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Nephrology Potpourri

Eberhard Ritz Klinikum der Universitat/Heidelberg, Medizinische Klinik/Sektion Nephrologie, Heidelberg, Germany Clin J Am Soc Nephrol 3: 1253–1259, 2008. doi: 10.2215/CJN.03500708

The effect of oral sodium phosphate drug tion settled the issue of whether phosphate-induced acute renal products on renal function in adults failure is always a reversible condition. It was not certain, undergoing bowel endoscopy. Arch Intern however, whether this observation represented only the peak Med 168: 592–597, 2008 of an iceberg. For clarification of this point, epidemiologic Khurana A, McLean L, Atkinson S, Foulks CJ information was necessary. One retrospective cohort study suggested that a non-negligi- Acute phosphate-induced kidney injury had been known for a ble proportion of patients who underwent using long time to be caused by conditions such as the acute tumor oral sodium phosphate (88 of 2325) developed incident renal lysis syndrome (1) or rhabdomyolysis (2,3). Furthermore, after dysfunction defined as estimated GFR (eGFR) Ͻ60 ml/min, some experimental (4) and clinical (5) observations, phosphate although, after multivariate adjustment, no significant differ- had been discussed as one factor that aggravates acute and ence was found between oral phosphate and polyethylene gly- chronic kidney injury (6). Although on both sides of the Atlan- col preparations. Importantly age Ͼ65 yr, black ethnicity, low tic occasional isolated cases of acute or subacute kidney injury baseline GFR, , and use of angiotensin-converting had been observed to be caused by oral phosphate therapy for enzyme inhibitors (ACEI) and thiazides were identified as risk various indications (7,8) as well as by phosphate-containing factors for a decrease in eGFR (17). The higher risk in older and (9–11), only recently has this problem emerged as a hypertensive patients as well as in the presumably hypovole- relatively frequent : The use of routine colonos- mic patients treated with a may be explained by the copy had increased after the procedure had been recommended fact that they generally experience higher postintervention se- for early diagnosis of colon cancer. In this context, phosphate- rum phosphate concentrations. This has been well documented containing preparations had been administered more fre- in the case of the elderly (18). Consequently, the recent gastro- quently (12), particularly after convenient, well-tolerated, low- enterologic recommendations point to adequate hydration as volume, hyperosmotic, low-cost oral phosphate preparations an item of paramount importance before, during, and after for colonoscopy had been shown to be superior to the alterna- bowel preparation (19). For accurate assessment of the epide- tive preparation (13). miologic magnitude of the problem, a prospective study would After several isolated reports (8–10,14), 3 yr ago, Markowitz be necessary. et al. (15) drew attention to this novel “epidemic” of what they Findings. Against this background, the recent article by called “acute phosphate nephropathy,” caused according to a Khurana et al. (20) provides welcome further evidence. This case report by intratubular deposits of hydroxyapatite with retrospective study evaluated patients who had lev- consecutive tubular damage (8). This complication had fol- els in the normal range and who during a 7-yr period from 1998 lowed oral sodium phosphate bowel purgatives. The authors to 2005 had undergone colonoscopy or flexible sigmoidoscopy appropriately concluded that this type of purgative constitutes using oral sodium phosphate solutions. The patients were fol- an underrecognized cause of chronic renal failure (16). Overall, lowed for 1 yr to assess the potential impact on long-term renal the study identified during a 4-yr period 31 patients with function. The results were compared with an age-matched con- among 7349 native renal , 21 of whom trol population. presented with normocalcemic acute renal failure and a history A total of 286 patients were selected in the study group and of recent colonoscopy preceded by bowel cleansing with oral 125 in the matched control group. Both groups had similar phosphate solution. The onset was rapid, and the median se- baseline characteristics. The baseline eGFR (Modification of rum creatinine was 3.9 mg/dl after a median of 1 mo. The Diet in Renal Disease [MDRD] equation) in the study group seriousness of this condition is underlined by the fact that all was 79 ml/min per 1.73 m2, which declined to 73 ml/min per patients had chronic renal insufficiency, and four of the 21 1.73 m2 at 6 mo after exposure to the oral sodium phosphate patients even required permanent . This observa- solution. No change in eGFR was seen in the control popula- tion. Although in the range investigated the eGFR, according to Ͼ Published online ahead of print. Publication date available at www.cjasn.org. the MDRD formula, is not reliable for values 60 ml/min per 1.73 m2 (21), the data are in line with the serum creatinine Correspondence: Dr. Eberhard Ritz, Nierenzentrum, Im Neuenheimer Feld 162, Ϯ Ϯ D-69120 Heidelberg, Germany. Phone: 49-6221-601705; Fax: 49-6221-603302; values: Baseline SD creatinine (mg/dl) was 0.92 0.22 versus E-mail: [email protected] 0.9 Ϯ 0.23 in the control group and had increased after 1 yr to

Copyright © 2008 by the American Society of ISSN: 1555-9041/305–1253 1254 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1253–1259, 2008

1.04 Ϯ 0.33 versus 0.96 Ϯ 0.33 in the control group (P Ͻ 0.001). matory drugs, renin-angiotensin system blockade)—it is wise To identify predisposing factors, the authors looked for inde- to be prudent with the indication for colonoscopy. pendent variables and found that the 6-mo creatinine value was The risk certainly remains low in general, but the challenge significantly related to baseline creatinine, , and use of for the gastroenterologist remains to identify the patients who are ACEI or angiotensin receptor blockers, confirming the conclu- at high risk. The message for the nephrologist is that the question sion of several previous authors that these factors predispose to of whether a given renal patient had a recent or distant colonos- after administration of oral sodium phos- copy should be part and parcel of the medical history, partic- phate solution. ularly of elderly patients with acute or chronic impairment of Commentary. The study of Khurana et al. (20) has the merit renal function. to draw attention to a renal complication of a procedure that carries a relatively low risk for renal damage but, given the increasing frequency of colonoscopy in recent years, is presum- References ably the underlying cause of a relatively high absolute number 1. Boles JM, Dutel JL, Briere J, Mialon P, Robasckiewicz M, of cases of acute and—presumably even more important— Garre M, Briere J: Acute renal failure caused by extreme chronic kidney injury resulting from nephrocalcinosis as a re- after chemotherapy of an acute lym- sult of “acute phosphate nephropathy” (16). The magnitude of phoblastic leukemia. Cancer 53: 2425–2429, 1984 the problem may even have been underestimated by the study 2. Kanfer A, Richet G, Roland J, Chatelet F: Extreme hyper- phosphataemia causing acute anuric nephrocalcinosis in of Khurana et al. (20), because patients with preexisting impair- lymphosarcoma. BMJ 1: 1320–1321, 1979 ment of renal function were excluded—the very patients who 3. Nakano Y, Simizu K, Ando M, Nakano S, Koyanagi R: are presumably at the highest risk for phosphate-induced acute Investigation of etiologies for acute renal failure due to kidney injury! rhabdomyolysis in 5 patients [in Japanese]. Nippon Jinzo Today this complication is known in the Gakkai Shi 32: 1221–1227, 1990 community after an early report from Canada (22) as well as 4. Haase P: The development of nephrocalcinosis in the rat several reports in the American literature (12,17,19). The num- following injections of neutral sodium phosphate. J Anat ber of gastroenterologic publications illustrates the appropriate 119: 19–37, 1975 concern about this emerging problem, which has led to reviews 5. Ibels LS, Alfrey AC, Huffer WE, Craswell PW, Weil R 3rd: directed to the gastroenterologic community (23) in which the in end-stage kidneys. Am J Med 71: 33–37, typical risk factors had been adequately described. Further- 1981 more, a consensus statement (24) on bowel preparation before 6. Dobyan DC, Bulger RE, Eknoyan G: The role of phosphate in the potentiation or amelioration of acute renal failure. colonoscopy has been published by the American Society of Miner Electrolyte Metab 17: 112–115, 1991 Colon and Rectal Surgeons, the American Society for Gastroin- 7. Ayala G, Chertow BS, Shah JH, Williams GA, Kukreja SC: testinal Endoscopy, and the Society of American Gastrointesti- Letter: Acute hyperphosphatemia and acute persistent re- nal and Endoscopic Surgeons. nal insufficiency induced by oral phosphate therapy. Ann It remains a matter of concern that the target group for Intern Med 83: 520–521, 1975 colonoscopy—the elderly, who are frequently hypovolemic and 8. Desmeules S, Bergeron MJ, Isenring P: Acute phosphate are treated with medication that is known to predispose to this nephropathy and renal failure. N Engl J Med 349: 1006– complication (ACEI, angiotensin receptor blockers, nonsteroi- 1007, 2003 dals)—is the very target group for preventive colonoscopy. 9. Orias M, Mahnensmith RL, Perazella MA: Extreme hyper- Recently, phosphate-induced renal malfunction has even phosphatemia and acute renal failure after a phosphorus- been observed in a further context: Acute renal failure after containing bowel regimen. Am J Nephrol 19: 60–63, 1999 10. Fine A, Patterson J: Severe hyperphosphatemia following continuous-flow irrigation in patients who are treated with phosphate administration for bowel preparation in pa- potassium-titanyl-phosphate laser vaporization of the prostate tients with renal failure: Two cases and a review of the (25). This observation further illustrates the potential of phos- literature. Am J Kidney Dis 29: 103–105, 1997 phate to induce renal damage. 11. Rose M, Karlstadt RG, Walker K: Renal failure following Several practical conclusions can be drawn. Phosphate-based bowel cleansing with a sodium phosphate purgative. Neph- preparations can no longer be considered as agents with a low rol Dial Transplant 20: 1518–1519, 2005 risk/benefit ratio (26). It is also no longer acceptable to pre- 12. Curran MP, Plosker GL: Oral sodium phosphate solution: scribe them with minimal previous evaluation of the patient’s A review of its use as a colorectal cleanser. Drugs 64: renal function and volume/electrolyte status. This problem has 1697–1714, 2004 by now been widely perceived in the community of gastroen- 13. Vanner SJ, MacDonald PH, Paterson WG, Prentice RS, Da Costa LR, Beck IT: A randomized prospective trial com- terologists (23): It has been recommended to correct the average paring oral sodium phosphate with standard polyethylene 1- to 2-L fluid loss from the split-dose hyperosmotic phosphate glycol-based lavage solution (Golytely) in the preparation preparations (27) by ingestion of oral fluid to lessen the risk for of patients for colonoscopy. Am J Gastroenterol 85: 422–427, . Patients must receive the respective information. 1990 In high-risk groups—the patient with chronic or 14. Ahmed M, Raval P, Buganza G: Oral sodium phosphate heart failure, the elderly, and the patient with medication that catharsis and acute renal failure. Am J Gastroenterol 91: increases the renal risk (e.g., , nonsteroidal anti-inflam- 1261–1262, 1996 Clin J Am Soc Nephrol 3: 1253–1259, 2008 Presse Re´nale 1255

15. Markowitz GS, Nasr SH, Klein P, Anderson H, Stack JI, Independent association of low serum 25- Alterman L, Price B, Radhakrishnan J, D’Agati VD: Renal hydroxyvitamin D and 1,25- failure due to acute nephrocalcinosis following oral so- dihydroxyvitamin D levels with all-cause dium phosphate bowel cleansing. Hum Pathol 35: 675–684, 2004 and cardiovascular mortality. Arch Intern 16. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati Med 168: 1340–1349, 2008 VD: Acute phosphate nephropathy following oral so- Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, dium phosphate bowel purgative: An underrecognized Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W cause of chronic renal failure. J Am Soc Nephrol 16: 3389– In the past, active vitamin D (1,25-dihydroxyvitamin D 3396, 2005 [1,25(OH) D ]) had been viewed to be relevant only for the 17. Russmann S, Lamerato L, Marfatia A, Motsko SP, Pezzullo 2 3 regulation of mineral metabolism (parathyroid, intestine, JC, Olds G, Jones JK: Risk of impaired renal function after bone), and the precursor 25-hydroxyvitamin D [25(OH)D] had colonoscopy: A cohort study in patients receiving either long been treated with benign neglect, mainly because its af- oral sodium phosphate or polyethylene glycol. Am J Gas- troenterol 102: 2655–2663, 2007 finity for the vitamin D receptor is lower by a factor of 100 and 18. Gumurdulu Y, Serin E, Ozer B, Gokcel A, Boyacioglu S: because the possibility of local production of 1,25(OH)2D3 by Age as a predictor of hyperphosphatemia after oral phos- tissues outside of the kidney had not been taken into consid- phosoda administration for colon preparation. J Gastroen- eration. This view has dramatically changed in recent years, but terol Hepatol 19: 68–72, 2004 the article by Dobnig et al. shows that much can still be learned. 19. Dykes C, Cash BD: Key safety issues of bowel preparations Today it is accepted that active vitamin D has important for colonoscopy and importance of adequate hydration. functions beyond the classical actions (1). Particularly relevant

Gastroenterol Nurs 31: 30–35, quiz 36–37, 2008 in a renal context are the action of 1,25(OH)2D3 to control renin 20. Khurana A, McLean L, Atkinson S, Foulks CJ: The effect of release from the juxtaglomerular apparatus (2) and its impor- oral sodium phosphate drug products on renal function in tant role in immune defense (3) and inflammation. adults undergoing bowel endoscopy. Arch Intern Med 168: Observational post hoc studies had suggested that treatment 593–597, 2008 with active vitamin D was associated with better outcome in 21. Stevens LA, Coresh J, Greene T, Levey AS: Assessing kid- dialysis patients (4–7), although this cannot yet be considered ney function: Measured and estimated glomerular filtra- as definitely proved (8). Controlled prospective data in dialysis tion rate. N Engl J Med 354: 2473–2483, 2006 patients are not available, but data in incident dialysis patients 22. Chan A, Depew W, Vanner S: Use of oral sodium phos- had shown a graded risk for early (within 90 d) overall (but not phate colonic lavage solution by Canadian colonoscopists: cardiovascular) mortality correlated to low 25(OH)D at baseline Pitfalls and complications. Can J Gastroenterol 11: 334–338, and apparently modified by treatment with active vitamin D 1997 23. Sica DA, Carl D, Zfass AM: Acute phosphate nephropathy: (9). The presence of an effect on all-cause but not on cardiovas- An emerging issue. Am J Gastroenterol 102: 1844–1847, 2007 cular mortality in this study could be due to the small sample 24. American Society of Colon and Rectal Surgeons (ASCRS), size and short observation period, limiting the detection of an American Society for Gastrointestinal Endoscopy (ASGE), impact on cardiovascular death or else indicate that 25(OH)D Society of American Gastrointestinal and Endoscopic Sur- has a greater or exclusive impact on noncardiovascular death. It

geons (SAGES), Wexner SD, Beck DE, Baron TH, Fanelli is also of interest that the relation of mortality to 1,25(OH)2D RD, Hyman N, Shen B, Wasco KE: A consensus document was less strong than that of 25(OH)D, possibly because of the on bowel preparation before colonoscopy: prepared by a longer half-life and stability of 25(OH)D or lesser assay vari- task force from the American Society of Colon and Rectal ability. Generally in multimorbid dialysis patients, a great Surgeons (ASCRS), the American Society for Gastrointes- number of potential confounders, specifically effects of serum tinal Endoscopy (ASGE), and the Society of American Gas- , and phosphate concentrations trointestinal and Endoscopic Surgeons (SAGES). Surg En- (because of their fluctuations values should be integrated over dosc 20: 1147–1160, 2006 time), but also many others, have to be considered, which 25. Kim MJ, Bachmann A, Mihatsch MJ, Ruszat R, Sulser T, might interfere with the results. The final proof of causality will Mayr M: Acute renal failure after continuous flow irriga- obviously have to wait for a randomized, controlled trial (8). tion in patients treated with potassium-titanyl-phosphate In view of these limitations of the available literature on renal laser vaporization of prostate. Am J Kidney Dis 51: e19–e24, patients, the large, prospective, single-center 3-yr observational 2008 cohort study of Dobnig et al. of nonrenal white patients who 26. Faigel DO, Eisen GM, Baron TH, Dominitz JA, Goldstein JL, Hirota WK, Jacobson BC, Johanson JF, Leighton JA, were referred for coronary angiography is of definite interest. It Mallery JS, Raddawi HM, Vargo JJ 2nd, Waring JP, Fanelli stands out because of the large number of patients included, the RD, Wheeler-Harbough J, Standards of Practice Commit- excellent characterization of the cardiovascular risk status, and tee. American Society for Gastrointestinal Endoscopy: the long follow-up. Preparation of patients for GI endoscopy. Gastrointest En- Findings. Dobnig et al. (10) examined 3258 consecutive male dosc 57: 446–450, 2003 and female patients who were aged 62 yr and underwent 27. Schiller LR: Clinical pharmacology and use of laxatives coronary angiography in a single tertiary center in the South of and lavage solutions. J Clin Gastroenterol 28: 11–18, 1999 Germany. Patients were followed up for a median of 7.7 yr, 1256 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1253–1259, 2008 during which 737 (22.6%) patients had died, 463 (62.8%) from diac abnormalities that predispose to vitamin D–dependent cardiovascular causes. The serum levels of 25(OH)D3 and mortality are.

1,25(OH)2D3 were measured with validated assay (coefficients These findings provide useful leads for the understanding of of variation Ͻ10%) and validation by liquid chromatography– the remarkably strong and consistent effects of vitamin D me- mass spectrometry. Fluctuation of the concentrations with the tabolites on cardiovascular risk. A link between vitamin D and seasons [89% difference of 25(OH)D between March and Au- coronary risk specifically in renal patients would also be very gust] were taken into consideration by calculating quartiles for plausible in view of the observation that in ESRD, both the study patients each month. 25(OH)D and 1,25(OH)2D3 are negatively related to indices of In the patients with the lowest 25(OH)D quartile, serum the function of another vascular bed, the conduit arteries (13). parathyroid hormone was 36% higher and 1,25(OH)2D31% lower. Overall correlation between 25(OH)D and 1,25(OH)2D3 References ϭ concentrations was modest (r 0.32) even after adjustment for 1. Holick MF: Vitamin D deficiency. N Engl J Med 357: 266– cystatin C. 281, 2007 Multivariate-adjusted hazard ratios for patients in the lower 2. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP: 1,25- two quartiles of 25(OH)D plasma concentrations (median 7.6 Dihydroxyvitamin D(3) is a negative endocrine regulator and 13.3 ng/ml, respectively) were higher for all-cause mortal- of the renin-angiotensin system. J Clin Invest 110: 229–238, ity (hazard ratio [HR] 2.08; [95% confidence interval (CI) 1.6 to 2002 2.7] and HR 1.53 [95% CI 1.17 to 2.01], respectively). The same 3. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, was true for cardiovascular mortality (HR 2.22 [95% CI 1.57 to Wagner M, Bals R, Steinmeyer A, Zu¨gel U, Gallo RL, 3.13] and HR 1.82 [95% CI 1.29 to 2.58], respectively) compared Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, with patients in the two upper 25(OH)D quartiles (median 28.4 Modlin RL: Toll-like receptor triggering of a vitamin D- ng/ml). Similar results were obtained for patients in the lowest mediated human antimicrobial response. Science 311: 1,25(OH)2D3 quartile. 1770–1773, 2006 The study had sufficient power to look into some specific 4. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, issues of interest with respect to the limitations posed by the Thadhani R: Survival of patients undergoing hemodialysis available evidence in renal patients as discussed (9): (1) The with paricalcitol or calcitriol therapy. N Engl J Med 349: relationship persisted when patients were categorized by 446–456, 2003 Charlson comorbidity index, New York Heart Association 5. Teng M, Wolf M, Ofsthun MN, Lazarus JM, Herna´n MA, functional class, and physical activity level; and (2) the all-cause Camargo CA Jr, Thadhani R: Activated injectable vitamin D and hemodialysis survival: A historical cohort study. mortality was increased in patients with lower 25(OH)D and J Am Soc Nephrol 16: 1115–1125, 2005 1,25(OH) D even when the grade of stenosis was Ͻ50 or 20%, 2 3 6. Tentori F, Hunt WC, Stidley CA, Rohrscheib MR, Bedrick respectively. EJ, Meyer KB, Johnson HK, Zager PG, Medical Directors of In view of potential pathomechanisms involved in the link Dialysis Clinic Inc.: Mortality risk among hemodialysis between 25(OH)D and 1,25(OH)2D3 on the one hand and car- patients receiving different vitamin D analogs. Kidney Int diovascular mortality on the other hand, it is of considerable 70: 1858–1865, 2006 interest that the authors found correlations between 25(OH)D 7. Shoji T, Shinohara K, Kimoto E, Emoto M, Tahara H, [as well as less pronounced 1,25(OH)2D] and indicators of inflam- Koyama H, Inaba M, Fukumoto S, Ishimura E, Miki T, mation (IL-6 and C-reactive protein) as well as indicators of inter- Tabata T, Nishizawa Y: Lower risk for cardiovascular mor- action of circulating cells with endothelial cells (intracellular ad- tality in oral 1alpha-hydroxy vitamin D3 users in a haemo- hesion molecule 1 and vascular cellular adhesion molecule 1). dialysis population. Nephrol Dial Transplant 19: 179–184, 2004 Comment. The study clearly identifies both 25(OH)D and 8. Al-Aly Z: Vitamin D as a novel nontraditional risk factor 1,25(OH)2D3 as cardiovascular risk factors specifically in pa- for mortality in hemodialysis patients: The need for ran- tients with coronary heart disease. In contrast to the study of domized trials. Kidney Int 72: 909–911, 2007 incident dialysis patients, in which the correlation to cardiovas- 9. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez cular death was NS (9), 25(OH)D—as well as 1,25(OH)2D3— H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani plasma concentrations were correlated to elevated cardiovas- R: Vitamin D levels and early mortality among incident cular risk. That both 25(OH)D and 1,25(OH)2D3 were predictive hemodialysis patients. Kidney Int 72: 1004–1013, 2007 is of note, because the correlation between the two was weak, 10. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, suggesting a synergistic effect on mortality by similar but in- Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W: Independent association of low serum 25-hydroxyvita- dependent pathways. min d and 1,25-dihydroxyvitamin d levels with all-cause In agreement with findings of other authors, a significant and cardiovascular mortality. Arch Intern Med 168: 1340– relation of low vitamin D metabolites to indices of inflamma- 1349, 2008 tion and to metalloproteinases was found (11), pointing to an 11. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, anti-inflammatory effect of vitamin D and an effect on plaque Syndercombe-Court D, Aganna E, Price CP, Boucher BJ: stability (12). The correlation to cardiovascular death was seen Circulating MMP9, vitamin D and variation in the TIMP-1 in both patients with and without major coronary heart disease response with VDR genotype: Mechanisms for inflamma- by angiography, raising the issue of what the alternative car- tory damage in chronic disorders? QJM 95: 787–796, 2002 Clin J Am Soc Nephrol 3: 1253–1259, 2008 Presse Re´nale 1257

12. Rahman A, Hershey S, Ahmed S, Nibbelink K, Simpson phase-advanced with significant fragmentation of diurnal ac- RU: Heart extracellular matrix gene expression profile in tivity. The study of Martino et al. now documents that such the vitamin D receptor knockout mice. J Steroid Biochem disrupted circadian organization is involved in the genesis of Mol Biol 103: 416–419, 2007 severe cardiac and renal disease, thereby explaining early death 13. London GM, Guerin AP, Verbeke FH, Pannier B, Boutouy- in the ϩ/tau mutant. rie P, Marchais SJ, Me¨tivier F: Mineral metabolism and In ϩ/tau animals on 24-h light-dark cycles, the authors arterial functions in end-stage renal disease: Potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol 18: found marked cardiomyopathy characterized by interstitial fibro- 613–620, 2007 sis and widespread collagen deposition. This was associated with impaired cardiac function documented by catheterization Circadian rhythm disorganization produces and transthoracic echocardiography. Catheterization showed profound cardiovascular and renal disease in with markedly decreased systolic, diastolic, and hamsters. Am J Physiol Regul Integr Comp mean arterial pressures; diastolic dysfunction with significantly increased left ventricular end diastolic pressure; and reduced Physiol 294: R1675–R1683, 2008 myocardial contractility assessed as dP/dt . Transthoracic Martino TA, Oudit GY, Herzenberg AM, Tata N, Koletar max MM, Kabir GM, Belsham DD, Backx PH, Ralph MR, Sole echocardiography confirmed impaired myocardial contractility MJ by showing elevated left ventricular end diastolic diameter and left ventricular end systolic diameter, respectively. Circadian rhythms (1) play a dramatic role in the regulation of It is interesting that cardiopathology was restricted to the cardiovascular (2,3) and renal (4–8) physiology and pathophys- heterozygotes ϩ/tau. The homozygous tau/tau hamsters were iology. Adverse cardiac events such as heart attacks or strokes unable to synchronize with a 24-h/d rhythm, failed to show show significant diurnal variations (3). A disrupted diurnal circadian dysregulation, and did not develop cardiac pathol- rhythm is found particularly in patients with mental disorders ogy. (9,10) or sleep-onset insomnia (11), transmeridian flight crews As a chance finding, the authors also noted renal abnormali- or time zone changes (12), shift work (13), and aging (14); in ties: Proximal tubular dilation and tubular cells exhibiting re- these groups the cardiovascular problems are more frequent generative and degenerative changes; pathology suggestive of (15,16). This issue is of particular note for the nephrologist glomerular ischemia was also noted, and collagen deposition because sleep disturbances (17–19) and abnormal autonomic occurred throughout the renal cortex. These findings were ac- rhythms (20–22) are commonly found in patients with ; companied by . The terminal deoxynucleotidyl they are attenuated or disappear after renal transplantation. transferase–mediated digoxigenin-deoxyuridine nick-end la- Against this background, the recent study by Martino et al. of beling assay showed presence of DNA fragments that resulted golden hamsters with a genetically caused disruption of the from apoptotic signaling cascades in the tubules. circadian rhythm is of considerable interest. It had been known These abnormalities were slow in evolution. At 4 mo of age, for a long time that life expectancy is reduced for some organ- no cardiac or renal abnormalities were demonstrable. When at isms when they are raised in light-dark cycles the periods of 4 mo of age the animals were exposed to the light-dark cycle which differ substantially from that of their own endogenous appropriate for their phenotype, no abnormalities were noted. circadian rhythm. This was documented in the fly by Aschoff et Similarly, when the suprachiasmatic nucleus was destroyed al. (23). Hurd and Ralph (24) then showed in mammalians (i.e., when the master circadian oscillator was eliminated so that (golden hamster) that circadian organization influences health and longevity. They studied heterozygous hamsters that carry there was no conflict between the central oscillator and the one copy of the period mutation tau, which results in speeding peripheral oscillators in heart and kidney), no pathology of up the clock and causing age-dependent fragmentation of heart and kidney was observed. rhythmic locomotor behavior in a running wheel worsening Comment. This study documents severe organ pathology with age. In these genetically modified golden hamsters, envi- that resulted from the conflict between the central clock and the ronmentally induced rhythm disruption (e.g., by light/dark peripheral clocks in different organs (27–30). It may provide a cycle out of phase with the endogenous biorhythm) reduced new dimension and perspective on widely known pathologies longevity. In contrast, the rhythm was reconsolidated by suc- of the circadian rhythm in patients with uremia. cessful grafting of a fetal suprachiasmatic nucleus where the Sleep disorders are common in dialysis patients, and insom- “master clock” is located. nia is reported in almost 70% of elderly dialysis patients; sleep Findings. Martino et al. (25) now carried this one step for- apnea syndrome, restless leg syndrome, and comorbidity in- ward to find out which organ pathology was associated with crease the risk (17). It is interesting that kidney transplantation this altered circadian organization. To this end they studied the reverses the restless leg syndrome as well as the sleep apnea above model of golden hamsters carrying the known circadian syndrome and excessive daytime sleepiness (17). One case re- period mutation tau (24,26). This mutant allele reduces the port suggested that parathyroidectomy improves the quality of circadian period from approximately 24 h in the wild type to sleep in dialyses patients with severe hyperparathyroidism approximately 22 h in ϩ/tau heterozygotes. Their longevity is (31); this is not a consistent observation and is certainly not compromised: When these animals are “entrained” (i.e., ex- generally applicable. posed to a 24-h light-dark cycle), their nocturnal behavior is A high frequency of sleep disorders has also been reported in 1258 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 3: 1253–1259, 2008 two large Asian studies: Chen et al. (18) studied patients who 12. Monk TH, Aplin LC: Spring and autumn daylight saving were on hemodialysis using the Pittsburgh sleep quality index, time changes: Studies of adjustment in sleep timings, the Epworth sleepiness scale, the Berlin questionnaire, and a mood, and efficiency. Ergonomics 23: 167–178, 1980 questionnaire related to periodic limb movement. Sleep distur- 13. 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