Research Article



Nazima Begum, Erram Fatima Khan, Maryam Sadiq, Khuba Raniya

Author's Affiliation


Oxalate is via way of means of product that is obviously present in the body for metabolism, and in everyday people it's far excreted harmlessly. Oxalate may be poisonous due to its tendency to crystallize at physiological pH and shape calcium oxalate crystal. There changed into a minute correlation oxidative strain and extrude in urine evaluation with the pomegranate extract supplement. Stone formers have extensively extended tiers of oxidative strain, renal tubular harm, and DNA oxidative damage. After administration of ethylene glycol, produce excessive tiers of urinary calcium oxalate, results in speedy crystal deposition and nephrolithiasis. Pomegranate extract supplementation with 1,000 mg polyphenol extract each day can also additionally present a few modest advantages in reducing supersaturation of calcium oxalate. The iNOS-mediated NO production is extensively excessive while there may be accelerated tiers of oxidative strain. Renal tubular molecular harm ends in the formation of cystic fibrosis stem cells. There are numerous promoters of stone formation just like the Tamm-Horsfall proteins and osteopontin. The THP make a contribution closer to stone formation while the ionic electricity is excessive and the pH is low. But if the THP gene is inactivated in mouse embryonic stem cells, it effects in impromptu formation of calcium crystals. The formation of stones relies upon the stability among the promoters and inhibitors of urolithiasis.


lipid peroxidation, oxalate, oxidative stress, Renal tubular injury, crystal deposition, pomegranate extract supplementation, singular serum constituents, hyperoxaluria

Cite This Article

Begum, N., Khan, E. F., Sadiq, M., Raniya, K. (2021). Kidney Stone Treatment By Pomegranate (Punica Granatum). International Journal for Pharmaceutical Research Scholars, 10(4);09 -19.


Hyperoxaluria (unrestricted urinary excretion of oxalate) is the major consequence for formation of stone disease[1].

Oxalate is by product which is naturally present in the body for metabolism, and in normal individuals it is excreted harmlessly. However, Oxalate can be toxic because of its tendency to crystallize at physiological pH and form calcium oxalate(CaOx) crystal which are deposited in the kidney[3,4].Acute and chronic production of CaOx crystals leads to lipid peroxidation; therefore, this process plays an important role in CaOx stone formation[5].

Oxalate and calcium oxalate crystals cause damage to Renal epithelial cells[6,7] and induces lipid peroxidation which leads to functional impairment of cellular components by reactive oxygen species (ROS) such as superoxide[8,9] . ROS act as mediators to signaling molecules such as p38-MAPK (mitogen-activated protein kinase) and transcription factors such as nuclear factor kappa-B (NF-kB) [10,11].

(NF-kB) is ubiquitous tanscriptional factors of the many genes including iNOS, host defences process[12] Mitogen-activated protein kinases (MAPK) are major mediators involved in the intracellular network of interaction proteins that transduce extracellular stimuli to intracellular responses[13].Three distinct MAPK pathways have been described: extracellular signal regulated and terminal kinase, and p38 MAPK[14].Both Ox and CaOx crystals selectively activated p38-MAPK signal transduction pathways in the proximal tubular epithelial cells[15,16]. The activation of p38-MAPK was found to be essential for the reinitiation of Ox- induced DNA synthesis.

Nitric oxide(NO) regulates inflammation and vasorelaxation and have a major role in eradication of tumor cells and pathogens[17]. Although in elevated production of NO is oxidized to ROS, which results in disruption of cell signaling and uncontrolled systemic inflammation[18].

Malondialdehyde (MDA) is a phenomenal marker of lipid peroxidation. In excessive amount it cause tissue injury and DNA damage. When combine with proteins, forms MDA- modified protein adducts[19].

Glutathione(GSH) is important intracellular antioxidant[20].


  • Pomegranate is a rich source of potent polyphenolic, glucose, ellagic acid, garlic acid , flavonoids (anthocyanin effective in inhibition of lipid peroxidation[22,23]). Fresh juice is enriched with vitamin C and polyphenolic compounds[32].
  • Edible parts of pomegranate fruit has 78% juice and 22% seeds[25].
  • Fresh fruit contains 85% water, 10% total sugars and 1.5% pectin, ascorbic acid and polyphenolic flavoids[1].

Pomegrante seed is rich source of crude pectin, fibres and sugars[28]. It shows that pomegranate can act as a NF-kB inhibitory effect on kidney stone formation[29].


Pomegranate has become more popular because of major effective physiological properties, such as anticancer,[42,43] cholesterol lowering, cardioprotective,[44]etc. Many experiments have reported that pomegranate and its derivatives have free radical scavenger and potent antioxidant activity.[45,46,47] It has also been shown that pomegranate can suppress NF-kB activation through a novel mechanism in vascular endothelial cells.[48]


Pomegranate is used as a traditional medicine from ancient time. It exhibit both anti- hypercalciuria and anti- urolithiasis effect . Its phytochemicals are responsible for muscle relaxation in the urinary tract which can easily remove stones from the kidney. The extract and juice of pomegranate inhibits the hyperoxaluria – induced oxidation renal tubular damages by reducing the levels of ROS, NO and NF-kB and regulates the level  of creatinine , urea, and uric acid[1,8,9,18].


Patients following, repetitive stone formers (RSFs; >2 earlier scenes), 18–70 years of age, were selected from our stone facility. Potential subjects needed to have been recently advised on broad dietary rules to diminish the “stone facility impact.” Only patients with calcium containing (non-irresistible, non-uric corrosive, noncystine) stones who had gone through something like a 24-hrs urine study were included. There were chosen from an information base of volunteers and coordinated with three to one as to age, sex, and weight record (BMI). Subjects as of now on clinical treatment for stone anticipation or with any clinical inclination to stone arrangement were prohibited (i.e., essential gout, LeschNyhan condition, Von Gierke infection, persistent loose bowels, insulin opposition, neoplastic issues, renal hyperuricosuria, hyperparathyroidism, renal cylindrical acidosis, innate hyperuricemia)[2].


Members got a solitary 1,000 mg pomegranate separate case day by day for 90 days administered by our exploration drug store. Pill checks were performed at the finish of the examination to evaluate adherence[2].


Urinary 8-hydroxy-deoxyguanosine (8-OHdG) is a marker of oxidative DNA get damage by receptive oxygen species (ROS)[33]. Lipid peroxidation (LPO) has been evidence to be associated with the pathogenesis of an assortment of infections, for example, end stage renal illness, coronary vein sickness, atherosclerosis, and stroke. As basal degrees of oxidation are regularly low and might be impacted by singular serum constituents, we utilized the free extreme generator 2.2′-azobis (2amidinopropane) hydrochloride to incite oxidation to quantify serum peroxides and assist with anticipating a person’s capacity to react to oxidative pressure[34] . Basal and inducible oxidative states were estimated for every persistent during each stage[34]. AAPH prompted serum lipid peroxidation was controlled by incubating serum tests (weakens x 4 with Phosphate-cushioned saline) with AAPH (100 mol/L) for 2 hrs at 37 °C [21]. The degree of lipid peroxidation was then estimated by the

TBARS[Thio barbituric corrosive responsive substances] examine and by the lipid peroxides test[24]. For correlation among gatherings, we used AAPH-prompted values, as it is the best address a person’s capacity to react to oxidative pressure.

Exceptionally sensitive C-receptive protein (hsCRP) has been linked in elevating the level of oxidative pressure in diabetes and coronary artery disease[2].


Values for demographic profile of patients, urine samples serum samples and oxidative stress markers were calculation for each individual patient earlier enlisted and following supplement intervention to pre and post examine. Linear mixed model analysis  for repeated measures was used to test for differences in urine values and oxidative stress values between non stone formers and stone formers at pre and post changes between the groups. For correlation analysis between urine values and oxidative stress among stone formers could be detected with 0.80 power [2].


17 recurrent stone formers, 5 non stone formers. There were no adverse effects reported from supplements during the study period. The standard age of participants was 40.4 years and 57% were female with standard BMI of 29. Baseline and post intervention values for markers of oxidative stress in RSFs and NSFs. RSFs patient had significantly increase oxidative state at baseline when compared to NSFs patient[2].

Urinary 8-OHdG was significantly increased in RSFs by 350%. Additionally, there was higher susceptibility of the patients’ serum to AAPH-induced lipid peroxidation as measured by lipid peroxides and TBARS. However, there was no baseline difference between RSFs and NSFs in serum PON1 activity, or in the inflammatory marker hsCRP. Following supplementation serum PON1 activity was seen increased significantly in RSFs patients. Supplementation decreased the serum hsCRP levels insignificant by 29 % in the RSFs patients. 24 hrs  urine analysis showed that RSFs had lower urinary pH and saturation of calcium phosphate and higher saturation of uric acid than NSFs at baseline. Following to pomegranate extract supplementation, the only difference in urinary analysis of RSFs patients was an increase in calcium, sodium, chloride, and magnesium for RSFs patient. Otherwise, no urinary risk factor Changes were seen significantly.  In general the was a minute correlation oxidative stress and change in urine analysis with the pomegrante extract supplement. Although there was a negative correlation between lipid peroxides and uric acid i.e, a patient with higher baseline lipid peroxides levels had a greater reduce in urinary uric acid with the following supplementation. Significant changes were seen in the levels of AAPH-induced serum TBARS, lipid peroxides, hsCRP, and urine 8-OHgG did not correlate with changes in urine analysis values following supplementation in RSFs. i.e, patients with high levels of PON1 pomegranate extract supplementation were more likely to have a decline in supersaturation of CaOx[2].


Stone disease has been linked to obesity, hypertension[35], diabetes[36], metabolic syndrome[37], and chronic kidney disease[38]. As these diseases have been associates to oxidative stress[39].

Oxidative stress also plays a pathophysiologic role in nephrolithiasis. Earlier studies in RSFs suggest that reactive oxygen species-induced renal cellular injury and inflammation are likely involved in idiopathic nephrolithiasis, as demonstrated by increased in level than normal levels of urinary gamma-glutamyl transpeptidase, angiotensin 1 converting enzyme, beta-galactosidase, Nacetyl-betaglucosaminidase (NAG) activity, TBARS, and 8-OHdG[33,40].

Stone formers have significantly increased levels of oxidative stress (in serum and urine), renal tubular injury, and DNA oxidative damage, than NSFs as showed by significant differences in urine 8-OHdG, serum TBARS, and lipid peroxide levels. The association between oxidative stress and calcium-containing crystals is not fully understood[2].

Tentatively studies suggested that renal epithelial exposure to high calcium oxalate results in significant increase in markers of oxidative stress[27], implicit that the stone constituents themselves may be an causing factor in renal tubular damage and ROS radical formation. Atypical, deposition of calcium apatite in the renal papillary interstitium may lead to production of ROS and recruitment of monocytes and macrophages, which phagocytize or coat crystals in macromolecules which causes further cellular damage[41]. If crystal formation continual unregulated, localized injury and inflammation cause collagen deposition, mineralization, and renal tubular damage, providing sites for crystal attachment. As crystals continue to enlarge, they ulcerate through the papillary urothelium, where exposure to pelvic urine leads to heterogeneous nucleation of calcium salts[50]. After administration of ethylene glycol produce high levels of urinary calcium oxalate, leads to rapid crystal deposition and nephrolithiasis [31].

Pomegranate plants, which are rich  source of antioxidants, including polyphenols hydrolyzable tannins, anthocyanins, and ellagic acid derivatives[52], have been shown to suppress NF-kappaB activation in vivo and inhibit lipid peroxidation. In a intended diet-controlled study,[51,53] demonstrated that prophylactic pomegranate juice administration in rats receiving ethylene glycol helpfully no crystal formation compared to the development of severe crystallization and epithelial degradation seen in animals without any supplementation. Eventually[8, 9], in a similar type of animal nephrolithiasis. Found that crystal accumulation, inducible oxide synthase (iNOS), p38-MAPK and p65NFκB activity, and oxidative stress markers were decreased by pomegranate supplementation[30].It is concluded that p38-MAPK and NF-kB pathways are activated in a variety of models of renal inflammatory disease, including nephritis[49].The iNOS-mediated NO production is significantly high when there is elevated levels oxidative stress[26].


Recurrent stone formers have markedly excessive levels of oxidative stress than NSFs. Pomegranate extract supplementation with 1,000 mg polyphenol extract daily may present some modest benefit in lowering supersaturation of calcium oxalate.

The correlation between elevated serum PON1 activity with lower saturation of calcium oxalate may help  explain the reduced risk of calcium oxalate stone formation with pomegranate shown in earlier animal studies[2].


Factors causing “nidus” formation: – Lithogenic drugs, Altered pH, Microorganisms, Gout, Genetic Disorder, Solute precipitation

Nidus/Nucleus formation

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Crystallization of nucleus

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Crystal growth

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Crystal aggregation on renal tubule



Crystal cell interaction



Renal tubular cell injury & these injured cells act as site of binding


Crystal retention




There are several promoters of stone formation like the Tamm-Horsfall proteins and osteopontin. Some of the proofs indicate that a primary interstitial apatite crystal formation leads to CaOx stone formation (54). The lipids in human cellular membranes are chiefly involved in the crystal nucleation (55). The renal cells which get injured due the crystal sell interaction produce PT-1 or other anionic proteins lead to COM crystal aggregation (56). The THP contribute towards stone formation when the ionic strength is high and the pH is low (57). The THP is also assumed to provide protection from the stone agglomeration when it has low ionic strength and high pH, as reported by Hess (58). The mucopolysaccharides also act as the binders by increasing nucleation and aggregation (59). But according to a study, if the THP gene is inactivated in the mouse embryonic stem cells, it results in impromptu formation of calcium crystals. This is a conclusive confirmation theta the THP is an important inhibitor of stone formation (60). The presence of ROS due to oxalate can damage the mitochondrial membrane leading to apoptosis (61).  According to a study, when oxalic acid is added to the HK-2 cells, it causes activation of IL-2R beta mRNA and IL-2R beta proteins that lead to inflammation. This whole process may activate the p38 MAPK signalling, however the mechanism is still not known (62). The promoters are the substances which promote urolithiasis by different mechanisms (63). The idiopathic stone formers are those in whom stone are formed due to various drugs. In these patients, the stones are attached to the interstitial site of the Randall’s plaque (64). Some molecules like phosphatidylserine, CD44 and hyaluronan also act as binders for the stones (65, 66). The stone formation can be prevented by blocking the binding molecules like the monocyte chemoattractant protein-1, hyaluronic acid (67). There are also some promoters of urolithiasis which are the calcitriol hormones (69), phospholipids, cholesterol, glycolipids (68), oxalic acid, cystine, sodium, low urine volume, calcium (70). The formation of stone primarily depends upon the balance between the promoters and the inhibitors.

There are certain food colours which may have adverse effect on the kidneys and liver. According to a study Tartrazine and Carmoisine were administered in two male albino rats by the oral route in two divided doses amongst which one was low and the other was high. This was continued for 30 days. After the completion of the pre-determined duration of drug administration the tissue and serum samples were collected and LFT, RFT, blood glucose, lipid profile was done.

The research data estimated an increase in the levels of urea, creatinine, albumin, ALT, AST, ALP, Total protein. The study concludes that both tartrazine and carmosine can unfavourably effect the biomarkers of organs like the liver and kidney not only at higher but also at lower doses (71).


Histopathology in livers of rats fed tartrazine (Tz) and ameliorative effects several doses of curcumin (CUR). A) Normal structure of liver tissue of control showing the central vein, normal arrangement of hepatic cords, normal blood sinusoids(s) and hepatocytes, HE, X 400; B) Liver tissue of rats exposed to Tz showing dilation of blood sinusoids, and central vein with hemorrhage and necrosis (*), HE, X 400; C) Liver tissue of rats fed Tz in combination with 1.0 g/ kg dry mass (dm) diet of CUR, showing less necrosis and moderate degenerative changes compared to the control and rats fed Tz alone (N), HE, X 400; D) Liver tissue of rats fed a diet containing Tz in combination with 2 g/ kg, dm diet of CUR, showing little necrosis (N) compared to the controls or rats exposed to lesser amounts of CUR. HE, X 400; E) Liver tissue of rats fed a diet containing Tz supplemented with 4.0 g/ kg, dm diet of CUR, showing little necrosis (N), H&E, X 400.



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