commentary
http://www.kidney-international.org & 2014 International Society of Nephrology
see clinical investigation on page 582
Prescriptions for dietary sodium in patients with chronic kidney disease: how will this shake out? John P. Middleton1 and Ruediger W. Lehrich1 Patients with chronic kidney disease (CKD) are at risk of exhibiting expanded extracellular volume, and low-sodium diets are often prescribed to limit clinical complications from this condition. Fan et al. performed a post hoc study from the database of the Modification of Diet in Renal Disease Study. Their article, as well as other recent observations, suggests that a low-sodium diet may not be as beneficial as previously thought in all CKD patients. Kidney International (2014) 86, 457–459. doi:10.1038/ki.2014.124
In the history of its relationship with man, near-magical benefits as well as subtle tragedies are associated with the use of sodium chloride. Purported benefits of salt throughout history include its use as a promoter of fertility, a preservative for food, a vital component of New World exploration, and an influence in international politics.1 Once established in our lexicon and accommodated for our palates, however, it became evident that chronic exposure to salt carries adverse effects. Dr Walter Kempner at Duke University first recognized the benefits of avoiding excess salt intake in patients with chronic kidney disease (CKD). For patients with CKD, he prescribed the ‘rice diet,’ a demanding regimen that limited daily sodium intake to 150 mg, in order to obviate complications of fluid overload.2 Over the past several decades, reduction of dietary salt became a mainstay of advice provided by practitioners in order to control blood pressure and limit cardiac and renal complications. The Center for Nutrition Policy and Promotion recom1 Division of Nephrology, Duke University, Durham, North Carolina, USA Correspondence: John P. Middleton, Division of Nephrology, Duke University, 2424 Erwin Road, Suite 605, Durham, North Carolina 27705, USA. E-mail: [email protected]
Kidney International (2014) 86
mends a daily sodium intake of less than 2300 mg in the general population and 1500 mg (equates to 65 mmol of sodium or 3750 mg of sodium chloride) for high-risk patients, including those with CKD.3 The Kidney Disease: Improving Global Outcomes (KDIGO) work group echoes this recommendation, but KDIGO also acknowledges that the guideline is based on inference rather than hard outcome data.4 According to the Centers for Disease Control and Prevention, the average sodium consumption in the adult US population is 3400 mg/d.5 When the dietary habits are carefully assessed, an analysis of a cohort of patients with CKD reveals a median sodium intake of 3720 mg/d.6 The United States spends a considerable amount on education, policy development, and implementation to close this gap between recommended and actual sodium consumption. The extent to which dietary sodium restriction benefits patients with CKD is not well understood. Several long-term studies suggest that reduction of dietary sodium might benefit certain patients with CKD. Lower sodium intake improved nephropathy in diabetic patients who received an angiotensin receptor blocker in the Irbesartan in Diabetic Nephropathy Trial and the Reduction of End Points
in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) trial.7 A post hoc analysis of the Ramipril Efficacy in Nephropathy (REIN) study suggested that in nondiabetic CKD patients, for every increase in sodium excretion of 100 mmol/g creatinine there was a 61% increased risk of the development of end-stage renal disease.8 More recently, in a small prospective trial of patients with CKD, McMahon and colleagues determined that a low-sodium diet (60–80 mmol/d) resulted in a reduction of 10 mm Hg systolic pressure compared with a high-sodium diet.9 The authors also demonstrated that the low-sodium diet in this trial reduced protein excretion by more than 300 mg/d. In contrast, there is also a large body of evidence suggesting that low dietary sodium is not beneficial. In a post hoc analysis of the Finnish Diabetic Nephropathy (FinnDiane) Study of patients with type 1 diabetes mellitus, Thomas and colleagues determined that subjects with the lowest sodium excretion had the highest risk of developing end-stage renal disease.10 Ekinci and colleagues reported a prospective study of 638 patients with type 2 diabetes, who were observed for 10 years.11 The baseline sodium excretion in this cohort was 184 mmol or 4230 mg sodium per day, and this remained stable throughout the observation period. Mortality was inversely related to sodium intake: for every increase in sodium excretion of 100 mmol/d, the associated all-cause mortality decreased by 28%. Low sodium intake also failed to associate with a clinical advantage in the participants of the African American Study of Kidney Disease and Hypertension (AASK).12 Lastly, in a large prospective population study in Europe, Stolarz-Skrzypek and colleagues observed that systolic blood pressure was higher in subjects with greater sodium intake. However, this did not translate into a higher risk of cardiovascular complications. In contrast, high sodium intake was protective in regard to 457
commentary
cardiovascular mortality.13 In summary, data derived from clinical trials do not universally support that reduction of dietary sodium will improve clinical outcomes in CKD patients. Now, Fan and colleagues14 (this issue) provide more information on the utility of dietary sodium restriction. Their article takes advantage of the well-characterized cohort of CKD patients from the Modification of Diet in Renal Disease (MDRD) trial. This trial performed in the 1990s, while perhaps best known as the origin of a popular method for estimating glomerular filtration rate, was an effort to determine whether reduced oral intake of protein reduced progression of kidney failure. Participants in the MDRD program had extensive dietary counseling provided by a dedicated staff of nutritionists. The MDRD infrastructure enabled the current study to address whether dietary sodium is good or bad for people who have CKD. In this post hoc study, the authors examined the associations among baseline 24-hour urinary sodium excretion, kidney failure, and a composite outcome of kidney failure or all-cause mortality. The authors determined that urinary sodium excretion, a surrogate for dietary sodium consumption, was not associated with kidney failure or the composite clinical outcome. When the interaction between dietary sodium and proteinuria was explored, a perplexing observation was made. In the MDRD participants with less than 3000 mg/d of sodium excretion, higher sodium intake was associated with increased risk of kidney failure if baseline proteinuria was less than 1.0 g/d and a lower risk of kidney failure in those with greater amounts of proteinuria. The interaction was not observed in the category of subjects who consumed more than 3000 mg of sodium per day. Since this was a small subset of patients, any conclusion from this latter observation is limited. Regardless, this article invites the question of whether public health leaders and practitioners should continue to dedicate efforts to reduce the dietary sodium of CKD patients. 458
This thought-provoking study does not allow us to ‘break the seal’ on highsalt diets for our patients, however, as the study has some limitations. First, the MDRD cohort did not include patients who had CKD as a result of diabetic nephropathy, which is the most common cause of end-stage renal disease in the United States. The generalizability of these observations is therefore called into question. Second, the intent of the prospective MDRD trial was not to examine the effect of dietary sodium on glomerular filtration rate, and thus the post hoc analysis could not fully account for confounders. Third, the MDRD program did not collect information on adjudicated events of acute kidney injury. Therefore, the observation of increased progression of CKD in the small subset of MDRD participants who consumed lower amounts of sodium could have been confounded by episodes of acute kidney injury. Fourth, diuretic use, not surprisingly, was common in the MDRD population, and diuretics were prescribed in 65% of patients who had more than 3000 mg/d of sodium excretion. It is possible that diuretic dosage confounded any association described with dietary sodium. Finally, the MDRD cohort apparently did not consist of high-salt consumers, as the mean baseline sodium excretion in the study (B3500 mg/d) was similar to the estimated daily average sodium intake in the United States.15 What contrary effects, particularly in patients with CKD, might limit any benefit of a low-sodium diet? A recent systematic review of the literature by the Cochrane Group suggests an explanation. Even though reduced sodium intake was associated with a moderate reduction in blood pressure and use of antihypertensive medications, significant increases in plasma renin, aldosterone, adrenaline, cholesterol, and triglycerides were observed.16 These changes could well explain some of the paradoxical clinical responses. In addition, the near-universal benefits of renin–angiotensin–aldosterone system blockade might be mitigated by adherence to a low-sodium diet. Finally, even
if it is prescribed, the actual delivery of low-sodium diet to patients remains a challenge. In formal clinical trials, including some studies where appropriate food was provided, actual intake of sodium exceeded the prescribed goal.17 So even if it is difficult to reach consensus on what clinicians should recommend to a patient with CKD, it is an even greater challenge to determine the best way to get a patient to adhere to a specific prescribed diet. Therefore, rather than assuming that a low-sodium diet is good for all, we need to keep an open mind on the matter. Especially in the field of nephrology, where some carefully performed clinical trials call into question benefits of ‘common-sense’ interventions, we probably should recognize that certain populations of patients will not benefit or may suffer complications from attempting to adhere to lowsodium diets. On this question, the message Paul provided to the Colossians may also apply to clinicians as they speak to patients: ‘Let your speech be always with grace, seasoned with salt, that ye may know how ye ought to answer every man’ (Colossians 4:6). DISCLOSURE
The authors declared no competing interests. REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
Kurlansky M. Salt. Penguin Books 2003. New York, NY. pp 484. Kempner W. Treatment of heart and kidney disease and of hypertensive and arteriosclerotic vascular disease with the rice diet. Ann Intern Med 1949; 31: 821–856. DiNicolantonio JJ, Niazi AK, Sadaf R et al. Dietary sodium restriction: take it with a grain of salt. Am J Med 2013; 126: 951–955. KDIGO. Kidney Disease: Improving Global Outcomes, Work Group: Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int 2012; 2: 337–414. Dietary guidelines for Americans, 2010. US Department of Health and Human Servicesohttp://health.gov/dietary guidelines/2010.asp4 2011. Weir MR, Townsend RR, Fink JC et al. Urinary sodium is a potent correlate of proteinuria: lessons from the chronic renal insufficiency cohort study. Am J Nephrol 2012; 36: 397–404. Lambers Heerspink HJ, Navis G, Ritz E. Salt intake in kidney disease—a missed therapeutic opportunity? Nephrol Dial Transplant 2012; 27: 3435–3442. Vegter S, Perna A, Postma MJ et al. Sodium intake, ACE inhibition, and progression to ESRD. J Am Soc Nephrol 2012; 23: 165–173. Kidney International (2014) 86
commentary
9.
10.
11.
12.
13.
McMahon EJ, Bauer JD, Hawley CM et al. A randomized trial of dietary sodium restriction in CKD. J Am Soc Nephrol 2013; 24: 2096–2103. Thomas MC, Moran J, Forsblom C et al. The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes. Diabetes Care 2011; 34: 861–866. Ekinci EI, Clarke S, Thomas MC et al. Dietary salt intake and mortality in patients with type 2 diabetes. Diabetes Care 2011; 34: 703–709. Norris KC, Greene T, Kopple J et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol 2006; 17: 2928–2936. Stolarz-Skrzypek K, Kuznetsova T, Thijs L et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in
14.
15.
16.
17.
relation to urinary sodium excretion. JAMA 2011; 305: 1777–1785. Fan L, Tighiouart H, Levey AS et al. Urinary sodium excretion and kidney failure in nondiabetic chronic kidney disease. Kidney Int 2014; 86: 582–588. Klahr S, Levey AS, Beck GJ et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330: 877–884. Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Cochrane Database Syst Rev [online] 2011; Issue 11, CD004022. McMahon EJ, Campbell KL, Mudge DW et al. Achieving salt restriction in chronic kidney disease. Int J Nephrol [online] 2012; 2012: 720429.
see clinical investigation on page 589
Autosomal dominant tubulointerstitial kidney disease: of names and genes Anthony J. Bleyer1 and Stanislav Kmoch2 Autosomal dominant tubulointerstitial kidney disease (ADTKD) refers to a group of conditions characterized by autosomal dominant inheritance, a bland urinary sediment with minimal blood and protein, pathologic changes of tubular and interstitial fibrosis, and slowly progressive chronic kidney disease. This commentary discusses recent advances in our medical knowledge of these conditions, including the recent identification of mutations in the MUC1 gene as a cause of ADTKD and changes in terminology proposed by Ekici et al. Kidney International (2014) 86, 459–461. doi:10.1038/ki.2014.125
In this issue of Kidney International, Ekici and colleagues1 provide us with both new information and a new perspective
1 Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA and 2Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic Correspondence: Anthony J. Bleyer, Section on Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27106, USA. E-mail: [email protected]
Kidney International (2014) 86
on autosomal dominant tubulointerstitial kidney disease (ADTKD). ADTKD is an easily understandable term for clinicians. The term ‘autosomal dominant’ refers to an inherited condition in which one of two gene alleles carries a mutation, and its presence results in clinical disease. An affected parent will have a 50% probability of passing on the mutated gene and its condition to his or her child. A well-recognized autosomal dominant condition in nephrology is autosomal dominant polycystic kidney disease
(ADPKD). Because of the mode of inheritance and late onset of the disease, families with ADPKD and ADTKD have many affected family members. The affected individual, one parent, and usually siblings, aunts or uncles, and one grandparent are affected. The term ‘tubulointerstitial’ refers to the fact that individuals with ADTKD have a bland urinary sediment, with minimal blood or protein. Kidney biopsy reveals tubulointerstitial fibrosis that is nonspecific. The kidney disease is progressive, with a gradual decline in glomerular filtration rate over time, resulting in the need for dialysis in the fourth through seventh decades of life. How do patients with ADTKD present? A typical patient is found to have an asymptomatic elevation of the serum creatinine on routine laboratory testing. The patient usually volunteers a strong family history of chronic kidney disease. The nephrologist then obtains a urine sample that does not contain blood or protein and recognizes this as a tubulointerstitial kidney disease. A renal ultrasound reveals normal to small kidneys, depending on the stage of chronic kidney disease. For the most common form of this disease (caused by mutations in the UMOD gene2), there is another important symptom: patients or family members often suffer from gout, frequently beginning in their teenage years. Often, at this point the nephrologist is unclear how to proceed. If he or she decides to perform a kidney biopsy, it reveals tubulointerstitial changes that do not afford a precise diagnosis. Genetic testing is available to diagnose these conditions, but many clinicians are unaware of this possibility. Why is it so hard for nephrologists to diagnose and recognize this condition? It would not seem that difficult— just autosomal dominant inheritance, bland urinary sediment, chronic kidney disease, and some families with a high preponderance of gout. The reason for the difficulty probably lies in the very confusing, historical terminology that has been used for these conditions. Primarily, these disorders have been described as medullary cystic kidney disease. This is problematic, because 459
http://www.kidney-international.org & 2014 International Society of Nephrology
see clinical investigation on page 582
Prescriptions for dietary sodium in patients with chronic kidney disease: how will this shake out? John P. Middleton1 and Ruediger W. Lehrich1 Patients with chronic kidney disease (CKD) are at risk of exhibiting expanded extracellular volume, and low-sodium diets are often prescribed to limit clinical complications from this condition. Fan et al. performed a post hoc study from the database of the Modification of Diet in Renal Disease Study. Their article, as well as other recent observations, suggests that a low-sodium diet may not be as beneficial as previously thought in all CKD patients. Kidney International (2014) 86, 457–459. doi:10.1038/ki.2014.124
In the history of its relationship with man, near-magical benefits as well as subtle tragedies are associated with the use of sodium chloride. Purported benefits of salt throughout history include its use as a promoter of fertility, a preservative for food, a vital component of New World exploration, and an influence in international politics.1 Once established in our lexicon and accommodated for our palates, however, it became evident that chronic exposure to salt carries adverse effects. Dr Walter Kempner at Duke University first recognized the benefits of avoiding excess salt intake in patients with chronic kidney disease (CKD). For patients with CKD, he prescribed the ‘rice diet,’ a demanding regimen that limited daily sodium intake to 150 mg, in order to obviate complications of fluid overload.2 Over the past several decades, reduction of dietary salt became a mainstay of advice provided by practitioners in order to control blood pressure and limit cardiac and renal complications. The Center for Nutrition Policy and Promotion recom1 Division of Nephrology, Duke University, Durham, North Carolina, USA Correspondence: John P. Middleton, Division of Nephrology, Duke University, 2424 Erwin Road, Suite 605, Durham, North Carolina 27705, USA. E-mail: [email protected]
Kidney International (2014) 86
mends a daily sodium intake of less than 2300 mg in the general population and 1500 mg (equates to 65 mmol of sodium or 3750 mg of sodium chloride) for high-risk patients, including those with CKD.3 The Kidney Disease: Improving Global Outcomes (KDIGO) work group echoes this recommendation, but KDIGO also acknowledges that the guideline is based on inference rather than hard outcome data.4 According to the Centers for Disease Control and Prevention, the average sodium consumption in the adult US population is 3400 mg/d.5 When the dietary habits are carefully assessed, an analysis of a cohort of patients with CKD reveals a median sodium intake of 3720 mg/d.6 The United States spends a considerable amount on education, policy development, and implementation to close this gap between recommended and actual sodium consumption. The extent to which dietary sodium restriction benefits patients with CKD is not well understood. Several long-term studies suggest that reduction of dietary sodium might benefit certain patients with CKD. Lower sodium intake improved nephropathy in diabetic patients who received an angiotensin receptor blocker in the Irbesartan in Diabetic Nephropathy Trial and the Reduction of End Points
in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) trial.7 A post hoc analysis of the Ramipril Efficacy in Nephropathy (REIN) study suggested that in nondiabetic CKD patients, for every increase in sodium excretion of 100 mmol/g creatinine there was a 61% increased risk of the development of end-stage renal disease.8 More recently, in a small prospective trial of patients with CKD, McMahon and colleagues determined that a low-sodium diet (60–80 mmol/d) resulted in a reduction of 10 mm Hg systolic pressure compared with a high-sodium diet.9 The authors also demonstrated that the low-sodium diet in this trial reduced protein excretion by more than 300 mg/d. In contrast, there is also a large body of evidence suggesting that low dietary sodium is not beneficial. In a post hoc analysis of the Finnish Diabetic Nephropathy (FinnDiane) Study of patients with type 1 diabetes mellitus, Thomas and colleagues determined that subjects with the lowest sodium excretion had the highest risk of developing end-stage renal disease.10 Ekinci and colleagues reported a prospective study of 638 patients with type 2 diabetes, who were observed for 10 years.11 The baseline sodium excretion in this cohort was 184 mmol or 4230 mg sodium per day, and this remained stable throughout the observation period. Mortality was inversely related to sodium intake: for every increase in sodium excretion of 100 mmol/d, the associated all-cause mortality decreased by 28%. Low sodium intake also failed to associate with a clinical advantage in the participants of the African American Study of Kidney Disease and Hypertension (AASK).12 Lastly, in a large prospective population study in Europe, Stolarz-Skrzypek and colleagues observed that systolic blood pressure was higher in subjects with greater sodium intake. However, this did not translate into a higher risk of cardiovascular complications. In contrast, high sodium intake was protective in regard to 457
commentary
cardiovascular mortality.13 In summary, data derived from clinical trials do not universally support that reduction of dietary sodium will improve clinical outcomes in CKD patients. Now, Fan and colleagues14 (this issue) provide more information on the utility of dietary sodium restriction. Their article takes advantage of the well-characterized cohort of CKD patients from the Modification of Diet in Renal Disease (MDRD) trial. This trial performed in the 1990s, while perhaps best known as the origin of a popular method for estimating glomerular filtration rate, was an effort to determine whether reduced oral intake of protein reduced progression of kidney failure. Participants in the MDRD program had extensive dietary counseling provided by a dedicated staff of nutritionists. The MDRD infrastructure enabled the current study to address whether dietary sodium is good or bad for people who have CKD. In this post hoc study, the authors examined the associations among baseline 24-hour urinary sodium excretion, kidney failure, and a composite outcome of kidney failure or all-cause mortality. The authors determined that urinary sodium excretion, a surrogate for dietary sodium consumption, was not associated with kidney failure or the composite clinical outcome. When the interaction between dietary sodium and proteinuria was explored, a perplexing observation was made. In the MDRD participants with less than 3000 mg/d of sodium excretion, higher sodium intake was associated with increased risk of kidney failure if baseline proteinuria was less than 1.0 g/d and a lower risk of kidney failure in those with greater amounts of proteinuria. The interaction was not observed in the category of subjects who consumed more than 3000 mg of sodium per day. Since this was a small subset of patients, any conclusion from this latter observation is limited. Regardless, this article invites the question of whether public health leaders and practitioners should continue to dedicate efforts to reduce the dietary sodium of CKD patients. 458
This thought-provoking study does not allow us to ‘break the seal’ on highsalt diets for our patients, however, as the study has some limitations. First, the MDRD cohort did not include patients who had CKD as a result of diabetic nephropathy, which is the most common cause of end-stage renal disease in the United States. The generalizability of these observations is therefore called into question. Second, the intent of the prospective MDRD trial was not to examine the effect of dietary sodium on glomerular filtration rate, and thus the post hoc analysis could not fully account for confounders. Third, the MDRD program did not collect information on adjudicated events of acute kidney injury. Therefore, the observation of increased progression of CKD in the small subset of MDRD participants who consumed lower amounts of sodium could have been confounded by episodes of acute kidney injury. Fourth, diuretic use, not surprisingly, was common in the MDRD population, and diuretics were prescribed in 65% of patients who had more than 3000 mg/d of sodium excretion. It is possible that diuretic dosage confounded any association described with dietary sodium. Finally, the MDRD cohort apparently did not consist of high-salt consumers, as the mean baseline sodium excretion in the study (B3500 mg/d) was similar to the estimated daily average sodium intake in the United States.15 What contrary effects, particularly in patients with CKD, might limit any benefit of a low-sodium diet? A recent systematic review of the literature by the Cochrane Group suggests an explanation. Even though reduced sodium intake was associated with a moderate reduction in blood pressure and use of antihypertensive medications, significant increases in plasma renin, aldosterone, adrenaline, cholesterol, and triglycerides were observed.16 These changes could well explain some of the paradoxical clinical responses. In addition, the near-universal benefits of renin–angiotensin–aldosterone system blockade might be mitigated by adherence to a low-sodium diet. Finally, even
if it is prescribed, the actual delivery of low-sodium diet to patients remains a challenge. In formal clinical trials, including some studies where appropriate food was provided, actual intake of sodium exceeded the prescribed goal.17 So even if it is difficult to reach consensus on what clinicians should recommend to a patient with CKD, it is an even greater challenge to determine the best way to get a patient to adhere to a specific prescribed diet. Therefore, rather than assuming that a low-sodium diet is good for all, we need to keep an open mind on the matter. Especially in the field of nephrology, where some carefully performed clinical trials call into question benefits of ‘common-sense’ interventions, we probably should recognize that certain populations of patients will not benefit or may suffer complications from attempting to adhere to lowsodium diets. On this question, the message Paul provided to the Colossians may also apply to clinicians as they speak to patients: ‘Let your speech be always with grace, seasoned with salt, that ye may know how ye ought to answer every man’ (Colossians 4:6). DISCLOSURE
The authors declared no competing interests. REFERENCES 1. 2.
3.
4.
5.
6.
7.
8.
Kurlansky M. Salt. Penguin Books 2003. New York, NY. pp 484. Kempner W. Treatment of heart and kidney disease and of hypertensive and arteriosclerotic vascular disease with the rice diet. Ann Intern Med 1949; 31: 821–856. DiNicolantonio JJ, Niazi AK, Sadaf R et al. Dietary sodium restriction: take it with a grain of salt. Am J Med 2013; 126: 951–955. KDIGO. Kidney Disease: Improving Global Outcomes, Work Group: Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int 2012; 2: 337–414. Dietary guidelines for Americans, 2010. US Department of Health and Human Servicesohttp://health.gov/dietary guidelines/2010.asp4 2011. Weir MR, Townsend RR, Fink JC et al. Urinary sodium is a potent correlate of proteinuria: lessons from the chronic renal insufficiency cohort study. Am J Nephrol 2012; 36: 397–404. Lambers Heerspink HJ, Navis G, Ritz E. Salt intake in kidney disease—a missed therapeutic opportunity? Nephrol Dial Transplant 2012; 27: 3435–3442. Vegter S, Perna A, Postma MJ et al. Sodium intake, ACE inhibition, and progression to ESRD. J Am Soc Nephrol 2012; 23: 165–173. Kidney International (2014) 86
commentary
9.
10.
11.
12.
13.
McMahon EJ, Bauer JD, Hawley CM et al. A randomized trial of dietary sodium restriction in CKD. J Am Soc Nephrol 2013; 24: 2096–2103. Thomas MC, Moran J, Forsblom C et al. The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes. Diabetes Care 2011; 34: 861–866. Ekinci EI, Clarke S, Thomas MC et al. Dietary salt intake and mortality in patients with type 2 diabetes. Diabetes Care 2011; 34: 703–709. Norris KC, Greene T, Kopple J et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol 2006; 17: 2928–2936. Stolarz-Skrzypek K, Kuznetsova T, Thijs L et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in
14.
15.
16.
17.
relation to urinary sodium excretion. JAMA 2011; 305: 1777–1785. Fan L, Tighiouart H, Levey AS et al. Urinary sodium excretion and kidney failure in nondiabetic chronic kidney disease. Kidney Int 2014; 86: 582–588. Klahr S, Levey AS, Beck GJ et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330: 877–884. Graudal NA, Hubeck-Graudal T, Jurgens G. Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride. Cochrane Database Syst Rev [online] 2011; Issue 11, CD004022. McMahon EJ, Campbell KL, Mudge DW et al. Achieving salt restriction in chronic kidney disease. Int J Nephrol [online] 2012; 2012: 720429.
see clinical investigation on page 589
Autosomal dominant tubulointerstitial kidney disease: of names and genes Anthony J. Bleyer1 and Stanislav Kmoch2 Autosomal dominant tubulointerstitial kidney disease (ADTKD) refers to a group of conditions characterized by autosomal dominant inheritance, a bland urinary sediment with minimal blood and protein, pathologic changes of tubular and interstitial fibrosis, and slowly progressive chronic kidney disease. This commentary discusses recent advances in our medical knowledge of these conditions, including the recent identification of mutations in the MUC1 gene as a cause of ADTKD and changes in terminology proposed by Ekici et al. Kidney International (2014) 86, 459–461. doi:10.1038/ki.2014.125
In this issue of Kidney International, Ekici and colleagues1 provide us with both new information and a new perspective
1 Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA and 2Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic Correspondence: Anthony J. Bleyer, Section on Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27106, USA. E-mail: [email protected]
Kidney International (2014) 86
on autosomal dominant tubulointerstitial kidney disease (ADTKD). ADTKD is an easily understandable term for clinicians. The term ‘autosomal dominant’ refers to an inherited condition in which one of two gene alleles carries a mutation, and its presence results in clinical disease. An affected parent will have a 50% probability of passing on the mutated gene and its condition to his or her child. A well-recognized autosomal dominant condition in nephrology is autosomal dominant polycystic kidney disease
(ADPKD). Because of the mode of inheritance and late onset of the disease, families with ADPKD and ADTKD have many affected family members. The affected individual, one parent, and usually siblings, aunts or uncles, and one grandparent are affected. The term ‘tubulointerstitial’ refers to the fact that individuals with ADTKD have a bland urinary sediment, with minimal blood or protein. Kidney biopsy reveals tubulointerstitial fibrosis that is nonspecific. The kidney disease is progressive, with a gradual decline in glomerular filtration rate over time, resulting in the need for dialysis in the fourth through seventh decades of life. How do patients with ADTKD present? A typical patient is found to have an asymptomatic elevation of the serum creatinine on routine laboratory testing. The patient usually volunteers a strong family history of chronic kidney disease. The nephrologist then obtains a urine sample that does not contain blood or protein and recognizes this as a tubulointerstitial kidney disease. A renal ultrasound reveals normal to small kidneys, depending on the stage of chronic kidney disease. For the most common form of this disease (caused by mutations in the UMOD gene2), there is another important symptom: patients or family members often suffer from gout, frequently beginning in their teenage years. Often, at this point the nephrologist is unclear how to proceed. If he or she decides to perform a kidney biopsy, it reveals tubulointerstitial changes that do not afford a precise diagnosis. Genetic testing is available to diagnose these conditions, but many clinicians are unaware of this possibility. Why is it so hard for nephrologists to diagnose and recognize this condition? It would not seem that difficult— just autosomal dominant inheritance, bland urinary sediment, chronic kidney disease, and some families with a high preponderance of gout. The reason for the difficulty probably lies in the very confusing, historical terminology that has been used for these conditions. Primarily, these disorders have been described as medullary cystic kidney disease. This is problematic, because 459
