- Email: [email protected]
Toward quantitating the burden of glomerulonephritis in the United States
commentary
8. Rutherford E, Talle MA, Mangion K, et al. Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping. Kidney Int. 2016;90:845–852.
9. Graham-Brown MPM, March DS, Churchward DR, et al. Novel cardiac nuclear magnetic resonance method for noninvasive assessment of myocardial fibrosis in hemodialysis patients. Kidney Int. 2016;90:835–844.
Toward quantitating the burden of glomerulonephritis in the United States Daniel C. Cattran1 Previous data attempting to quantitate the national burden of glomerulonephritis (GN) have been derived from regional biopsy series or end-stage renal disease registries. Wetmore et al. is the first to address this question based on claims data extracted from 2 large U.S. health care systems. Although there are limitations, it provides broad-based epidemiological data that demonstrate a significant underestimate of the extent of GN disease and provide an important first step in its quantitation. Kidney International (2016) 90, 732–734; http://dx.doi.org/10.1016/j.kint.2016.06.004 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 853
G
lomerulonephritis (GN) remains among the most commonly recognized causes of end-stage renal disease (ESRD), but its overall incidence and prevalent rates and numbers within each specific histologic category remains largely unknown. Available data has been derived from regional biopsy series or ESRD registries and has not had a broad-based epidemiological perspective.1 Although chronic kidney disease has been defined as an epidemic, it contains many widely divergent diseases.2 GN is among them with welldescribed histologic subtypes, each with their own presentations, outcomes, management strategies, and specific therapies.3 There are 2 underappreciated and underestimated
1 Department of Medicine, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
Correspondence: DC Cattran, Suite 8N184, 585 University Avenue, Toronto, Ontario M5G2N2, Canada. E-mail: [email protected] 732
elements to GN. The first is that histologic variants can be successfully treated and the disease stabilized and, in some cases, reversed even after renal impairment is present.4 The second is the extremely high numbers and cost of renal replacement therapy that at least in part stems from our inability to identify and treat the primary causes of renal failure. Current U.S. Medicaid expenditures for renal replacement therapy are estimated at $29 billion per year.2 Although the precise dollars attributable to the GN population is unknown, its prevalence rate of 20% to 30% of the renal replacement therapy population would put the annual cost of managing ESRD GN patients in the billions. None of the available figures accounts for the additional burden to the system and to the individual from the high unemployment rates during their GN disease course, the draw on social assistance/disability insurance, and the enormous burden to the patient and their family’s quality of life, nor does it include the known marked
increase of cardiovascular events in this population.5 Given this data, and knowing the long natural history of most GNs combined with the knowledge of available and effective therapies, it seems remarkable that we have no accurate data on incidence/prevalence rates except those found in biopsy series and ESRD registries. Wetmore et al.6 (2016) addresses this question in the United States based on claims data from 2 large, >18-millionpatients, health-care-administrative datasets including a Medicare sample and a private indemnity Optum Clinformatics Employer Group Health Plan. Wetmore et al.6 calculated the incidence and prevalence rates based on an algorithm that identified claim codes that indicated a diagnosis of GN with the added requirement of codes supporting clinical evidence of kidney disease such as hematuria and proteinuria. To identify secondary GN, the investigators required additional claim codes that indicated an associated systemic disease process over a period from 2008 to 2011. In the Medicaid cohort, which was composed of patients >65 years old, they found an incidence rate of primary GN per 1000 patient-years of 57 and a secondary GN rate of 134, and in the private health care plan, the numbers per 1000 patient-years of 20 and 10, respectively. They also found a period prevalence rate per 100,000 population of the combined primary and secondary GNs in the Medicaid cohort of 1223 and in the private health care cohort of 123. The National Institutes of Health defines an orphan disease as one with a prevalence rate of under 200,000 in the United States,2 and GNs are included in this category. In their article,6 the combined primary and secondary GN rate vastly exceeds this number in the Medicaid population with >1200 patients per 100,000 (and although lower in the younger aged private health care plan still significant at 30 per 100,000 population), suggesting there are tens of thousands of patients in the United States with GN. Wetmore et al.6 found Kidney International (2016) 90, 724–739
commentary
the ESRD rate, perhaps not surprisingly, is an order or 2 of magnitude greater than their non-GN population, and its frequency more common in primary than secondary GN. They speculated this could be because of more aggressive (and successful) treatment of the systemic disorders associated with secondary GN versus the more indolent course and therefore conservative therapeutic approach to primary GN. More surprising was that the mortality rate was 3.9-fold higher in the secondary and 2.7-fold higher in the primary GN compared with the rest of their Medicaid population. This increased mortality rate in the secondary versus primary GN may explain some of the reverse findings in the ESRD rates. Although the investigators rightfully claim this is the first large-scale U.S. population database to report this GN mortality risk, others have reported similar higher than standard incident rates for both death and ESRD in a well-defined chronic kidney disease population–based European community that included GN patients.7 The investigators also found differences in outcomes in GN patients of different ethnicities, the white population did better than the black, and in sex, with female patients doing better than male patients. Although of interest, this data is not radically different from what has been previously documented. The accuracy of the data extraction is somewhat challenged by the dramatic differences noted in rates based on age. Wetmore et al.6 found overall a 10 times greater rate of GN in their Medicare cohort compared with their private health care cohort. They speculate this might be due to the older age of onset of primary GNs compared with what earlier GN publications reported, and they support this contention by referring to data on systemic lupus erythematosus that indicates the disease is twice as common in patients over the age of 50 years than in those <30 years. Although this interpretation may be correct, it might also be that patients are living longer with these conditions, are largely asymptomatic, and perhaps are presenting to a physician later in the Kidney International (2016) 90, 724–739
disease course. The investigators comment that their methodological approach, used to determine incidence/ prevalence rates, may substantially overestimate the GN frequency, and it certainly does when compared with GN biopsy series. But we know that many GN cases are not biopsied, including potentially a substantial percentage of ESRD patients labeled “hypertensive nephrosclerosis,” supporting the notion that the real incidence/prevalence rates of GN are somewhere between these 2 extremes.1 There are additional limitations worth emphasizing. The data Wetmore et al.6 uses are not extracted from medical records, and specific renal histology cannot be determined by this method. In the International Classification of Diseases (ICD)-9 coding scheme (which will be improved substantially by the ICD-10 coding system initiated in October 2015), several GN-specific histologic types do not even have a claim code including the world’s most common variant, IgA nephropathy. This obviously is a major limitation and prevents accurate histologic-specific incidence/prevalence rates. An additional important issue raised by the investigators is the increased hospitalization frequency of GN patients. Although this may in part relate to the biopsy procedures or its complications, these alone are insufficient to explain the marked difference versus non-GN patients. However, there are many additional possibilities including that many histologic variants of GNs can be directly linked to cancer and the hospitalization frequency may in part be related to its management. This occurs, for instance in up to 25% of cases of membranous nephropathy, the most common cause of adult nephrotic syndrome. In addition, the incidence of late onset cancers is substantially higher than the standard incident ratio, which likely is a result of exposure to potent immunosuppressive therapy.8 None of these issues can be sorted out based on claims data. Lastly, it must be recalled that this methodology for identification and selection of their cohort relates to databases that identify issues by specific
U.S. claims code, preventing or at least potentially limiting the generalizability of their data to countries other than the United States. Regardless of these limitations, Wetmore et al.6 clearly identify a gap in our knowledge base related to the incidence/prevalence GN numbers in the United States. There has been a recent marked increase of interest in GN as illustrated by an ongoing major National Institute of Diabetes and Digestive and Kidney Diseasessponsored consortium that is targeting the identification and documentation of the natural history, as well as studying the underlying pathobiology of the common progressive GN types.9 Ultimately aiming to move GN from the classic histopathology classification to a molecular-based taxonomy. What is equally critical, as identified by Wetmore et al.,6 is a more precise estimate of the GN population. Making GN a reportable disorder and mandating a countrywide requirement for all biopsy-proven cases to be registered is feasible and should be seriously considered. This has been done in other countries and is a wellestablished process in cancer epidemiology.10 This article is timely and has identified clearly this knowledge gap in rates of GN in the United States. It should focus us on not only identifying the depth and breadth of GN but on establishing a tracking mechanism for these conditions so that advances that are being made in the basic underlying mechanisms and new treatment strategies can be rapidly translated into improved patient care. DISCLOSURE
The author declared no competing interest.
REFERENCES 1. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transpl. 2011;26:414– 430. http://dx.doi.org/10.1093/ndt/gfq665. 2. Collins AJ, Foley RN, Chavers B, et al. United States Renal Data System 2011 Annual Data Report: atlas of chronic kidney disease and end-stage renal disease in the United States. Am J Kidney Dis. 2011;59(suppl 1):A7, e1–e420. http://dx.doi.org/10.1053/j.ajkd. 2011.11.015.
733
commentary
3. Sethi S, Haas M, Markowitz GS, et al. Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN. J Am Soc Nephrol. 2016;27:1278–1287. 4. Kidney Disease Improving Global Outcomes. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2: 139–274. 5. Lee T, Derebail VK, Kshirsagar AV, et al. Patients with primary membranous nephropathy are at high risk of cardiovascular events. Kidney Int. 2016;89: 1111–1118. 6. Wetmore JB, Guo H, Liu J, et al. The incidence, prevalence, and outcomes of glomerulonephritis derived from a large retrospective analysis. Kidney Int. 2016;90: 853–860.
7. Eriksen BO, Ingebretsen OC. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. Kidney Int. 2006;69:375–382. 8. van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF. Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2014;9: 1066–1073. 9. Gadegbeku CA, Gipson DS, Holzman LB, et al. Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int. 2013;83:749–756. 10. Barbour S, Beaulieu M, Gill J, et al. An overview of the British Columbia Glomerulonephritis network and registry: integrating knowledge generation and translation within a single framework. BMC Nephrol. 2013;14:236.
Mineral metabolism disturbances in kidney donors: smoke, no fire (yet) Pieter Evenepoel1 and Maarten Naesens1 Kasiske and colleagues studied mineral and bone metabolism after unilateral donor nephrectomy. Similar as to what is observed early in the course of chronic kidney disease, fibroblast growth factor 23 and parathyroid hormone concentrations were shown to be increased following kidney donation. High fibroblast growth factor 23 and parathyroid hormone concentrations most probably are a compensatory mechanism to maintain normophosphatemia. Bone biomarker profiles in the study suggest increased bone turnover as trade-off. Limitations inherent to the assessed biomarkers, however, warrant a prudent interpretation. Kidney International (2016) 90, 734–736; http://dx.doi.org/10.1016/j.kint.2016.07.001 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 861
F
rom a recipient perspective, living donor kidney transplantation is the preferred treatment for endstage renal disease, because it is associated with improved graft and patient survival compared with transplantation from a deceased donor. Living kidney
1 KU Leuven, Department of Immunology and Microbiology, Laboratory of Nephrology, B-3000 Leuven, Belgium
Correspondence: P. Evenepoel, Department of Nephrology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] 734
donation, however, relies on the altruism of kidney donors, who voluntarily undergo major surgery with no personal physical health benefit. Kidney donation inevitably leads to a reduction in nephron mass, which translates to a significantly increased risk of end-stage renal failure, as was illustrated in several recent epidemiological studies.1 The magnitude of the relative risk, however, shows important variation, likely reflecting differences in the background characteristics of the control population. Importantly, the increased relative
risk in kidney donors compared with matched controls must be interpreted against the limited increase in absolute risk.1 The metabolic and endocrine consequences of decreased renal function after living kidney donation have been studied only scarcely, and the few studies that are available were hampered by their small size and inadequate design. In the current issue of Kidney International, Kasiske et al. (2016) report on changes in mineral and bone metabolism in kidney donors up to 3 years after donation.2 The data were obtained through the Assessing Long Term Outcomes in Living Kidney Donors (ALTOLD) study, which is a prospective, controlled study of living kidney donors and paired controls, investigating the medical consequences of live kidney donation. Understanding the effects of kidney donation on mineral and bone metabolism is important, not only to ensure the safety of kidney donation, but also to elucidate the effect of the loss of renal function on bone and mineral metabolism in the absence of confounding factors usually found in chronic kidney disease, such as associated glomerular or tubular disease. In agreement with previous studies, the authors observed a significantly higher fractional excretion of phosphate in kidney donors than in controls. This phosphate wasting was attributed to elevated concentrations of the phosphaturic hormones parathyroid hormone and fibroblast growth factor 23. Previous studies investigating parathyroid hormone and fibroblast growth factor 23 concentrations in kidney donors yielded inconsistent findings, with some investigators reporting increased and others reporting unaltered concentrations. Thus, direct tubular adaptation or the involvement of another phosphaturic agent should also be considered as factors contributing to post-donation phosphate wasting. Particularly Klotho should be mentioned in this regard, because recent animal data demonstrate increased expression of Klotho in the remnant kidney.3 Cleaved or secreted Klotho may not only induce Kidney International (2016) 90, 724–739
8. Rutherford E, Talle MA, Mangion K, et al. Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping. Kidney Int. 2016;90:845–852.
9. Graham-Brown MPM, March DS, Churchward DR, et al. Novel cardiac nuclear magnetic resonance method for noninvasive assessment of myocardial fibrosis in hemodialysis patients. Kidney Int. 2016;90:835–844.
Toward quantitating the burden of glomerulonephritis in the United States Daniel C. Cattran1 Previous data attempting to quantitate the national burden of glomerulonephritis (GN) have been derived from regional biopsy series or end-stage renal disease registries. Wetmore et al. is the first to address this question based on claims data extracted from 2 large U.S. health care systems. Although there are limitations, it provides broad-based epidemiological data that demonstrate a significant underestimate of the extent of GN disease and provide an important first step in its quantitation. Kidney International (2016) 90, 732–734; http://dx.doi.org/10.1016/j.kint.2016.06.004 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 853
G
lomerulonephritis (GN) remains among the most commonly recognized causes of end-stage renal disease (ESRD), but its overall incidence and prevalent rates and numbers within each specific histologic category remains largely unknown. Available data has been derived from regional biopsy series or ESRD registries and has not had a broad-based epidemiological perspective.1 Although chronic kidney disease has been defined as an epidemic, it contains many widely divergent diseases.2 GN is among them with welldescribed histologic subtypes, each with their own presentations, outcomes, management strategies, and specific therapies.3 There are 2 underappreciated and underestimated
1 Department of Medicine, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
Correspondence: DC Cattran, Suite 8N184, 585 University Avenue, Toronto, Ontario M5G2N2, Canada. E-mail: [email protected] 732
elements to GN. The first is that histologic variants can be successfully treated and the disease stabilized and, in some cases, reversed even after renal impairment is present.4 The second is the extremely high numbers and cost of renal replacement therapy that at least in part stems from our inability to identify and treat the primary causes of renal failure. Current U.S. Medicaid expenditures for renal replacement therapy are estimated at $29 billion per year.2 Although the precise dollars attributable to the GN population is unknown, its prevalence rate of 20% to 30% of the renal replacement therapy population would put the annual cost of managing ESRD GN patients in the billions. None of the available figures accounts for the additional burden to the system and to the individual from the high unemployment rates during their GN disease course, the draw on social assistance/disability insurance, and the enormous burden to the patient and their family’s quality of life, nor does it include the known marked
increase of cardiovascular events in this population.5 Given this data, and knowing the long natural history of most GNs combined with the knowledge of available and effective therapies, it seems remarkable that we have no accurate data on incidence/prevalence rates except those found in biopsy series and ESRD registries. Wetmore et al.6 (2016) addresses this question in the United States based on claims data from 2 large, >18-millionpatients, health-care-administrative datasets including a Medicare sample and a private indemnity Optum Clinformatics Employer Group Health Plan. Wetmore et al.6 calculated the incidence and prevalence rates based on an algorithm that identified claim codes that indicated a diagnosis of GN with the added requirement of codes supporting clinical evidence of kidney disease such as hematuria and proteinuria. To identify secondary GN, the investigators required additional claim codes that indicated an associated systemic disease process over a period from 2008 to 2011. In the Medicaid cohort, which was composed of patients >65 years old, they found an incidence rate of primary GN per 1000 patient-years of 57 and a secondary GN rate of 134, and in the private health care plan, the numbers per 1000 patient-years of 20 and 10, respectively. They also found a period prevalence rate per 100,000 population of the combined primary and secondary GNs in the Medicaid cohort of 1223 and in the private health care cohort of 123. The National Institutes of Health defines an orphan disease as one with a prevalence rate of under 200,000 in the United States,2 and GNs are included in this category. In their article,6 the combined primary and secondary GN rate vastly exceeds this number in the Medicaid population with >1200 patients per 100,000 (and although lower in the younger aged private health care plan still significant at 30 per 100,000 population), suggesting there are tens of thousands of patients in the United States with GN. Wetmore et al.6 found Kidney International (2016) 90, 724–739
commentary
the ESRD rate, perhaps not surprisingly, is an order or 2 of magnitude greater than their non-GN population, and its frequency more common in primary than secondary GN. They speculated this could be because of more aggressive (and successful) treatment of the systemic disorders associated with secondary GN versus the more indolent course and therefore conservative therapeutic approach to primary GN. More surprising was that the mortality rate was 3.9-fold higher in the secondary and 2.7-fold higher in the primary GN compared with the rest of their Medicaid population. This increased mortality rate in the secondary versus primary GN may explain some of the reverse findings in the ESRD rates. Although the investigators rightfully claim this is the first large-scale U.S. population database to report this GN mortality risk, others have reported similar higher than standard incident rates for both death and ESRD in a well-defined chronic kidney disease population–based European community that included GN patients.7 The investigators also found differences in outcomes in GN patients of different ethnicities, the white population did better than the black, and in sex, with female patients doing better than male patients. Although of interest, this data is not radically different from what has been previously documented. The accuracy of the data extraction is somewhat challenged by the dramatic differences noted in rates based on age. Wetmore et al.6 found overall a 10 times greater rate of GN in their Medicare cohort compared with their private health care cohort. They speculate this might be due to the older age of onset of primary GNs compared with what earlier GN publications reported, and they support this contention by referring to data on systemic lupus erythematosus that indicates the disease is twice as common in patients over the age of 50 years than in those <30 years. Although this interpretation may be correct, it might also be that patients are living longer with these conditions, are largely asymptomatic, and perhaps are presenting to a physician later in the Kidney International (2016) 90, 724–739
disease course. The investigators comment that their methodological approach, used to determine incidence/ prevalence rates, may substantially overestimate the GN frequency, and it certainly does when compared with GN biopsy series. But we know that many GN cases are not biopsied, including potentially a substantial percentage of ESRD patients labeled “hypertensive nephrosclerosis,” supporting the notion that the real incidence/prevalence rates of GN are somewhere between these 2 extremes.1 There are additional limitations worth emphasizing. The data Wetmore et al.6 uses are not extracted from medical records, and specific renal histology cannot be determined by this method. In the International Classification of Diseases (ICD)-9 coding scheme (which will be improved substantially by the ICD-10 coding system initiated in October 2015), several GN-specific histologic types do not even have a claim code including the world’s most common variant, IgA nephropathy. This obviously is a major limitation and prevents accurate histologic-specific incidence/prevalence rates. An additional important issue raised by the investigators is the increased hospitalization frequency of GN patients. Although this may in part relate to the biopsy procedures or its complications, these alone are insufficient to explain the marked difference versus non-GN patients. However, there are many additional possibilities including that many histologic variants of GNs can be directly linked to cancer and the hospitalization frequency may in part be related to its management. This occurs, for instance in up to 25% of cases of membranous nephropathy, the most common cause of adult nephrotic syndrome. In addition, the incidence of late onset cancers is substantially higher than the standard incident ratio, which likely is a result of exposure to potent immunosuppressive therapy.8 None of these issues can be sorted out based on claims data. Lastly, it must be recalled that this methodology for identification and selection of their cohort relates to databases that identify issues by specific
U.S. claims code, preventing or at least potentially limiting the generalizability of their data to countries other than the United States. Regardless of these limitations, Wetmore et al.6 clearly identify a gap in our knowledge base related to the incidence/prevalence GN numbers in the United States. There has been a recent marked increase of interest in GN as illustrated by an ongoing major National Institute of Diabetes and Digestive and Kidney Diseasessponsored consortium that is targeting the identification and documentation of the natural history, as well as studying the underlying pathobiology of the common progressive GN types.9 Ultimately aiming to move GN from the classic histopathology classification to a molecular-based taxonomy. What is equally critical, as identified by Wetmore et al.,6 is a more precise estimate of the GN population. Making GN a reportable disorder and mandating a countrywide requirement for all biopsy-proven cases to be registered is feasible and should be seriously considered. This has been done in other countries and is a wellestablished process in cancer epidemiology.10 This article is timely and has identified clearly this knowledge gap in rates of GN in the United States. It should focus us on not only identifying the depth and breadth of GN but on establishing a tracking mechanism for these conditions so that advances that are being made in the basic underlying mechanisms and new treatment strategies can be rapidly translated into improved patient care. DISCLOSURE
The author declared no competing interest.
REFERENCES 1. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transpl. 2011;26:414– 430. http://dx.doi.org/10.1093/ndt/gfq665. 2. Collins AJ, Foley RN, Chavers B, et al. United States Renal Data System 2011 Annual Data Report: atlas of chronic kidney disease and end-stage renal disease in the United States. Am J Kidney Dis. 2011;59(suppl 1):A7, e1–e420. http://dx.doi.org/10.1053/j.ajkd. 2011.11.015.
733
commentary
3. Sethi S, Haas M, Markowitz GS, et al. Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN. J Am Soc Nephrol. 2016;27:1278–1287. 4. Kidney Disease Improving Global Outcomes. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2: 139–274. 5. Lee T, Derebail VK, Kshirsagar AV, et al. Patients with primary membranous nephropathy are at high risk of cardiovascular events. Kidney Int. 2016;89: 1111–1118. 6. Wetmore JB, Guo H, Liu J, et al. The incidence, prevalence, and outcomes of glomerulonephritis derived from a large retrospective analysis. Kidney Int. 2016;90: 853–860.
7. Eriksen BO, Ingebretsen OC. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age. Kidney Int. 2006;69:375–382. 8. van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF. Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2014;9: 1066–1073. 9. Gadegbeku CA, Gipson DS, Holzman LB, et al. Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int. 2013;83:749–756. 10. Barbour S, Beaulieu M, Gill J, et al. An overview of the British Columbia Glomerulonephritis network and registry: integrating knowledge generation and translation within a single framework. BMC Nephrol. 2013;14:236.
Mineral metabolism disturbances in kidney donors: smoke, no fire (yet) Pieter Evenepoel1 and Maarten Naesens1 Kasiske and colleagues studied mineral and bone metabolism after unilateral donor nephrectomy. Similar as to what is observed early in the course of chronic kidney disease, fibroblast growth factor 23 and parathyroid hormone concentrations were shown to be increased following kidney donation. High fibroblast growth factor 23 and parathyroid hormone concentrations most probably are a compensatory mechanism to maintain normophosphatemia. Bone biomarker profiles in the study suggest increased bone turnover as trade-off. Limitations inherent to the assessed biomarkers, however, warrant a prudent interpretation. Kidney International (2016) 90, 734–736; http://dx.doi.org/10.1016/j.kint.2016.07.001 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical investigation on page 861
F
rom a recipient perspective, living donor kidney transplantation is the preferred treatment for endstage renal disease, because it is associated with improved graft and patient survival compared with transplantation from a deceased donor. Living kidney
1 KU Leuven, Department of Immunology and Microbiology, Laboratory of Nephrology, B-3000 Leuven, Belgium
Correspondence: P. Evenepoel, Department of Nephrology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected] 734
donation, however, relies on the altruism of kidney donors, who voluntarily undergo major surgery with no personal physical health benefit. Kidney donation inevitably leads to a reduction in nephron mass, which translates to a significantly increased risk of end-stage renal failure, as was illustrated in several recent epidemiological studies.1 The magnitude of the relative risk, however, shows important variation, likely reflecting differences in the background characteristics of the control population. Importantly, the increased relative
risk in kidney donors compared with matched controls must be interpreted against the limited increase in absolute risk.1 The metabolic and endocrine consequences of decreased renal function after living kidney donation have been studied only scarcely, and the few studies that are available were hampered by their small size and inadequate design. In the current issue of Kidney International, Kasiske et al. (2016) report on changes in mineral and bone metabolism in kidney donors up to 3 years after donation.2 The data were obtained through the Assessing Long Term Outcomes in Living Kidney Donors (ALTOLD) study, which is a prospective, controlled study of living kidney donors and paired controls, investigating the medical consequences of live kidney donation. Understanding the effects of kidney donation on mineral and bone metabolism is important, not only to ensure the safety of kidney donation, but also to elucidate the effect of the loss of renal function on bone and mineral metabolism in the absence of confounding factors usually found in chronic kidney disease, such as associated glomerular or tubular disease. In agreement with previous studies, the authors observed a significantly higher fractional excretion of phosphate in kidney donors than in controls. This phosphate wasting was attributed to elevated concentrations of the phosphaturic hormones parathyroid hormone and fibroblast growth factor 23. Previous studies investigating parathyroid hormone and fibroblast growth factor 23 concentrations in kidney donors yielded inconsistent findings, with some investigators reporting increased and others reporting unaltered concentrations. Thus, direct tubular adaptation or the involvement of another phosphaturic agent should also be considered as factors contributing to post-donation phosphate wasting. Particularly Klotho should be mentioned in this regard, because recent animal data demonstrate increased expression of Klotho in the remnant kidney.3 Cleaved or secreted Klotho may not only induce Kidney International (2016) 90, 724–739