Thermoablative Treatment of De Novo Tumor in Kidney Allograft.

BACKGROUND: The overall cancer risk increases in transplant patients, including in kidney allografts. This study aimed to analyze the outcome of patients with kidney allograft malignant tumors who underwent percutaneous thermal ablation. METHODS: We included 26 renal allograft tumors, including 7 clear-cell renal cell carcinoma (RCCs), 16 papillary RCCs, 1 clear-cell papillary RCC, and 2 tubulocystic RCCs, treated in 19 ablation sessions. Outcomes of thermal ablation therapy were assessed, including technical success, adverse events, local tumor progression, development of metastases, survival after thermal ablation, and changes in renal function. RESULTS: Success rate was achieved in all ablation sessions (primary success rate: 96%; secondary success rate: 100%). No adverse events were observed in grades 3, 4, or 5. The median follow-up period was of 34 mo (15-69 mo). Two patients died during follow-up from a cause independent of renal cancer. The median decrease in estimated glomerular filtration rate 1 y after procedure was -4 (interquartile range, -7 to 0) mL/min/1.73 m 2 . One patient returned to dialysis within the year of the procedure. CONCLUSIONS: Percutaneous thermal ablation shows convincing results for treating malignant renal graft tumors and should be a useful treatment option. The shorter hospitalization time, the advantage of avoiding a potentially challenging dissection of the transplant, and the excellent preservation of allograft function appear encouraging to extend this indication.

Clinical and Prognostic Factors in Patients with IgG4-Related Kidney Disease.

BACKGROUND: IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related factors in patients with IgG4-related kidney disease are insufficiently defined. METHODS: We conducted an observational cohort study using data from 35 sites in two European countries. Clinical, biologic, imaging, and histopathologic data; treatment modalities; and outcomes were collected from medical records. Logistic regression was performed to identify the possible factors related to an eGFR ≤30 ml/min per 1.73 m 2 at the last follow-up. Cox proportional hazards model was performed to assess the factors associated with the risk of relapse. RESULTS: We studied 101 adult patients with IgG4-related disease with a median follow-up of 24 (11-58) months. Of these, 87 (86%) patients were male, and the median age was 68 (57-76) years. Eighty-three (82%) patients had IgG4-related kidney disease confirmed by kidney biopsy, with all biopsies showing tubulointerstitial involvement and 16 showing glomerular lesions. Ninety (89%) patients were treated with corticosteroids, and 18 (18%) patients received rituximab as first-line therapy. At the last follow-up, the eGFR was below 30 ml/min per 1.73 m 2 in 32% of patients; 34 (34%) patients experienced a relapse, while 12 (13%) patients had died. By Cox survival analysis, the number of organs involved (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.55) and low C3 and C4 concentrations (HR, 2.31; 95% CI, 1.10 to 4.85) were independently associated with a higher risk of relapse, whereas first-line therapy with rituximab was protective (HR, 0.22; 95% CI, 0.06 to 0.78). At their last follow-up, 19 (19%) patients had an eGFR ≤30 ml/min per 1.73 m 2 . Age (odd ratio [OR], 1.11; 95% CI, 1.03 to 1.20), peak serum creatinine (OR, 2.74; 95% CI, 1.71 to 5.47), and serum IgG4 level ≥5 g/L (OR, 4.46; 95% CI, 1.23 to 19.40) were independently predictive for severe CKD. CONCLUSIONS: IgG4-related kidney disease predominantly affected middle-aged men and manifested as tubulointerstitial nephritis with potential glomerular involvement. Complement consumption and the number of organs involved were associated with a higher relapse rate, whereas first-line therapy with rituximab was associated with lower relapse rate. Patients with high serum IgG4 concentrations (≥5 g/L) had more severe kidney disease.

Percutaneous Thermal Ablation for Renal Tumors in Patients with Birt-Hogg-Dubé Syndrome.

BHD syndrome is characterized by an increased risk of bilateral and multifocal renal cell carcinoma (RCCs), but is rarely metastatic. Our report aims to analyze the outcome of patients with BHD syndrome who underwent percutaneous thermal ablation (TA). The present report included six BHD syndrome patients (five men) with a mean age of 66 ± 11 (SD) years who had a proven germline FLCN gene mutation and underwent TA for a renal tumor. Nineteen renal tumors (median two tumors per patient; range: 1-3), including seven chromophobe RCCs, five clear-cell RCCs, four papillary RCCs, two clear-cell papillary RCC, and one hybrid oncocytic/chromophobe tumor were treated in 14 ablation sessions. The mean size of the tumors was 21 ± 11 (SD) mm (median: 20 mm; interquartile range (IQR): 14-25 mm) for a mean volume of 7 ± 11 (SD) mL (median: 3; IQR: 1-5 mL). Technical success was achieved in all ablation sessions (primary success rate, 100%). The procedure was well tolerated under conscious sedation with no significant Clavien-Dindo complication (grade 2, 3, 4). All patients were alive with no distant metastasis during a median follow-up period of 74 months (range: 33-83 months). No local tumor progression was observed. The mean decrease in estimated glomerular filtration rate was 8 mL/min/1.73 m2. No patients required dialysis or renal transplantation. In this case series, percutaneous TA appeared as a safe and efficient nephron-sparing treatment for treating RCCs associated with BHD syndrome, even in the case of advanced chronic kidney disease.

Efficacy of Prolonged Antibiotic Therapy for Renal Cyst Infections in Polycystic Kidney Disease.

OBJECTIVE: To determine the impact of antibiotic therapy (ATBT) on outcomes of renal cyst infection (CyI) in patients with polycystic kidney disease. PATIENTS AND METHODS: We undertook a single-center retrospective study of CyI in autosomal dominant polycystic kidney disease (January 1, 2000, through December 31, 2018). Cyst infections were classified as definite (microbiologically proven), probable (radiologic signs), or possible (clinical or biologic signs only). We studied the determinants of ATBT failure (persistence of infection beyond 72 hours of microbiologically adequate initial ATBT, with requirement for ATBT change, cyst drainage, or nephrectomy) and recurrences (>14 days after the end of ATBT). RESULTS: Among 90 patients, 139 CyIs (11 definite, 74 probable, 54 possible) were compiled. Cultures were positive in 106 of 139 (76%) episodes, with Escherichia coli found in 89 of 106 (84%). Treatment failures and recurrences within 1 year of follow-up were more frequent in definite/probable CyI (20/85 [34%] and 16/85 [19%]) than in possible CyI (2/54 [4%] and 4/54 [7%]; P<.01 and P=.08, respectively). Male sex (odds ratio [OR], 7.79; 95% CI, 1.72 to 46.68; P<.01), peak C-reactive protein level above 250 mg/L (OR, 7.29; 95% CI, 1.78 to 35.74; P<.01; to convert C-reactive protein values to nmol/L, multiply by 9.524), and cyst wall thickening (OR, 7.70; 95% CI, 1.77 to 43.47; P=.01) but not the modalities of initial ATBT were independently associated with higher risk of failure. In a Cox proportional hazards model, kidney transplant recipients exhibited higher risk of recurrence (hazard ratio, 3.76; 95% CI, 1.06 to 13.37; P=.04), whereas a total duration of ATBT of 28 days or longer was protective (hazard ratio, 0.02; 95% CI, 0.00 to 0.16; P<.001), with an inverse correlation between duration and recurrence (81% for treatment <21 days, 47% for 21 to 27 days, 2% for ≥28 days; P<.0001). CONCLUSION: Initial first-line ATBT had no significant effect on renal CyI treatment failure. Treatment duration of 28 days and longer reduced recurrences.

Long-term impact of COVID-19 among maintenance haemodialysis patients.

BACKGROUND: Maintenance haemodialysis (MHD) patients have a high risk of initial mortality from coronavirus disease 2019 (COVID-19). However, long-term consequences of this disease in the MHD population are poorly described. We report the clinical presentation, outcome and long-term follow-up of MHD patients affected by COVID-19 in a multicentric cohort from the Paris, France area. METHODS: We conducted a retrospective analysis of clinical presentation and long-term follow-up of MHD patients affected by COVID-19 in 19 MHD centres in the Paris, France area. RESULTS: In this cohort of 248 patients with an initial mortality rate of 18%, age, comorbidities, dyspnoea and previous immunosuppressive treatment were associated with death at <30 days. Among the 203 surviving patients following the acute phase, long-term follow-up (median 180 days) was available for 189 (93%) patients. Major adverse events occurred in 30 (16%) patients during follow-up, including 12 deaths (6%) after a median of 78 days from onset of symptoms. Overall, cardiovascular events, infections and gastrointestinal bleeding were the main major adverse events. Post-COVID-19 cachexia was observed in 25/189 (13%) patients. Lower initial albuminaemia was significantly associated with this cachexia. No reinfection with severe acute respiratory syndrome coronavirus 2 was observed. CONCLUSIONS: This work demonstrates the long-term consequences of COVID-19 in MHD patients, highlighting both initial and long-term severity of the disease, including severe cachexia.

Kidney Biopsy in Type 2 Diabetes: A Multicenter Cross-Sectional Study.

INTRODUCTION: Kidney biopsies (KBs) are performed in patients with type 2 diabetes (T2D) to diagnose non-diabetic or hypertensive kidney disease (NDHKD) potentially requiring specific management compared to diabetic and or hypertensive nephropathy (absence of NDHKD). Indications for KB are based on the presence of atypical features compared to the typical course of diabetic nephropathy. In this study, we assessed the association of different patterns of atypical features, or KB indications, with NDHKD. METHODS: Native KBs performed in patients with T2D were analyzed. Data were collected from the patients' records. KB indications were determined according to the presence of different atypical features considered sequentially: (1) presence of any feature suggesting NDHKD which is not among the following ones, (2) recent onset of nephrotic syndrome, (3) low or rapidly declining estimated glomerular filtration rate (eGFR), (4) rapid increase in proteinuria, (5) short duration of diabetes, (6) presence of hematuria, or (7) normal retinal examination. RESULTS: Among the 463 KBs analyzed, NDHKD was diagnosed in 40% of the total population and 54, 40, 24, and 7% of the KBs performed for indications 1-4 respectively. Conversely, no patient who underwent KB for indications 5-7 displayed NDHKD. Logistic regression analyses identified eGFRCKD-EPI >15 mL/min/1.73 m2, urinary protein-to-Cr ratio <0.3 g/mmol, hematuria, HbA1c <7%, and diabetes duration <5 years as predictors of NDHKD, independently from the indication group. CONCLUSION: NDHKD is frequent in T2D. Despite the association of hematuria with NDHKD, our results suggest that presence of hematuria and absence of DR are insufficient to indicate KB in the absence of concurrent atypical features. Conversely, rapid progression of proteinuria and rapid deterioration of eGFR are major signals of NDHKD.

Encrusted Urinary Tract Infections Due to Corynebacteria Species.

INTRODUCTION: Encrusted pyelitis and cystitis are peculiar disorders characterized by the calcification of the vesical, the pyelic, and/or the ureteral walls. These calcifications are composed of struvite and calcium carbonate‒apatite due to the presence of Corynebacterium urealyticum. METHODS: We have identified the clinical features and outcomes of 17 patients with encrusted pyelitis (n = 15) or encrusted cystitis (n = 2). Diagnosis was based on computed tomography scan and sonography including thickening and calcified lesions of the urinary tract. RESULTS: The main clinical presentation was suggestive of subacute urinary tract infection with fever and urologic symptoms, mostly gross hematuria. Biologic features were characterized by the presence of struvite crystals and alkaline urine. Acute kidney injury was reported in 70.6% of cases. Predisposing factors were mostly due to urologic background (82.4%) with a history of urologic procedure (71%) and prior exposure to antibiotics (59%). All patients received appropriate antibiotherapy and 15 were treated with topical urinary acidification. A significant reduction of encrusted calcifications was observed in 88% of cases. Renal function improved in 71% of the patients. Nevertheless, poor tolerance of the treatment and side effects were common, affecting 71% of patients, with Gram-negative bacilli urinary tract infections (53%) being the most frequent. At last follow-up, 4 patients (23.5%) progressed to end-stage renal disease and only 1 had a clinical relapse. CONCLUSIONS: Encrusted urinary tract infections are rare, characterized by a severe renal and overall prognosis in the absence of appropriate treatment. Topical urinary acidification and appropriate antibiotherapy are efficient but may be burdened by significant adverse events.

Ifosfamide nephrotoxicity in adult patients.

BACKGROUND: Ifosfamide, a widely prescribed antineoplasic agent, is frequently associated with kidney dysfunction. Its nephrotoxicity is well documented in children, but data are lacking in adult patients. METHODS: The aim of this retrospective study was to describe the clinical, biological and histological characteristics of ifosfamide nephrotoxicity. RESULTS: We report 34 patients (median age: 41 years) admitted in six French nephrology departments for kidney failure and/or tubular dysfunction. Fifteen patients (44.1%) received cisplatin as part of their chemotherapy. In 6 patients (17.7%), ifosfamide nephrotoxicity was revealed by a proximal tubular dysfunction (PTD), in 5 patients (14.4%) by an acute kidney injury (AKI), in 6 patients (17.7%) by a chronic kidney disease (CKD) and in 17 patients (49.7%) by an association of PTD and AKI. Fourteen renal biopsies (41.2%) were performed and revealed acute tubular necrosis (85.7%), vacuolation (78.6%) and nuclear atypias (71.4%) of renal epithelial cells, interstitial inflammation (71.4%) and fibrosis (57.1%). Electron microscopy showed mitochondrial enlargement and dysmorphic changes suggestive of mitochondrial toxicity. Ten patients (29.4%) progressed to Stage 5 CKD, six (17.6%) required haemodialysis and six patients died during a median follow-up period of 31 months. Risk factors for Stage 5 CKD were age and cisplatin co-administration.

Continuous Wound Infiltration With Ropivacaine After Mastectomy: A Randomized Controlled Trial.

BACKGROUND: To evaluate the efficacy of continuous wound infiltration with ropivacaine to reduce acute postoperative pain in patients undergoing mastectomy for carcinoma of the breast. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled trial was conducted. One hundred fifty patients were randomly assigned to receive continuous ropivacaine (0.2%) (group A, n = 74) or saline solution (0.9%) (group B, n = 76) at 10 mL/h for 48 h through a multilumen catheter placed during the surgical procedure. Postoperative morphine consumption and visual analog scale (VAS) pain scores were recorded. A quality of life score (Quality of life questionnaire Core 30) and a VAS score were obtained at 1, 3, and 6 mo after surgery. RESULTS: The difference in mean morphine consumption between the two groups was close to significance during the first 48 h postsurgery (P = 0.056; 10.8 ± 16.5 versus 4.8 ± 10.4 mg). At day 1, patients in the ropivacaine-infusion group had lower morphine consumption than the control group (P = 0.0026). The link between local ropivacaine infiltration and a decrease in mean postoperative VAS scores reached significance for the first 24 h postsurgery (P = 0.039). No significant difference was found between the two arms for VAS pain scores (P = 0.36) or for quality of life (overall QLQ-C30 score, P = 0.09) at 1, 3, or 6 mo. CONCLUSIONS: Continuous wound infiltration with ropivacaine is efficacious in reducing postoperative pain. Quality of life and chronic pain at 1, 3, and 6 mo were not improved by ropivacaine wound infiltration.

Predicting Pain Trajectories in the One Year Following Breast Cancer Diagnosis-An Observational Study.

The impact of psychosocial vulnerability on pain in the year following breast cancer diagnosis has been little studied. To identify a score of psychosocial vulnerability (cognitive, emotional, quality of life and precariousness parameters) as a predictor of a pain trajectory, we conducted an observational prospective study and included women with newly diagnosed breast cancer. One year follow-up with 3 visits (day of breast cancer diagnosis; 6 and 12 months) aimed to identify distinct pain-time trajectories. Baseline psychosocial vulnerability was characterized by z-score transformation, a higher score representing a more vulnerable patient. A total of 89 patients were included (59.3 ± 10.7 years). Two trajectories of pain were identified-"Transient Pain trajectory" (TP) (39/89 patients) and "Persistent Pain trajectory" (PP) (50/89). A significant difference of pain over time between trajectories (PP vs. TP at 6 months: 2.23 ± 0.23 vs. 0.27 ± 0.09, p < 0.001) was observed. Psychosocial vulnerability showed a large effect size (d, -0.82; 95% CI, -1.25 to -0.38; p < 0.001) and a higher score in "Persistent pain trajectory" (PP vs. TP: 0.12 ± 0.36 vs. -0.14 ± 0.26, p < 0.001). A predictive vulnerability marker of pain development is proposed and could be used at cancer diagnosis to orientate the care pathway of patients experiencing breast cancer.

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

OBJECTIVE: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. PATIENTS AND METHODS: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria. RESULTS: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001). CONCLUSION: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

Preventive effect of oral magnesium in postmastectomy pain: protocol for a randomised, double-blind, controlled clinical trial.

INTRODUCTION: Breast cancer affects 1 in 10 women worldwide, and mastectomy is a cause of chronic pain with neuropathic characteristics. N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine, memantine, dextromethorphan or magnesium are used to treat refractory pain by blocking NMDAR. Oral memantine has been shown to prevent postmastectomy pain and cognitive impact and to maintain quality of life. Likewise, the present study is intended to assess the preventive effect of oral magnesium, administered ahead of mastectomy, on the development of neuropathic pain. As a physiological blocker of NMDAR, magnesium could be an interesting candidate to prevent postoperative pain and associated comorbidities, including cognitive and emotional disorders, multiple analgesic consumption and impaired quality of life. METHODS AND ANALYSIS: A randomised double-blind controlled clinical trial (NCT03063931) will include 100 women with breast cancer undergoing mastectomy at the Oncology Hospital, Clermont-Ferrand, France. Magnesium (100 mg/day; n=50) or placebo (n=50) will be administered for 6 weeks, starting 2 weeks before surgery. Intensity of pain, cognitive and emotional function and quality of life will be assessed by questionnaires. The primary endpoint is pain intensity on a 0-10 numerical rating scale at 1 month postmastectomy. Data analysis will use mixed models; all tests will be two-tailed, with type-I error set at α=0.05. ETHICS AND DISSEMINATION: The study protocol and informed consent form were approved in December 2016 by the French Research Ethics Committee (South East VI Committee). Results will be communicated in various congresses and published in international publications. TRIAL REGISTRATION NUMBER: NCT03063931.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

[Renal toxicity of high-dose methotrexate]. / Toxicité rénale du méthotrexate à haute dose.

INTRODUCTION: High-dose methotrexate (at least 1g/m2) is used to treat haematologic malignancies and osteosarcomas. Acute kidney injury is a well-known adverse-event after high-dose methotrexate and may lead to delayed drug elimination. Besides usual therapeutics (hyperhydration, urine alkalinisation, leucovorin rescue, renal replacement therapy), a costly specific enzymatic treatment (glucarpidase) is now available but its clinical impact remains elusive. PATIENTS AND METHODS: We analysed high-dose methotrexate prescription charts in 11 clinical centres during the last 15 years to identify and describe adult patients who developed acute kidney injury (according to KDIGO classification). Glucarpidase use was recorded (French temporary regulatory approval criteria: methotrexate at least 10µmol/L at 48h or at least 3µmol/L at 48h associated with acute kidney injury). RESULTS: Seventy-six acute kidney injury cases have been studied. Mean peak creatinine was 206µmol/L after a mean delay of 5.6 days, with 19 cases of stage 1 acute kidney injury (25%), 29 cases of stage 2 (38%) and 27 cases of stage 3 (36%). Anuria (one case) and need for renal replacement therapy (four cases) were unusual whereas fluid overload was often observed (29%). Three months after high-dose methotrexate treatment, mortality-rate was 17%, and 12% of surviving patients developed renal sequelae. CONCLUSION: Sixty-one percent of patients received a glucarpidase perfusion during acute kidney injury. Despite a dramatic decrease of methotrexate serum levels, glucarpidase as compared with conservative treatment did not modify acute kidney injury stage, recovery delay, need for renal replacement therapy or the incidence of extrarenal toxicities. Net clinical benefit was not observed even after stratification according to eligibility criteria for glucarpidase use. Glucarpidase has probably no or little effects on methotrexate localized into tubular lumen or proximal tubular cells and that may account for the absence of nephroprotective effect for enzymatic treatment.

Hepatic Production of Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease.

Context: The bone-derived hormone fibroblast growth factor (FGF) 23 controls phosphate homeostasis and urinary phosphate excretion. FGF23 plasma levels increase in the early stage of renal insufficiency to prevent hyperphosphatemia. Recent evidence suggests that this increase has effects on cardiac and immune cells that compromise patients' health. Patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported to have higher FGF23 concentrations than other patients with similar renal function. The significance of this finding has remained unknown. Methods and Results: Analyzing the FGF23 plasma levels in 434 patients with ADPKD and 355 control subjects with a measured glomerular filtration rate (mGFR) between 60 and 120 mL/min per 1.73 m2, we confirmed that patients with ADPKD had higher FGF23 plasma concentrations than controls. Remarkably, this difference did not translate into renal phosphate leakage. Using different assays for FGF23, we found that this discrepancy was explained by a predominant increase in the cleaved C-terminal fragment of FGF23, which lacks phosphaturic activity. We found that FGF23 plasma concentration independently correlated with the severity of cystic liver disease in ADPKD. We observed that, in contrast to control liver tissues, the cystic liver from patients with ADPKD markedly expressed FGF23 messenger RNA and protein. In line with this finding, the surgical reduction of polycystic liver mass was associated with a decrease in FGF23 plasma levels independently of any modification in mGFR, phosphate, or iron status. Conclusion: Our findings demonstrate that severely polycystic livers produce FGF23 and increase levels of circulating FGF23 in patients with ADPKD.