Chronic Kidney Disease at High Altitude : Journal of the American Society of Nephrology

Journal Logo

UP FRONT MATTERS

Chronic Kidney Disease at High Altitude

Luks, Andrew M.*; Johnson, Richard J.; Swenson, Erik R.*, ‡

Author Information
Journal of the American Society of Nephrology 19(12):p 2262-2271, December 2008. | DOI: 10.1681/ASN.2007111199
  • Free

Abstract

With the increasing popularity of travel to and residence in mountainous regions (E.G., 15% of Colorado citizens live above 2100 m) and the 10 to 11% prevalence rate for adult chronic kidney disease (CKD) in the developed world,1 it is likely that many people with CKD will visit or reside at high altitude. Although the adverse effects of high altitude are well defined for healthy individuals, little is known about the risks and management strategies for patients with CKD. Even in the healthy kidney, regions of marginal oxygenation arise from the complex structure–function relationships of normal renal physiology. Coupled with emerging evidence of a critical role of intrarenal hypoxia in the pathogenesis of CKD,24 there is reasonable concern that arterial hypoxemia during long-term high-altitude exposure and its neurohumoral responses could worsen intrarenal oxygenation and accelerate progression of CKD to ESRD. In this review, we discuss what is known about the effects of high altitude on patients with CKD.

NORMAL KIDNEY PHYSIOLOGY AT HIGH ALTITUDE

Changes in renal function at high altitude arise from the direct effects of hypoxia on the kidney as well as from multiple compensatory adaptations, including changes in ventilation, cardiac output, sympathetic nervous activity, and erythropoiesis. Urine output and sodium excretion vary with the inspired partial pressure of oxygen (Po2). Diuresis and natriuresis with accompanying potassium and bicarbonate excretion occur with acute reductions of inspired oxygen (Figure 1) and are mediated by oxygen-sensitive peripheral chemoreceptors.5,6 Urine and serum osmolality are not altered because volume and solute output rise in parallel.7 As with the hypoxic ventilatory response mediated by the peripheral chemoreceptors, acute hypoxic diuretic and natriuretic responses during the first 24 to 48 h vary almost 10-fold among individuals. The efferent signaling pathway is not linked to changes in renin, angiotensin, aldosterone, atrial natriuretic peptide, vasopressin, endogenous digitalis-like substances, or inhibition of renal sympathetic tone.5 This may be due to the known effect of hypoxia to increase nitric oxide (NO) release (via stimulation of hypoxia-inducible factor [HIF-1α]), although this has not been formally examined. With severe hypoxia, (fraction of inspired oxygen < 0.1), antidiuresis and sodium retention ensue as a result of intense sympathetic nervous system activation and increased upregulation of angiotensin, aldosterone, and vasopressin.5 After acclimatization, individuals may again experience diuresis and natriuresis with further elevation in altitude.8

Renal blood flow (RBF) increases 8 to 20% during acute hypoxia,911 then returns to baseline after several days.11,12 The effect on GFR is similar.12,13 In high-altitude residents, RBF is decreased 12% and renal plasma flow by 30 to 40% largely as a result of secondary polycythemia. Because the filtration fraction increases by 39%, however, GFR falls by only 12%.14,15 In addition, whole organ oxygen delivery, arteriovenous content gradients, and consumption are also maintained at levels equal to sea-level values.16 Similar findings are present in chronically hypoxic rats.17

Because RBF is maintained with acute mild to moderate hypoxia, tubular function remains unaltered.5 Tubular characteristics, including tubular maximum for glucose, and organic acid and β2-microglobulin excretion are preserved over a wide range of inspired oxygen concentrations.10,18,19 Long-term residence above 4500 m may reduce RBF and GFR, but tubular function is maintained because a lower GFR reduces reabsorptive work and oxygen consumption. Sodium excretion in response to angiotensin infusion and the capacity to excrete water and salt loads and maximally concentrate urine with water deprivation or vasopressin are also preserved in chronic hypoxia.14,20,21 The intact responses to water loading and deprivation occur even though high-altitude natives have lower total body water content than lowlanders (42 versus 52% of total body weight).20

Acute hypoxia generates acute hypocapnia. Over several days, the kidneys increase bicarbonate excretion to compensate for this respiratory alkalosis, thereby blunting the inhibitory effect of respiratory alkalosis on the hypoxic ventilatory response and improving oxygenation over time at altitude. The compensatory response is largely independent of sodium intake and, thus, does not seem to be linked to the natriuretic effect of hypoxia.22 Acid-base regulation is maintained in high-altitude natives.14

Acute hypoxia causes a two- to three-fold increase in urinary protein excretion.23,24 The mechanism is unclear but may involve changes in capillary permeability,19 glomerular filtration,25 or tubular reabsorption of protein.26 Proteinuria is greater in patients at high altitude who smoke and have hyperlipidemia27 and in those who develop high-altitude illness.24,28

In response to a low arterial Po2, cortical interstitial cells increase erythropoietin production by stimulating HIF-2α.29 The subsequent rise in hematocrit helps maintain tissue oxygen delivery. Erythropoietin release begins 1 to 2 h after hypoxic exposure, peaks at 24 to 48 h, and declines to baseline over several weeks as the hematocrit rises and feedback suppression occurs.30 Subsequent ascents to higher elevations generate new erythropoietin production.31

Owing to its high perfusion (1 L/min fully oxygenated blood), the kidney is not conventionally thought to be hypoxic, yet as a consequence of its complex structure–function relationships and marked perfusion–metabolism heterogeneity, which subserve its ability to form a substantial glomerular filtrate and then concentrate or dilute it as needed, regions of the kidney, particularly the outer medulla, are marginally oxygenated even at sea level. Microelectrode and spectroscopic Po2 measurements in normoxic blood-perfused kidneys reveal considerable variations in regional Po23236 and remarkably low oxygen tensions in the medulla. Although mean cortical Po2 is 40 to 60 mmHg and mean medullary Po2 is approximately 10 to 15 mmHg, there is a wide variation, resulting in 1 to 10% of the cortex and 10 to 30% of the medulla having Po2 values as low as 10 mmHg (Figure 2).37 In cortical regions, low Po2 values result from a preglomerular oxygen diffusion shunt arising from close proximity of preglomerular arterioles and adjoining veins.34 Three reasons account for the lower medullary Po2: Reduced perfusion (10%) relative to the cortex, countercurrent circulation that creates an arteriovenous diffusion shunt, and high metabolic demands from mitochondria-rich proximal and medullary thick ascending limb tubular epithelial cells.38 These regions thus verge on a borderline hypoxic state with little reserve for compromised oxygen delivery or increased metabolic demands. In fact, even in normoxic individuals, medullary regions are vulnerable to hypoxic injury, such as acute tubular necrosis from transient anoxic insults.39

Few studies have investigated how arterial hypoxemia might further impair marginal renal oxygenation. In rats breathing 10% O2 (equivalent to an altitude of 5600 m), mean cortical Po2 declined from 30 ± 6 to 12 ± 2 mmHg, and medullary Po2 declined from 15 ± 3 to 6 ± 1 mmHg.40 Another study using similar hypoxic conditions showed that the mean cortical Po2 fell from 61 ± 9 to 39 ± 5 mmHg and medullary Po2 declined from 39 ± 5 to 15 ± 2 mmHg.33 This study also found that 10% O2 increased the fraction of cortex below 7.5 mmHg from 5 to 62% and the fraction of medulla below the same threshold from 10 to 76% (Figure 3). Reflecting this hypoxic stress, healthy rats, after 6 h at an equivalent altitude of 5600 m, demonstrated subtle microvascular (endothelial cell swelling) and tubulointerstitial injury, inflammation, and fibrosis involving primarily the medulla but also the cortex.41 To place these results in perspective, 5600 m is well above the highest permanent human settlements and is generally reached only by skilled mountaineers; there are no data for more relevant altitudes of 2500 to 4500 m.

Other factors that may exacerbate renal hypoxia include anemia and hypertension. Severe normovolemic hemodilution (hemoglobin 7.7 g/dl) in healthy rats reduced cortical microvascular Po2 from 70 to 37 mmHg and medullary Po2 from 53 to 28 mmHg.42 The combined effects of anemia and hypoxemia on renal oxygenation may be more severe in diseased kidneys, because, as nephrons are lost, oxygen consumption in remaining hyperfunctioning nephrons increases.43 Hypertension may also create further hypoxic stress as suggested by data in normoxic hypertensive rats, in which renal cortical Po2 was 10 mmHg lower and O2 cost of Na+ reabsorption was higher than in normotensive rats,44 possibly as a result of reduced NO production from decreased NO synthase expression.45

Although many regions of the “normoxic” kidney are at the threshold of classic “hypoxia,” there is little evidence of subsequent injury or altered function in individuals without kidney disease at sea level and/or high altitude. The protective cellular mechanisms include activation of hypoxia-induced transcription factors (HIF-1α and HIF-2α), which stimulate production of erythropoietin, heme oxygenase (generating the antioxidant carbon monoxide), inducible and endothelial NO synthase–mediated NO production, enzymes, and angiogenic factors,46 all of which improve O2 delivery and/or utilization. In addition, the acute natriuretic effect of hypoxia may be protective by decreasing the metabolic work of sodium reabsorption and oxygen consumption. The protective mechanisms engaged with acute hypoxic exposure, including HIF production, may not be sustained with chronic hypoxia47 and aging,48 which, in turn, lead to progressive microvascular loss as a result of decreased expression of vascular endothelial growth factor and other cytoprotective molecules.41

PATIENTS WITH KIDNEY DISEASE AT HIGH ALTITUDE

To date, few studies have addressed the effects of acute or chronic altitude exposure on patients with preexisting kidney disease. It is unlikely that substantive pathophysiologic studies will be done in CKD at sea level compared with high altitude for reasons of low number of study patients and various ethical reasons. Drawing on the limited available literature and an understanding of the pathophysiology of kidney disease, it is possible, however, to draw tentative conclusions about potential outcomes at high altitude.

Because renal insufficiency impairs urinary concentration and dilution capacity, there could be an increased risk for either volume depletion or overload. Although there is no direct evidence of impaired diuretic responses to hypoxia in patients with CKD, there is some evidence that hemodialysis patients may be at increased risk for volume overload, which may predispose to pulmonary edema and greater arterial hypoxemia. Although patients with lesser degrees of renal insufficiency have not been studied, dialysis-dependent patients at a modest altitude of 2000 m for 2 wk had greater weight gain (0.7 ± 0.3 kg) between dialysis sessions than at 576 m.49 The cause of this greater weight gain was not investigated.

As a result of impaired erythropoietin production and shortened red cell survival,50 patients with CKD do not have the expected erythropoietic response to high altitude and show little to no change in hemoglobin concentration, reticulocyte count, and erythropoietin production over 2 wk at altitudes between 2000 and 4600 m.5153 Reduced oxygen delivery arising from failure to increase red cell mass may be partially mitigated by changes in hemoglobin–O2 affinity, but limited data do not consistently demonstrate significant changes in 2,3 diphosphoglycerate or hemoglobin P50.51,52 Whereas hematocrits of 30 to 34% may be adequate at sea level, the impaired hematologic compensation at high altitude may decrease oxygen delivery and limit physical activity.

Last, patients with CKD often have coexisting cardiovascular disease from comorbidities such as diabetes and hypertension,54 which put them at risk for cardiac complications at high altitude. The interaction between heart disease and high altitude has been reviewed elsewhere.55

Travel to high altitude predisposes all individuals to several acute illnesses: Acute mountain sickness (AMS), high-altitude cerebral edema, or high-altitude pulmonary edema (HAPE). The clinical features and management of these diseases have been reviewed elsewhere5658 and are summarized in Tables 1 and 2, respectively. Unfortunately, no studies have evaluated the risks of these illnesses in patients with CKD and whether proven prophylactic therapies for healthy people are effective in this population.

From a theoretical standpoint, by stimulating ventilation and increasing arterial Po2, the mild metabolic acidosis of renal insufficiency might protect against AMS, assuming that all other aspects of their kidney disease have little to no impact on acute altitude tolerance. All individuals develop a hypoxic ventilatory response at high altitude, which results in hypocapnia and respiratory alkalemia. The ventilatory response is blunted to some degree by the alkalemia, but the full response is restored over a period of 1 to 2 d by renal compensation. Any preexisting metabolic acidosis, however, may help maintain greater ventilation during the initial period at high altitude and better defend the arterial Po2 when compared with a patient who has normal renal function and will require more time or the use of the carbonic anhydrase inhibitor acetazolamide to reach similar levels of bicarbonate loss.59 Given that a poor hypoxic ventilatory response at high altitude may predispose to AMS,6062 mild metabolic acidosis might, therefore, be protective.

Despite this potential protective effect, several aspects of CKD may heighten the risk for altitude illness. Anemia could decrease oxygen delivery and predispose to AMS. Furthermore, metabolic acidosis enhances hypoxic pulmonary vasoconstriction,63 which, given the central role of exaggerated hypoxic pulmonary vasoconstriction in the pathophysiology of HAPE, could unmask or exacerbate this acute altitude illness.57 In ESRD, there is also a 40% prevalence of mild to moderate pulmonary hypertension of unknown cause.64 Because HAPE can develop in patients with various forms of pulmonary hypertension,6567 patients with ESRD and similar pulmonary hemodynamics may have a heightened risk for this complication. Whether the prevalence of pulmonary hypertension is as high in patients with CKD before dialysis has not been studied.

Chronic systemic hypoxia associated with long-term residence at high altitude may also contribute to renal progression in patients with CKD. Renal hypoxia has a central role in the progression of renal insufficiency.24 The mechanisms by which this effect occurs are displayed in Figure 4.2 Glomerulosclerosis and tubulointerstitial disease damage renal arterioles and peritubular capillaries, leading to diminished vascular supply to the tubules.68 Interstitial fibrosis compounds the hypoxia by altering the diffusion distance between viable vessels and remaining functional tubules. In animal models of renal injury, semiquantitative intrarenal Po2 measurements revealed greater intrarenal hypoxia, beyond that detected normally in the medulla of healthy kidneys.4 Severe hypoxia activates fibroblasts69 and induces tubular epithelial-mesenchymal transition.2,70 Chronic hypoxia also increases expression of thrombospondin 1, an antiangiogenic factor, decreases expression of vascular endothelial growth factor,71 and triggers production of hypoxia-inducible transcription factors whose downstream targets exert both pro- and antiapoptotic effects.3 Finally, hypoxia produces oxidative stress in the rat kidney without a parallel upregulation of antioxidant enzymes.72 In humans, this effect is reflected by increased urinary excretion of 8-isoPGF2a, an oxidation product of arachidonic acid.73

Given that proteinuria is a marker of and possible contributor to the progression of kidney disease,74,75 increased protein excretion seen at high altitude may also be problematic. Of additional concern is that protein reabsorption may carry high energy and, therefore, oxygen costs for the kidney. Recent data suggested that as the healthy kidney filters nephrotic-range amounts of albumin, the work of near-complete retrieval by the proximal tubule may not be trivial.76 Because endocytotic protein reabsorption requires energy,77 increased protein reuptake could lower intrarenal Po2. Tubular cells are also activated by luminal protein to produce chemoattractants, proinflammatory and profibrotic cytokines, and matrix proteins,78 which stimulate interstitial inflammation and fibrosis, processes that might also increase local oxygen consumption and decrease intrarenal Po2.

These considerations lead us to propose that long-term high-altitude residence in patients with CKD may lead to faster progression to ESRD when compared with sea-level residence. Limited reports suggested that this concern may be warranted. Navajo Indians living at altitude between 1600 and 3200 m, for example, have a four-fold higher rate of ESRD than the average American population and twice that of all Native Americans, most of whom live at lower elevations.79 Although other factors including diabetes, income, and access to medical care were considered possible determinants in this study, the role of altitude was not considered. A comparison of outcomes in patients with type 2 diabetes and nephropathy living at sea level and at an elevation of 1700 m showed that despite similar glycemic control, high-altitude residents had greater protein excretion (146 versus 89 μg/min), higher prevalence of proteinuria (57 versus 33%), higher serum creatinine levels (1.04 versus 0.84 mg/dl), and lower GFR (83 versus 91 ml/min) than the sea-level residents80; however, this study did not include data on disease progression or the need for dialysis.

In the absence of direct evidence for an adverse effect of high altitude on CKD progression, one might consider diseases causing nephropathy and evaluate whether their control is worse at high altitude. The data on glycemic control in patients with diabetes81,82 and BP control in nonhypertensive individuals8386 at high altitude are mixed. No equivalent studies have been undertaken of individuals with baseline hypertension. The important point is that some individuals do experience loss of glycemic and BP control that could lead to decline of renal function.

PHARMACOLOGY AT HIGH ALTITUDE IN PATIENTS WITH KIDNEY DISEASE

With both short- and long-term high altitude exposure, consideration should be given to the proper management of patients’ preexisting medications and the selection of medications for the management of high-altitude illness. Patients who have CKD and ascend to high altitude for short periods should remain on their regular medications, and, in most cases, dosage adjustments should not be necessary. Those on diuretic therapy should be advised to monitor their weight daily and increase their diuretic dosage accordingly if weight gain occurs or if fluid retention develops with AMS. Given the uncertainty regarding BP and glycemic control at high altitude, we recommend close monitoring of any patient with CKD, with the anticipation that further treatment might be necessary in some individuals. Analgesia with nonsteroidal anti-inflammatory drugs should be avoided because of their ability to inhibit cyclo-oxygenase–mediated renal vasodilation (reduced O2 delivery) and stimulate sodium reabsorption (increased O2 consumption).

The impact of greater proteinuria at high altitude80 is unknown, but, because proteinuria is associated with progressive renal function decline,74,75 it may be important to limit its increase with angiotensin-converting enzyme (ACE) inhibition.87 For patients who are already on an ACE inhibitor, one might add an angiotensin II receptor blocker, because combined therapy can further decrease proteinuria.88,89 Although renin-angiotensin system blockade blunts renal erythropoietin formation and possibly responsiveness,90,91 we do not believe it is warranted to withhold ACE inhibitors or angiotensin II receptor blockers at high altitude. Instead, these medications can be used with close follow-up of the patient's hematologic status, BP, and erythropoietin requirements.

Patients on multiple medications for BP control should consider avoiding treatment with nifedipine or other dihydropyridine calcium channel blockers, which can increase proteinuria.92,93 Although tolerable for a few days if nifedipine use is necessary for HAPE prophylaxis or treatment, a sustained increased proteinuria at high altitude would be of concern.

Although it is obvious that anemia and failure to mount an erythropoietic response at high altitude may be problematic for patients with CKD, the appropriate erythropoietin dosing and hemoglobin goal are unknown. The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines94 limit sea-level hemoglobin levels to 11 to 12 g/dl because of concerns of hypertension, thrombosis, and increased cardiovascular mortality with higher targeting. Interestingly, despite their suppressed erythropoietin responses at high altitude, studies of patients with CKD found they needed smaller dosages compared with sea-level requirements and had more thrombotic events and hypertension than with conventional dosing.95,96 These surprising findings therefore preclude any firm recommendations beyond that of close monitoring of hematocrit and erythropoietin dosage.

Although undertaking an appropriately slow ascent remains the best means to prevent high-altitude illness and descent remains the most effective treatment, pharmacologic measures are sometimes necessary for these purposes. Table 2 presents dosing recommendations for the standard medications used in the prevention and treatment of altitude illness for patients with CKD. These recommendations and their rationale have been reviewed more thoroughly elsewhere.97 Physicians should also consider a supervised trial of any prophylactic medication deemed necessary to determine whether it can be tolerated before travel to high altitude.

CONCLUSIONS AND DIRECTIONS FOR FUTURE RESEARCH

Limited available data suggest that patients with CKD can tolerate short-term stays at modest altitudes, but theoretical considerations point to a faster progression to ESRD. Further research is warranted to define these risks better and should include basic research on the effects of clinically relevant inspired Po2 levels on renal function; well-designed epidemiologic studies to address critical factors such as BP, hematocrit, erythropoietin dosing, proteinuria, and rate of GFR decline between high-altitude and low-altitude populations; and clinical trials designed to assess the best means for reducing proteinuria and slowing kidney disease progression at high altitude. Finally, studies on acute altitude illness should include patients with CKD to permit these patients to enjoy the mountain environment more safely.

DISCLOSURES

None.

F1-7
Figure 1:
Summary of 32 high-altitude and normobaric hypoxic studies of humans in which sodium excretion was measured between 1 and 24 h of indicated fractional inspired oxygen (Fio2). Sodium excretion with hypoxia is given as the percentage change above or below the preceding normoxic baseline period. Reprinted with permission from reference.5
F2-7
Figure 2:
Stepwise reduction in Fio2 resulted in a decline in cortical (dark blue bars) and medullary (light blue bars) microvascular Po2 (μPo2). Data are means ± SD; n = 5. Reprinted with permission from reference.33
F3-7
Figure 3:
Histograms showing oxygen distributions in the cortex (top) and outer medulla (bottom) of the rat kidney at 10 and 20% inspired oxygen. Reprinted with permission from reference.33
F4-7
Figure 4:
Multiple mechanisms of chronic hypoxia in the kidney. (A through G) Mechanisms of hypoxia in the kidney of patients with CKD include loss of peritubular capillaries (A), decreased oxygen diffusion from peritubular capillaries to tubular and interstitial cells as a result of fibrosis of the kidney (B), stagnation of peritubular capillary blood flow induced by sclerosis of “parent” glomeruli (C), decreased peritubular capillary blood flow as a result of imbalance of vasoactive substances (D), inappropriate energy use as a result of uncoupling of mitochondrial respiration induced by oxidative stress (E), increased metabolic demands of tubular cells (F), and decreased oxygen delivery as a result of anemia (G). Reprinted with permission from reference.2
T1-7
Table 1:
Summary of clinical features and management of acute high-altitude illnessesa
T2-7
Table 2:
Dosing of altitude illness medications in patient with and without CKD

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

REFERENCES

1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41: 1–12, 2003
2. Nangaku M: Chronic hypoxia and tubulointerstitial injury: A final common pathway to end-stage renal failure. J Am Soc Nephrol 17: 17–25, 2006
3. Eckardt KU, Bernhardt WM, Weidemann A, Warnecke C, Rosenberger C, Wiesener MS, Willam C: Role of hypoxia in the pathogenesis of renal disease. Kidney Int Suppl S46–S51, 2005
4. Fine NG, Norman JT: Chronic hypoxia as a mechanism of progression of chronic kidney disease: from hypothesis to novel therapeutics. Kidney Int 74: 867–872, 2008
5. Swenson ER: Renal function and fluid homeostasis. In: High Altitude: An Exploration of Human Adaptation, edited by Hornbein TF, Schoene RB, New York, Marcel Dekker, 2001, pp 525–568
6. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalosis: The effect of sustained hyperventilation on renal regulation of acid-base equilibrium. N Engl J Med 324: 1394–1401, 1991
7. Ullmann E: Acute anoxia and the excretion of water and electrolyte. J Physiol 155: 417–437, 1961
8. Loeppky JA, Roach RC, Selland MA, Scotto P, Luft FC, Luft UC: Body fluid alterations during head-down bed rest in men at moderate altitude. Aviat Space Environ Med 64: 265–274, 1993
9. Ashack R, Farber MO, Weinberger MH, Robertson GL, Fineberg NS, Manfredi F: Renal and hormonal responses to acute hypoxia in normal individuals. J Lab Clin Med 106: 12–16, 1985
10. Axelrod DR, Pitts RF: Effects of hypoxia on renal tubular function. J Appl Physiol 4: 593–601, 1952
11. Vidiendal Olsen N, Christensen H, Klausen T, Fogh-Andersen N, Plum I, Kanstrup IL, Hansen JM: Effects of hyperventilation and hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans. Anesthesiology 89: 1389–1400, 1998
12. Olsen NV, Kanstrup IL, Richalet JP, Hansen JM, Plazen G, Galen FX: Effects of acute hypoxia on renal and endocrine function at rest and during graded exercise in hydrated subjects. J Appl Physiol 73: 2036–2043, 1992
13. Pauli HG, Truniger B, Larsen JK, Mulhausen RO: Renal function during prolonged exposure to hypoxia and carbon monoxide: II. Electrolyte handling. Scand J Clin Lab Invest Suppl 103: 61–67, 1968
14. Winslow RM, Monge C: Renal function in high-altitude polycythemia. In: Hypoxia, Polycythemia, and Chronic Mountain Sickness, edited by Winslow RM, Monge C, Baltimore, Baltimore, Johns Hopkins University Press, 1987, pp 119–141
15. Lozano R, Monge C: Renal function in high-altitude natives and in natives with chronic mountain sickness. J Appl Physiol 20: 1026–1027, 1965
16. Rennie D, Lozano R, Monge C, Sime F, Whittembury J: Renal oxygenation in male Peruvian natives living permanently at high altitude. J Appl Physiol 30: 450–456, 1971
17. Ou LC, Silverstein J, Edwards BR: Renal function in rats chronically exposed to high altitude. Am J Physiol 247: F45–F49, 1984
18. Brull L, Divry A: Metabolic and secretory activity of the kidney under anoxemia. Arch Int Physiol 58: 415–423, 1951
19. Hansen JM, Olsen NV, Feldt-Rasmussen B, Kanstrup IL, Dechaux M, Dubray C, Richalet JP: Albuminuria and overall capillary permeability of albumin in acute altitude hypoxia. J Appl Physiol 76: 1922–1927, 1994
20. Ramirez G, Pineda D, Bittle PA, Rabb H, Rosen R, Vesely D, Sasaki S: Partial renal resistance to arginine vasopressin as an adaptation to high altitude living. Aviat Space Environ Med 69: 58–65, 1998
21. Ramirez G, Bittle PA, Agosti SJ, Dietz J, Colice GL: Salt loading test in a population adapted to moderately high altitude living (3,000 m). Aviat Space Environ Med 64: 831–838, 1993
22. Hohne C, Boemke W, Schleyer N, Francis RC, Krebs MO, Kaczmarczyk G: Low sodium intake does not impair renal compensation of hypoxia-induced respiratory alkalosis. J Appl Physiol 92: 2097–2104, 2002
23. Winterborn MH, Bradwell AR, Chesner IM, Jones GT: The origin of proteinuria at high altitude. Postgrad Med J 63: 179–181, 1987
24. Pines A: High-altitude acclimatization and proteinuria in East Africa. Br J Dis Chest 72: 196–198, 1978
25. Olsen NV, Hansen JM, Kanstrup IL, Richalet JP, Leyssac PP: Renal hemodynamics, tubular function, and response to low-dose dopamine during acute hypoxia in humans. J Appl Physiol 74: 2166–2173, 1993
26. Rosenberg ME, Hostetter TE: Proteinuria. In: The Kidney: Physiology and Pathophysiology, edited by Seldin DW, Giebisch G, New York, Raven, 2000, pp 3039–3061
27. Wada K, Mizuguchi Y, Wada Y, Ohno Y, Iino Y: Hyperlipidaemia, lack of sleep and smoking as risk factors for proteinuria among high altitude mountain trekkers. Nephrology (Carlton) 11: 131–136, 2006
28. Bradwell AR, Delamere JP: The effect of acetazolamide on the proteinuria of altitude. Aviat Space Environ Med 53: 40–43, 1982
29. Eckardt KU, Kurtz A: Regulation of erythropoietin production. Eur J Clin Invest 35 [Suppl 3]: 13–19, 2005
30. Schmidt W, Spielvogel H, Eckardt KU, Quintela A, Penaloza R: Effects of chronic hypoxia and exercise on plasma erythropoietin in high-altitude residents. J Appl Physiol 74: 1874–1878, 1993
31. Knaupp W, Khilnani S, Sherwood J, Scharf S, Steinberg H: Erythropoietin response to acute normobaric hypoxia in humans. J Appl Physiol 73: 837–840, 1992
32. Leichtweiss HP, Lubbers DW, Weiss C, Baumgartl H, Reschke W: The oxygen supply of the rat kidney: Measurements of intrarenal pO2. Pflugers Arch 309: 328–349, 1969
33. Johannes T, Mik EG, Ince C: Dual-wavelength phosphorimetry for determination of cortical and subcortical microvascular oxygenation in rat kidney. J Appl Physiol 100: 1301–1310, 2006
34. Schurek HJ, Jost U, Baumgartl H, Bertram H, Heckmann U: Evidence for a preglomerular oxygen diffusion shunt in rat renal cortex. Am J Physiol 259: F910–F915, 1990
35. Baumgartl H, Leichtweiss HP, Lubbers DW, Weiss C, Huland H: The oxygen supply of the dog kidney: Measurements of intrarenal pO2. Microvasc Res 4: 247–257, 1972
    36. Lubbers DW, Baumgartl H: Heterogeneities and profiles of oxygen pressure in brain and kidney as examples of the pO2 distribution in the living tissue. Kidney Int 51: 372–380, 1997
    37. Epstein FH: Oxygen and renal metabolism. Kidney Int 51: 381–385, 1997
    38. Evans RG, Gardiner BS, Smith DW, O'Connor PM: Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis. Am J Physiol Renal Physiol 2008 Jun 11 [Epub ahead of print]
    39. Nakagawa T, Kang DH, Ohashi R, Suga S, Herrera-Acosta J, Rodriguez-Iturbe B, Johnson RJ: Tubulointerstitial disease: Role of ischemia and microvascular disease. Curr Opin Nephrol Hypertens 12: 233–241, 2003
    40. Leong CL, Anderson WP, O'Connor PM, Evans RG: Evidence that renal arterial-venous oxygen shunting contributes to dynamic regulation of renal oxygenation. Am J Physiol Renal Physiol 292: F1726–F1733, 2007
    41. Mazzali M, Jefferson JA, Ni Z, Vaziri ND, Johnson RJ: Microvascular and tubulointerstitial injury associated with chronic hypoxia-induced hypertension. Kidney Int 63: 2088–2093, 2003
    42. Johannes T, Mik EG, Nohe B, Unertl KE, Ince C: Acute decrease in renal microvascular PO2 during acute normovolemic hemodilution. Am J Physiol Renal Physiol 292: F796–F803, 2007
    43. Nath KA, Croatt AJ, Hostetter TH: Oxygen consumption and oxidant stress in surviving nephrons. Am J Physiol 258: F1354–F1362, 1990
    44. Welch WJ, Baumgartl H, Lubbers D, Wilcox CS: Nephron pO2 and renal oxygen usage in the hypertensive rat kidney. Kidney Int 59: 230–237, 2001
    45. Adler S, Huang H: Impaired regulation of renal oxygen consumption in spontaneously hypertensive rats. J Am Soc Nephrol 13: 1788–1794, 2002
    46. Haase VH: Hypoxia-inducible factors in the kidney. Am J Physiol 291: F271–F281, 2006
    47. Kang DH, Johnson RJ: Vascular endothelial growth factor: A new player in the pathogenesis of renal fibrosis. Curr Opin Nephrol Hypertens 12: 43–49, 2003
    48. Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA, Gordon KL, Oyama TT, Hughes J, Hugo C, Kerjaschki D, Schreiner GF, Johnson RJ: Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 37: 601–611, 2001
    49. Mairbaurl H, Schobersberger W, Hasibeder W, Knapp E, Hopferwieser T, Humpeler E, Loeffler HD, Wetzels E, Wybitul K, Baumgartl P, et al.: Exercise performance of hemodialysis patients during short-term and prolonged exposure to altitude. Clin Nephrol 32: 31–39, 1989
    50. Eschbach JW: Erythropoietin 1991: An overview. Am J Kidney Dis 18: 3–9, 1991
    51. Blumberg A, Keller H, Marti HR: Effect of altitude on erythropoiesis and oxygen affinity in anaemic patients on maintenance dialysis. Eur J Clin Invest 3: 93–97, 1973
    52. Mairbaurl H, Schobersberger W, Hasibeder W, Knapp E, Hopferwieser T, Dittrich P: Increase in Hb-O2-affinity at moderate altitude (2000 m) in patients on maintenance hemodialysis. Clin Nephrol 31: 198–203, 1989
    53. Quick J, Eichenberger A, Binswanger U: Stimulation of erythropoietin in renal insufficiency by hypobaric hypoxia. Nephrol Dial Transplant 7: 1002–1006, 1992
    54. Yao Q, Pecoits-Filho R, Lindholm B, Stenvinkel P: Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease. Scand J Urol Nephrol 38: 405–416, 2004
    55. Bartsch P, Gibbs JS: The effect of altitude on the heart and lungs. Circulation 116: 2191–2202, 2007
    56. Hackett PH, Roach RC: High-altitude illness. N Engl J Med 345: 107–114, 2001
    57. Bartsch P, Mairbaurl H, Maggiorini M, Swenson ER: Physiological aspects of high-altitude pulmonary edema. J Appl Physiol 98: 1101–1110, 2005
    58. Basnyat B Murdoch DR: High-altitude illness. Lancet 361: 1967–1974, 2003
    59. Swenson ER: Carbonic anhydrase inhibitors and ventilation: A complex interplay of stimulation and suppression. Eur Respir J 12: 1242–1247, 1998
    60. Hackett PH, Roach RC, Schoene RB, Harrison GL, Mills WJ Jr: Abnormal control of ventilation in high-altitude pulmonary edema. J Appl Physiol 64: 1268–1272, 1988
    61. King AB, Robinson SM: Ventilation response to hypoxia and acute mountain sickness. Aerosp Med 43: 419–421, 1972
      62. Moore LG, Harrison GL, McCullough RE, McCullough RG, Micco AJ, Tucker A, Weil JV, Reeves JT: Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness. J Appl Physiol 60: 1407–1412, 1986
      63. Lejeune P, Brimioulle S, Leeman M, Hallemans R, Melot C, Naeije R: Enhancement of hypoxic pulmonary vasoconstriction by metabolic acidosis in dogs. Anesthesiology 73: 256–264, 1990
      64. Abassi Z, Nakhoul F, Khankin E, Reisner SA, Yigla M: Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: Pathogenesis and therapeutic prospective. Curr Opin Nephrol Hypertens 15: 353–360, 2006
      65. Rios B, Driscoll DJ, McNamara DG: High-altitude pulmonary edema with absent right pulmonary artery. Pediatrics 75: 314–317, 1985
      66. Torrington KG: Recurrent high-altitude illness associated with right pulmonary artery occlusion from granulomatous mediastinitis. Chest 96: 1422–1424, 1989
        67. Naeije R, De Backer D, Vachiery JL, De Vuyst P: High-altitude pulmonary edema with primary pulmonary hypertension. Chest 110: 286–289, 1996
        68. Yu HT: Progression of chronic renal failure. Arch Intern Med 163: 1417–1429, 2003
        69. Norman JT, Clark IM, Garcia PL: Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 58: 2351–2366, 2000
        70. Manotham K, Tanaka T, Matsumoto M, Ohse T, Inagi R, Miyata T, Kurokawa K, Fujita T, Ingelfinger JR, Nangaku M: Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int 65: 871–880, 2004
        71. Kang DH, Joly AH, Oh SW, Hugo C, Kerjaschki D, Gordon KL, Mazzali M, Jefferson JA, Hughes J, Madsen KM, Schreiner GF, Johnson RJ: Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol 12: 1434–1447, 2001
        72. Nakanishi K, Tajima F, Nakamura A, Yagura S, Ookawara T, Yamashita H, Suzuki K, Taniguchi N, Ohno H: Effects of hypobaric hypoxia on antioxidant enzymes in rats. J Physiol 489: 869–876, 1995
        73. Jefferson JA, Simoni J, Escudero E, Hurtado ME, Swenson ER, Wesson DE, Schreiner GF, Schoene RB, Johnson RJ, Hurtado A: Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol 5: 61–69, 2004
        74. Ruggenenti P, Perna A, Mosconi L, Pisoni R Remuzzi G: Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int 53: 1209–1216, 1998
        75. Hunsicker LG, Adler S, Caggiula A, England BK, Greene T, Kusek JW, Rogers NL, Teschan PE: Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 51: 1908–1919, 1997
        76. Russo LM, Sandoval RM, McKee M, Osicka TM, Collins AB, Brown D, Molitoris BA, Comper WD: The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: retrieval is disrupted in nephrotic states. Kidney Int 71: 504–513, 2007
        77. Meyer TW: Tubular injury in glomerular disease. Kidney Int 63: 774–787, 2003
        78. Abbate M, Zoja C, Remuzzi G: How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17: 2974–2984, 2006
        79. Hochman ME, Watt JP, Reid R, O'Brien KL: The prevalence and incidence of end-stage renal disease in Native American adults on the Navajo reservation. Kidney Int 71: 931–937, 2007
        80. Sayarlioglu H, Erkoc R, Dogan E, Topal C, Algun E, Erem C, Atmaca H, Kocak E, Yilmaz R, Erdol H, Cinal A: Nephropathy and retinopathy in type 2 diabetic patients living at moderately high altitude and sea level. Ren Fail 27: 67–71, 2005
        81. Moore K, Vizzard N, Coleman C, McMahon J, Hayes R, Thompson CJ: Extreme altitude mountaineering and type 1 diabetes: The Diabetes Federation of Ireland Kilimanjaro Expedition. Diabet Med 18: 749–755, 2001
        82. Pavan P, Sarto P, Merlo L, Casara D, Ponchia A, Biasin R, Noventa D, Avogaro A: Extreme altitude mountaineering and type 1 diabetes: The Cho Oyu alpinisti in Alta Quota expedition. Diabetes Care 26: 3196–3197, 2003
        83. Bender PR, Groves BM, McCullough RE, McCullough RG, Huang SY, Hamilton AJ, Wagner PD, Cymerman A, Reeves JT: Oxygen transport to exercising leg in chronic hypoxia. J Appl Physiol 65: 2592–2597, 1988
        84. Wolfel EE, Groves BM, Brooks GA, Butterfield GE, Mazzeo RS, Moore LG, Sutton JR, Bender PR, Dahms TE, McCullough RE, et al.: Oxygen transport during steady-state submaximal exercise in chronic hypoxia. J Appl Physiol 70: 1129–1136, 1991
          85. Marticorena E, Ruiz L, Severino J, Galvez J, Penaloza D: Systemic blood pressure in white men born at sea level: Changes after long residence at high altitudes. Am J Cardiol 23: 364–368, 1969
            86. Canepa A, Chavez R, Hurtado A, Rotta A, Velasquez T: Pulmonary circulation at sea level and at high altitudes. J Appl Physiol 9: 328–336, 1956
            87. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 334: 939–945, 1996
            88. Tsouli SG, Liberopoulos EN, Kiortsis DN, Mikhailidis DP, Elisaf MS: Combined treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: A review of the current evidence. J Cardiovasc Pharmacol Ther 11: 1–15, 2006
            89. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD: Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: A systematic review of the efficacy and safety data. Am J Kidney Dis 48: 8–20, 2006
            90. Albitar S, Genin R, Fen-Chong M, Serveaux MO, Bourgeon B: High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 13: 1206–1210, 1998
            91. Odabas AR, Cetinkaya R, Selcuk Y, Keles S, Bilen H: The effect of high dose losartan on erythropoietin resistance in patients undergoing haemodialysis. Panminerva Med 45: 59–62, 2003
            92. Marin R, Ruilope LM, Aljama P, Aranda P, Segura J, Diez J: A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease. J Hypertens 19: 1871–1876, 2001
            93. Jerums G, Allen TJ, Campbell DJ, Cooper ME, Gilbert RE, Hammond JJ, Raffaele J, Tsalamandris C: Long-term comparison between perindopril and nifedipine in normotensive patients with type 1 diabetes and microalbuminuria. Am J Kidney Dis 37: 890–899, 2001
            94. IV. NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney disease: Update 2000. Am J Kidney Dis 37: S182–S238, 2001
            95. Hussein MM, Bakir N, Roujouleh H: Low-dose recombinant human erythropoietin in dialysis patients living at high altitude. Nephrol Dial Transplant 7: 173–174, 1992
            96. Brookhart MA, Schneeweiss S, Avron J, Bardbury BD, Rothman KJ, Fischer M, Mehta J, Winkelmeyer WC: The effect of altitude on dosing and response to erythropoietin in ESRD. J Am Soc Nephrol 19: 1389–1395, 2008
            97. Luks AM, Swenson ER: Medication and dosage considerations in the prophylaxis and treatment of high-altitude illness. Chest 133: 744–755, 2007
            98. Bennett WM, Aronoff GR, Golper TA: Drug Prescribing in Renal Failure, Philadelphia, American College of Physicians, 1987
              99. Paisley KE, Tomson CR: Calcium phosphate stones during long-term acetazolamide treatment for epilepsy. Postgrad Med J 75: 427–428, 1999
                100. Pepys MB: Acetazolamide and renal stone formation. Lancet 1: 837, 1970
                  101. Maggiorini M, Brunner-La Rocca HP, Peth S, Fischler M, Bohm T, Bernheim A, Kiencke S, Bloch KE, Dehnert C, Naeije R, Lehmann T, Bartsch P, Mairbaurl H: Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: A randomized trial. Ann Intern Med 145: 497–506, 2006
                    102. Tadalafil (Cialis®) US Prescribing Information, Indianapolis, Lilly ICOS LLC, 2006
                      103. Forgue ST, Phillips DL, Bedding AW, Payne CD, Jewell H, Patterson BE, Wrishko RE, Mitchell MI: Effects of gender, age, diabetes mellitus and renal and hepatic impairment on tadalafil pharmacokinetics. Br J Clin Pharmacol 63: 24–35, 2007
                        104. Product Information Revatio® (Sildenafil Citrate) Oral Tabs, New York, Pfizer, 2006
                          105. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, Scherrer U: Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 346: 1631–1636, 2002
                            Copyright © 2008 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.