Vitamin D and Glomerulonephritis

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Guido Gembillo	+ 2556 word(s)	2556	2021-03-01 10:11:35	\|
2	format correct	Bruce Ren	-21 word(s)	2535	2021-03-02 03:51:47	\| \|
3	format correct	Conner Chen	Meta information modification	2535	2021-10-11 09:51:59	\|

This entry is adapted from the peer-reviewed paper 10.3390/medicina57020186

Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeo-stasis. It is an efficient endocrine regulator of the Renin–Angiotensin–Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is im-paired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding pro-tein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin–megalin–amnionless receptor complex in the renal proximal tubule. In Glomeru-lonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodu-lating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Acti-vated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibi-tors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulo-nephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the hepa-ranase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in un-bound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage.

glomerulonephritis vitamin D calcitriol glomerular disease VDR CKD paricalcitol

1. Introduction

Glomerular diseases are the third most common cause of end-stage kidney disease (ESKD) in the United States and represent 25% of chronic kidney disease (CKD) cases in the world ^[1]^[2].

In our review, we investigated the connection between Glomerulonephritis (GN) and one of the most used supplements in CKD patients, Vitamin D.

The synthesis of vitamin D active form, the 1α,25-dihydroxyvitamin D3, (calcitriol) takes place mostly in the kidneys by 1α-hydroxylase (CYP27B1), but its action declines as the nephron mass declines ^[3]. Several mechanisms can stimulate calcitriol renal production: parathormone, low calcium and phosphate serum levels, while elevated phosphate and FGF23 concentrations inhibit its production.

Vitamin D shows pleiotropic effects that encompass skeletal and non-skeletal functions: its active form has the power to modulate the action of renin–angiotensin–aldosterone system (RAAS) ^[4], stimulate the erythropoiesis ^[5], can reduce the incidence of cardiovascular events in CKD patients ^[6], while low vitamin D levels are associated to cardiovascular and all-cause mortality ^[7].

Patients with renal impairment are at higher risk of Vitamin D deficiency for multiple causes: NS, diabetic nephropathy and GN can cause the loss of its major carrier, the vitamin D-binding protein (DBP); the restriction of nutrients containing Vitamin D to avoid imbalance in phosphorus absorption; the sporadic sunlight exposure ^[8] and the dysfunction of the cubilin–megalin–amnionless receptor complex in the renal proximal tubule ^[9].

The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend that CKD patients who have vitamin D insufficiency (<30 ng/mL) should receive vitamin D supplementation ^[10].

Vitamin D deficiency is a diffuse issue with high prevalence in CKD, but the best form and posology to prevent and slow the CKD progression and prevent the onset of GN manifestations is still on debate ^[11].

The primary biomarker of vitamin D status is represented by serum 25(OH)D because it reflects both dietary and ultraviolet radiation influence, presents a longer half-life compared to the active form 1,25(OH)2D and can be measured accurately and reliably. In patients with NS or proteinuric kidney diseases, determination of free 25(OH)D should be preferred to total 25(OH)D levels to diagnose Vitamin D deficiency and establish the therapy ^[12].

Vitamin D and its receptor (VDR) modulation have been demonstrated to lessen severity of proteinuria in patients with renal impairment, one of GN’s main features ^[13]. VDR are directly regulated using active Vitamin D such Calcitriol, that also modulates the transcription of several Vitamin D-dependent genes ^[14].

The best strategies for a correct Vitamin D regulation in CKD and GN are still in discussion, the number of compounds that can be selected for this purpose is rising through the years.

Calcitriol activates VDR directly with an affinity three times higher than that of the Vitamin D analog Paricalcitol, with a ten-times stronger calcemic and phosphatemic power ^[15]. Doxercalciferol presents similar effects compared with Calcitriol ^[16], but needs a further hepatic metabolization to be activated. This intermediate step makes Doxercalciferol potentially more modulable compared to the activated form of Vitamin D. This compound is more structurally similar to Vitamin D2, the plant-derived version of Vitamin D, than with the animal-derived version. The Vitamin D3 equivalent of Doxercalciferol is the Alphacalcidol, that is also hydrolysed by the liver in a kidney-independent pathway for its activation.

Vitamin D mimetics such Paricalcitol and Maxacalcitol exerts a milder calcemic effect than Vitamin D active forms. Their bioavailability rises to peak levels and operates on the target tissue following rapid deactivation ^[17]. This class of drugs decreases the serum levels of intrinsic 1α,25(OH)₂D, while Vitamin D analogues increases them. Maxacalcitol structurally differs from Calcitriol by the substitution of an oxygen for C22. This modification leads to a reduced affinity of Maxacalcitol for VDR and DBP, guaranteeing a better clearance of this compound ^[18].

Large comparative studies on different classes of Vitamin D analogs and Vitamin D mimetics conducted in CKD and GN populations are needed to establish the best pharmacological strategies.

Cholecalciferol administration seems to ameliorate albuminuria in CKD patients, even if the data in literature are not conclusive: Molina et al. ^[19] treated 101 non-dialysis CKD patients with 666 IU/day oral cholecalciferol, with urinary albumin-to-creatinine ratio (uACR) decreasing from 284 (189–425) to 167 mg/g (105–266) at 6 months (geometric mean with 95% CI, p < 0.001).

Wu et al. ^[20] demonstrated that an oral dose of calcitriol (0.25 μg, three times weekly) significantly reduced proteinuria in CKD patients at 8, 16 and 24 weeks of treatment (p < 0.05 vs. baseline). A dosage of 0.5 µg calcitriol twice a week has shown efficacy in reducing the proteinuria in patients with IgA nephropathy ^[21]^[22] (see Section 4).

In two small randomized controlled trials (RCTs), the investigators demonstrated that patients treated with Paricalcitol had lower urinary protein-to-creatinine ratio (PCR) and 24-h albumin excretion, in comparison to placebo control ^[23]^[24].

The VITAL study ^[25] validated the antiproteinuric effect of the addition of 2 μg/day of paricalcitol to a RAAS inhibitor in diabetic patients: this synergistic effect guaranteed a reduction of residual albuminuria, ranging from –18% to –28% (p = 0.014 vs. placebo). In the paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) study ^[26], 2 μg/d×12 weeks of paricalcitol promoted vasodilatation of vascular smooth muscle and cardiovascular in subjects with CKD stage 3–4. Aperis et al. ^[27] demonstrated that 1–2 μg daily of Paricalcitol could ameliorate proteinuria in patients with glomerular damage, even if there was a better response in subjects with diabetic nephropathy compared to patients with other types of GN. Other small clinical studies have also shown the potential effects of Paricalcitol in diabetic patients with and without renal involvement ^[28]^[29]^[30].

Vitamin D deficiency is linked to a complex web of severe metabolic abnormalities including inflammation, cardiovascular insults, fibrosis that have far reaching implications for health, leading to progression of renal impairment and ESKD.

The action of the different forms of vitamin D can potentiate the nephroprotective effects of RAAS inhibitors, adding a precious contribution as immunomodulators and anti-inflammatory drugs ^[31].

2. Vitamin D and VDR in Experimental Models of GN

Vitamin D is an efficient endocrine regulator of the RAAS and operates predominantly as a suppressor of renin biosynthesis; on the other hand, dysregulation of VDR leads to elevated renin and angiotensin II production, subsequent hypertension and cardiac hypertrophy ^[32]. In the kidney, the VDR not only has a major role in the modulation of renin gene expression but is also implicated in the control of inflammation, epithelial-to-mesenchymal transition, and podocyte integrity ^[33]. Both vitamin D and VDR are involved in the regulation of apoptosis of cultured mouse podocytes and in modulation of transforming growth factor β (TGFβ) via the nuclear factor κB (NF-κB) pathway upon lipopolysaccharide stimulation ^[34]. In fact, vitamin D demonstrates potent antiproliferative, prodifferentiative, and immunomodulating activities, inhibiting kidney inflammation via VDR-mediated sequestration of NF-κB signaling ^[35]. Vitamin D inhibits NFκB transactivation also through the modulation of advanced glycation end-products and their receptor (AGE-RAGE system) ^[36], a mechanism at the basis of progression of different kidney diseases such as diabetic nephropathy, hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, amyloidosis, autosomal dominant polycystic kidney disease, and septic acute kidney injury ^[37].

Vitamin D also contributes to preserving mitochondrial morphology in the renal tissue ^[38], while VDR activation contributes to mitochondrial integrity, by controlling the permeability transition pore (MPTP) in a ligand-independent way ^[39]. Mitochondrial preservation is at the basis of cellular function for adenosine triphosphate production, modulation of Ca²⁺ signaling, regulating reactive oxygen species (ROS) status and oxidation-reduction reactions ^[40].

2.1. Calcitriol Use in Experimental GN

Vitamin D has a pivotal role in the kidney’s filtration homeostasis and plays an essential part in podocyte preservation. Podocytes damage and the impairment of the structural integrity of the slit diaphragm have been recognized as a fundamental process in the evolution of glomerulosclerosis ^[41]. In particular, calcitriol preserves the structural integrity of the slit diaphragm and significantly prevents the loss of nephrin and tight junction protein-1 of rats with membranoproliferative GN ^[42]. It exerts an antiproliferative effect in course of compensatory growth of nephrons due to subtotal nephrectomy; this action helps to improve glomerular sclerosis and albuminuria ^[43]. One of its functions is the inhibition of the proliferation of mesangial cells ^[44] with the capacity of lowering Ki67 mRNA expression and its protein production ^[45]. Ki67 represents a marker of proliferation, used both as an indicator of excessive cell replication and GN’s progression ^[46]. Calcitriol found its rationale in experimental studies on IgA nephropathy (IgAN), by the immunomodulation of T helper-regulatory (Th17-Treg) cells balance and by reducing proteinuria in rats ^[47].

Treatment with Calcitriol can modulate the transient receptor potential cation channel C6 (TRPC6) action in mice’s podocytes, while its deficiency is linked to a dysregulated action of these cation channels, podocyte foot process effacement and proteinuria ^[48]. These findings have also been demonstrated in diabetic rats: in the study of Zhang et al. ^[49] treatment with calcitriol increased VDR levels, normalized TRPC6 expression and reduced proteinuria.

Calcitriol also controls the podocyte density through a modulation of mRNA and protein expressions of nephrin and podocin, α3β1 integrin and α/β dystroglycan, contrasting podocyte detachment and podocytopenia ^[50]. Both podocyturia and nephrinuria are indicators of podocyte damage and markers of worsening of NS; their control has a pivotal role in reducing renal damage progression ^[51].

Calcitriol also showed a modulatory effect on the urokinase receptor (uPAR), a structure implicated in podocyte damage and development of focal segmental glomerulosclerosis (FSGS). A correct modulation of uPAR has a nephroprotective function, leading to a better control of proteinuria ^[52]^[53].

Supplementation with calcitriol has a protective function in controlling the degrading enzyme heparanase expression and subsequent reduction of proteinuria ^[54]. Garsen et al. ^[55] demonstrated that through VDR action, calcitriol treatment could regulate the heparanase promoter activity in the podocyte, guaranteeing its preservation.

Yuan et al. ^[56] revealed in experimental models of IgA nephropathy a positive effect of the association of tacrolimus and vitamin D in the reduction of glomerular mesangial cells hyperplasia, thickening of the glomerular basement membrane, and glomerular infiltration of inflammatory cells, in comparison to placebo and the tacrolimus alone control group. The vitamin D plus tacrolimus group showed a better modulation of NF-κB/TLR4 pathway and reduced levels of TGF-β1, IL-5, and IL-4.

2.2. Paricalcitol Use in Experimental GN

Paricalcitol exerts positive effects in the control of proteinuria, glomerulosclerosis, interstitial fibrosis, in the prevention of tubular atrophy and may contrast lymphangiogenesis, another cause of progression of renal disease ^[57]^[58]. It also has a cardiorenal protective effect in uremic rats by reducing myocardial fibrosis ^[59]. Finch et al. ^[60] confirmed that paricalcitol’s action might be amplified with enalapril addition, decreasing interstitial infiltration of mononuclear cells and oxidative stress, and the association of both drugs is more effective than each compound alone. This pharmacological association has also been tested by Mizobuchi et al. ^[61] that demonstrated that the use of paricalcitol and enalapril slows the progression of renal insufficiency through the modulation of the TGF-β signaling pathway. Based on this effect, there is the suppression of RAAS gene expression: in fact, paricalcitol lowers angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA status ^[62]. The association of paricalcitol, enalapril and atrasentan leads to even greater protective power, preventing cardiorenal damage and decreasing cardiomyocyte size to normal levels in uremic rats.

VDR stimulation through the paricalcitol also reduces proteinuria of diabetic nephropathy mice and ameliorate high-glucose-induced injury of kidneys and podocytes ^[63].

2.3. Maxacalcitol in Experimental GN

Maxacalcitol, also known as 22-oxa-calcitriol (OCT), prevents progression of by the control of glomerular volume and glomerular cell number, albumin excretion and rise in creatinine ^[64]. OCT inhibits mesangial cell proliferation, reducing the mRNA expression of Smooth Muscle Alpha-Actin (alpha-SMA), an actin isoform with a relevant role in fibrogenesis, type I and type IV collagens ^[65].

The positive effects of OCT on albuminuria and glomerulosclerosis have been also studied in combination with telmisartan ^[66]. This co-treatment provided a recovery of the slit diaphragm associated proteins with protective effects on podocytes: in fact, it contributes to the restoration of the expression of nephrin, CD2AP and podocin ^[67].

One of the main differences between OCT and different active forms of Vitamin D, such as calcitriol, is that the first has a lower affinity to DBP, about 1/600 compared to calcitriol ^[68]. This overcomes calcitriol’s main side effects such as the risk of hypercalcemia, hyperphosphatemia and calcifications; OCT circulates principally as the unbound form with easier availability to target tissues. Hirata et al. ^[69] showed, in sub-totally nephrectomized rats, that OCT can regulate parathyroid hormone suppression with lower risk of cardiovascular calcification or worsening of residual renal function in comparison with calcitriol.

Sanai et al. ^[70] demonstrated that an intraperitoneal dose of 0.2 mcg/kg calcitriol three times a week, can accelerate renal deterioration in the course of experimental chronic renal failure, while OCT can attenuate renal histologic lesions. These findings are partially in contrast with the data of Matsui et al. ^[71] that demonstrated that both treatments with high doses of OCT (2.0 μg/kg/day) and high doses of Calcitriol (0.4 μg/kg/day) have a nephroprotective function, significantly suppressing proteinuria.

2.4. Doxercalciferol in Experimental GN

In obese mice, doxercalciferol was effective in decreasing proteinuria, prevented loss of podocyte, decreased mesangial expansion, extracellular matrix protein proliferation, oxidative stress, inflammation and Sterol regulatory element-binding protein 1 and 2 (SREBP-1 and -2), two critical proteins in the control of lipogenesis and mediators of kidney fibrosis ^[72]^[73]. Doxercalciferol combined with losartan has a marked power in renin and angiotensinogen suppression: in diabetic mice, it prevents albuminuria, restores glomerular filtration barrier structure and reduces glomerulosclerosis in a dose-dependent manner ^[74]. The promising use of this compound has been partially assessed in human models, where Doxercalciferol and Paricalcitol demonstrated a lower incidence of hypercalcemia and hypercalciuria than Calcitriol ^[75].

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