonic of diabetic nephropathy. The other histological findings in these two cases, such as basement membrane thickening and hyaline thickening of blood vessels, are also considered to be characteristic features of diabetic nephropathy. The patients were not, however, demonstrably diabetic by the 1985 WHO criteria: the first case had normal glucose tolerance and the second patient had impaired glucose tolerance. It is possible that patient 2 had long-standing impaired glucose tolerance producing retinopathy and nephropathy. Also, chronic renal failure^/- se is associated with impaired glucose tolerance [5] irrespective of the cause of the renal
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