- Email: [email protected]
Ratio of donor kidney weight to recipient bodyweight as an index of graft function
RESEARCH LETTERS
The pathogenesis of chronic graft dysfunction cannot be explained solely by antigen-dependent mechanisms.1 The Transplant Registry lists several antigen-independent risk factors for chronic graft dysfunction or rejection: elderly donors or recipients; female donors; long preservation; African-American donors or recipients; high recipient body-mass index; a child recipient; and recipient hypertension.2 Reduced donor kidney mass due to any cause resulting in failure to meet the metabolic demands of the recipient, could be an important determinant of chronic graft failure.3,4 Mechanisms for the effect of most non-immunological factors on long-term graft survival are partly explained by the underlying effects of donor nephron mass on recipients. To assess the effect of renal mass we should look at body surface area, bodyweight, body-mass index, donor kidney volume, or donor kidney weight. However, data vary and are inconclusive because most studies were not controlled for the effects of preservation, acute rejection, or graft glomerulonephritis. Furthermore, most investigators probably used calculated kidney weight rather than directly measured weight as an index.4 We restricted the study cohort to live donor transplants that had neither preservation injury, nor acute rejection in the first year after transplantation, nor biopsy-proven glomerulonephritis during follow-up. We weighed the kidney after cold flush, calculated the ratio between the donor kidney weight (g) and recipient bodyweight (kg), and assessed the effect of this ratio on graft function in the first 3 years after transplantation. We identified and followed up 82 adult recipients for at least 36 months. Patients were routinely prescribed ciclosporin and steroids. 59 patients received donor kidneys from relatives, and all grafts functioned immediately. All patients survived and there was no graft loss. As indices of graft function, serum creatinine, 24 h creatinine clearance rate, and 24 h urinary excretion of protein were measured yearly after transplantation. We noted transplant history, age, sex, relationship, degree of HLA matching, and ABO blood group compatibility of the donor and recipient. We used a mixed-model regression analysis, including the intercept for a random effect, to assess the relation between the index value of the kidney weight, the bodyweight ratio and every renal value. SAS (version 6.12) was used for these analyses. No patients had pretransplant diabetes or diabetic nephropathy. Mean age of recipients and donors was 35·9 years (SD 9·3) and 38·1 years (11·1), respectively. 60 (73%) recipients and 50 (61%) donors were men. Four recipients and 15 donors were aged older than 50 years at transplantation. The mean donor kidney weight to
1180
Serum creatinine (mol/L)
Reduced renal mass or mismatching kidney size are risk factors for chronic allograft nephropathy. We assessed the effect of mismatching donor kidney weight and recipient bodyweight on renal graft function in 82 live donor kidney transplant recipients who did not have acute rejection. We calculated the donor kidney weight to recipient bodyweight ratio, and established the relation between this ratio and renal indices with a mixed model regression. We showed that recipients with a high ratio had better graft function.
300
Year 1 Year 2 Year 3
250 200 150 100 50 0 2
3
4
5
6
7
B 160 Creatinine clearance (mL/min/BSA)
Yu Seun Kim, Jang Il Moon, Dong Kee Kim, Soon Il Kim, Kiil Park
A
140 120 100 80 60 40
Year 1 Year 2 Year 3
20 0 2
3
4
5
6
7
C 4·0 3·0 2·0
Log urinary protein (g/day)
Ratio of donor kidney weight to recipient bodyweight as an index of graft function
Year 1 Year 2 Year 3
1·0 0·5 0·4 0·3 0·2 0·1 0·05 0·04 0·03 0·02 0·01
2
3 4 5 6 Kidney weight to body weight ratio (g/kg)
7
Mixed model regression analyses of kidney weight, recipient bodyweight ratio, and serum creatinine (A), creatinine clearance (B), and 24h urinary protein (C).
recipient bodyweight ratio was 3·86 (0·78, range 2·23–6·24). 24 h urinary protein (except in the first year after transplantation), serum creatinine, and creatinine clearance rate correlated with the ratio every year, which showed that graft function was affected by this ratio (figure). Recipients with a high ratio had improvements in graft function every year. These correlations were
THE LANCET • Vol 357 • April 14, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Variables
Coefficient
SE
p value
Regression line in first year Regression line in second year Regression line in third year Sex Age ABO blood group compatibility Degree of HLA match Types of donor Bodyweight of the recipients
13·456 15·624 16·033 8·49 0·03 ⫺1·26 ⫺1·87 ⫺3·59 ⫺0·18
3·756 3·756 3·762 5·92 0·26 6·26 1·72 6·16 0·36
0·0005 0·0001 0·0001 0·1532 0·9147 0·8404 0·2800 0·5608 0·6285
Intercept for each year was used for a random effect. KW/BW=kidney weight of donor to bodyweight of the patients in g/kg.
Mixed model regression analysis for creatinine clearance rate
also seen for other variables (table). Sex, age, and bodyweight of the recipients, and blood group compatibility, degree of HLA match, and relationship between recipient and donor were judged as having a small effect on creatinine clearance. However, the donor kidney weight to bodyweight ratio strongly affected creatinine clearance in the first year after transplantation (p=0·0005). The regression coefficients of the ratio for creatinine clearance rate increased every year. The effect of the ratio on creatinine clearance was larger than its effect on serum creatinine and urinary protein (data not shown). A reduction in functioning renal mass, initially or after transplantation, might place recipients at risk of progressive hyperfiltration. However, this hypothesis has been difficult to prove, and the role of hyperfiltration is controversial, since a method for measuring the number of functioning nephrons has not been developed, and there might be a substantial variability in nephron number across otherwise healthy populations.3,5 Although donor kidney weight seems to be the best surrogate index for nephron number, routine weighing of donor kidneys at time of transplantation is not normal practice.4 However, since late 1994 we have recorded donor kidney weight and measured kidney weight to bodyweight ratio. This ratio has proved to have a strong correlation with graft function in the first 3 years after transplantation in recipients without acute rejection. Our findings provide direct evidence of the substantial effect of initial nephron mass on graft function. During donor and recipient matching, both the potential sizes of the donor kidney and the recipient should be considered in terms of graft function, until we develop a method to measure renal parenchymal volume more accurately . This study was supported by the BK 21 Project for Medical Science, Yonsei University, and in part by a grant-in-aid from Roche Korea. 1 2
3
4
5
Velosa JA. Strategies to prolong long-term renal allograft function. Transplant Rev 1998; 12: 1–13. Chertow GM, Brenner BM, Mackenzie HS, Milford EL. Nonimmunologic predictors of chronic renal allograft failure: data from the United Network of Organ Sharing. Kidney Int 1995; 48 (suppl 52): S48–51. Brenner BM, Milford EL. Nephron underdosing: a programmed cause of chronic renal allograft failure. Am J Kidney Dis 1993; 21 (suppl 2): 66–72. Taal MW, Tilney NL, Brenner BM, Makenzie HS. Renal mass: an important determinant of late allograft outcome. Transplant Rev 1998; 12: 74–84. Kasiske BL. Clinical correlates to chronic renal allograft rejection. Kidney Int 1997; 52 (suppl 63): S71–74.
Departments of Surgery (Y S Kim MD, J I Moon MD, S I Kim MD, K Park MD) and Biostatistics (D K Kim PhD), Yonsei University College of Medicine, Seoul 120-752, Korea Correspondence to: Dr Yu Seun Kim (e-mail: [email protected])
THE LANCET • Vol 357 • April 14, 2001
Germline SDHD mutation in familial phaeochromocytoma Dewi Astuti, Fiona Douglas, Thomas W J Lennard, Irene A Aligianis, Emma R Woodward, D Gareth R Evans, Charis Eng, Farida Latif, Eamonn R Maher The genetic basis for familial phaeochromocytoma is unknown in many cases. Since the disorder has been reported in some cases of familial head and neck paraganglioma, which is caused by a mutation in the gene encoding succinate dehydrogenase complex subunit D (SDHD), we investigated this gene in kindreds with familial phaeochromocytoma. A germline SDHD frameshift mutation was identified in a two-generation family consisting of four children with phaeochromocytoma, but somatic mutations were not detected in 24 sporadic phaeochromocytoma tumours. Germline SDHD mutation analysis should be done in individuals with familial, multiple, or earlyonset phaeochromocytomas even if a personal or family history of head and neck paraganglioma is absent.
Phaeochromocytoma is a chromaffin-staining catecholamineproducing tumour which usually arises within the adrenal medulla. About 10% are extra-adrenal, 10% are malignant, and 10% are familial. Phaeochromocytoma is a feature of dominantly inherited familial cancer syndromes such as von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2, and neurofibromatosis type 1. Familial phaeochromocytoma without evidence of these syndromes also occurs, and up to 50% of affected families have germline mutations in the VHL gene. Extra-adrenal phaeochromocytomas are sometimes referred to as paragangliomas, although the catecholamine-secreting phaeochromocytomas are distinct from the non-chromaffin tumours seen in paraganglioma. Hereditary paraganglioma is characterised by the development of benign vascularised tumours of the head and neck, most commonly in the carotid body,1 and is associated with a mutation in the gene encoding succinate dehydrogenase complex subunit D (SDHD). Occasional reports of patients with isolated or familial phaeochromocytoma as well as carotid-body tumours suggested a possible aetiological link.2,3 We therefore investigated SDHD as a candidate phaeochromocytoma gene. We studied four kindreds with familial phaeochromocytoma. All probands had tested negative for germline mutations in VHL and the RET (REarranged in Transfection) proto-oncogene, which is expressed in tumours of neural-crest origin.4 Single-stranded conformational polymorphism analysis was done with published primers and conditions.1 An aberrant band-shift was identified in an exon 2 amplicon in the proband from family 330, and was also detected in three relatives (two affected and one obligate carrier; figures 1 and 2). Sequencing of the exon 2 fragment in the three affected individuals revealed a 2 bp frameshift deletion at nucleotides 6799–6800, which was predicted to produce a truncated protein of 66 aminoacids (compared with 159 in the wild-type protein). The truncated protein lacked the transmembrane, signal, and haem-binding domains. This mutation was not present in the unaffected parents, an at-risk sibling, nor more than 80 normal control chromosomes. Tumour studies in inherited paraganglioma show loss of the wild-type allele, which is consistent with SDHD functioning as a tumour-suppressor gene with two events required for inactivation. Although tumour tissue from kindred 330 was not available for analysis, we investigated the hypothesis that somatic mutations of SDHD might be implicated in the pathogenesis of sporadic phaeochromocytoma. However, SDHD mutations were not detected in 24
1181
For personal use. Only reproduce with permission from The Lancet Publishing Group.
The pathogenesis of chronic graft dysfunction cannot be explained solely by antigen-dependent mechanisms.1 The Transplant Registry lists several antigen-independent risk factors for chronic graft dysfunction or rejection: elderly donors or recipients; female donors; long preservation; African-American donors or recipients; high recipient body-mass index; a child recipient; and recipient hypertension.2 Reduced donor kidney mass due to any cause resulting in failure to meet the metabolic demands of the recipient, could be an important determinant of chronic graft failure.3,4 Mechanisms for the effect of most non-immunological factors on long-term graft survival are partly explained by the underlying effects of donor nephron mass on recipients. To assess the effect of renal mass we should look at body surface area, bodyweight, body-mass index, donor kidney volume, or donor kidney weight. However, data vary and are inconclusive because most studies were not controlled for the effects of preservation, acute rejection, or graft glomerulonephritis. Furthermore, most investigators probably used calculated kidney weight rather than directly measured weight as an index.4 We restricted the study cohort to live donor transplants that had neither preservation injury, nor acute rejection in the first year after transplantation, nor biopsy-proven glomerulonephritis during follow-up. We weighed the kidney after cold flush, calculated the ratio between the donor kidney weight (g) and recipient bodyweight (kg), and assessed the effect of this ratio on graft function in the first 3 years after transplantation. We identified and followed up 82 adult recipients for at least 36 months. Patients were routinely prescribed ciclosporin and steroids. 59 patients received donor kidneys from relatives, and all grafts functioned immediately. All patients survived and there was no graft loss. As indices of graft function, serum creatinine, 24 h creatinine clearance rate, and 24 h urinary excretion of protein were measured yearly after transplantation. We noted transplant history, age, sex, relationship, degree of HLA matching, and ABO blood group compatibility of the donor and recipient. We used a mixed-model regression analysis, including the intercept for a random effect, to assess the relation between the index value of the kidney weight, the bodyweight ratio and every renal value. SAS (version 6.12) was used for these analyses. No patients had pretransplant diabetes or diabetic nephropathy. Mean age of recipients and donors was 35·9 years (SD 9·3) and 38·1 years (11·1), respectively. 60 (73%) recipients and 50 (61%) donors were men. Four recipients and 15 donors were aged older than 50 years at transplantation. The mean donor kidney weight to
1180
Serum creatinine (mol/L)
Reduced renal mass or mismatching kidney size are risk factors for chronic allograft nephropathy. We assessed the effect of mismatching donor kidney weight and recipient bodyweight on renal graft function in 82 live donor kidney transplant recipients who did not have acute rejection. We calculated the donor kidney weight to recipient bodyweight ratio, and established the relation between this ratio and renal indices with a mixed model regression. We showed that recipients with a high ratio had better graft function.
300
Year 1 Year 2 Year 3
250 200 150 100 50 0 2
3
4
5
6
7
B 160 Creatinine clearance (mL/min/BSA)
Yu Seun Kim, Jang Il Moon, Dong Kee Kim, Soon Il Kim, Kiil Park
A
140 120 100 80 60 40
Year 1 Year 2 Year 3
20 0 2
3
4
5
6
7
C 4·0 3·0 2·0
Log urinary protein (g/day)
Ratio of donor kidney weight to recipient bodyweight as an index of graft function
Year 1 Year 2 Year 3
1·0 0·5 0·4 0·3 0·2 0·1 0·05 0·04 0·03 0·02 0·01
2
3 4 5 6 Kidney weight to body weight ratio (g/kg)
7
Mixed model regression analyses of kidney weight, recipient bodyweight ratio, and serum creatinine (A), creatinine clearance (B), and 24h urinary protein (C).
recipient bodyweight ratio was 3·86 (0·78, range 2·23–6·24). 24 h urinary protein (except in the first year after transplantation), serum creatinine, and creatinine clearance rate correlated with the ratio every year, which showed that graft function was affected by this ratio (figure). Recipients with a high ratio had improvements in graft function every year. These correlations were
THE LANCET • Vol 357 • April 14, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Variables
Coefficient
SE
p value
Regression line in first year Regression line in second year Regression line in third year Sex Age ABO blood group compatibility Degree of HLA match Types of donor Bodyweight of the recipients
13·456 15·624 16·033 8·49 0·03 ⫺1·26 ⫺1·87 ⫺3·59 ⫺0·18
3·756 3·756 3·762 5·92 0·26 6·26 1·72 6·16 0·36
0·0005 0·0001 0·0001 0·1532 0·9147 0·8404 0·2800 0·5608 0·6285
Intercept for each year was used for a random effect. KW/BW=kidney weight of donor to bodyweight of the patients in g/kg.
Mixed model regression analysis for creatinine clearance rate
also seen for other variables (table). Sex, age, and bodyweight of the recipients, and blood group compatibility, degree of HLA match, and relationship between recipient and donor were judged as having a small effect on creatinine clearance. However, the donor kidney weight to bodyweight ratio strongly affected creatinine clearance in the first year after transplantation (p=0·0005). The regression coefficients of the ratio for creatinine clearance rate increased every year. The effect of the ratio on creatinine clearance was larger than its effect on serum creatinine and urinary protein (data not shown). A reduction in functioning renal mass, initially or after transplantation, might place recipients at risk of progressive hyperfiltration. However, this hypothesis has been difficult to prove, and the role of hyperfiltration is controversial, since a method for measuring the number of functioning nephrons has not been developed, and there might be a substantial variability in nephron number across otherwise healthy populations.3,5 Although donor kidney weight seems to be the best surrogate index for nephron number, routine weighing of donor kidneys at time of transplantation is not normal practice.4 However, since late 1994 we have recorded donor kidney weight and measured kidney weight to bodyweight ratio. This ratio has proved to have a strong correlation with graft function in the first 3 years after transplantation in recipients without acute rejection. Our findings provide direct evidence of the substantial effect of initial nephron mass on graft function. During donor and recipient matching, both the potential sizes of the donor kidney and the recipient should be considered in terms of graft function, until we develop a method to measure renal parenchymal volume more accurately . This study was supported by the BK 21 Project for Medical Science, Yonsei University, and in part by a grant-in-aid from Roche Korea. 1 2
3
4
5
Velosa JA. Strategies to prolong long-term renal allograft function. Transplant Rev 1998; 12: 1–13. Chertow GM, Brenner BM, Mackenzie HS, Milford EL. Nonimmunologic predictors of chronic renal allograft failure: data from the United Network of Organ Sharing. Kidney Int 1995; 48 (suppl 52): S48–51. Brenner BM, Milford EL. Nephron underdosing: a programmed cause of chronic renal allograft failure. Am J Kidney Dis 1993; 21 (suppl 2): 66–72. Taal MW, Tilney NL, Brenner BM, Makenzie HS. Renal mass: an important determinant of late allograft outcome. Transplant Rev 1998; 12: 74–84. Kasiske BL. Clinical correlates to chronic renal allograft rejection. Kidney Int 1997; 52 (suppl 63): S71–74.
Departments of Surgery (Y S Kim MD, J I Moon MD, S I Kim MD, K Park MD) and Biostatistics (D K Kim PhD), Yonsei University College of Medicine, Seoul 120-752, Korea Correspondence to: Dr Yu Seun Kim (e-mail: [email protected])
THE LANCET • Vol 357 • April 14, 2001
Germline SDHD mutation in familial phaeochromocytoma Dewi Astuti, Fiona Douglas, Thomas W J Lennard, Irene A Aligianis, Emma R Woodward, D Gareth R Evans, Charis Eng, Farida Latif, Eamonn R Maher The genetic basis for familial phaeochromocytoma is unknown in many cases. Since the disorder has been reported in some cases of familial head and neck paraganglioma, which is caused by a mutation in the gene encoding succinate dehydrogenase complex subunit D (SDHD), we investigated this gene in kindreds with familial phaeochromocytoma. A germline SDHD frameshift mutation was identified in a two-generation family consisting of four children with phaeochromocytoma, but somatic mutations were not detected in 24 sporadic phaeochromocytoma tumours. Germline SDHD mutation analysis should be done in individuals with familial, multiple, or earlyonset phaeochromocytomas even if a personal or family history of head and neck paraganglioma is absent.
Phaeochromocytoma is a chromaffin-staining catecholamineproducing tumour which usually arises within the adrenal medulla. About 10% are extra-adrenal, 10% are malignant, and 10% are familial. Phaeochromocytoma is a feature of dominantly inherited familial cancer syndromes such as von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2, and neurofibromatosis type 1. Familial phaeochromocytoma without evidence of these syndromes also occurs, and up to 50% of affected families have germline mutations in the VHL gene. Extra-adrenal phaeochromocytomas are sometimes referred to as paragangliomas, although the catecholamine-secreting phaeochromocytomas are distinct from the non-chromaffin tumours seen in paraganglioma. Hereditary paraganglioma is characterised by the development of benign vascularised tumours of the head and neck, most commonly in the carotid body,1 and is associated with a mutation in the gene encoding succinate dehydrogenase complex subunit D (SDHD). Occasional reports of patients with isolated or familial phaeochromocytoma as well as carotid-body tumours suggested a possible aetiological link.2,3 We therefore investigated SDHD as a candidate phaeochromocytoma gene. We studied four kindreds with familial phaeochromocytoma. All probands had tested negative for germline mutations in VHL and the RET (REarranged in Transfection) proto-oncogene, which is expressed in tumours of neural-crest origin.4 Single-stranded conformational polymorphism analysis was done with published primers and conditions.1 An aberrant band-shift was identified in an exon 2 amplicon in the proband from family 330, and was also detected in three relatives (two affected and one obligate carrier; figures 1 and 2). Sequencing of the exon 2 fragment in the three affected individuals revealed a 2 bp frameshift deletion at nucleotides 6799–6800, which was predicted to produce a truncated protein of 66 aminoacids (compared with 159 in the wild-type protein). The truncated protein lacked the transmembrane, signal, and haem-binding domains. This mutation was not present in the unaffected parents, an at-risk sibling, nor more than 80 normal control chromosomes. Tumour studies in inherited paraganglioma show loss of the wild-type allele, which is consistent with SDHD functioning as a tumour-suppressor gene with two events required for inactivation. Although tumour tissue from kindred 330 was not available for analysis, we investigated the hypothesis that somatic mutations of SDHD might be implicated in the pathogenesis of sporadic phaeochromocytoma. However, SDHD mutations were not detected in 24
1181
For personal use. Only reproduce with permission from The Lancet Publishing Group.