The Risk of Chronic Kidney Disease Associated with Urolithiasis and its Urological Treatments: A Review.

PURPOSE: Urolithiasis can impair kidney function. This literature review focuses on the risk of kidney impairment in stone formers, the specific conditions associated with this risk and the impact of urological surgery. MATERIALS AND METHODS: The PubMed® and Embase® databases were searched for publications on urolithiasis, its treatment, and the risk of chronic kidney disease, end stage renal disease and nephrectomy in stone formers. RESULTS: In general, renal stone formers have twice the risk of chronic kidney disease or end stage renal disease, and for female and overweight stone formers the risk is even higher. Patients with frequent urinary tract infections, struvite stones, urinary malformations and diversions, malabsorptive bowel conditions and some monogenic disorders are at high risk for chronic kidney disease/end stage renal disease. Shock wave lithotripsy or minimally invasive urological interventions for stones do not adversely affect renal function. Declines in renal function generally occur in patients with preexisting chronic kidney disease or a large stone burden requiring repeated and/or complex surgery. CONCLUSIONS: Although the effect size is modest, urolithiasis may cause chronic kidney disease and, thus, it is mandatory to assess patients with renal stones for the risk of chronic kidney disease/end stage renal disease. We suggest that all guidelines dealing with renal stone disease should include assessment of this risk.

Changes in urinary risk profile after short-term low sodium and low calcium diet in recurrent Swiss kidney stone formers.

BACKGROUND: Kidney stone disease is common in industrialized countries. Recently, it has attracted growing attention, because of its significant association with adverse renal outcomes, including end stage renal disease. Calcium-containing kidney stones are frequent with high recurrence rates. While hypercalciuria is a well-known risk factor, restricted intake of animal protein and sodium, combined with normal dietary calcium, has been shown to be more effective in stone prevention compared with a low-calcium diet. Notably, the average sodium intake in Switzerland is twice as high as the WHO recommendation, while the intake of milk and dairy products is low. METHODS: We retrospectively analyzed Swiss recurrent kidney stone formers (rKSF) to test the impact of a low-sodium in combination with a low-calcium diet on the urinary risk profile. In patients with recurrent calcium oxalate containing stones, we investigated both, the consequence of a low-sodium diet on urinary volume and calcium excretion, and the influence of a low-sodium low-calcium diet on urinary oxalate excretion. RESULTS: Of the 169 patients with CaOx stones, 49 presented with hypercalciuria at baseline. The diet resulted in a highly significant reduction in 24-h urinary sodium and calcium excretion: from 201 ± 89 at baseline to 128 ± 88 mmol/d for sodium (p < 0.0001), and from 5.67 ± 3.01 to 4.06 ± 2.46 mmol/d (p < 0.0001) for calcium, respectively. Urine volume remained unchanged. Notably, no increase in oxalate excretion occurred on the restricted diet (0.39 ± 0.26 vs 0.39 ± 0.19 mmol/d, p = 0.277). Calculated Psf (probability of stone formation) values were only predictive for the risk of calcium phosphate stones. CONCLUSION: A diet low in sodium and calcium in recurrent calcium oxalate stone formers resulted in a significant reduction of urinary calcium excretion, but no change in urine volume. In this population with apparently low intake of dairy products, calcium restriction does not necessarily result in increased urinary oxalate excretion. However, based on previous studies, we recommend a normal dietary calcium intake to avoid a potential increase in urinary oxalate excretion and unfavorable effects on bone metabolism in hypercalciuric KSFs.

What is nephrocalcinosis?

The available publications on nephrocalcinosis are wide-ranging and have documented multiple causes and associations of macroscopic or radiological nephrocalcinosis, most often located in the renal medulla, with various metabolic and genetic disorders; in fact, so many and various are these that it is difficult to define a common underlying mechanism. We have reviewed nephrocalcinosis in relation to its definition, genetic associations, animal models, and putative mechanisms. We have concluded, and hypothesized, that nephrocalcinosis is primarily a renal interstitial process, resembling metastatic calcification, and that it may have some features in common with, and pathogenic links to, vascular calcification.

Renal expression of FGF23 and peripheral resistance to elevated FGF23 in rodent models of polycystic kidney disease.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked to cardiovascular disease and all-cause mortality in chronic kidney disease. FGF23 rises in patients with CKD stages 2-3, but in patients with autosomal dominant polycystic kidney disease, the increase of FGF23 precedes the first measurable decline in renal function. The mechanisms governing FGF23 production and effects in kidney disease are largely unknown. Here we studied the relation between FGF23 and mineral homeostasis in two animal models of PKD. Plasma FGF23 levels were increased 10-fold in 4-week-old cy/+ Han:SPRD rats, whereas plasma urea and creatinine concentrations were similar to controls. Plasma calcium and phosphate levels as well as TmP/GFR were similar in PKD and control rats at all time points examined. Expression and activity of renal phosphate transporters, the vitamin D3-metabolizing enzymes, and the FGF23 co-ligand Klotho in the kidney were similar in PKD and control rats through 8 weeks of age, indicating resistance to FGF23, although phosphorylation of the FGF receptor substrate 2α protein was enhanced. In the kidneys of rats with PKD, FGF23 mRNA was highly expressed and FGF23 protein was detected in cells lining renal cysts. FGF23 expression in bone and spleen was similar in control rats and rats with PKD. Similarly, in an inducible Pkd1 knockout mouse model, plasma FGF23 levels were elevated, FGF23 was expressed in kidneys, but renal phosphate excretion was normal. Thus, the polycystic kidney produces FGF23 but is resistant to its action.

The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule.

The proximal tubule uses a complex process of apical acid secretion and basolateral bicarbonate absorption to regulate both luminal acidification and fluid absorption. One of the primary regulators of apical acid secretion is the luminal sodium-hydrogen exchanger expressed along the apical membrane of the proximal tubule. Similarly, the calcium-sensing receptor (CaSR) is also located along the luminal membrane of the proximal tubule. Here we investigated the role of CaSR in proton secretion and fluid reabsorption in proximal tubules by modulating luminal calcium concentration, using both in vivo micropuncture in rats and in vitro perfused mouse proximal tubules. Using CaSR knockout mice and a calcimimetic agent, we found that increased proton secretion and fluid reabsorption were CaSR dependent. Activating CaSR by either raising the luminal calcium ion concentration or by the calcimimetic caused a concomitant increase in sodium-dependent proton extrusion and fluid reabsorption, whereas in proximal tubules isolated from CaSR knockout mice varying calcium ion concentration had no effect. Application of a calcimimetic in lower concentrations of calcium ion stimulated these processes in vitro and in vivo. Thus, in both rats and mice, increased luminal calcium concentration leads to enhanced fluid reabsorption in the proximal tubule, a process related to activation of CaSR.

Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study.

BACKGROUND: Klotho and fibroblast growth factor 23 (FGF23) are key regulators of mineral metabolism in renal insufficiency. FGF23 levels have been shown to increase early in chronic kidney disease (CKD); however, the corresponding soluble Klotho levels at the different CKD stages are not known. METHODS: Soluble Klotho, FGF23, parathyroid hormone (PTH), 1,25-dihydroxy vitamin D(3) (1,25D) and other parameters of mineral metabolism were measured in an observational cross-sectional study in 87 patients. Locally weighted scatter plot smoothing function of these parameters were plotted versus estimated glomerular filtration rate (eGFR) to illustrate the pattern of the relationship. Linear and non-linear regression analyses were performed to estimate changes in mineral metabolism parameters per 1mL/min/1.73 m(2) decline. RESULTS: In CKD 1-5, Klotho and 1,25D linearly decreased, whereas both FGF23 and PTH showed a baseline at early CKD stages and then a curvilinear increase. Crude mean Klotho level declined by 4.8 pg/mL (95% CI 3.5-6.2 pg/mL, P < 0.0001) and 1,25D levels by 0.30 ng/L (95% CI 0.18-0.41 ng/L, P < 0.0001) as GFR declined by 1 mL/min/1.73 m(2). After adjustment for age, gender, serum 25-hydroxyvitamin D levels and concomitant medications (calcium, supplemental vitamin D and calcitriol), we estimated that the mean Klotho change was 3.2 pg/mL (95% CI 1.2-5.2 pg/mL, P = 0.0019) for each 1 mL/min/1.73 m(2) GFR change. FGF23 departed from the baseline at an eGFR of 47 mL/min/1.73 m(2) (95% CI 39-56 mL/min/1.73 m(2)), whereas PTH departed at an eGFR of 34 mL/min/1.73 m(2) (95% CI 19-50 mL/min/1.73 m(2)). CONCLUSIONS: Soluble Klotho and 1,25D levels decrease and FGF23 levels increase at early CKD stages, whereas PTH levels increase at more advanced CKD stages.

Calcium deficiency reduces circulating levels of FGF23.

Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia.

Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate.

Fibroblast growth factor 23 (FGF23) and parathyroid hormone blood levels rise following progressive loss of renal function. Here we measured parameters of phosphate metabolism in 100 patients with autosomal dominant polycystic kidney disease (ADPKD) in stage 1 or 2 of chronic kidney disease, 20 patients with non-diabetic chronic kidney disease, and 26 with type 2 diabetes. Twenty healthy volunteers served as controls. The mean levels of FGF23 were significantly (4-fold) higher in ADPKD compared to non-diabetic and diabetic patients, and healthy volunteers. Mean serum phosphate levels were significantly lower in ADPKD patients compared to non-diabetic and diabetic patients, and the healthy volunteers. The prevalence of hypophosphatemia was 38, 25, 27, and 5% in ADPKD, non-diabetic and diabetic patients, and healthy volunteers, respectively. The tubular maximum of phosphate reabsorption per glomerular filtration rate was lowest in ADPKD patients with a significantly high positive correlation with serum phosphate levels. Estimated glomerular filtration rates were approximately 100 ml/min per 1.73 m² in all groups and parathyroid hormone and vitamin D metabolite levels were in the normal range. Thus, FGF23 was substantially elevated in ADPKD patients compared to other CKD patients matched for glomerular filtration rate, and was associated with increased renal phosphate excretion. The mechanism for this anomaly will require further study.

Intravenous zoledronic acid in postmenopausal women with low bone mineral density.

BACKGROUND: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. METHODS: We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. RESULTS: There were similar increases in bone mineral density in all the zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent higher than those in the placebo group (P<0.001) and values for the femoral neck that were 3.1 to 3.5 percent higher than those in the placebo group (P<0.001). Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. Myalgia and pyrexia occurred more commonly in the zoledronic acid groups, but treatment-related dropout rates were similar to that in the placebo group. CONCLUSIONS: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

Vitamin D deficiency is prevalent among idiopathic stone formers, but does correction pose any risk?

While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD ≤30 nmol/L; ≤12 ng/mL) with vitD insufficient (31-75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24-h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients.

Fabry disease in patients with end-stage renal failure: the potential benefits of screening.

BACKGROUND/AIMS: Alpha-galactosidase A (alpha-GLA) deficiency (Fabry disease) is an X-linked lysosomal storage disorder. The associated visceral complications are progressive and multiorgan; renal involvement is common, usually leading to end-stage renal failure (ESRF). The reported benefits of specific enzyme replacement therapy (ERT) indicate the importance of screening for Fabry disease in high-risk populations, as this approach should make it possible to identify other family members with little or no clinical features of the disease, and for them to be considered for early preventive treatment. METHODS: We screened for Fabry disease in 106 patients on hemodialysis in our hospital-based hemodialysis unit. We did this by measuring alpha-GLA enzyme activity in blood leukocytes taken from each patient and we then carried out gene analysis when indicated. RESULTS: We were able to discover 1 patient with low residual alpha-GLA activity (a prevalence of 0.94%). Alpha-GLA gene analysis identified a point mutation within the coding region producing a N215S amino acid substitution in the protein. Among the relatives of this index case, molecular testing found 7 family members with the same N215S alpha-GLA mutation. Of these, 3 had reduced alpha-GLA activity and clinical features of Fabry disease, and for which ERT was subsequently given. CONCLUSION: Screening for Fabry disease is simple and although the yield is small, it is potentially significant and of possible benefit to the relatives of affected cases in this 'at-risk' ESRF population, many of who do not have a clear renal diagnosis.

An uncommon cause of foot pain: the cuboid insufficiency stress fracture.

We report a case of bone insufficiency fracture of the cuboid in a 33-year-old female patient with many risk factors of bone insufficiency: long term steroid treatment for lupus erythematosus, renal failure, hemodialysis since 3 years and severe secondary hyperparathyroidism. Early diagnosis was established using magnetic resonance imaging (MRI), and confirmed 4 months later on radiography, showing typical line of sclerosis perpendicular to bone trabeculae. Literature review shows only few detailed cuboid stress fracture case reports: four cases in young athletes, one case complicating plantar fascia disruption and one case after plantar fasciotomy. Insufficiency fracture of the foot bones involves mainly the metatarsals, the calcaneus, the talus, whereas cuboid location seems exceedingly rare. Physiopathological characteristics of this uncommon fracture are mentioned.

[Effects of tacrolimus vs cyclosporin-A on bone metabolism after kidney transplantation: a cross-sectional study in 28 patients]. / Comparaison des effets de la ciclosporine-A et du tacrolimus sur le métabolisme osseux des patients transplantés rénaux: une étude transversale chez 28 patients.

BACKGROUND: Controversy exists about the effects of calcineurin inhibitors on bone metabolism. We decided to compare the effects of CyA vs FK506 on bone metabolism of kidney recipients. PATIENTS AND METHODS: From 94 patients grafted at the University Hospital of Nice between 1996 and 1999 treated either by CyA (N=49) or by FK506 (N=45), we selected 14 pairs (18 M, 10F), matched for gender, BMI, time lapsed since transplantation and gonadal status in females. Patients with>1 transplantation or>1 rejection episode were excluded. Cumulative dose of steroids was recorded. Bone mineral density (BMD) was mesured at heel and forearm, as well as serum concentration of calcium, phosphate, parathyroid hormone (PTH), vitamin D metabolites, C-telopeptide (CTX), creatinine, estradiol as well as Bone Alkaline Phosphatase (BAP) activity. RESULTS: Despite the matching, time on hemodialysis was longer in FK506 group. Cumulative dose of steroids was similar between groups. There was no difference between groups in BMD and biochemical parameters except for estradiol serum levels which were dramatically lower in FK506 than in CsA (P=0,02) and for a trend (p=0,08) for BAP and CTX to be higher in FK506 than in CsA. CONCLUSIONS: BMD is not lower in FK506- than in CsA-treated patients although exposure to hyperparathyroidism was longer and estradiol levels were lower in the FK506 than in the CsA group. These data suggest that FK506 may have a favorable bone effect to compensate for these deleterious factors. This hypothesis remains to be tested in longitudinal studies.

Tacrolimus pain syndrome in renal transplant patients: report of two cases.

We report two renal transplant patients who experienced onset of severe bilateral knee pain 1 and 3 months after transplantation, respectively, while on tacrolimus therapy. Tacrolimus, like cyclosporine A, is an immunosuppressive agent that inactivates the enzyme calcineurin phosphatase. A bone pain syndrome was reported in 1989 in organ transplant recipients treated with cyclosporine A. Our cases suggest that tacrolimus may induce the same syndrome. Technetium 99m bone scanning shows increased uptake in the affected areas, and magnetic resonance imaging changes are consistent with bone marrow edema. The tacrolimus dosage need not be reduced unless trough levels are too high. The symptoms resolve completely within a few months. Imaging studies should be done to rule out avascular necrosis. The pathophysiology of this syndrome is discussed. Since tacrolimus was introduced recently, similar cases should be published.

Distal phalangeal brachydactyly and osteosclerosis in a case of secondary hyperparathyroidism.

A case of severe hyperparathyroidism (HPT), secondary to chronic renal failure, with massive distal phalangeal osteolysis is reported. After parathyroidectomy, brachydactyly and osteosclerosis of the distal phalanges were observed; the phalanx of the thumbs healed with shortened and sclerotic beaked appearance. These radiographic findings are actually uncommon because of more efficient treatment of renal osteodystrophy. Pathophysiology of this bone sclerotic lesion is discussed, and other causes of distal phalangeal osteosclerosis are mentioned.

Longitudinal bone insufficiency fracture of the tibia in a renal transplant recipient.

We report a case of longitudinal tibial fracture as the first manifestation of bone insufficiency in a 50-year-old patient who had received a renal transplant 12 years earlier. The epidemiological, clinical, and imaging features of these fractures are reviewed. Bone loss occurs in the long term in about half of renal transplant recipients. The main causes are preexisting renal osteodystrophy; glucocorticoid therapy; and hyperparathyroidism, whether residual or secondary to imperfect graft function. The effects of cyclosporine therapy on bone metabolism remain unclear. Identification of patients at very high risk of fracture and available options for early prophylaxis are discussed.

Soluble klotho and autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: FGF23 and klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, ≥90 ml/min per 1.73 m(2); CKD stage 2, 60-89 ml/min per 1.73 m(2)). RESULTS: ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher klotho levels than those without. Serum klotho values correlated inversely with cyst volume and kidney growth. CONCLUSIONS: Loss of klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.