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Published ahead of print on August 13, 2008
Clin J Am Soc Nephrol 3: 1253-1259, 2008
© 2008 American Society of Nephrology
doi: 10.2215/CJN.03500708
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Presse Rénale

Nephrology Potpourri

Eberhard Ritz

Klinikum der Universitat/Heidelberg, Medizinische Klinik/Sektion Nephrologie, Heidelberg, Germany

Correspondence: Dr. Eberhard Ritz, Nierenzentrum, Im Neuenheimer Feld 162, D-69120 Heidelberg, Germany. Phone: 49-6221-601705; Fax: 49-6221-603302; E-mail: prof.e.ritz{at}t-online.de


   The effect of oral sodium phosphate drug products on renal function in adults undergoing bowel endoscopy. Arch Intern Med 168: 592–597, 2008 Khurana A, McLean L, Atkinson S, Foulks CJ
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Acute phosphate-induced kidney injury had been known for a long time to be caused by conditions such as the acute tumor lysis syndrome (1) or rhabdomyolysis (2,3). Furthermore, after some experimental (4) and clinical (5) observations, phosphate had been discussed as one factor that aggravates acute and chronic kidney injury (6). Although on both sides of the Atlantic occasional isolated cases of acute or subacute kidney injury had been observed to be caused by oral phosphate therapy for various indications (7,8) as well as by phosphate-containing enemas (9–11), only recently has this problem emerged as a relatively frequent complication: The use of routine colonoscopy had increased after the procedure had been recommended for early diagnosis of colon cancer. In this context, phosphate-containing preparations had been administered more frequently (12), particularly after convenient, well-tolerated, low-volume, hyperosmotic, low-cost oral phosphate preparations for colonoscopy had been shown to be superior to the alternative polyethylene glycol preparation (13).

After several isolated reports (8–10,14), 3 yr ago, Markowitz et al. (15) drew attention to this novel "epidemic" of what they called "acute phosphate nephropathy," caused according to a case report by intratubular deposits of hydroxyapatite with consecutive tubular damage (8). This complication had followed oral sodium phosphate bowel purgatives. The authors appropriately concluded that this type of purgative constitutes an underrecognized cause of chronic renal failure (16). Overall, the study identified during a 4-yr period 31 patients with nephrocalcinosis among 7349 native renal biopsies, 21 of whom presented with normocalcemic acute renal failure and a history of recent colonoscopy preceded by bowel cleansing with oral phosphate solution. The onset was rapid, and the median serum creatinine was 3.9 mg/dl after a median of 1 mo. The seriousness of this condition is underlined by the fact that all patients had chronic renal insufficiency, and four of the 21 patients even required permanent hemodialysis. This observation settled the issue of whether phosphate-induced acute renal failure is always a reversible condition. It was not certain, however, whether this observation represented only the peak of an iceberg. For clarification of this point, epidemiologic information was necessary.

One retrospective cohort study suggested that a non-negligible proportion of patients who underwent colonoscopy using oral sodium phosphate (88 of 2325) developed incident renal dysfunction defined as estimated GFR (eGFR) <60 ml/min, although, after multivariate adjustment, no significant difference was found between oral phosphate and polyethylene glycol preparations. Importantly age >65 yr, black ethnicity, low baseline GFR, hypertension, and use of angiotensin-converting enzyme inhibitors (ACEI) and thiazides were identified as risk factors for a decrease in eGFR (17). The higher risk in older and hypertensive patients as well as in the presumably hypovolemic patients treated with a diuretic may be explained by the fact that they generally experience higher postintervention serum phosphate concentrations. This has been well documented in the case of the elderly (18). Consequently, the recent gastroenterologic recommendations point to adequate hydration as an item of paramount importance before, during, and after bowel preparation (19). For accurate assessment of the epidemiologic magnitude of the problem, a prospective study would be necessary.

Findings.
Against this background, the recent article by Khurana et al. (20) provides welcome further evidence. This retrospective study evaluated patients who had creatinine levels in the normal range and who during a 7-yr period from 1998 to 2005 had undergone colonoscopy or flexible sigmoidoscopy using oral sodium phosphate solutions. The patients were followed for 1 yr to assess the potential impact on long-term renal function. The results were compared with an age-matched control population.

A total of 286 patients were selected in the study group and 125 in the matched control group. Both groups had similar baseline characteristics. The baseline eGFR (Modification of Diet in Renal Disease [MDRD] equation) in the study group was 79 ml/min per 1.73 m2, which declined to 73 ml/min per 1.73 m2 at 6 mo after exposure to the oral sodium phosphate solution. No change in eGFR was seen in the control population. Although in the range investigated the eGFR, according to 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 values: Baseline ± SD creatinine (mg/dl) was 0.92 ± 0.22 versus 0.9 ± 0.23 in the control group and had increased after 1 yr to 1.04 ± 0.33 versus 0.96 ± 0.33 in the control group (P < 0.001). To identify predisposing factors, the authors looked for independent variables and found that the 6-mo creatinine value was significantly related to baseline creatinine, diabetes, and use of ACEI or angiotensin receptor blockers, confirming the conclusion of several previous authors that these factors predispose to acute kidney injury after administration of oral sodium phosphate solution.

Commentary.
The study of Khurana et al. (20) has the merit 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 presumably the underlying cause of a relatively high absolute number of cases of acute and—presumably even more important—chronic kidney injury resulting from nephrocalcinosis as a result of "acute phosphate nephropathy" (16). The magnitude of the problem may even have been underestimated by the study of Khurana et al. (20), because patients with preexisting impairment of renal function were excluded—the very patients who are presumably at the highest risk for phosphate-induced acute kidney injury!

Today this complication is known in the gastroenterology community after an early report from Canada (22) as well as several reports in the American literature (12,17,19). The number of gastroenterologic publications illustrates the appropriate concern about this emerging problem, which has led to reviews directed to the gastroenterologic community (23) in which the typical risk factors had been adequately described. Furthermore, a consensus statement (24) on bowel preparation before colonoscopy has been published by the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons.

It remains a matter of concern that the target group for colonoscopy—the elderly, who are frequently hypovolemic and are treated with medication that is known to predispose to this complication (ACEI, angiotensin receptor blockers, nonsteroidals)—is the very target group for preventive colonoscopy.

Recently, phosphate-induced renal malfunction has even been observed in a further context: Acute renal failure after continuous-flow irrigation in patients who are treated with potassium-titanyl-phosphate laser vaporization of the prostate (25). This observation further illustrates the potential of phosphate to induce renal damage.

Several practical conclusions can be drawn. Phosphate-based preparations can no longer be considered as agents with a low risk/benefit ratio (26). It is also no longer acceptable to prescribe them with minimal previous evaluation of the patient's renal function and volume/electrolyte status. This problem has by now been widely perceived in the community of gastroenterologists (23): It has been recommended to correct the average 1- to 2-L fluid loss from the split-dose hyperosmotic phosphate preparations (27) by ingestion of oral fluid to lessen the risk for hypovolemia. Patients must receive the respective information. In high-risk groups—the patient with chronic kidney disease or heart failure, the elderly, and the patient with medication that increases the renal risk (e.g., diuretics, nonsteroidal anti-inflammatory drugs, renin-angiotensin system blockade)—it is wise to be prudent with the indication for colonoscopy.

The risk certainly remains low in general, but the challenge for the gastroenterologist remains to identify the patients who are at high risk. The message for the nephrologist is that the question of whether a given renal patient had a recent or distant colonoscopy should be part and parcel of the medical history, particularly of elderly patients with acute or chronic impairment of renal function.


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Published online ahead of print. Publication date available at www.cjasn.org.


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  2. Kanfer A, Richet G, Roland J, Chatelet F: Extreme hyperphosphataemia causing acute anuric nephrocalcinosis in lymphosarcoma. BMJ1 :1320 –1321,1979[Free Full Text]
  3. Nakano Y, Simizu K, Ando M, Nakano S, Koyanagi R: Investigation of etiologies for acute renal failure due to rhabdomyolysis in 5 patients [in Japanese]. Nippon Jinzo Gakkai Shi32 :1221 –1227,1990[Medline]
  4. Haase P: The development of nephrocalcinosis in the rat following injections of neutral sodium phosphate. J Anat119 :19 –37,1975[Medline]
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  8. Desmeules S, Bergeron MJ, Isenring P: Acute phosphate nephropathy and renal failure. N Engl J Med349 :1006 –1007,2003[Free Full Text]
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  11. Rose M, Karlstadt RG, Walker K: Renal failure following bowel cleansing with a sodium phosphate purgative. Nephrol Dial Transplant20 :1518 –1519,2005[Free Full Text]
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  16. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD: Acute phosphate nephropathy following oral sodium phosphate bowel purgative: An underrecognized cause of chronic renal failure. J Am Soc Nephrol16 :3389 –3396,2005[Abstract/Free Full Text]
  17. Russmann S, Lamerato L, Marfatia A, Motsko SP, Pezzullo JC, Olds G, Jones JK: Risk of impaired renal function after colonoscopy: A cohort study in patients receiving either oral sodium phosphate or polyethylene glycol. Am J Gastroenterol102 :2655 –2663,2007[CrossRef][Medline]
  18. Gumurdulu Y, Serin E, Ozer B, Gokcel A, Boyacioglu S: Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation. J Gastroenterol Hepatol19 :68 –72,2004[CrossRef][Medline]
  19. Dykes C, Cash BD: Key safety issues of bowel preparations for colonoscopy and importance of adequate hydration. Gastroenterol Nurs31 :30 –35, quiz 36–37,2008[CrossRef][Medline]
  20. Khurana A, McLean L, Atkinson S, Foulks CJ: The effect of oral sodium phosphate drug products on renal function in adults undergoing bowel endoscopy. Arch Intern Med168 :593 –597,2008[Abstract/Free Full Text]
  21. Stevens LA, Coresh J, Greene T, Levey AS: Assessing kidney function: Measured and estimated glomerular filtration rate. N Engl J Med354 :2473 –2483,2006[Free Full Text]
  22. Chan A, Depew W, Vanner S: Use of oral sodium phosphate colonic lavage solution by Canadian colonoscopists: Pitfalls and complications. Can J Gastroenterol11 :334 –338,1997[Medline]
  23. Sica DA, Carl D, Zfass AM: Acute phosphate nephropathy: An emerging issue. Am J Gastroenterol102 :1844 –1847,2007[CrossRef][Medline]
  24. American Society of Colon and Rectal Surgeons (ASCRS), American Society for Gastrointestinal Endoscopy (ASGE), Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Wexner SD, Beck DE, Baron TH, Fanelli RD, Hyman N, Shen B, Wasco KE: A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc20 :1147 –1160,2006[CrossRef][Medline]
  25. Kim MJ, Bachmann A, Mihatsch MJ, Ruszat R, Sulser T, Mayr M: Acute renal failure after continuous flow irrigation in patients treated with potassium-titanyl-phosphate laser vaporization of prostate. Am J Kidney Dis51 :e19 –e24,2008[CrossRef][Medline]
  26. Faigel DO, Eisen GM, Baron TH, Dominitz JA, Goldstein JL, Hirota WK, Jacobson BC, Johanson JF, Leighton JA, Mallery JS, Raddawi HM, Vargo JJ 2nd, Waring JP, Fanelli RD, Wheeler-Harbough J, Standards of Practice Committee. American Society for Gastrointestinal Endoscopy: Preparation of patients for GI endoscopy. Gastrointest Endosc57 :446 –450,2003[CrossRef][Medline]
  27. Schiller LR: Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol28 :11 –18,1999[CrossRef][Medline]
 

Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med 168: 1340–1349, 2008 Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W

In the past, active vitamin D (1,25-dihydroxyvitamin D [1,25(OH)2D3]) had been viewed to be relevant only for the regulation of mineral metabolism (parathyroid, intestine, bone), and the precursor 25-hydroxyvitamin D [25(OH)D] had long been treated with benign neglect, mainly because its affinity for the vitamin D receptor is lower by a factor of 100 and because the possibility of local production of 1,25(OH)2D3 by tissues outside of the kidney had not been taken into consideration. This view has dramatically changed in recent years, but the article by Dobnig et al. shows that much can still be learned.

Today it is accepted that active vitamin D has important functions beyond the classical actions (1). Particularly relevant in a renal context are the action of 1,25(OH)2D3 to control renin release from the juxtaglomerular apparatus (2) and its important role in immune defense (3) and inflammation.

Observational post hoc studies had suggested that treatment with active vitamin D was associated with better outcome in dialysis patients (4–7), although this cannot yet be considered as definitely proved (8). Controlled prospective data in dialysis patients are not available, but data in incident dialysis patients had shown a graded risk for early (within 90 d) overall (but not cardiovascular) mortality correlated to low 25(OH)D at baseline and apparently modified by treatment with active vitamin D (9). The presence of an effect on all-cause but not on cardiovascular mortality in this study could be due to the small sample size and short observation period, limiting the detection of an impact on cardiovascular death or else indicate that 25(OH)D has a greater or exclusive impact on noncardiovascular death. It is also of interest that the relation of mortality to 1,25(OH)2D was less strong than that of 25(OH)D, possibly because of the longer half-life and stability of 25(OH)D or lesser assay variability. Generally in multimorbid dialysis patients, a great number of potential confounders, specifically effects of serum parathyroid hormone, calcium and phosphate concentrations (because of their fluctuations values should be integrated over time), but also many others, have to be considered, which might interfere with the results. The final proof of causality will obviously have to wait for a randomized, controlled trial (8).

In view of these limitations of the available literature on renal patients, the large, prospective, single-center 3-yr observational cohort study of Dobnig et al. of nonrenal white patients who were referred for coronary angiography is of definite interest. It stands out because of the large number of patients included, the excellent characterization of the cardiovascular risk status, and the long follow-up.


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Dobnig et al. (10) examined 3258 consecutive male and female patients who were aged 62 yr and underwent coronary angiography in a single tertiary center in the South of Germany. Patients were followed up for a median of 7.7 yr, during which 737 (22.6%) patients had died, 463 (62.8%) from cardiovascular causes. The serum levels of 25(OH)D3 and 1,25(OH)2D3 were measured with validated assay (coefficients of variation <10%) and validation by liquid chromatography–mass spectrometry. Fluctuation of the concentrations with the seasons [89% difference of 25(OH)D between March and August] were taken into consideration by calculating quartiles for the study patients each month.

In the patients with the lowest 25(OH)D quartile, serum parathyroid hormone was 36% higher and 1,25(OH)2D31% lower. Overall correlation between 25(OH)D and 1,25(OH)2D3 concentrations was modest (r = 0.32) even after adjustment for cystatin C.

Multivariate-adjusted hazard ratios for patients in the lower two quartiles of 25(OH)D plasma concentrations (median 7.6 and 13.3 ng/ml, respectively) were higher for all-cause mortality (hazard ratio [HR] 2.08; [95% confidence interval (CI) 1.6 to 2.7] and HR 1.53 [95% CI 1.17 to 2.01], respectively). The same was true for cardiovascular mortality (HR 2.22 [95% CI 1.57 to 3.13] and HR 1.82 [95% CI 1.29 to 2.58], respectively) compared with patients in the two upper 25(OH)D quartiles (median 28.4 ng/ml). Similar results were obtained for patients in the lowest 1,25(OH)2D3 quartile.

The study had sufficient power to look into some specific issues of interest with respect to the limitations posed by the available evidence in renal patients as discussed (9): (1) The relationship persisted when patients were categorized by Charlson comorbidity index, New York Heart Association functional class, and physical activity level; and (2) the all-cause mortality was increased in patients with lower 25(OH)D and 1,25(OH)2D3 even when the grade of stenosis was <50 or 20%, respectively.

In view of potential pathomechanisms involved in the link between 25(OH)D and 1,25(OH)2D3 on the one hand and cardiovascular mortality on the other hand, it is of considerable interest that the authors found correlations between 25(OH)D [as well as less pronounced 1,25(OH)2D] and indicators of inflammation (IL-6 and C-reactive protein) as well as indicators of interaction of circulating cells with endothelial cells (intracellular adhesion molecule 1 and vascular cellular adhesion molecule 1).


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The study clearly identifies both 25(OH)D and 1,25(OH)2D3 as cardiovascular risk factors specifically in patients with coronary heart disease. In contrast to the study of incident dialysis patients, in which the correlation to cardiovascular death was NS (9), 25(OH)D—as well as 1,25(OH)2D3—plasma concentrations were correlated to elevated cardiovascular risk. That both 25(OH)D and 1,25(OH)2D3 were predictive is of note, because the correlation between the two was weak, suggesting a synergistic effect on mortality by similar but independent pathways.

In agreement with findings of other authors, a significant relation of low vitamin D metabolites to indices of inflammation and to metalloproteinases was found (11), pointing to an anti-inflammatory effect of vitamin D and an effect on plaque stability (12). The correlation to cardiovascular death was seen in both patients with and without major coronary heart disease by angiography, raising the issue of what the alternative cardiac abnormalities that predispose to vitamin D–dependent mortality are.

These findings provide useful leads for the understanding of the remarkably strong and consistent effects of vitamin D metabolites on cardiovascular risk. A link between vitamin D and coronary risk specifically in renal patients would also be very plausible in view of the observation that in ESRD, both 25(OH)D and 1,25(OH)2D3 are negatively related to indices of the function of another vascular bed, the conduit arteries (13).


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  1. Holick MF: Vitamin D deficiency. N Engl J Med357 :266 –281,2007[Free Full Text]
  2. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP: 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest110 :229 –238,2002[CrossRef][Medline]
  3. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science311 :1770 –1773,2006[Abstract/Free Full Text]
  4. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R: Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med349 :446 –456,2003[Abstract/Free Full Text]
  5. Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernán MA, Camargo CA Jr, Thadhani R: Activated injectable vitamin D and hemodialysis survival: A historical cohort study. J Am Soc Nephrol16 :1115 –1125,2005[Abstract/Free Full Text]
  6. Tentori F, Hunt WC, Stidley CA, Rohrscheib MR, Bedrick EJ, Meyer KB, Johnson HK, Zager PG, Medical Directors of Dialysis Clinic Inc.: Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int70 :1858 –1865,2006[CrossRef][Medline]
  7. Shoji T, Shinohara K, Kimoto E, Emoto M, Tahara H, Koyama H, Inaba M, Fukumoto S, Ishimura E, Miki T, Tabata T, Nishizawa Y: Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant19 :179 –184,2004[Abstract/Free Full Text]
  8. Al-Aly Z: Vitamin D as a novel nontraditional risk factor for mortality in hemodialysis patients: The need for randomized trials. Kidney Int72 :909 –911,2007[CrossRef][Medline]
  9. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani R: Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int72 :1004 –1013,2007[CrossRef][Medline]
  10. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W: Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med168 :1340 –1349,2008[Abstract/Free Full Text]
  11. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ: Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: Mechanisms for inflammatory damage in chronic disorders? QJM95 :787 –796,2002[Abstract/Free Full Text]
  12. Rahman A, Hershey S, Ahmed S, Nibbelink K, Simpson RU: Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. J Steroid Biochem Mol Biol103 :416 –419,2007[CrossRef][Medline]
  13. London GM, Guerin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Mëtivier F: Mineral metabolism and arterial functions in end-stage renal disease: Potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol18 :613 –620,2007[Abstract/Free Full Text]
 

Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. Am J Physiol Regul Integr Comp Physiol 294: R1675–R1683, 2008 Martino TA, Oudit GY, Herzenberg AM, Tata N, Koletar MM, Kabir GM, Belsham DD, Backx PH, Ralph MR, Sole MJ

Circadian rhythms (1) play a dramatic role in the regulation of cardiovascular (2,3) and renal (4–8) physiology and pathophysiology. Adverse cardiac events such as heart attacks or strokes show significant diurnal variations (3). A disrupted diurnal rhythm is found particularly in patients with mental disorders (9,10) or sleep-onset insomnia (11), transmeridian flight crews or time zone changes (12), shift work (13), and aging (14); in these groups the cardiovascular problems are more frequent (15,16). This issue is of particular note for the nephrologist because sleep disturbances (17–19) and abnormal autonomic rhythms (20–22) are commonly found in patients with uremia; they are attenuated or disappear after renal transplantation.

Against this background, the recent study by Martino et al. of golden hamsters with a genetically caused disruption of the circadian rhythm is of considerable interest. It had been known for a long time that life expectancy is reduced for some organisms when they are raised in light-dark cycles the periods of which differ substantially from that of their own endogenous circadian rhythm. This was documented in the fly by Aschoff et al. (23). Hurd and Ralph (24) then showed in mammalians (golden hamster) that circadian organization influences health and longevity. They studied heterozygous hamsters that carry one copy of the period mutation tau, which results in speeding up the clock and causing age-dependent fragmentation of rhythmic locomotor behavior in a running wheel worsening with age. In these genetically modified golden hamsters, environmentally induced rhythm disruption (e.g., by light/dark cycle out of phase with the endogenous biorhythm) reduced longevity. In contrast, the rhythm was reconsolidated by successful grafting of a fetal suprachiasmatic nucleus where the "master clock" is located.


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Martino et al. (25) now carried this one step forward to find out which organ pathology was associated with this altered circadian organization. To this end they studied the above model of golden hamsters carrying the known circadian period mutation tau (24,26). This mutant allele reduces the circadian period from approximately 24 h in the wild type to approximately 22 h in +/tau heterozygotes. Their longevity is compromised: When these animals are "entrained" (i.e., exposed to a 24-h light-dark cycle), their nocturnal behavior is phase-advanced with significant fragmentation of diurnal activity. The study of Martino et al. now documents that such disrupted circadian organization is involved in the genesis of severe cardiac and renal disease, thereby explaining early death in the +/tau mutant.

In +/tau animals on 24-h light-dark cycles, the authors found marked cardiomyopathy characterized by interstitial fibrosis and widespread collagen deposition. This was associated with impaired cardiac function documented by catheterization and transthoracic echocardiography. Catheterization showed hypotension with markedly decreased systolic, diastolic, and mean arterial pressures; diastolic dysfunction with significantly increased left ventricular end diastolic pressure; and reduced myocardial contractility assessed as dP/dtmax. Transthoracic echocardiography confirmed impaired myocardial contractility by showing elevated left ventricular end diastolic diameter and left ventricular end systolic diameter, respectively.

It is interesting that cardiopathology was restricted to the heterozygotes +/tau. The homozygous tau/tau hamsters were unable to synchronize with a 24-h/d rhythm, failed to show circadian dysregulation, and did not develop cardiac pathology.

As a chance finding, the authors also noted renal abnormalities: Proximal tubular dilation and tubular cells exhibiting regenerative and degenerative changes; pathology suggestive of glomerular ischemia was also noted, and collagen deposition occurred throughout the renal cortex. These findings were accompanied by proteinuria. The terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling assay showed presence of DNA fragments that resulted from apoptotic signaling cascades in the tubules.

These abnormalities were slow in evolution. At 4 mo of age, no cardiac or renal abnormalities were demonstrable. When at 4 mo of age the animals were exposed to the light-dark cycle appropriate for their phenotype, no abnormalities were noted. Similarly, when the suprachiasmatic nucleus was destroyed (i.e., when the master circadian oscillator was eliminated so that there was no conflict between the central oscillator and the peripheral oscillators in heart and kidney), no pathology of heart and kidney was observed.


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This study documents severe organ pathology that resulted from the conflict between the central clock and the peripheral clocks in different organs (27–30). It may provide a new dimension and perspective on widely known pathologies of the circadian rhythm in patients with uremia.

Sleep disorders are common in dialysis patients, and insomnia is reported in almost 70% of elderly dialysis patients; sleep apnea syndrome, restless leg syndrome, and comorbidity increase the risk (17). It is interesting that kidney transplantation reverses the restless leg syndrome as well as the sleep apnea syndrome and excessive daytime sleepiness (17). One case report suggested that parathyroidectomy improves the quality of sleep in dialyses patients with severe hyperparathyroidism (31); this is not a consistent observation and is certainly not generally applicable.

A high frequency of sleep disorders has also been reported in two large Asian studies: Chen et al. (18) studied patients who were on hemodialysis using the Pittsburgh sleep quality index, the Epworth sleepiness scale, the Berlin questionnaire, and a questionnaire related to periodic limb movement. Sleep disturbances were common—insomnia (66%) and daytime sleepiness (17.8%)—and both commonly were associated with the restless leg syndrome. In 201 patients who were on continuous ambulatory peritoneal dialysis (32), daytime sleepiness was the most frequent symptom (77.1%), and frequent awakening occurred in 69% of patients. A confounding factor is the administration of the use of hypnotic drugs (33); another potential cause is poor quality of dialysis (19).

Evidence of the fragmentation of autonomic rhythms is provided by the impact of dialysis procedure on the variability of heart rate and duration of hypoxemia during sleep (34,35) as well as the finding of abnormal cardiovascular (36) and endocrine (37) biorhythms. The role of kidney malfunction as an index of cardiac autonomic neuropathy is illustrated by—at least partial—reversal after transplantation (21) and reversal of abnormal diurnal rhythm of BP (38).


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