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Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene RA, Wetzels JF: Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome. Nephrol Dial Transplant 1999 Jul;14(7):1723-31. Division of Nephrology, University Hospital Nijmegen, The Netherlands.

BACKGROUND: Dense deposit disease (DDD) is an uncommon cause of end-stage renal disease (ESRD). As a consequence, information on the outcome of renal transplantation in patients with DDD comes from series with a limited number of patients. METHODS: We present the histological and clinical data of 13 adult patients with DDD, who received their first allograft in our centre in the period between 1983 and 1994. RESULTS: Renal transplant biopsies were performed in 11 patients, at 2.9 months after transplantation (median; range 0.4-13.8 months). The indication for taking the biopsy was in all instances a raised serum creatinine level. Five patients also had a significant proteinuria. In only one patient, light microscopy showed alterations in the capillary walls suggestive of a recurrence of DDD. However, by immunofluorescence or electron microscopy, we found glomerular deposits compatible with a recurrence of DDD in all 11 patients. Three patterns of glomerular C3 deposition were found: globular depositions only in the mesangium; mesangial accumulation with linear deposits in the capillary wall; and prominent linear presence in the capillary wall with only a few mesangial granules. The findings by electron microscopy matched the immunofluorescence results. The linear C3 accumulation in the capillary wall was visible ultrastructurally as electron-dense ribbon-like transformation of the glomerular basement membrane. Mesangial C3 deposits were seen ultrastructurally as local electron-dense deposits in the mesangium. Four patients showed a pronounced glomerular influx of neutrophils, accompanied by crescents in three patients. In these three latter patients, the recurrence of DDD was the only histological lesion. In the other patients, the recurrence was merely a coincidence, the biopsy demonstrating an additional histological lesion (three chronic vascular rejection, two acute rejection, one ischaemic necrosis and two cyclosporin A toxicity). Eight patients with a recurrence of DDD have progressed to ESRD at an average of 14 months (range 0.2-38 months) after transplantation. The recurrence was the sole cause of graft loss in the three patients with crescents. The patients in whom the C3 deposits were confined to the mesangium appeared to have a better prognosis. CONCLUSIONS: The histological recurrence rate of DDD is high. The histological picture is quite diverse, and in most patients abnormalities are only found by immunofluorescence and electron microscopy. Up to one-quarter of the patients with DDD lost their grafts because of a recurrence.

Joh K, Aizawa S, Matsuyama N, Yamaguchi Y, Kitajima T, Sakai O, Mochizuki H, Usui N, Hamaguchi K, Mitarai T: Morphologic variations of dense deposit disease: light and electron microscopic, immunohistochemical and clinical findings in 10 patients. 1: Acta Pathol Jpn 1993 Oct;43(10):552-65. Department of Pathology, Jikei University School of Medicine, Tokyo, Japan.

Twenty-one renal biopsy specimens obtained from 10 patients with dense deposit disease (DDD) were investigated using light microscopy, electron microscopy and immunohistochemistry. The patients included four females and six males aged 6 to 35 years (mean 16.1 years). A morphological diagnosis of DDD was made following the ultrastructural detection of continuous intramembranous dense deposits (CIMDD) in some capillary loops of at least one of the series of the repeated biopsies from each patient. With light microscopy, six patients showed membranoproliferative glomerulonephritis (MPGN). The other four patients showed diffuse proliferative glomerulonephritis (DPGN) with acute lesions showing intraglomerular neutrophilic infiltration, hump formation and endothelial swelling in three and minor glomerular abnormalities in one. Follow-up biopsies were obtained in six patients. Two patients progressed from DPGN to MPGN within 7 months, whereas three patients with MPGN showed morphologic improvement that featured increased capillary patency and regional disappearance of dense deposits along with the reduction of proteinuria. Dense deposit disease did not always feature typical amorphous and osmiophilic CIMDD spreading across the whole width of the lamina densa. This classical ultrastructural manifestation was mainly found in the patients with histologic non-MPGN and a linear peripheral pattern of complement component (C3) deposition. The MPGN patients with a granular peripheral pattern of C3 deposition also had CIMDD, but also additionally featured less dense subepithelial deposits superimposed on the CIMDD to produce an appearance simulating membranous transformation.

Mathew TH: Recurrence of disease following renal transplantation. 1: Am J Kidney Dis 1988 Aug;12(2):85-96. Renal Unit, Queen Elizabeth Hospital, Woodville South, South Australia.

The diagnosis of recurrent renal disease after transplantation is dependent on an accurate and complete diagnosis of the initial cause of renal failure and a similar determination of the cause of graft failure. To be classified as recurrent, the disease in the renal graft must be identical to that seen in the native kidneys. Recurrence of disease accounts for less than 2% of all graft failures, but the overall incidence of recurrent disease is probably 5 to 10 times more common. The most frequent cause of recurrent disease is glomerulonephritis, which was first recognized to recur soon after renal transplantation was introduced. It was then recognized that a variety of metabolic disorders would recur, but it has taken 25 years of experience for a clear picture to emerge of recurrence in most conditions. No initial cause of renal failure poses a contraindication to at least one attempt at transplantation, although with Fabry's disease and oxalosis, a special assessment of the risks for the individual recipient is warranted. In some patients, experience has shown the need for a delay in the commitment to transplantation (eg, in those with anti-glomerular basement membrane [GBM] antibody glomerulonephritis or Henoch Schonlein purpura), the need for the choice of a particular immunosuppressive regimen (eg, in hemolytic uremic syndrome [HUS]), the need for avoidance of primary nonfunction (eg, in oxalosis), and the desirability of avoiding live kidney donation (eg, in heterozygote donors in Fabry's disease, high-risk recipients with focal glomerulosclerosis, and in recipients with HUS). Probably all types of glomerulonephritis recur, but with great variation in frequency and severity. In some forms of glomerulonephritis, recurrence may be frequent and definite on histopathological criteria but may only have a minor clinical expression (eg, dense deposit disease, anti-GBM antibody glomerulonephritis, IgA nephropathy), but in others, recurrence is less predictable yet it is clearly associated with premature graft failure (eg, focal glomerulosclerosis, membranous nephropathy). A common theme emerging is that where the initial glomerulonephritis is aggressive and causes kidney failure over a short time, recurrence is more likely, and when present, it will lead to graft failure with an increased frequency. Clinical manifestations, the frequency of recurrence, and the prognosis of the graft are now identified for most conditions. Unexpected observations have included the rarity of recurrent systemic lupus erythematosus (SLE), the immediate return of heavy proteinuria in focal glomerulosclerosis, and the predictable return of dense deposit disease.

The Southwest Pediatric Nephrology Study Group. Dense deposit disease in children: prognostic value of clinical and pathologic indicators. Am J Kidney Dis 1985 Sep;6(3):161-9..

Clinical and pathological features were examined in 16 children with dense deposit disease. The children ranged in age from 5 to 15 years (mean: 9.3 years). There were nine boys and seven girls. Semiquantitative grading of renal biopsy findings was performed in these patients and compared to clinical features at the time of presentation, and at the time of latest follow-up. Initial clinical features included hypertension and decreased glomerular filtration rate in 50% of patients, nephrotic syndrome in 69%, and gross hematuria in 73%. Serum C3 concentrations were low in nine of nine patients. All but one of the patients subsequently received steroid therapy, the dosage of which varied. Of the 16 patients, six developed progressive renal insufficiency, six have normal renal function after a period of 7 to 12 years, and four have normal renal function but have been followed for less than 6 years. When these different subgroups were compared, clinical and laboratory features were not helpful outcome indicators. By contrast, poor outcome was correlated with the following pathologic features: excessive prominence of glomerular lobules, severe mesangial hypercellularity and sclerosis, severe glomerular loop obliteration, and mesangial electron dense deposit alteration. We conclude that the course of dense deposit disease is variable and that certain pathologic features may be helpful in predicting clinical outcome. Whether alternate-day prednisone therapy may have been of benefit for the patients in this study is uncertain.

REFERENCES DDGN	REFERENCIAS GNDD
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Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene RA, Wetzels JF: Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome. Nephrol Dial Transplant 1999 Jul;14(7):1723-31. Division of Nephrology, University Hospital Nijmegen, The Netherlands. BACKGROUND: Dense deposit disease (DDD) is an uncommon cause of end-stage renal disease (ESRD). As a consequence, information on the outcome of renal transplantation in patients with DDD comes from series with a limited number of patients. METHODS: We present the histological and clinical data of 13 adult patients with DDD, who received their first allograft in our centre in the period between 1983 and 1994. RESULTS: Renal transplant biopsies were performed in 11 patients, at 2.9 months after transplantation (median; range 0.4-13.8 months). The indication for taking the biopsy was in all instances a raised serum creatinine level. Five patients also had a significant proteinuria. In only one patient, light microscopy showed alterations in the capillary walls suggestive of a recurrence of DDD. However, by immunofluorescence or electron microscopy, we found glomerular deposits compatible with a recurrence of DDD in all 11 patients. Three patterns of glomerular C3 deposition were found: globular depositions only in the mesangium; mesangial accumulation with linear deposits in the capillary wall; and prominent linear presence in the capillary wall with only a few mesangial granules. The findings by electron microscopy matched the immunofluorescence results. The linear C3 accumulation in the capillary wall was visible ultrastructurally as electron-dense ribbon-like transformation of the glomerular basement membrane. Mesangial C3 deposits were seen ultrastructurally as local electron-dense deposits in the mesangium. Four patients showed a pronounced glomerular influx of neutrophils, accompanied by crescents in three patients. In these three latter patients, the recurrence of DDD was the only histological lesion. In the other patients, the recurrence was merely a coincidence, the biopsy demonstrating an additional histological lesion (three chronic vascular rejection, two acute rejection, one ischaemic necrosis and two cyclosporin A toxicity). Eight patients with a recurrence of DDD have progressed to ESRD at an average of 14 months (range 0.2-38 months) after transplantation. The recurrence was the sole cause of graft loss in the three patients with crescents. The patients in whom the C3 deposits were confined to the mesangium appeared to have a better prognosis. CONCLUSIONS: The histological recurrence rate of DDD is high. The histological picture is quite diverse, and in most patients abnormalities are only found by immunofluorescence and electron microscopy. Up to one-quarter of the patients with DDD lost their grafts because of a recurrence.
Joh K, Aizawa S, Matsuyama N, Yamaguchi Y, Kitajima T, Sakai O, Mochizuki H, Usui N, Hamaguchi K, Mitarai T: Morphologic variations of dense deposit disease: light and electron microscopic, immunohistochemical and clinical findings in 10 patients. 1: Acta Pathol Jpn 1993 Oct;43(10):552-65. Department of Pathology, Jikei University School of Medicine, Tokyo, Japan. Twenty-one renal biopsy specimens obtained from 10 patients with dense deposit disease (DDD) were investigated using light microscopy, electron microscopy and immunohistochemistry. The patients included four females and six males aged 6 to 35 years (mean 16.1 years). A morphological diagnosis of DDD was made following the ultrastructural detection of continuous intramembranous dense deposits (CIMDD) in some capillary loops of at least one of the series of the repeated biopsies from each patient. With light microscopy, six patients showed membranoproliferative glomerulonephritis (MPGN). The other four patients showed diffuse proliferative glomerulonephritis (DPGN) with acute lesions showing intraglomerular neutrophilic infiltration, hump formation and endothelial swelling in three and minor glomerular abnormalities in one. Follow-up biopsies were obtained in six patients. Two patients progressed from DPGN to MPGN within 7 months, whereas three patients with MPGN showed morphologic improvement that featured increased capillary patency and regional disappearance of dense deposits along with the reduction of proteinuria. Dense deposit disease did not always feature typical amorphous and osmiophilic CIMDD spreading across the whole width of the lamina densa. This classical ultrastructural manifestation was mainly found in the patients with histologic non-MPGN and a linear peripheral pattern of complement component (C3) deposition. The MPGN patients with a granular peripheral pattern of C3 deposition also had CIMDD, but also additionally featured less dense subepithelial deposits superimposed on the CIMDD to produce an appearance simulating membranous transformation.
Mathew TH: Recurrence of disease following renal transplantation. 1: Am J Kidney Dis 1988 Aug;12(2):85-96. Renal Unit, Queen Elizabeth Hospital, Woodville South, South Australia. The diagnosis of recurrent renal disease after transplantation is dependent on an accurate and complete diagnosis of the initial cause of renal failure and a similar determination of the cause of graft failure. To be classified as recurrent, the disease in the renal graft must be identical to that seen in the native kidneys. Recurrence of disease accounts for less than 2% of all graft failures, but the overall incidence of recurrent disease is probably 5 to 10 times more common. The most frequent cause of recurrent disease is glomerulonephritis, which was first recognized to recur soon after renal transplantation was introduced. It was then recognized that a variety of metabolic disorders would recur, but it has taken 25 years of experience for a clear picture to emerge of recurrence in most conditions. No initial cause of renal failure poses a contraindication to at least one attempt at transplantation, although with Fabry's disease and oxalosis, a special assessment of the risks for the individual recipient is warranted. In some patients, experience has shown the need for a delay in the commitment to transplantation (eg, in those with anti-glomerular basement membrane [GBM] antibody glomerulonephritis or Henoch Schonlein purpura), the need for the choice of a particular immunosuppressive regimen (eg, in hemolytic uremic syndrome [HUS]), the need for avoidance of primary nonfunction (eg, in oxalosis), and the desirability of avoiding live kidney donation (eg, in heterozygote donors in Fabry's disease, high-risk recipients with focal glomerulosclerosis, and in recipients with HUS). Probably all types of glomerulonephritis recur, but with great variation in frequency and severity. In some forms of glomerulonephritis, recurrence may be frequent and definite on histopathological criteria but may only have a minor clinical expression (eg, dense deposit disease, anti-GBM antibody glomerulonephritis, IgA nephropathy), but in others, recurrence is less predictable yet it is clearly associated with premature graft failure (eg, focal glomerulosclerosis, membranous nephropathy). A common theme emerging is that where the initial glomerulonephritis is aggressive and causes kidney failure over a short time, recurrence is more likely, and when present, it will lead to graft failure with an increased frequency. Clinical manifestations, the frequency of recurrence, and the prognosis of the graft are now identified for most conditions. Unexpected observations have included the rarity of recurrent systemic lupus erythematosus (SLE), the immediate return of heavy proteinuria in focal glomerulosclerosis, and the predictable return of dense deposit disease.
The Southwest Pediatric Nephrology Study Group. Dense deposit disease in children: prognostic value of clinical and pathologic indicators. Am J Kidney Dis 1985 Sep;6(3):161-9.. Clinical and pathological features were examined in 16 children with dense deposit disease. The children ranged in age from 5 to 15 years (mean: 9.3 years). There were nine boys and seven girls. Semiquantitative grading of renal biopsy findings was performed in these patients and compared to clinical features at the time of presentation, and at the time of latest follow-up. Initial clinical features included hypertension and decreased glomerular filtration rate in 50% of patients, nephrotic syndrome in 69%, and gross hematuria in 73%. Serum C3 concentrations were low in nine of nine patients. All but one of the patients subsequently received steroid therapy, the dosage of which varied. Of the 16 patients, six developed progressive renal insufficiency, six have normal renal function after a period of 7 to 12 years, and four have normal renal function but have been followed for less than 6 years. When these different subgroups were compared, clinical and laboratory features were not helpful outcome indicators. By contrast, poor outcome was correlated with the following pathologic features: excessive prominence of glomerular lobules, severe mesangial hypercellularity and sclerosis, severe glomerular loop obliteration, and mesangial electron dense deposit alteration. We conclude that the course of dense deposit disease is variable and that certain pathologic features may be helpful in predicting clinical outcome. Whether alternate-day prednisone therapy may have been of benefit for the patients in this study is uncertain.