The Relationship Between Obesity and Calciphylaxis: A Review of the Literature

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Ostomy Wound Management 2016;62(1):12-18
Janet M. Davis, MSN, RN, GNP, CWOCN

Abstract

Calciphylaxis is characterized by calcification in the medium and small vessel arterioles and can be a life-threatening complication often associated with chronic kidney disease (CKD). A review of the literature was conducted to explore existing evidence about the relationship between obesity and calciphylaxis.

A total of 54 publications (published between 1962 and 2015) were identified. Most studies noted a variety of risk factors for calciphylaxis, including CKD, female gender, Caucasian race, liver disease, and lower serum albumin. Obesity was identified as a risk factor in 6 of the 8 studies reviewed. In one study, obesity was found to increase the risk of calciphylaxis 4-fold. The majority of calciphylaxis lesions in obese persons were proximal in distribution; all studies report proximal lesions are associated with a higher mortality rate than distal lesions. The mortality rate of persons with CKD and calciphylaxis is 8 times higher than that of persons with CKD without calciphylaxis. There is no definitive evidence to support the belief current epidemic rates of obesity, diabetes, (diabesity), and chronic renal disease will predispose more patients to the development of calciphylaxis. However, until more information from the calciphylaxis registries and other studies is available, clinicians should maintain a high index of suspicion when a patient presents with indurated, painful nodules or necrotic ulcers, especially if the patient also has CKD. 

 

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), was first described in 1898 by Bryant and White, but the term calciphylaxis was not coined until 1961 when Hans Seyle induced a calcification process in a rodent model by introducing both a sensitizer and a challenger to create what he believed was an anaphylactic inflammation and calcification process.1 Although it has been described in patients with normal renal function and calcium/phosphate metabolism, CUA is considered a more accurate term than calciphylaxis because this syndrome most often occurs in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism.2-14

Calciphylaxis (CUA) is considered to be rare, occurring in approximately 1% to 5% of people on dialysis due to end-stage renal disease (ESRD).2-19 Even though information is limited and difficult to interpret because some studies report prevalence while others report incidence, many believe the rate of CUA has been increasing each year.2-14,19-25 Inability to determine the precise prevalence and incidence of calciphylaxis is likely due to under-recognition of early disease, misdiagnosis, and a lack of centralized data collection through registries.2,24,26,27 Currently, 3 calciphylaxis registries in the world are studying this disorder: the University of Kansas Medical Center (KUMC) in the United States28 and 1 each in the United Kingdom29 and Germany.27 So far, the German registry reports (from small international surveys) an incidence range of 1:1.000 to 1:1.500 cases per year in patients who are on chronic renal replacement therapy (dialysis or renal transplant).27 All US clinicians are encouraged to enter data at www2.KUMC.edu/calciphylaxisregistry regarding patients with a confirmed diagnosis of calciphylaxis.28

Pathophysiology. The calcification process in the medium and small vessel arterioles leads to skin ischemia and often to ulcerations, the hallmark sign of the disease.2,30,31 Early disease presentation of the syndrome is characterized by soft-tissue calcifications that manifest as painful nodules with a mottled or a livedo reticularis pattern (see Figure 1).2,32,33 Not all patients who present with early disease progress to the ulcerative state. In their case series, Fine and Zacharias20 recognized early presentation of calciphylaxis (indurated plaques in the legs) in 80% of a group of 36 patients. Only 20% of the 36 patients presented with late disease or ulcerations. The mortality rate in this group was 67%. Half of these patients were treated with prednisone therapy; 80% improved. Of those not treated, more than half worsened and died with ulcerations. With such dramatic results, the center began treating all patients with early disease with steroid therapy. owm_0116_davis_figure1

In late disease or metastatic calciphylaxis, the disorder has progressed and the skin is ischemic and painful; dense nodules ultimately become necrotic and ulcerate2-5,7-13,14,16,17,19,24,31,34 (see Figure 2). Ninety percent (90%) of ulcerations have a sacral or distal distribution (eg, forearms, hands, fingers, genitalia, calves, feet, and toes); proximal lesions (10%) occur in areas with more adipose tissue (eg, shoulders, breasts, trunk, thighs, and buttocks) and have a poorer prognosis. 2,3,7,10,11,20,24,25,35 owm_0116_davis_figure2

Calciphylaxis or CUA is generally a clinical diagnosis; however, histopathological features of intravascular calcium depositions in the media of the dermal and subcutaneous arterioles confirm the clinical appearance.2,5,7,8,13,24 Morbidity and mortality of CUA range from 60% to 80%; mortality is higher when open ulcers become infected, leading to sepsis and death. Survival is higher in patients with distal or sacral lesions (75.5% sacral versus 26.2% proximal). Bhambri and Del Rosso3 reviewed a retrospective study of 64 patients31 and a case series36 of 5 patients with calciphylaxis: more than half of the patients died within 1 year of diagnosis and most did not survive longer than 1 to 6 months after developing necrotic ulcerations.3,7,8,9,13,14,18-20,22,24,26,31,34,37,38

The exact pathogenesis of this disorder in humans is not completely understood; however, many researchers now believe this devastating condition to be of a multifactorial etiology.13,22,37 The following risk factors for calciphylaxis have been identified: CKD/renal failure, dialysis, secondary hyperparathyroidism, hypercalcemia, hyperphosphatemia, an elevated calcium phosphate end product (Ca2+ x PO4 >70mg2/dL2), use of corticosteroids and/or warfarin, a hypercoagulable state, diabetes mellitus, malnutrition, low serum albumin, female gender, Caucasian race, and obesity.2,4,6,8,10,11,14,16,20-25,31,36

Obesity. The World Health Organization39 (WHO) defines overweight as a body mass index (BMI) >25 kg/m2 and obesity as a BMI >30 kg/m2. According to the WHO, obesity has more than doubled since 1980. In 2013, 42 million children <5 years of age were overweight or obese. Childhood obesity is associated with future risks of obesity as people age, premature death, and disability in adulthood. In 2014, more than 600 million of the more than 1.9 billion overweight adults (>18 years) were obese. This epidemic and the related illnesses are the leading cause of 200,000 annual preventable deaths.40 The Centers for Disease Control and Prevention41 (CDC) reports obesity has hit epidemic proportions: 35.7% of adults in the US are obese and 71.1% are either overweight or obese. These statistics regarding obesity are staggering, and most of the world’s population now lives in countries where being overweight or obese is killing more people than being underweight39,42 (see Figure 3). owm_0116_davis_figure3

Renal failure. Chronic renal failure, like obesity, is an escalating health problem throughout the world. From 1980 –1990 and 1996–2000, a 10-fold increase of obesity-related glomerulopathy was observed.43 Long-term prognosis of the obese patient with focal segmental glomerulosclerosis is poor; almost 50% develop advanced renal failure. Predictions a decade ago estimated that end-stage kidney disease (ESKD) in the general population would double, approximately 600,000 people would be on dialysis by the year 2010, and 20 million people would have either persistent proteinuria or substantial kidney damage (hypertension and type 2 diabetes mellitus accounting for a large proportion).44-46 Based on a report on the National Kidney and Urologic Disease Information Clearinghouse47 website, this prediction was accurate.

Now, more than 20 million American adults have CKD and among them more than 637,000 are on some form of renal replacement therapy such as dialysis and/or renal transplant.43,48,49 The purpose of this narrative review is to explore existing evidence about the relationship between obesity and calciphylaxis.

Methods and Procedures

An initial search of PubMed, CINAHL, MEDLINE, Nursing Reference Center, Scopus, and The Cochrane Library was performed using the terms calciphylaxis, calcific uremic arteriolopathy, dialysis, risk factor, kidney disease, and obesity. Inclusion criteria for articles to review and/or reference were based on article content containing information about etiology, diagnostics in determining calciphylaxis, and review of prior literature; articles written in English with date restrictions of 1962 – 2015 were used. Articles excluded had a primary focus of discussing treatment for calciphylaxis.

A spreadsheet was developed listing each definition of calciphylaxis, all risk factors listed, if the risk factors were studied and found to be statistically significant, prevalence/incidence, morbidity/mortality, and any explanation of obesity’s role in calciphylaxis. Once all data were reviewed, the variables collected were sorted by number of times cited.

Results

Fifty-four (54) references, published between 1962 and 2015, were identified. Of these, 42 publications were not reviewed in this study because they were either a review of calciphylaxis, obesity, or renal disease; did not provide data; or had a sample size of only 1 to 5. The remaining 12 were published primarily in peer-reviewed journals by nephrologists, followed by dermatologists. Obesity was cited in 25 out of 35 references, and it was found to be the third highest occurring risk factor behind hemodialysis and ESRD.

In a retrospective case-controlled study from December 1989 to January 2000 to determine risk factors and mortality in ESRD uremic calciphylaxis, Mazhar et al23 compared 19 cases of calciphylaxis to 54 control cases matched to date of initiation of hemodialysis and alive at the time of diagnosis of calciphylaxis in the study group. The risk factors identified to be most associated with ESRD-related calciphylaxis were female gender (OR = 6.04, 95% CI 1.62–22.6, P = 0.007), hyperphosphatemia (OR = 1.19, 95% CI 1.00–1.40, P = 0.045), and a low serum albumin rate (OR=0.80, 95% CI 0.67–0.96, P = 0.019); BMI and diabetes mellitus were not independently predictive of calciphylaxis. Of the 19 cases of calciphylaxis, 14 had proximal distribution of CUA ulcers and 9 had both proximal and distal lesions. The majority of patients who died (11 out of 14) had proximal lesions. A diagnosis of calciphylaxis was independently associated with an 8-fold risk of death (OR = 8.58, 95% CI 3.26–22.6, P <0.001).

In a computer-based, case-controlled study of skin biopsy pathology reports between 1990 and 1996, Bleyer et al25 found Caucasian race, morbid obesity, and poor nutritional status were risk factors associated with proximal calciphylaxis in ESRD patients on dialysis. Despite referrals from dialysis units with approximately 50% African-Americans, all CUA patients were Caucasian. Nine CUA patients studied were consistently obese to extremely obese (highest proportion at BMI >40 kg/m2) as compared to the 347 control patients (data extracted from 1995 cross-sectional survey of patients in a hemodialysis unit that compared age, race, duration of time in dialysis, blood pressure, CPP, and height/weight [highest proportion at BMI 20–25 kg/m2]). Although the control group had 7 obese patients with a BMI >35 kg/m2, these patients did not develop CUA. Significantly lower serum albumin levels also were found in these CUA patients at the time of diagnosis. Obese patients who did not develop calciphylaxis had higher serum albumin levels (3.9 ± 0.19 g/dL versus 2.9 ± 0.63 g/dL; P <0.01).

Naguib37 reported on Bleyer’s25 work that obesity was implicated as a risk factor in the development of calciphylaxis in patients with CKD. Based on Bleyer’s clinical series with markedly obese patients who had fewer calcium and phosphate metabolism imbalances, Naguib concluded obesity is a more important risk factor than calcium and phosphate imbalances in the development of calciphylaxis.

Fine and Zacharias20 conducted a prospective descriptive study involving 36 consecutive patients with calciphylaxis presenting to their center in a period of 7 years. Dense, nonulcerating plaques in the calves were the most common presentation (considered to be early disease); only 20% had ulcers (considered late disease) on presentation. In their simultaneous case control study, for every patient presenting with “calciphylaxis,” 2 patients with nonulcerating plaques were studied. During the last 3 years of the 7-year period, the authors found an increased rate of calciphylaxis in dialysis patients. Based on their findings, a rate of 4.5/100 patient-years over the last 3 years of their study supported the theory calciphylaxis is no longer rare and incidence has increased. Elevations in phosphate (univariate: OR = 2.40, 95% CI 1.009–5.714, P = 0.048; multivariate: OR = 2.6, 95% CI 1.05 – 6.45, P = 0.038) and calcium-phosphate product (univariate: OR = 1.43, 95% CI 1.013–2.02, P = 0.042; multivariate: OR = 1.46, 95% CI 1.02–20.9, P = 0.038) along with 3 to 4 months of calcium salts and vitamin D therapy also increased the likelihood of disease (univariate: OR = 3.25, 95% CI 1.009 – 10.529, P = 0.048; multivariate: OR = 4.05, 95% CI 1.14 – 14.5, P = 0.03). In many instances, the condition could be improved because most cases presented with early disease and were treated with steroids. Of the 36 new cases, persons who presented with early disease (n = 27) had a mortality rate of 33%; persons who ulcerated or developed late disease had an 80% mortality rate.

Angelis et al’s2 prevalence study retrospectively reviewed the charts of 242 patients with ESRD receiving hemodialysis to determine the prevalence and characteristics of patients who had calciphylaxis. The researchers found a 4.1% prevalence (10 out of 242). However, the study did not reveal if the clinical variables of height, weight, or BMI, were collected, so obesity as a risk factor could not be assessed. The demographics studied revealed dialysis patients were younger (49 versus 60 years; P = 0.01) and had been on dialysis longer (80 versus 20 months; P <0.0001). The ranges for age and months on dialysis were 27 to 66 years (median of 45.5 years) and 41 to 209 months (range 3.42 years to 17.42 years), respectively. The other significant findings were slightly elevated calcium (9.7 mg/dL versus 9.2 mg/dL; P = 0.03), serum phosphate (8.2 mg/dL versus 5.7 mg/dL; P = 0.001), and alkaline phosphatase levels (188 IU/L versus 89 IU/L; P = 0.0001) and calcium phosphate product (81.5 versus 52.9; P = 0.0004). However, the authors concluded increases in cases of calciphylaxis are likely due to the increasing number of patients undergoing long-term dialysis.

 Weenig et al’s31 retrospective 11-year (1992–2002) study of 64 patients showed a 4-fold increase in the likelihood of calciphylaxis among patients who were obese and at risk (univariate OR = 3.91, P = 0.001; multivariate OR = 4.77, P <0.001); for every 1-unit increase in BMI, the risk increased by 10% (OR = 1.10, P <0.001). Steroid use was 3 times more common in the dialysis group (univariate OR = 3.19, P = 0.005; multivariate OR = 2.89, P = 0.026). Another independent risk factor was liver disease, with an 8-fold risk (univariate OR = 8.0, P = 0.007; multivariate OR = 14.9 P = 0.002). Seventy-seven percent (77%) of calciphylaxis patients were on dialysis (23% were nondialysis patients with moderate to severe renal impairment). The results of this study led researchers to conclude this condition is multifactorial.

Sowers and Hayden8 believe the increasing incidence of calciphylaxis is likely due to increases in the prevalence of CKD and the associated epidemic of obesity.6,20 They found an increased reporting of calciphylaxis in the literature from 2005 to 2010, noting that case reports appeared almost monthly.

Nigwekar et al14 theorized they could more accurately identify cases of CUA and determine incidence and mortality using a novel algorithm in the Partners Research Patient Data Registry (clinical data warehouse of 1.8 million patients from January 2002 to December 2011). In October 2006, calciphylaxis was added to the International Classification of Disease- 9th version50 (ICD-9) code 275,Other Disorders of Calcium Metabolism. Calciphylaxis is the only disorder in this ICD-9 code requiring a skin biopsy to confirm the diagnosis. When the ICD-9 and Current Procedure Terminology (CPT) codes were applied simultaneously to claims in the United States Renal Data System (USRDS), Nigwekar et al26 found 649 cases of CUA. The original study period was from January 2002 to December 2011, but with the ICD-9 coding change in 2006, the group focused their study on the years 2007 to 2011. Incidence of CUA in the USRDS was calculated by dividing the number of new cases in a given year by the number of the total chronic hemodialysis patients for that year. The number of dialysis patients increased from 188,598 in the year 2002 to 252,569 in 2011. A steady increase in incidence from 2007 to 2011 was statistically significant (r = 0.91, P = 0.02). In 2007, the incidence per 10,000 chronic hemodialysis patients was 3.7; in 2011, the incidence was 5.7. The mortality rates ranged from 2.5 to 3 times higher for patients with CUA as compared to the average mortality rate (200 to 210 deaths per 1,000 patients)26 among chronic hemodialysis patients.

In her review, Feeser24 hypothesized the increased incidence of calciphylaxis may be due to the “epidemic of obesity and metabolic syndrome resulting in an increased incidence of both type 2 diabetes mellitus and ESRD.”

In 2006, Janigan and Hirsch4 explored whether obesity plays a role in the pathogenesis of CUA. In a subgroup of 69 obese and overweight patients, the majority of the cases were women who had proximal calciphylaxis. Based on Janigan and Hirsch’s past observations, their unpublished case series of 9 additional patients, and 2 case-controlled studies showing obesity as a significant risk factor, they concluded excess adipose tissue exerts chronic tension on the septa and associated arterioles, thus predisposing a person to or exacerbating the risk of obese patients developing proximal calciphylaxis.

A case report from Kalajian et al22 in 2009 found the prevalence of calciphylaxis is increasing in nonuremic patients despite the lack of collective analysis of reported cases. For instance, a 58-year-old morbidly obese (defined as a BMI            >35 kg/m2) woman presenting with proximal ulcerating calciphylaxis was studied. The authors’ examination revealed active stage IIIc endometrial carcinoma treated with surgery and chemotherapy, venous thromboembolism, and a Pseudomonas aeruginosa lower urinary tract infection. Her comorbidities included morbid obesity (BMI = 53), hypertension, anemia, hypothyroidism, and lower extremity venous disease. Despite having proximal calciphylaxis (ulcerations and necrosis of thigh, hips, and pannus), which carries a greater risk of death, this patient survived. This patient was not uremic and her levels of calcium, phosphorus, parathyroid hormone, and alkaline phosphatase were normal. The authors note contradictions are present in statistically associated risk factors due to small case series and reviews.

Hayden et al21 reviewed the pathophysiology of vascular ossification-calcification and the effects on people with pro-atherosclerotic disease processes such as diabetes, obesity, and metabolic syndrome and found the incidence of calciphylaxis is rising. The authors hypothesized the increase is likely due to improved recognition and reporting of the syndrome by nephrologists, dialysis centers, and dermatologists. Additionally, the authors believe the rise in CKD and ESRD patients could lead to near epidemic rates of calciphylaxis given the current and continued epidemic of obesity, diabetes, and metabolic syndrome.

Obesity sets off a domino effect of morbidity- and mortality-related illnesses, but the progression of kidney disease is rarely mentioned.44 When BMI increases, so does the risk of cardiovascular disease, diabetes (including prediabetes, insulin-resistance, and hyperinsulinemia), hypertension, musculoskeletal disorders, cancers, single nephron hyperfiltration, CKD, and ESRD.21,31,37,39,44,49 Obesity is an important and often preventable risk factor for all these diseases, including chronic renal failure. Ejerblad et al’s research49 of the Swedish population and a review of the literature44,48,49 has shown obese persons of any age are 3 to 4 times more likely to develop chronic renal failure. For women, morbid obesity is a risk factor for chronic renal failure.38,49 Risk also increases for overweight persons (persons who did not have BMI >30 kg/m2), with risk tripling for both men and women >20 years of age with a BMI >25 kg/m2. It is estimated obesity causes 15% of chronic renal failure in men and 11% in women in Sweden. The author postulates that the percentage of men and women with CKD in the US is higher due to the greater prevalence of obesity.49

Obesity as a risk factor for diabetes and hypertension is widely known. Diabetes and hypertension are also known risk factors for CKD.30 The development of CKD seems to be causally linked to obesity by a high prevalence of hypertension and/or type 2 diabetes.49 Obesity also is associated with an increased risk of albuminuria and glomerulosclerosis and worsens the course of CKD regardless of the primary renal disease.43,45,49

Discussion

The purpose of this review of the literature was to explore existing evidence about the relationship between obesity and calciphylaxis. The evidence for increasing frequency of calciphylaxis is lacking; the scarcity of comparative studies on calciphylaxis is astonishing considering how long the condition has been identified and how potentially lethal it often becomes. The literature primarily reports opinions, but occasionally incidence or prevalence rates are reported for short time frames. In a 1996 prevalence study,2 researchers found a 4.1% prevalence but failed to disclose a time period or a comparison. Another facility documented an incidence rate of 4.5/100 patient-years from 1999–2001.20 Kalajian et al22 and Nigwekar et al14 both reported the prevalence of calciphylaxis is increasing in nonuremic patients despite the lack of collective analysis of reported cases. Nigwekar et al26 examined incidence over a period of 11 years using pathology results to confirm a calciphylaxis diagnosis and found an incidence ranging from 3.7 to 5.7 per 10,000 chronic hemodialysis patients during 2007–2011. Without standardized reporting of both prevalence and incidence rates, it becomes difficult to determine if the incidence of calciphylaxis is changing.

Small case series and reviews4,51 show differences in associated risk factors. Sowers and Hayden8 believe the incidence of calciphylaxis is increasing, likely due to increases in the prevalence of CKD. As previously noted, the associated epidemic of obesity is believed to be a significant factor in the rising numbers of people with CKD.43-46 Angelis2 found younger patients on dialysis contribute to the increasing incidence of calciphylaxis. Obesity is theorized to exert chronic tension on the septa and associated arterioles from excess adipose tissue, thus predisposing a person to, or exacerbating the risk of, developing proximal calciphylaxis.4,52 The weight of adipose tissue is known to place pressure on vessels, thus obstructing the inflow of arterial blood to the subcutaneous adipose tissue causing ischemia and obstructing the outflow of venous blood and lymph and facilitating an increase in metabolic wastes, toxins, and localized lymphedema.34,53,54 However, the role of obesity as a predisposing factor for tissue ischemia remains uncertain, and physical or structural disturbances within adipose tissue may contribute to a localized role in impairing tissue perfusion.26,36,54

Although Caucasian, morbidly obese, dialysis patients were uncommon in 1990–1996, morbid obesity, Caucasian race, and lower serum albumin level are risk factors for developing calciphylaxis.25 During those years, the percentage of adults who were obese was 11.6% to 15.9%, as compared to 29.4% in 2014.39,42

Because female gender is one of the most commonly associated risk factors6 and because women have a higher proportion of adipose tissue, proximal distribution of lesions could be more likely.23 In addition, although the literature reports 90% of lesions are distal, the proximal lesions tend to be more challenging to manage and carry a higher mortality rate (80% to 89%).6 Reported mortality rates are 2.5 to 3 times higher for patients with CUA as compared to chronic hemodialysis patients (per the USRDS).26

According to Mazhar et al,23 a diagnosis of calciphylaxis carries an 8-fold risk of death; however, the group concluded BMI did not independently predict calciphylaxis. Without further research linking obesity, understanding the epidemiology, pathophysiology, and treatment, this challenging problem is believed to likely grow in light of the current obesity epidemic4,6,8,21,24,25,31,55 and diabetes rate,6,8,21,24,55 as well as the rising number of people with CDK requiring renal replacement therapies.2,25

If clinicians begin entering calciphylaxis patient data into a calciphylaxis registry, more comparative and retrospective studies can be done with larger sample sizes. Ultimately, as data are collected, these registries could facilitate the provision of valuable information toward the discovery of the etiology, prevalence, incidence, risk factors, and treatment of this puzzling condition.

Conclusion

With obesity linked to diabetes mellitus (a pro-atherosclerotic disease process) and CKD, increasing rates of obesity may contribute to increasing rates of calciphylaxis. Although obesity was found to be associated with calciphylaxis, a definitive correlation has yet to be established. Additional research will likely validate the current belief this devastating condition is multifactorial and continue to categorize obesity as one of many risk factors and not causation for the development of calciphylaxis.3,4,6,17,18,31 The literature available on calciphylaxis offers no definitive cause(s). With rising rates of obesity and obesity-related sequelae such as pre-diabetes, diabetes, insulin resistance, hyperinsulinemia, hypertension, CKD, and the potential risk factors for calciphylaxis, it is not out of the realm of belief that calciphylaxis rates are rising and that more of the affected patients will be obese. If more obese patients develop calciphylaxis, especially in proximal locations, not only will they have a high mortality rate, but they also will have increased morbidity with the sequelae.19,25 The literature to date shows calciphylaxis is multifactorial and more research needs to be undertaken to determine the role other factors, along with obesity. Clinicians are advised to maintain a high index of suspicion when faced with indurated, painful nodules or necrotic ulcers especially in patients with CKD. Hopefully, calciphylaxis registries around the world will be able to offer more statistically significant data and unlock the mysteries of this deadly disorder.

Acknowledgment

The author thanks Susan Gallagher, PhD, RN for her invitation to provide the manuscript and her support through the writing/editing process.

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Ms. Davis is a Clinical Skin and Wound Care Specialist, 3M Critical and Chronic Care Solutions Division, St. Paul, MN. Please address correspondence to: Janet M. Davis, MSN, RN, GNP, CWOCN, 2631 Southwick Street, Houston, TX  77080; email: jdavis4@mmm.com.

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