Cleveland Clinic Journal of Medicine

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

DIFFERENTIAL DIAGNOSIS

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

DIFFERENTIAL DIAGNOSIS

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

DIFFERENTIAL DIAGNOSIS

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

In this issue, Dr. Herbert Wiedemann, Chairman of the Department of Pulmonary, Allergy, and Critical Care Medicine at Cleveland Clinic, discusses the results of the Fluids and Catheters Treatment Trial (FACTT), of which he was cochair, and the impact that these results should have on the management of patients with acute lung injury and acute respiratory distress syndrome (ARDS).

The results are reasonably clear. Patients with ARDS should be treated with a strategy of low tidal volume ventilation (as previously shown) and also with fluid restriction and diuretics as needed in an attempt to reach the targeted low filling pressures (a central venous pressure < 4 mm Hg). But even with this aggressive fluid management approach, there was no consistent benefit from the early use of pulmonary artery catheters for pressure monitoring.

So my former attendings in the intensive care unit were right after all! I still remember them during my residency explaining how, with careful physical examination and vigilance, I could avoid the need for pulmonary catheters even as I attempted to avoid lung-stretching by “running the patient dry” and using lower ventilatory volumes. And they taught this on the basis of their knowledge of physiology and their clinical observations—the clinical trials had not yet been performed.

Multicenter networks of clinicians conducting trials such as FACTT represent major accomplishments of the medical system. These multicenter trials have the potential to generate useful information about complicated and sometimes uncommon diseases, and to change the way we practice medicine. But to me, the real accomplishments are made by the clinician in the trenches who, with eyes wide open,processes observational experiences and generates the questions that ultimately get tested in experimental trials.

The networks can accomplish patient recruitment, the “number crunchers” can generate the P values and perform their regression analyses, but it is the clinician with the bedside skills who often generates the meaningful questions.

So as we begin another year, certain to be filled with new and important research successes, I offer a toast to those clinicians who, despite the pressures of time, continue to hone their observational prowess, synthesize the published literature, develop the hypotheses that studies like FACTT address, and pass them on to their students—who may fondly remember them 25 years later.

In this issue, Dr. Herbert Wiedemann, Chairman of the Department of Pulmonary, Allergy, and Critical Care Medicine at Cleveland Clinic, discusses the results of the Fluids and Catheters Treatment Trial (FACTT), of which he was cochair, and the impact that these results should have on the management of patients with acute lung injury and acute respiratory distress syndrome (ARDS).

The results are reasonably clear. Patients with ARDS should be treated with a strategy of low tidal volume ventilation (as previously shown) and also with fluid restriction and diuretics as needed in an attempt to reach the targeted low filling pressures (a central venous pressure < 4 mm Hg). But even with this aggressive fluid management approach, there was no consistent benefit from the early use of pulmonary artery catheters for pressure monitoring.

So my former attendings in the intensive care unit were right after all! I still remember them during my residency explaining how, with careful physical examination and vigilance, I could avoid the need for pulmonary catheters even as I attempted to avoid lung-stretching by “running the patient dry” and using lower ventilatory volumes. And they taught this on the basis of their knowledge of physiology and their clinical observations—the clinical trials had not yet been performed.

Multicenter networks of clinicians conducting trials such as FACTT represent major accomplishments of the medical system. These multicenter trials have the potential to generate useful information about complicated and sometimes uncommon diseases, and to change the way we practice medicine. But to me, the real accomplishments are made by the clinician in the trenches who, with eyes wide open,processes observational experiences and generates the questions that ultimately get tested in experimental trials.

The networks can accomplish patient recruitment, the “number crunchers” can generate the P values and perform their regression analyses, but it is the clinician with the bedside skills who often generates the meaningful questions.

So as we begin another year, certain to be filled with new and important research successes, I offer a toast to those clinicians who, despite the pressures of time, continue to hone their observational prowess, synthesize the published literature, develop the hypotheses that studies like FACTT address, and pass them on to their students—who may fondly remember them 25 years later.

In this issue, Dr. Herbert Wiedemann, Chairman of the Department of Pulmonary, Allergy, and Critical Care Medicine at Cleveland Clinic, discusses the results of the Fluids and Catheters Treatment Trial (FACTT), of which he was cochair, and the impact that these results should have on the management of patients with acute lung injury and acute respiratory distress syndrome (ARDS).

The results are reasonably clear. Patients with ARDS should be treated with a strategy of low tidal volume ventilation (as previously shown) and also with fluid restriction and diuretics as needed in an attempt to reach the targeted low filling pressures (a central venous pressure < 4 mm Hg). But even with this aggressive fluid management approach, there was no consistent benefit from the early use of pulmonary artery catheters for pressure monitoring.

So my former attendings in the intensive care unit were right after all! I still remember them during my residency explaining how, with careful physical examination and vigilance, I could avoid the need for pulmonary catheters even as I attempted to avoid lung-stretching by “running the patient dry” and using lower ventilatory volumes. And they taught this on the basis of their knowledge of physiology and their clinical observations—the clinical trials had not yet been performed.

Multicenter networks of clinicians conducting trials such as FACTT represent major accomplishments of the medical system. These multicenter trials have the potential to generate useful information about complicated and sometimes uncommon diseases, and to change the way we practice medicine. But to me, the real accomplishments are made by the clinician in the trenches who, with eyes wide open,processes observational experiences and generates the questions that ultimately get tested in experimental trials.

The networks can accomplish patient recruitment, the “number crunchers” can generate the P values and perform their regression analyses, but it is the clinician with the bedside skills who often generates the meaningful questions.

So as we begin another year, certain to be filled with new and important research successes, I offer a toast to those clinicians who, despite the pressures of time, continue to hone their observational prowess, synthesize the published literature, develop the hypotheses that studies like FACTT address, and pass them on to their students—who may fondly remember them 25 years later.

Guidelines for treating diabetes mellitus are mostly based on clinical studies in middle-aged people, and recommendations tend to be the same for everyone, whether young and strong or elderly and frail. But diabetes management should be individualized, especially in the elderly, taking into account each patient’s medical history, functional ability, home care situation, and life expectancy. Aggressive glycemic control is less important than avoiding hypoglycemia and achieving a good quality of life.

This article reviews the general principles for recognizing and managing diabetes in elderly patients, focusing on the management of blood sugar per se. In a future issue of this journal, we will discuss some of the many complications of diabetes in the elderly.

DIABETES DIFFERS IN ELDERLY PATIENTS

“The elderly” is a heterogeneous group with widely varying physiologic profiles, functional capabilities, and life expectancy (on average, about 88 years for men and 90 years for women in the United States). Although the elderly are sometimes classified as “young-old” (age 65–80) and “old-old” (80+), this distinction is too simplistic for clinical decision-making.

Diabetes mellitus in the elderly also is heterogeneous. One distinction is the age at which the disease developed.

Aging is associated with declining beta-cell function and lower blood insulin levels independent of insulin resistance, and with insulin resistance itself. The risk of developing type 2 diabetes mellitus increases with obesity, lack of physical activity, and loss of muscle mass, all of which often develop with aging.¹

Middle-aged patients with diabetes have increased fasting hepatic glucose production, increased insulin resistance, and an abnormal insulin response to a glucose load. On the other hand, patients who develop diabetes at an older age tend to have normal hepatic glucose production. Older patients who are lean secrete markedly less insulin in response to a glucose load but have relatively less insulin resistance.² Patients who develop type 2 diabetes in old age are more likely to have near-normal fasting blood glucose levels but significant postprandial hyperglycemia.^3,4 Elderly patients who developed diabetes during middle age have metabolic abnormalities more typical of middle-aged patients with type 2 diabetes.

DIABETES IS COMMON, AND INCREASING IN PREVALENCE

By age 75, 40% of people in the United States have either glucose intolerance or diabetes mellitus.⁵ Metabolic syndrome, which is the constellation of insulin resistance (type 2 diabetes mellitus), hyperlipidemia, hypertension, and obesity, is more prevalent in people age 65 to 74 years than in younger and older people.³

The National Diabetes Surveillance System of the US Centers for Disease Control and Prevention estimated that the prevalence of diabetes mellitus in people 65 to 74 years old in 2005 was 18.5%, about 12 times the prevalence among those younger than 45years.⁶ The prevalence has been gradually increasing and has nearly doubled over the past 25 years, with certain groups—native Americans, Hispanics, and African-Americans—at particularly high risk of developing the disease.

Although the prevalence of diabetes in people older than 75 years is lower than among people in the 65-to-74-year range, the elderly segment of our population is increasing, and the impact of diabetes and its associated burden of death and disease from vascular complications is enormous.

SYMPTOMS ARE OFTEN NONSPECIFIC

Unfortunately, diabetes is underdiagnosed and frequently undertreated, resulting in even more disease and death.^7–9

Diabetes is often missed in the elderly because its presenting symptoms may be nonspecific, eg, failure to thrive, low energy, falls, dizziness, confusion, nocturia (with or without incontinence), and urinary tract infection.The classic symptoms of frequent urination (often leading to worsening incontinence), thirst, and increased hunger usually occur only when plasma glucose levels are above 200 mg/dL. Weight loss, blurred vision, and dehydration may also be present with high blood glucose levels. With lesser degrees of hyperglycemia, patients may have no symptoms or present with weight loss or signs and symptoms of chronic infection, especially of the genitourinary tract, skin, or mouth.

Hyperglycemia in elderly patients is also associated with reduced cognitive function (which may improve with blood glucose control).¹⁰

The American Diabetes Association recommends screening by measuring the fasting plasma glucose level every 3 years beginning at 45 years.¹¹ However, some experts believe that this method is inadequate for the elderly¹²; some suggest that screening should be done more often in those with risk factors for diabetes, including obesity, inactivity, hypertension, and dyslipidemia, all of which are common in the elderly. Targeted screening in patients with hypertension may be the most cost-effective strategy.¹³

Screening with hemoglobin A_1c levels is not recommended because of lack of standardization among laboratories.¹⁴

INDIVIDUALIZED MANAGEMENT IS BEST

Despite disease differences, the general goals for diabetes care are the same for all ages:

• To control hyperglycemia and its symptoms
• To prevent, evaluate, and treat macrovascular and microvascular complications
• To teach patients to manage themselves
• To maintain or improve the patient’s general health status.

Unfortunately, most specific recommendations are based on studies in younger people. Guidelines should ideally reflect the complexities of a particular clinical situation, but most recommendations are applied to the young and old alike, as well as to the relatively healthy and the frail and ill.^15–17 Consideration should be given to a patient’s health beliefs, severity of vascular complications and other medical problems, economic situation, life expectancy ,functional status, and availability of support services. In addition, some patients prefer aggressive treatment, while others would rather compromise some aspects of care in order to maintain a certain quality of life, to save money, or to avoid having caregivers provide treatment.

Age-related changes in pharmacokinetics as well as polypharmacy increase the risk of drug interactions and adverse effects, especially drug-induced hypoglycemia. In addition, age-associated changes in cognitive, visual, and physical function, dentition, and taste perception can reduce a patient’s ability to carry out treatment. Frequent hospitalizations also disrupt outpatient regimens.

Comorbidities make treatment more challenging, but some conditions—such as hypertension, renal insufficiency and eye disorders—make doctors more likely to control hyperglycemia more aggressively, fearing that the loss of a little more function in an impaired organ may lead to failure.

The benefits of tight glycemic control should be weighed against the risks and the realities of an individual situation. Priority should be given to achieving the best quality of life possible.¹⁷ Recent guidelines from the California Health Foundation and the American Geriatrics Association focused on the major health threats to older patients and prioritizing care for each person.¹⁵ The guidelines recommend screening for geriatric syndromes that are more prevalent inpatients with diabetes or are strongly affected by the disease or its treatment. Diabetes care should be examined in the setting of common geriatric problems: depression, polypharmacy, cognitive impairment, urinary incontinence, falls, and pain.

Heart risk trumps glycemic control

The expert panel¹⁵ concluded that rates of disease and death can be reduced more by targeting cardiovascular risk factors than by intensively managing hyperglycemia. One rationale is that it takes 8 years for aggressive glycemic control to reduce the risk of diabetic retinopathy or renal disease but only 2 years of treating hypertension and dyslipidemia to reduce the risk of cardiovascular disease.^15,17–21 A recent Japanese study found normal mortality rates in elderly patients under long-term, intensive multifactorial diabetes control.²² High-functioning, motivated patients could benefit from therapy aimed at achieving most or all of the recommended goals, but frail patients may suffer from applying all therapies and may benefit from only some of them.

If appropriate goals cannot be met, it may help to refer patients to a geriatric specialist to evaluate possible barriers to adherence such as depression or poor cognition, physical functioning, or support.

MANAGEMENT STRATEGIES

Weight loss and exercise help prevent diabetes

The Diabetes Prevention Program²³ randomized 3,234 people (mean age 51 years) with impaired glucose tolerance to receive either metformin (Fortamet, Glucophage) 850 mg twice daily or placebo or to undertake lifestyle modifications with goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. Compared with the placebo group, the lifestyle modification group had a 58% lower incidence of diabetes while those in the metformin group had only a 31% lower incidence. Among those older than 60 years, the advantage of lifestyle modification over metformin was even greater.

• Hemoglobin A_1c levels < 7.0%
• Preprandial blood glucose levels 90–130 mg/dL
• Bedtime blood glucose levels 110–150 mg/dL.

Guidelines from the Department of Veterans Affairs²⁴ and the American Geriatrics Society¹⁵ are slightly different, and are based on randomized trials in younger patients, primarily the Diabetes Control and Complications Trial (DCCT)²⁵ and the United Kingdom Prospective Diabetes Study(UKPDS).^21,26 A recent position statement from the American College of Physicians, based on a review of all the major guidelines, recommends the following: “Statement 1: To prevent microvascular complication of diabetes, the goal for glycemic control should be as low as is feasible without undue risk for adverse events or an unacceptable burden on patients. Treatment goals should be based on a discussion of the benefits and harms of specific levels of glycemic control with the patient. A hemoglobin A_1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients. Statement 2: The goal for hemoglobin A_1c should be based on individualized assessment of risk for complication from diabetes, comorbidity, life expectancy, and patient preferences.”²⁷

Although few data exist for elderly patients, these guidelines are the most current approach to treating diabetes in the elderly. Less stringent goals are appropriate for patients who have limited life expectancy, hypoglycemia unawareness (lack of autonomic warning symptoms of low blood sugar), seizures, dementia, psychiatric illness, or alcoholism. It is important to keep in mind the following as one strives for lower A_1c levels: Although the relative risk reduction accomplished by lowering hemoglobin A_1c is linear, the absolute risk reduction is log-linear—more benefit is gained by lowering hemoglobin A_1c from 9% to 8% than from 8% to 7%.²⁸

Hypoglycemia is a major limiting factor in glycemic control. Many risk factors for hypoglycemia are common in the elderly (Table 2). Hypoglycemia was a chief adverse event in both the DCCT and the UKPDS, with a twofold to threefold higher rate in patients who were intensively treated.²⁹ Even mild hypoglycemia in the elderly can result in an injurious fall, which can lead to long-term functional decline. The rate of severe or fatal hypoglycemia—the major risk of tight glycemic treatment—increases exponentially with age.^30–33

As people age, the mechanisms that regulate blood sugar are impaired: the glucagon response is diminished, which increases dependence on the epinephrine response to prevent hypoglycemia.³⁴ Medications such as beta-blockers, which can suppress the symptoms of hypoglycemia, may further impair the response. Consequently, older patients may be less aware of hypoglycemia, and the symptoms may be less intense. Renal insufficiency may also exacerbate the problem by reducing clearance of oral agents. In addition, confused patients may take extra doses of medications.

Patients with type 2 diabetes treated with insulin, sulfonylureas, or meglitinides should be evaluated for symptoms of hypoglycemia. Older patients may have more neuroglycopenic symptoms (eg, dizziness, weakness, confusion, nightmares, violent behavior) than adrenergic symptoms (eg, sweating, palpitations, tremors), although both types should be asked about during an evaluation.^2,32,33 Hypoglycemia may also present as transient hemiparesis, coma, or falls.³⁵

We carefully evaluate the glycemic regimen and care environment of any elderly patient who presents with a blood glucose level below 100 mg/dL. The regimen should be altered for less strict control if the patient is cognitively impaired, is at risk of falling, or has an unstable care situation (eg, has irregular meals or needs assistance with daily activities and does not have a regular caregiver). Patients at significant risk of hypoglycemia should be encouraged to check their blood glucose level with a fingerstick before driving.

Tight control in the hospital is controversial

Glycemic control in the hospital has traditionally been designed primarily to maintain “safe” blood glucose levels, ie, to prevent hyperglycemia-induced dehydration and catabolism while avoiding hypoglycemia. Recent studies have suggested that tighter glycemic control may reduce the rates of complications and death perioperatively and in patients with myocardial infarction or who are seriously ill in the intensive care unit, although the evidence is mixed.^36–38 Specific targets are controversial, and although studies have included some elderly patients, results cannot be generalized to this group.

DIABETES CARE TAKES A TEAM

Geriatric patients have complex problems. In the face of multiple comorbidities, difficult social situations, and polypharmacy, the physician can best address the drug therapy and lifestyle changes that diabetes management requires by working with a certified diabetes educator, dietitian, social worker, and pharmacist.

Nonpharmacologic therapy

The first step in therapy for glycemic control is diet and exercise, although such measures are often limited in the elderly.

Diet. Carbohydrate control can maintain euglycemia in some patients with type 2 diabetes. But for the elderly, especially those living in long-term health care facilities, malnutrition may be of more concern than obesity, making dietary restrictions harmful. Patients in danger of malnutrition should be given unrestricted menus with consistent amounts of carbohydrate at meals and snacks. Medications should be adjusted to control blood glucose levels if necessary.³⁹

For patients living in the community, dietary therapy should be individualized by a dietitian. Medicare covers up to 10 hours of diabetes education with a certified diabetes educator or registered dietitian within a 12-month period if at least one of the following criteria are met: the patient is newly diagnosed with diabetes, the hemoglobin A_1c level is higher than 8.5%, medication has been recently started, or the risk of complications is high.

Supplementation of vitamins and minerals is prudent. Supplemental magnesium, zinc, and vitamins C and E may improve glycemic control.^40–44

Exercise reduces insulin resistance, weight, and blood pressure; increases muscle mass; and improves lipid levels. Both aerobic and nonaerobic activity are beneficial.^45–47 The best time to exercise is 1 to 2 hours after a meal, when glucose levels tend to be highest. Either hypoglycemia or hyperglycemia may occur up to 24 hours following exercise, and medications may need to be adjusted.

Oral medications

Insulin

Insulin therapy is necessary if oral combination therapy proves insufficient. Insulin is generally required for patients with moderate or severe hyperglycemia, especially for those with renal or hepatic insufficiency.^52,53 Before prescribing insulin therapy to elderly patients, we need to consider their visual acuity, manual dexterity and sensation, cognitive function, family support, and financial situation.However, several studies showed that quality of life improves in the year after starting insulin for patients whose blood sugar was previously poorly controlled with oral agents.^54,55

An evening dose of neutral protamine Hagedorn (NPH) insulin is a good way to start. More complex regimens may be necessary, depending on glycemic goals.

A number of premixed preparations of various types of insulin with different durations of action are available. They may improve accuracy, acceptability, and ease of insulin administration, although glycemic control and the risk of hypoglycemia may not change or in fact may be worse.⁵⁶ Some patients may not achieve adequate glucose control with fixed-dose regimens.^57,58

Frequent, small, titrated doses of short-acting agents control hyperglycemia better, particularly postprandial hyperglycemia,resulting in less hypoglycemia. However, these regimens may be too complex for many elderly patients; a patient’s support system must be evaluated before recommending this type of therapy.

Most insulins are available in vials and in pens, the latter of which are quick and easy to use, provide precise doses, and can be managed by many elderly patients. Pens require the user to attach a needle, set the dose by a dial, and depress the plunger to inject the dose. Some are prefilled and disposable, others have refillable cartridges. Studies in patients older than 60 years have shown the pen systems to be more acceptable, safer, and more effective than conventional syringes.

If conventional syringes are used, low-dose syringes (30-unit or 50-unit), which have more visible unit markings, should be prescribed whenever possible rather than the 100-unit sizes. Magnifying devices that attach to a syringe are also available.

Studies have also shown that continuous subcutaneous insulin infusion is safe for selected elderly patients.

Incretin mimetics: Possibly well-suited

Incretins, such as glucagon-like peptide-1, are hormones released from the gastrointestinal tract in response to eating. They stimulate insulin secretion by non-glucose-related pathways.

Exenatide (Byetta), a 39-amino-acid peptide incretin mimetic, is a synthetic version of exendin-4, an incretin isolated from the saliva of the Gila monster. Recently approved for treating type 2 diabetes, it is given subcutaneously.^59,60 Oral dipeptidyl peptidase-4 inhibitors (sitagliptin and vildagliptin) decrease the degradation of endogenous incretin and thus prolong its action.⁶¹ Because a decline in glucose-mediated beta-cell insulin secretion is a major contributor to the development of diabetes in the elderly, the drug may be especially helpful for this population.However, further clinical research and experience is needed before specific recommendations for elderly patients can be made.

SELF-MANAGEMENT IS IMPORTANT

Patient education is critical

Patient education is a cornerstone of diabetes self-management,^62–66 and is especially important for patients who are cognitively impaired or who have limited language proficiency.Patient education is covered under Medicare Part B. Ample resources are available in print and electronic formats. Community resources can also be important.

Home glucose monitoring is simpler now

A patient’s insulin regimen should ideally be tailored according to home blood glucose level monitoring before and after meals and at bedtime. Medicare reimburses for once daily testing for patients who are not taking insulin and for three-times-daily testing for those taking insulin.

Elderly patients can be taught to reliably monitor their own blood glucose levels without diminishing their quality of life. Monitoring is now easier with new glucometers and test strips that use small amounts of blood. Testing can now also be performed on blood taken from the forearm, upper arm, thigh, or calf with the FreeStyle (TheraSense), One Touch Ultra (LifeScan) and Soft Tac (MediSense) meters. The Soft Tac meter lances skin and automatically transfers blood to the test strip, making use even easier. Talking glucometers are available for blind patients.

Coordination counts

A variety of models of chronic care delivery have been proposed. Regardless of which model is chosen, the complexities of management call for a multidisciplinary team approach, and coordination of care in order to ensure appropriate information flow becomes critical.

Editor’s note: In next month’s issue of this journal, Drs. Hornick and Aron will discuss the management of diabetic complications in the elderly, including coronary artery disease, neuropathy, and kidney disease.

Guidelines for treating diabetes mellitus are mostly based on clinical studies in middle-aged people, and recommendations tend to be the same for everyone, whether young and strong or elderly and frail. But diabetes management should be individualized, especially in the elderly, taking into account each patient’s medical history, functional ability, home care situation, and life expectancy. Aggressive glycemic control is less important than avoiding hypoglycemia and achieving a good quality of life.

This article reviews the general principles for recognizing and managing diabetes in elderly patients, focusing on the management of blood sugar per se. In a future issue of this journal, we will discuss some of the many complications of diabetes in the elderly.

DIABETES DIFFERS IN ELDERLY PATIENTS

“The elderly” is a heterogeneous group with widely varying physiologic profiles, functional capabilities, and life expectancy (on average, about 88 years for men and 90 years for women in the United States). Although the elderly are sometimes classified as “young-old” (age 65–80) and “old-old” (80+), this distinction is too simplistic for clinical decision-making.

Diabetes mellitus in the elderly also is heterogeneous. One distinction is the age at which the disease developed.

Aging is associated with declining beta-cell function and lower blood insulin levels independent of insulin resistance, and with insulin resistance itself. The risk of developing type 2 diabetes mellitus increases with obesity, lack of physical activity, and loss of muscle mass, all of which often develop with aging.¹

Middle-aged patients with diabetes have increased fasting hepatic glucose production, increased insulin resistance, and an abnormal insulin response to a glucose load. On the other hand, patients who develop diabetes at an older age tend to have normal hepatic glucose production. Older patients who are lean secrete markedly less insulin in response to a glucose load but have relatively less insulin resistance.² Patients who develop type 2 diabetes in old age are more likely to have near-normal fasting blood glucose levels but significant postprandial hyperglycemia.^3,4 Elderly patients who developed diabetes during middle age have metabolic abnormalities more typical of middle-aged patients with type 2 diabetes.

DIABETES IS COMMON, AND INCREASING IN PREVALENCE

By age 75, 40% of people in the United States have either glucose intolerance or diabetes mellitus.⁵ Metabolic syndrome, which is the constellation of insulin resistance (type 2 diabetes mellitus), hyperlipidemia, hypertension, and obesity, is more prevalent in people age 65 to 74 years than in younger and older people.³

The National Diabetes Surveillance System of the US Centers for Disease Control and Prevention estimated that the prevalence of diabetes mellitus in people 65 to 74 years old in 2005 was 18.5%, about 12 times the prevalence among those younger than 45years.⁶ The prevalence has been gradually increasing and has nearly doubled over the past 25 years, with certain groups—native Americans, Hispanics, and African-Americans—at particularly high risk of developing the disease.

Although the prevalence of diabetes in people older than 75 years is lower than among people in the 65-to-74-year range, the elderly segment of our population is increasing, and the impact of diabetes and its associated burden of death and disease from vascular complications is enormous.

SYMPTOMS ARE OFTEN NONSPECIFIC

Unfortunately, diabetes is underdiagnosed and frequently undertreated, resulting in even more disease and death.^7–9

Diabetes is often missed in the elderly because its presenting symptoms may be nonspecific, eg, failure to thrive, low energy, falls, dizziness, confusion, nocturia (with or without incontinence), and urinary tract infection.The classic symptoms of frequent urination (often leading to worsening incontinence), thirst, and increased hunger usually occur only when plasma glucose levels are above 200 mg/dL. Weight loss, blurred vision, and dehydration may also be present with high blood glucose levels. With lesser degrees of hyperglycemia, patients may have no symptoms or present with weight loss or signs and symptoms of chronic infection, especially of the genitourinary tract, skin, or mouth.

Hyperglycemia in elderly patients is also associated with reduced cognitive function (which may improve with blood glucose control).¹⁰

The American Diabetes Association recommends screening by measuring the fasting plasma glucose level every 3 years beginning at 45 years.¹¹ However, some experts believe that this method is inadequate for the elderly¹²; some suggest that screening should be done more often in those with risk factors for diabetes, including obesity, inactivity, hypertension, and dyslipidemia, all of which are common in the elderly. Targeted screening in patients with hypertension may be the most cost-effective strategy.¹³

Screening with hemoglobin A_1c levels is not recommended because of lack of standardization among laboratories.¹⁴

INDIVIDUALIZED MANAGEMENT IS BEST

Despite disease differences, the general goals for diabetes care are the same for all ages:

• To control hyperglycemia and its symptoms
• To prevent, evaluate, and treat macrovascular and microvascular complications
• To teach patients to manage themselves
• To maintain or improve the patient’s general health status.

Unfortunately, most specific recommendations are based on studies in younger people. Guidelines should ideally reflect the complexities of a particular clinical situation, but most recommendations are applied to the young and old alike, as well as to the relatively healthy and the frail and ill.^15–17 Consideration should be given to a patient’s health beliefs, severity of vascular complications and other medical problems, economic situation, life expectancy ,functional status, and availability of support services. In addition, some patients prefer aggressive treatment, while others would rather compromise some aspects of care in order to maintain a certain quality of life, to save money, or to avoid having caregivers provide treatment.

Age-related changes in pharmacokinetics as well as polypharmacy increase the risk of drug interactions and adverse effects, especially drug-induced hypoglycemia. In addition, age-associated changes in cognitive, visual, and physical function, dentition, and taste perception can reduce a patient’s ability to carry out treatment. Frequent hospitalizations also disrupt outpatient regimens.

Comorbidities make treatment more challenging, but some conditions—such as hypertension, renal insufficiency and eye disorders—make doctors more likely to control hyperglycemia more aggressively, fearing that the loss of a little more function in an impaired organ may lead to failure.

The benefits of tight glycemic control should be weighed against the risks and the realities of an individual situation. Priority should be given to achieving the best quality of life possible.¹⁷ Recent guidelines from the California Health Foundation and the American Geriatrics Association focused on the major health threats to older patients and prioritizing care for each person.¹⁵ The guidelines recommend screening for geriatric syndromes that are more prevalent inpatients with diabetes or are strongly affected by the disease or its treatment. Diabetes care should be examined in the setting of common geriatric problems: depression, polypharmacy, cognitive impairment, urinary incontinence, falls, and pain.

Heart risk trumps glycemic control

The expert panel¹⁵ concluded that rates of disease and death can be reduced more by targeting cardiovascular risk factors than by intensively managing hyperglycemia. One rationale is that it takes 8 years for aggressive glycemic control to reduce the risk of diabetic retinopathy or renal disease but only 2 years of treating hypertension and dyslipidemia to reduce the risk of cardiovascular disease.^15,17–21 A recent Japanese study found normal mortality rates in elderly patients under long-term, intensive multifactorial diabetes control.²² High-functioning, motivated patients could benefit from therapy aimed at achieving most or all of the recommended goals, but frail patients may suffer from applying all therapies and may benefit from only some of them.

If appropriate goals cannot be met, it may help to refer patients to a geriatric specialist to evaluate possible barriers to adherence such as depression or poor cognition, physical functioning, or support.

MANAGEMENT STRATEGIES

Weight loss and exercise help prevent diabetes

The Diabetes Prevention Program²³ randomized 3,234 people (mean age 51 years) with impaired glucose tolerance to receive either metformin (Fortamet, Glucophage) 850 mg twice daily or placebo or to undertake lifestyle modifications with goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. Compared with the placebo group, the lifestyle modification group had a 58% lower incidence of diabetes while those in the metformin group had only a 31% lower incidence. Among those older than 60 years, the advantage of lifestyle modification over metformin was even greater.

• Hemoglobin A_1c levels < 7.0%
• Preprandial blood glucose levels 90–130 mg/dL
• Bedtime blood glucose levels 110–150 mg/dL.

Guidelines from the Department of Veterans Affairs²⁴ and the American Geriatrics Society¹⁵ are slightly different, and are based on randomized trials in younger patients, primarily the Diabetes Control and Complications Trial (DCCT)²⁵ and the United Kingdom Prospective Diabetes Study(UKPDS).^21,26 A recent position statement from the American College of Physicians, based on a review of all the major guidelines, recommends the following: “Statement 1: To prevent microvascular complication of diabetes, the goal for glycemic control should be as low as is feasible without undue risk for adverse events or an unacceptable burden on patients. Treatment goals should be based on a discussion of the benefits and harms of specific levels of glycemic control with the patient. A hemoglobin A_1c level less than 7% based on individualized assessment is a reasonable goal for many but not all patients. Statement 2: The goal for hemoglobin A_1c should be based on individualized assessment of risk for complication from diabetes, comorbidity, life expectancy, and patient preferences.”²⁷

Although few data exist for elderly patients, these guidelines are the most current approach to treating diabetes in the elderly. Less stringent goals are appropriate for patients who have limited life expectancy, hypoglycemia unawareness (lack of autonomic warning symptoms of low blood sugar), seizures, dementia, psychiatric illness, or alcoholism. It is important to keep in mind the following as one strives for lower A_1c levels: Although the relative risk reduction accomplished by lowering hemoglobin A_1c is linear, the absolute risk reduction is log-linear—more benefit is gained by lowering hemoglobin A_1c from 9% to 8% than from 8% to 7%.²⁸

Hypoglycemia is a major limiting factor in glycemic control. Many risk factors for hypoglycemia are common in the elderly (Table 2). Hypoglycemia was a chief adverse event in both the DCCT and the UKPDS, with a twofold to threefold higher rate in patients who were intensively treated.²⁹ Even mild hypoglycemia in the elderly can result in an injurious fall, which can lead to long-term functional decline. The rate of severe or fatal hypoglycemia—the major risk of tight glycemic treatment—increases exponentially with age.^30–33

As people age, the mechanisms that regulate blood sugar are impaired: the glucagon response is diminished, which increases dependence on the epinephrine response to prevent hypoglycemia.³⁴ Medications such as beta-blockers, which can suppress the symptoms of hypoglycemia, may further impair the response. Consequently, older patients may be less aware of hypoglycemia, and the symptoms may be less intense. Renal insufficiency may also exacerbate the problem by reducing clearance of oral agents. In addition, confused patients may take extra doses of medications.

Patients with type 2 diabetes treated with insulin, sulfonylureas, or meglitinides should be evaluated for symptoms of hypoglycemia. Older patients may have more neuroglycopenic symptoms (eg, dizziness, weakness, confusion, nightmares, violent behavior) than adrenergic symptoms (eg, sweating, palpitations, tremors), although both types should be asked about during an evaluation.^2,32,33 Hypoglycemia may also present as transient hemiparesis, coma, or falls.³⁵

We carefully evaluate the glycemic regimen and care environment of any elderly patient who presents with a blood glucose level below 100 mg/dL. The regimen should be altered for less strict control if the patient is cognitively impaired, is at risk of falling, or has an unstable care situation (eg, has irregular meals or needs assistance with daily activities and does not have a regular caregiver). Patients at significant risk of hypoglycemia should be encouraged to check their blood glucose level with a fingerstick before driving.

Tight control in the hospital is controversial

Glycemic control in the hospital has traditionally been designed primarily to maintain “safe” blood glucose levels, ie, to prevent hyperglycemia-induced dehydration and catabolism while avoiding hypoglycemia. Recent studies have suggested that tighter glycemic control may reduce the rates of complications and death perioperatively and in patients with myocardial infarction or who are seriously ill in the intensive care unit, although the evidence is mixed.^36–38 Specific targets are controversial, and although studies have included some elderly patients, results cannot be generalized to this group.

DIABETES CARE TAKES A TEAM

Geriatric patients have complex problems. In the face of multiple comorbidities, difficult social situations, and polypharmacy, the physician can best address the drug therapy and lifestyle changes that diabetes management requires by working with a certified diabetes educator, dietitian, social worker, and pharmacist.

Nonpharmacologic therapy

The first step in therapy for glycemic control is diet and exercise, although such measures are often limited in the elderly.

Diet. Carbohydrate control can maintain euglycemia in some patients with type 2 diabetes. But for the elderly, especially those living in long-term health care facilities, malnutrition may be of more concern than obesity, making dietary restrictions harmful. Patients in danger of malnutrition should be given unrestricted menus with consistent amounts of carbohydrate at meals and snacks. Medications should be adjusted to control blood glucose levels if necessary.³⁹

For patients living in the community, dietary therapy should be individualized by a dietitian. Medicare covers up to 10 hours of diabetes education with a certified diabetes educator or registered dietitian within a 12-month period if at least one of the following criteria are met: the patient is newly diagnosed with diabetes, the hemoglobin A_1c level is higher than 8.5%, medication has been recently started, or the risk of complications is high.

Supplementation of vitamins and minerals is prudent. Supplemental magnesium, zinc, and vitamins C and E may improve glycemic control.^40–44

Exercise reduces insulin resistance, weight, and blood pressure; increases muscle mass; and improves lipid levels. Both aerobic and nonaerobic activity are beneficial.^45–47 The best time to exercise is 1 to 2 hours after a meal, when glucose levels tend to be highest. Either hypoglycemia or hyperglycemia may occur up to 24 hours following exercise, and medications may need to be adjusted.

Oral medications

Insulin

Insulin therapy is necessary if oral combination therapy proves insufficient. Insulin is generally required for patients with moderate or severe hyperglycemia, especially for those with renal or hepatic insufficiency.^52,53 Before prescribing insulin therapy to elderly patients, we need to consider their visual acuity, manual dexterity and sensation, cognitive function, family support, and financial situation.However, several studies showed that quality of life improves in the year after starting insulin for patients whose blood sugar was previously poorly controlled with oral agents.^54,55

An evening dose of neutral protamine Hagedorn (NPH) insulin is a good way to start. More complex regimens may be necessary, depending on glycemic goals.

A number of premixed preparations of various types of insulin with different durations of action are available. They may improve accuracy, acceptability, and ease of insulin administration, although glycemic control and the risk of hypoglycemia may not change or in fact may be worse.⁵⁶ Some patients may not achieve adequate glucose control with fixed-dose regimens.^57,58

Frequent, small, titrated doses of short-acting agents control hyperglycemia better, particularly postprandial hyperglycemia,resulting in less hypoglycemia. However, these regimens may be too complex for many elderly patients; a patient’s support system must be evaluated before recommending this type of therapy.

Most insulins are available in vials and in pens, the latter of which are quick and easy to use, provide precise doses, and can be managed by many elderly patients. Pens require the user to attach a needle, set the dose by a dial, and depress the plunger to inject the dose. Some are prefilled and disposable, others have refillable cartridges. Studies in patients older than 60 years have shown the pen systems to be more acceptable, safer, and more effective than conventional syringes.

If conventional syringes are used, low-dose syringes (30-unit or 50-unit), which have more visible unit markings, should be prescribed whenever possible rather than the 100-unit sizes. Magnifying devices that attach to a syringe are also available.

Studies have also shown that continuous subcutaneous insulin infusion is safe for selected elderly patients.

Incretin mimetics: Possibly well-suited

Incretins, such as glucagon-like peptide-1, are hormones released from the gastrointestinal tract in response to eating. They stimulate insulin secretion by non-glucose-related pathways.

Exenatide (Byetta), a 39-amino-acid peptide incretin mimetic, is a synthetic version of exendin-4, an incretin isolated from the saliva of the Gila monster. Recently approved for treating type 2 diabetes, it is given subcutaneously.^59,60 Oral dipeptidyl peptidase-4 inhibitors (sitagliptin and vildagliptin) decrease the degradation of endogenous incretin and thus prolong its action.⁶¹ Because a decline in glucose-mediated beta-cell insulin secretion is a major contributor to the development of diabetes in the elderly, the drug may be especially helpful for this population.However, further clinical research and experience is needed before specific recommendations for elderly patients can be made.

SELF-MANAGEMENT IS IMPORTANT

Patient education is critical

Patient education is a cornerstone of diabetes self-management,^62–66 and is especially important for patients who are cognitively impaired or who have limited language proficiency.Patient education is covered under Medicare Part B. Ample resources are available in print and electronic formats. Community resources can also be important.

Home glucose monitoring is simpler now

A patient’s insulin regimen should ideally be tailored according to home blood glucose level monitoring before and after meals and at bedtime. Medicare reimburses for once daily testing for patients who are not taking insulin and for three-times-daily testing for those taking insulin.

Elderly patients can be taught to reliably monitor their own blood glucose levels without diminishing their quality of life. Monitoring is now easier with new glucometers and test strips that use small amounts of blood. Testing can now also be performed on blood taken from the forearm, upper arm, thigh, or calf with the FreeStyle (TheraSense), One Touch Ultra (LifeScan) and Soft Tac (MediSense) meters. The Soft Tac meter lances skin and automatically transfers blood to the test strip, making use even easier. Talking glucometers are available for blind patients.

Coordination counts

A variety of models of chronic care delivery have been proposed. Regardless of which model is chosen, the complexities of management call for a multidisciplinary team approach, and coordination of care in order to ensure appropriate information flow becomes critical.

Editor’s note: In next month’s issue of this journal, Drs. Hornick and Aron will discuss the management of diabetic complications in the elderly, including coronary artery disease, neuropathy, and kidney disease.

Guidelines for treating diabetes mellitus are mostly based on clinical studies in middle-aged people, and recommendations tend to be the same for everyone, whether young and strong or elderly and frail. But diabetes management should be individualized, especially in the elderly, taking into account each patient’s medical history, functional ability, home care situation, and life expectancy. Aggressive glycemic control is less important than avoiding hypoglycemia and achieving a good quality of life.

This article reviews the general principles for recognizing and managing diabetes in elderly patients, focusing on the management of blood sugar per se. In a future issue of this journal, we will discuss some of the many complications of diabetes in the elderly.

DIABETES DIFFERS IN ELDERLY PATIENTS

“The elderly” is a heterogeneous group with widely varying physiologic profiles, functional capabilities, and life expectancy (on average, about 88 years for men and 90 years for women in the United States). Although the elderly are sometimes classified as “young-old” (age 65–80) and “old-old” (80+), this distinction is too simplistic for clinical decision-making.

Diabetes mellitus in the elderly also is heterogeneous. One distinction is the age at which the disease developed.

Aging is associated with declining beta-cell function and lower blood insulin levels independent of insulin resistance, and with insulin resistance itself. The risk of developing type 2 diabetes mellitus increases with obesity, lack of physical activity, and loss of muscle mass, all of which often develop with aging.¹

Middle-aged patients with diabetes have increased fasting hepatic glucose production, increased insulin resistance, and an abnormal insulin response to a glucose load. On the other hand, patients who develop diabetes at an older age tend to have normal hepatic glucose production. Older patients who are lean secrete markedly less insulin in response to a glucose load but have relatively less insulin resistance.² Patients who develop type 2 diabetes in old age are more likely to have near-normal fasting blood glucose levels but significant postprandial hyperglycemia.^3,4 Elderly patients who developed diabetes during middle age have metabolic abnormalities more typical of middle-aged patients with type 2 diabetes.

DIABETES IS COMMON, AND INCREASING IN PREVALENCE

By age 75, 40% of people in the United States have either glucose intolerance or diabetes mellitus.⁵ Metabolic syndrome, which is the constellation of insulin resistance (type 2 diabetes mellitus), hyperlipidemia, hypertension, and obesity, is more prevalent in people age 65 to 74 years than in younger and older people.³

The National Diabetes Surveillance System of the US Centers for Disease Control and Prevention estimated that the prevalence of diabetes mellitus in people 65 to 74 years old in 2005 was 18.5%, about 12 times the prevalence among those younger than 45years.⁶ The prevalence has been gradually increasing and has nearly doubled over the past 25 years, with certain groups—native Americans, Hispanics, and African-Americans—at particularly high risk of developing the disease.

Although the prevalence of diabetes in people older than 75 years is lower than among people in the 65-to-74-year range, the elderly segment of our population is increasing, and the impact of diabetes and its associated burden of death and disease from vascular complications is enormous.

SYMPTOMS ARE OFTEN NONSPECIFIC

Unfortunately, diabetes is underdiagnosed and frequently undertreated, resulting in even more disease and death.^7–9

Diabetes is often missed in the elderly because its presenting symptoms may be nonspecific, eg, failure to thrive, low energy, falls, dizziness, confusion, nocturia (with or without incontinence), and urinary tract infection.The classic symptoms of frequent urination (often leading to worsening incontinence), thirst, and increased hunger usually occur only when plasma glucose levels are above 200 mg/dL. Weight loss, blurred vision, and dehydration may also be present with high blood glucose levels. With lesser degrees of hyperglycemia, patients may have no symptoms or present with weight loss or signs and symptoms of chronic infection, especially of the genitourinary tract, skin, or mouth.

Hyperglycemia in elderly patients is also associated with reduced cognitive function (which may improve with blood glucose control).¹⁰

The American Diabetes Association recommends screening by measuring the fasting plasma glucose level every 3 years beginning at 45 years.¹¹ However, some experts believe that this method is inadequate for the elderly¹²; some suggest that screening should be done more often in those with risk factors for diabetes, including obesity, inactivity, hypertension, and dyslipidemia, all of which are common in the elderly. Targeted screening in patients with hypertension may be the most cost-effective strategy.¹³

Screening with hemoglobin A_1c levels is not recommended because of lack of standardization among laboratories.¹⁴

INDIVIDUALIZED MANAGEMENT IS BEST

Despite disease differences, the general goals for diabetes care are the same for all ages:

• To control hyperglycemia and its symptoms
• To prevent, evaluate, and treat macrovascular and microvascular complications
• To teach patients to manage themselves
• To maintain or improve the patient’s general health status.

Unfortunately, most specific recommendations are based on studies in younger people. Guidelines should ideally reflect the complexities of a particular clinical situation, but most recommendations are applied to the young and old alike, as well as to the relatively healthy and the frail and ill.^15–17 Consideration should be given to a patient’s health beliefs, severity of vascular complications and other medical problems, economic situation, life expectancy ,functional status, and availability of support services. In addition, some patients prefer aggressive treatment, while others would rather compromise some aspects of care in order to maintain a certain quality of life, to save money, or to avoid having caregivers provide treatment.

Age-related changes in pharmacokinetics as well as polypharmacy increase the risk of drug interactions and adverse effects, especially drug-induced hypoglycemia. In addition, age-associated changes in cognitive, visual, and physical function, dentition, and taste perception can reduce a patient’s ability to carry out treatment. Frequent hospitalizations also disrupt outpatient regimens.

Comorbidities make treatment more challenging, but some conditions—such as hypertension, renal insufficiency and eye disorders—make doctors more likely to control hyperglycemia more aggressively, fearing that the loss of a little more function in an impaired organ may lead to failure.

The benefits of tight glycemic control should be weighed against the risks and the realities of an individual situation. Priority should be given to achieving the best quality of life possible.¹⁷ Recent guidelines from the California Health Foundation and the American Geriatrics Association focused on the major health threats to older patients and prioritizing care for each person.¹⁵ The guidelines recommend screening for geriatric syndromes that are more prevalent inpatients with diabetes or are strongly affected by the disease or its treatment. Diabetes care should be examined in the setting of common geriatric problems: depression, polypharmacy, cognitive impairment, urinary incontinence, falls, and pain.

Heart risk trumps glycemic control

The expert panel¹⁵ concluded that rates of disease and death can be reduced more by targeting cardiovascular risk factors than by intensively managing hyperglycemia. One rationale is that it takes 8 years for aggressive glycemic control to reduce the risk of diabetic retinopathy or renal disease but only 2 years of treating hypertension and dyslipidemia to reduce the risk of cardiovascular disease.^15,17–21 A recent Japanese study found normal mortality rates in elderly patients under long-term, intensive multifactorial diabetes control.²² High-functioning, motivated patients could benefit from therapy aimed at achieving most or all of the recommended goals, but frail patients may suffer from applying all therapies and may benefit from only some of them.

If appropriate goals cannot be met, it may help to refer patients to a geriatric specialist to evaluate possible barriers to adherence such as depression or poor cognition, physical functioning, or support.