CKD is closely related to the aging of the population and the high prevalence of diabetes and hypertension.30 Onset of kidney disease is directly related to risk factors that are highly prevalent in patients with psoriasis, such as hypertension, diabetes, obesity, dyslipidemia, and metabolic syndrome, all of which are also independent CV risk factors.31 Therefore, any of these abnormalities can develop and contribute to the progression of kidney disease.32

Since all these conditions are independent risk factors for CKD, risk is further increased by the presence of more than one of them. It is not surprising, therefore, that patients with psoriasis, who may have several of these conditions, are more likely to develop CKD. Hypertension, whether systolic or diastolic, is an independent predictor of kidney disease.33 Diabetes is also an important risk factor for vascular disease with renal involvement. Diabetic nephropathy occurs in 25% to 40% of patients with a long history of type 1 or type 2 diabetes, and is also a CV risk factor.34 Obesity and metabolic syndrome are also well known risk factors for impaired renal function.35

Many isolated cases of associations between psoriasis and different types of glomerulonephritis have been reported, but few authors have studied this relationship in a comprehensive way. In a recent study, in which 4344 patients with psoriasis were followed up for 5 years, the authors reported an increased incidence of glomerulonephritis (HR, 1.50; 95% CI, 1.24-1.81), which may contribute to the impairment of renal function observed in this setting.26 In that study, the risk increased with severity, being higher in patients with more severe disease and those with psoriatic arthritis. The type of glomerulonephritis most frequently reported in association with psoriasis is mesangial proliferative glomerulonephritis, with and without immunoglobulin A deposits.29,36 This type of glomerulonephritis is common in infectious and autoimmune diseases and—although the pathophysiologic mechanisms are poorly understood—the increased synthesis of polymeric immunoglobulin present in such diseases would appear to be a factor in its pathogenesis.37

There is lack of consensus in the literature on the relationship between CKD and psoriasis and on the role played by certain drugs used to treat psoriatic disease—CsA and methotrexate—because of the well known nephrotoxicity of both of these drugs.

The use of CsA has been linked to hypertension, kidney disease, and lymphoproliferative processes. Consequently, treatment with CsA for more than 2 years is not recommended.38 Because it causes vasoconstriction of afferent arterioles, CsA can also cause acute renal failure. Renal function improves within 5 to 7 days following cessation of treatment.39

However, prolonged treatment with CsA may cause irreversible CKD. The recommended cumulative duration of treatment and the risk associated with CsA vary from case to case, but the study that originally detected kidney damage caused by treatment with CsA concluded that patients treated for more than 12 months were at increased risk for renal impairment.40 There is evidence that the risk is not reduced by intermittent use and outcomes reported for intermittent regimens are similar to those reported for continuous treatment.41 Multiple studies in liver transplant patients have found no differences in renal function between groups receiving high and low doses of CsA and no increased association with kidney disease in patients on higher doses of the drug.42

In the case of methotrexate, 90% of the drug is eliminated through the kidneys and the damage may be caused by renal precipitation or by the direct effect of the drug on renal tubules. Methotrexate toxicity depends on the blood concentrations achieved after administration. Levels greater than 10 μM at 24 h or greater than 1 μM at 48h are associated with a high probability of nephrotoxicity, especially in older patients.43 Some studies have reported methotrexate nephrotoxicity in patients with psoriasis.44,45 Although the doses used to treat psoriasis are low and few cases have been reported, dermatologists should be aware that nephrotoxic doses may be reached because the threshold varies a great deal from patient to patient.

The use of nonsteroidal anti-inflammatory drugs has been linked to increased kidney damage in patients with moderate to severe psoriasis (relative risk, 1.69).26 In many cases, nonsteroidal anti-inflammatory agents are used in combination with methotrexate, a practice that could increase the risk of kidney damage.

The literature on biologic drugs includes multiple cases of autoimmune kidney disease caused by biologic therapy in patients with various diseases, including psoriasis.46–53 In most of these cases, the patients had membranous glomerulonephritis, although granulomatous nephritis has also been reported. These cases can be categorized as follows: glomerulonephritis associated with systemic vasculitis, glomerulonephritis in lupus-like syndromes, and isolated autoimmune renal disorders. Most of the cases reported are associated with tumor necrosis factor inhibitors.54 Notwithstanding these findings and given their lack of end-organ toxicity, biologic agents can be a good therapeutic option in patients with CKD and even end-stage renal disease. Cases have been reported of successful treatment of psoriasis with biologic drugs in patients on hemodialysis.55

CKD is a major public health problem affecting 10% of the adult population and more than 20% of people over 60 years of age.56 Moreover, it is well known that the disease is underdiagnosed. CKD is an independent risk factor for CV disease, and the risk of CV mortality in patients with CKD is greater than the risk of progression to dialysis or transplant.57 CV disease associated with CKD is treatable and potentially preventable.57

It is important to be aware of the association between impaired renal function, the onset of CV disease, and death. In clinical practice, renal function should be monitored in patients in the at-risk population, who should also be routinely tested for proteinuria (albuminuria). Monitoring is essential owing to the high incidence of kidney disease in patients with psoriasis. Once a persistent elevation of albumin in the urine (microalbuminuria) is confirmed, CV risk exists even when renal function is normal. The risk increases as renal function deteriorates. In patients with end-stage renal disease, the risk of CV disease is 20 to 30 times that of the general population.58

The severity of renal impairment is assessed by measuring the GFR and by the presence of microalbuminuria (30-300 mg/24h) or macroalbuminuria (> 300 mg/24h). A GFR estimated at below 60 mL/min is defined as kidney failure and represents a significant increase in CV risk. A low GFR is often accompanied by albuminuria, and the effect of the two factors is additive. It is important to monitor and control risk factors in patients with renal impairment from the outset. Patients with renal impairment and ischemic heart disease and/or heart failure often do not receive all the treatment they should; in such cases, special attention should be paid to improving survival.59

In patients with renal failure, the kidneys gradually lose the ability to excrete phosphorus. This deficit is compensated by phosphaturic mechanisms that boost the urinary excretion of phosphorus, such as increases in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), which maintain the normal phosphaturic capacity. The role of FGF23, a phosphatonin with 251 amino acids, is to maintain normal phosphorus levels in the body. It does this by downregulating the activity of the type II sodium/phosphate cotransporters in the proximal tubule, thereby decreasing renal tubular phosphate reabsorption. However, it also inhibits the activity of 1 alpha hydroxylase, thereby reducing synthesis of 1-25 dihydroxycholecalciferol from its precursor calcidiol, and increases 24 alpha hydroxylase, which in turn increases vitamin D catabolism. Thus, vitamin D is decreased in patients with kidney failure.60 The increases in PTH and FGF23, together with the decrease in vitamin D, increases CV risk.61

Patients with psoriasis have decreased vitamin D levels and increased PTH levels. In winter, the prevalence of vitamin D deficiency can reach as high as 80% in patients with psoriasis.62 While the origin of vitamin D deficiency in psoriasis has not been studied in depth, it may have multiple implications. First, vitamin D deficiency can cause osteoporosis, reduce the patient's immune response, or increase CV mortality and the risk of diabetes.63,64 Vitamin D deficiency also has important implications in the pathogenesis of psoriasis because certain vitamin D receptors are responsible for the growth and differentiation of keratinocytes and for the immune functions of T cells and dendritic cells.65 In fact, topical vitamin D derivatives have been used to treat psoriasis and it is also possible that an increase in endogenous vitamin D production may be one of the mechanisms of action of phototherapy in this setting.66,67 Increased serum PTH has also been observed in patients with psoriasis and this may have direct implications on CV risk in these patients.68 While it may be the result of vitamin D deficiency, increased PTH could also be a phosphaturic mechanism triggered by the decreased renal elimination of phosphorus.

At least in patients with moderate to severe forms of psoriasis, as in other inflammatory disorders, kidney function should be assessed at least once a year, including measurement of microalbuminuria, creatinine, and GFR (estimated using formulas). The most commonly used formulas are those taken from the Modification of Diet in Renal Disease (MDRD) study, known as MDRD-4,69 and those devised by the Chronic Kidney Disease Epidemiology Collaboration, known as CKD-EPI.70 Some authors recommend testing urine albumin levels (microalbuminuria), creatinine, and estimating GFR in any patient who has plaque psoriasis affecting more than 3% of the body surface and taking particular care if the patient is on nephrotoxic drugs, such as methotrexate or CsA, irrespective of the underlying disease.20 Even closer monitoring of renal function is needed when the patient is taking potentially nephrotoxic drugs.15 Nephrotoxic drugs are contraindicated in patients with kidney injury. Treatment with drugs such as CsA should never exceed 2 years. Prescribing treatments that are not nephrotoxic may be a reasonable alternative to reduce this risk.

When monitoring detects a decrease in GFR or a higher value for microalbuminuria compared to prior measurements, the patient should be carefully assessed, if necessary by a nephrologist. We must not forget that psoriasis is a chronic disease and that early diagnosis of renal impairment will facilitate prompt stabilization of the condition, which is important since the damage is irreversible.

To prevent CV events, it is essential to monitor the classic CV risk factors (hypertension, diabetes, dyslipidemia, and excess weight/obesity) in patients with psoriasis, especially those with moderate to severe disease. Patients with extensive psoriasis and those who have extracutaneous symptoms, such as arthritis, have a higher risk of comorbid disease.

The key messages of this study are shown in Table 3.