Kidney Disease Risk in Patients With Psoriasis
Kidney Disease Risk in Patients With Psoriasis
To our knowledge this is the first population based cohort study to compare the incidence of moderate to advanced chronic kidney disease in patients with and without psoriasis, thus providing generalizability and allowing us to assess the temporal relation between psoriasis and chronic kidney disease. We found that severe psoriasis, defined by treatment patterns, is an independent risk factor for moderate to advanced chronic kidney disease. These findings were confirmed when we evaluated the prevalence of chronic kidney disease based on severity of psoriasis as determined by the general practitioner's categorization of affected body surface area. The combined results indicate that, although no association is seen in patients with truly mild disease (less than 2% body surface area affected), as consistent with previous studies, associations are seen in moderate and severe psoriasis, which are estimated to affect over 20% of patients with psoriasis worldwide. The relative risk of chronic kidney disease is especially increased in younger patients, similar to previous findings for myocardial infarction in psoriasis. Nevertheless, despite attenuation of the association with increasing age, the clinical relevance of the absolute risk of chronic kidney disease attributable to psoriasis increases with age. In patients aged 40-50 with severe disease based on treatment patterns, psoriasis accounts for one extra case of chronic kidney disease per 134 patients per year, and in those aged 50-60, it accounts for one additional case per 62 patients per year.
Our results are consistent with previous descriptive work showing a higher prevalence of renal failure in patients with severe psoriasis. The increased relative risk of end stage renal disease among patients with severe psoriasis also fits with earlier findings of increased renal related mortality in those individuals. Furthermore, most previous studies evaluating renal disease in patients with psoriasis have focused on indicators of subclinical glomerular dysfunction, such as urinary albumin excretion. Although these markers can be used to predict nephropathy, they might not indicate the presence of or subsequent progression to severe renal insufficiency. Moreover, studies examining these markers have had mixed results, with a handful of studies failing to find any differences in urinary albumin excretion or creatinine clearance between patients with psoriasis and healthy individuals. These null findings might have been caused by small sample sizes, but it is also possible that patients with and without psoriasis differ not with respect to subclinical glomerular dysfunction but rather in the eventual development of moderate to advanced renal insufficiency, as assessed in this study.
We adjusted for confounders such as diabetes, hypertension, and use of nephrotoxic drugs, factors that had served as exclusion criteria or were altogether not evaluated in previous studies. Our results suggest that there is an association between psoriasis and chronic kidney disease independent of comorbidities in psoriasis, such as diabetes and cardiovascular disease. Furthermore, we found that the association between severe psoriasis and renal insufficiency is not driven by joint disease or associated use of nephrotoxic drugs. Sensitivity analyses excluding patients with psoriatic arthritis, rheumatoid arthritis, or osteoarthritis showed results similar to the primary model. Our findings also remained robust when we adjusted for frequency of use of non-steroidal anti-inflammatory drugs both at baseline and averaged over follow-up. As cyclosporine and methotrexate can induce nephrotoxicity, we conducted sensitivity analyses excluding patients who used these drugs and found that the higher relative risk of chronic kidney disease persisted among patients with severe psoriasis who had not received cyclosporine or methotrexate. Lastly, to ensure that we were capturing incident and not prevalent chronic kidney disease, we performed additional analyses restricted to patients who had received a diagnosis of chronic kidney disease at least one year after their start date and found similar results.
While moderate to advanced chronic kidney disease is a distinct outcome, its development stems from a heterogeneous group of kidney diseases. The mechanisms mediating renal injury in psoriasis remain thus unclear. Numerous case reports have described the coexistence of psoriasis and glomerulonephritis, most commonly IgA nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy, suggesting that immunologic mechanisms such as defects in T cell function and increased levels of immune complexes underlie glomerular injury in psoriasis. On the other hand, tubular injury induced by raised uric acid concentrations in people with psoriasis is another theoretical mechanism. Examination of specific renal diseases is warranted to better characterize renal insufficiency among patients with psoriasis.
As with all studies, there are important limitations to consider. First, misclassification bias is possible when systemic treatments are used as a marker of severity of psoriasis. As direct measurements of the extent of psoriasis are not encoded within THIN, the identification of severe disease was based on treatment patterns. Nevertheless, use of treatments as a proxy measure of severity has been widely accepted. Direct measurements of the extent of body surface area affected by psoriasis were also examined in the nested analysis, which corroborated our primary findings. As azathioprine can be prescribed for other dermatologic disorders such as eczema and use of phototherapy can indicate acute flares rather than chronic severe psoriasis, we also performed sensitivity analyses excluding patients who received these treatments and found results consistent with the primary analysis. Notably, the prevalence of biologic therapy in our cohort was low, probably because most biologics are exclusively prescribed by specialists and thus might not be fully captured in THIN. Moreover, biologic therapy did not become prevalent for psoriasis treatment in the UK until after 2005. While outcome misclassification is also a potential limitation, particularly in database studies, the practitioners collecting THIN data were unaware of the hypotheses being tested, and thus any bias would probably be non-differential and bias findings towards the null. Our outcome is further strengthened by our use of the standard laboratory based definition of chronic kidney disease in addition to diagnostic codes, thereby minimizing misclassification. It is worth noting, however, that current definitions of chronic kidney disease are controversial, and some researchers argue that they lead to the overdiagnosis of subclinical chronic kidney disease. Nevertheless, this potentially increased capture of chronic kidney disease is likely non-differential between patients with and without psoriasis. Furthermore, we performed sensitivity analyses examining each specific stage within moderate to severe chronic kidney disease and observed an increased risk across all severities of renal dysfunction among patients with psoriasis. Our finding of an association between psoriasis and dialysis dependent end stage renal disease further argues that the association between psoriasis and chronic kidney disease is not driven solely by the overdiagnosis of subclinical renal impairment.
Second, it is conceivable that patients with psoriasis might visit their physicians more often or are screened earlier and more often for chronic kidney disease, thus leading to ascertainment bias. End stage renal disease, an outcome more robust to screening bias, however, was also significantly associated with severe psoriasis and argues against ascertainment bias, supporting our results for chronic kidney disease. In other words, even if mild renal disease were more likely to be detected because of increased surveillance among patients with psoriasis, dialysis dependent renal disease should present clinically, regardless of screening frequency. We also performed sensitivity analyses restricted to patients with similar frequencies of screening for chronic kidney disease or contact with the healthcare system and found similar results. Third, unmeasured and unknown confounders could exist, though we accounted for all major confounders in our primary analysis as well as many other possible confounders in sensitivity analyses. Lastly, The Health Improvement Network does not contain data on race, which could lead to underestimation of renal function among black patients as the MDRD formula for estimating glomerular filtration rate from serum creatinine involves a correction factor for black race. This inherent limitation to The Health Improvement Network data cannot be overcome and was unlikely to impact our results as only an estimated 3% of the UK population is black.
In conclusion, moderate to severe psoriasis is associated with moderate to advanced chronic kidney disease independent of traditional risk factors. Closer monitoring for renal insufficiency, such as routine screening urinalysis for microalbuminuria and serum creatinine and blood urea nitrogen testing, should be considered for patients with psoriasis affecting 3% or more of the body surface area. Increased screening efforts will allow for earlier detection and intervention to reduce the substantial morbidity and mortality associated with chronic kidney disease. Additionally, the risk versus benefit of potentially nephrotoxic drugs in patients with moderate to severe psoriasis should be carefully considered. Future studies are warranted to confirm our findings, determine the mechanisms mediating renal insufficiency in psoriasis, and examine the impact of treatment for psoriasis on the risk of chronic kidney disease.
Discussion
Principal Findings
To our knowledge this is the first population based cohort study to compare the incidence of moderate to advanced chronic kidney disease in patients with and without psoriasis, thus providing generalizability and allowing us to assess the temporal relation between psoriasis and chronic kidney disease. We found that severe psoriasis, defined by treatment patterns, is an independent risk factor for moderate to advanced chronic kidney disease. These findings were confirmed when we evaluated the prevalence of chronic kidney disease based on severity of psoriasis as determined by the general practitioner's categorization of affected body surface area. The combined results indicate that, although no association is seen in patients with truly mild disease (less than 2% body surface area affected), as consistent with previous studies, associations are seen in moderate and severe psoriasis, which are estimated to affect over 20% of patients with psoriasis worldwide. The relative risk of chronic kidney disease is especially increased in younger patients, similar to previous findings for myocardial infarction in psoriasis. Nevertheless, despite attenuation of the association with increasing age, the clinical relevance of the absolute risk of chronic kidney disease attributable to psoriasis increases with age. In patients aged 40-50 with severe disease based on treatment patterns, psoriasis accounts for one extra case of chronic kidney disease per 134 patients per year, and in those aged 50-60, it accounts for one additional case per 62 patients per year.
Comparison With Other Studies
Our results are consistent with previous descriptive work showing a higher prevalence of renal failure in patients with severe psoriasis. The increased relative risk of end stage renal disease among patients with severe psoriasis also fits with earlier findings of increased renal related mortality in those individuals. Furthermore, most previous studies evaluating renal disease in patients with psoriasis have focused on indicators of subclinical glomerular dysfunction, such as urinary albumin excretion. Although these markers can be used to predict nephropathy, they might not indicate the presence of or subsequent progression to severe renal insufficiency. Moreover, studies examining these markers have had mixed results, with a handful of studies failing to find any differences in urinary albumin excretion or creatinine clearance between patients with psoriasis and healthy individuals. These null findings might have been caused by small sample sizes, but it is also possible that patients with and without psoriasis differ not with respect to subclinical glomerular dysfunction but rather in the eventual development of moderate to advanced renal insufficiency, as assessed in this study.
Strengths and Limitations of Study
We adjusted for confounders such as diabetes, hypertension, and use of nephrotoxic drugs, factors that had served as exclusion criteria or were altogether not evaluated in previous studies. Our results suggest that there is an association between psoriasis and chronic kidney disease independent of comorbidities in psoriasis, such as diabetes and cardiovascular disease. Furthermore, we found that the association between severe psoriasis and renal insufficiency is not driven by joint disease or associated use of nephrotoxic drugs. Sensitivity analyses excluding patients with psoriatic arthritis, rheumatoid arthritis, or osteoarthritis showed results similar to the primary model. Our findings also remained robust when we adjusted for frequency of use of non-steroidal anti-inflammatory drugs both at baseline and averaged over follow-up. As cyclosporine and methotrexate can induce nephrotoxicity, we conducted sensitivity analyses excluding patients who used these drugs and found that the higher relative risk of chronic kidney disease persisted among patients with severe psoriasis who had not received cyclosporine or methotrexate. Lastly, to ensure that we were capturing incident and not prevalent chronic kidney disease, we performed additional analyses restricted to patients who had received a diagnosis of chronic kidney disease at least one year after their start date and found similar results.
While moderate to advanced chronic kidney disease is a distinct outcome, its development stems from a heterogeneous group of kidney diseases. The mechanisms mediating renal injury in psoriasis remain thus unclear. Numerous case reports have described the coexistence of psoriasis and glomerulonephritis, most commonly IgA nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy, suggesting that immunologic mechanisms such as defects in T cell function and increased levels of immune complexes underlie glomerular injury in psoriasis. On the other hand, tubular injury induced by raised uric acid concentrations in people with psoriasis is another theoretical mechanism. Examination of specific renal diseases is warranted to better characterize renal insufficiency among patients with psoriasis.
As with all studies, there are important limitations to consider. First, misclassification bias is possible when systemic treatments are used as a marker of severity of psoriasis. As direct measurements of the extent of psoriasis are not encoded within THIN, the identification of severe disease was based on treatment patterns. Nevertheless, use of treatments as a proxy measure of severity has been widely accepted. Direct measurements of the extent of body surface area affected by psoriasis were also examined in the nested analysis, which corroborated our primary findings. As azathioprine can be prescribed for other dermatologic disorders such as eczema and use of phototherapy can indicate acute flares rather than chronic severe psoriasis, we also performed sensitivity analyses excluding patients who received these treatments and found results consistent with the primary analysis. Notably, the prevalence of biologic therapy in our cohort was low, probably because most biologics are exclusively prescribed by specialists and thus might not be fully captured in THIN. Moreover, biologic therapy did not become prevalent for psoriasis treatment in the UK until after 2005. While outcome misclassification is also a potential limitation, particularly in database studies, the practitioners collecting THIN data were unaware of the hypotheses being tested, and thus any bias would probably be non-differential and bias findings towards the null. Our outcome is further strengthened by our use of the standard laboratory based definition of chronic kidney disease in addition to diagnostic codes, thereby minimizing misclassification. It is worth noting, however, that current definitions of chronic kidney disease are controversial, and some researchers argue that they lead to the overdiagnosis of subclinical chronic kidney disease. Nevertheless, this potentially increased capture of chronic kidney disease is likely non-differential between patients with and without psoriasis. Furthermore, we performed sensitivity analyses examining each specific stage within moderate to severe chronic kidney disease and observed an increased risk across all severities of renal dysfunction among patients with psoriasis. Our finding of an association between psoriasis and dialysis dependent end stage renal disease further argues that the association between psoriasis and chronic kidney disease is not driven solely by the overdiagnosis of subclinical renal impairment.
Second, it is conceivable that patients with psoriasis might visit their physicians more often or are screened earlier and more often for chronic kidney disease, thus leading to ascertainment bias. End stage renal disease, an outcome more robust to screening bias, however, was also significantly associated with severe psoriasis and argues against ascertainment bias, supporting our results for chronic kidney disease. In other words, even if mild renal disease were more likely to be detected because of increased surveillance among patients with psoriasis, dialysis dependent renal disease should present clinically, regardless of screening frequency. We also performed sensitivity analyses restricted to patients with similar frequencies of screening for chronic kidney disease or contact with the healthcare system and found similar results. Third, unmeasured and unknown confounders could exist, though we accounted for all major confounders in our primary analysis as well as many other possible confounders in sensitivity analyses. Lastly, The Health Improvement Network does not contain data on race, which could lead to underestimation of renal function among black patients as the MDRD formula for estimating glomerular filtration rate from serum creatinine involves a correction factor for black race. This inherent limitation to The Health Improvement Network data cannot be overcome and was unlikely to impact our results as only an estimated 3% of the UK population is black.
Conclusions and Policy Implications
In conclusion, moderate to severe psoriasis is associated with moderate to advanced chronic kidney disease independent of traditional risk factors. Closer monitoring for renal insufficiency, such as routine screening urinalysis for microalbuminuria and serum creatinine and blood urea nitrogen testing, should be considered for patients with psoriasis affecting 3% or more of the body surface area. Increased screening efforts will allow for earlier detection and intervention to reduce the substantial morbidity and mortality associated with chronic kidney disease. Additionally, the risk versus benefit of potentially nephrotoxic drugs in patients with moderate to severe psoriasis should be carefully considered. Future studies are warranted to confirm our findings, determine the mechanisms mediating renal insufficiency in psoriasis, and examine the impact of treatment for psoriasis on the risk of chronic kidney disease.
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