Xujian Li

Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease

There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28+/-5 days) or placebo for 1 year. The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI. Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests. Thirty-four patients had ADPKD, and eight had ADPLD. Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25%+/-7.53%) in the octreotide group but increased by 8.61%+/-10.07% in the placebo group (P=0.045). Changes in GFR were similar in both groups. Octreotide was well tolerated; treated individuals reported an improved perception of bodily pain and physical activity. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.

Kidney stones and the risk for chronic kidney disease.

BACKGROUND AND OBJECTIVES Kidney stones lead to chronic kidney disease (CKD) in people with rare hereditary disorders (e.g., primary hyperoxaluria, cystinuria), but it is unknown whether kidney stones are an important risk factor for CKD in the general population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Among Olmsted County, MN, residents, all stone formers (n = 4774) whose condition was diagnosed in 1986 through 2003 were matched 1:3 to control subjects (n = 12,975). Cox proportional hazards models adjusted for age, gender, and comorbidities (hypertension, diabetes, obesity, dyslipidemia, gout, alcohol abuse, tobacco use, coronary artery disease, heart failure, cerebral infarct, and peripheral vascular disease) were used to assess the risk for incident CKD defined as a clinical diagnosis (diagnostic codes), ESRD or death with CKD, sustained (>90 d) elevated serum creatinine (>1.3 mg/dl in men, >1.1 mg/dl in women), or sustained estimated GFR <60 ml/min per 1.73 m(2). RESULTS During a mean of 8.6 yr of follow-up, stone formers were at increased risk for a clinical diagnosis of CKD, but an increased risk for ESRD or death with CKD was NS. Among patients with follow-up serum creatinine levels, stone formers were at increased risk for a sustained elevated serum creatinine and a sustained reduced GFR. CONCLUSIONS Kidney stones are a risk factor for CKD, and studies are warranted to assess screening and preventive measures for CKD in stone formers.

Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption

The mechanisms by which phosphorus homeostasis is preserved in mammals are not completely understood. We demonstrate the presence of a mechanism by which the intestine detects the presence of increased dietary phosphate and rapidly increases renal phosphate excretion. The mechanism is of physiological relevance because it maintains plasma phosphate concentrations in the normal range after ingestion of a phosphate-containing meal. When inorganic phosphate is infused into the duodenum, there is a rapid increase in the renal fractional excretion of phosphate (FE Pi). The phosphaturic effect of intestinal phosphate is specific for phosphate because administration of sodium chloride does not elicit a similar response. Phosphaturia after intestinal phosphate administration occurs in thyro-parathyroidectomized rats, demonstrating that parathyroid hormone is not essential for this effect. The increase in renal FE Pi in response to the intestinal administration of phosphate occurs without changes in plasma concentrations of phosphate (filtered load), parathyroid hormone, FGF-23, or secreted frizzled related protein-4. Denervation of the kidney does not attenuate phosphaturia elicited after intestinal phosphate administration. Phosphaturia is not elicited when phosphate is instilled in other parts of the gastrointestinal tract such as the stomach. Infusion of homogenates of the duodenal mucosa increases FE Pi, which demonstrates the presence of one or more substances within the intestinal mucosa that directly modulate renal phosphate reabsorption. Our experiments demonstrate the presence of a previously unrecognized phosphate gut–renal axis that rapidly modulates renal phosphate excretion after the intestinal administration of phosphate.

Rituximab therapy in idiopathic membranous nephropathy: a 2-year study.

BACKGROUND AND OBJECTIVES It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty patients with MN and proteinuria >5 g/24 h received RTX (375 mg/m(2) × 4), with re-treatment at 6 months regardless of proteinuria response. PK analysis was conducted simultaneously with immunological analyses of T and B cells to ascertain the effect of RTX on lymphocyte subpopulations. RESULTS Baseline proteinuria of 11.9 g/24 h decreased to 4.2 and 2.0 g/24 h at 12 and 24 months, respectively, whereas creatinine clearance increased from 72.4 ml/min per 1.73 m(2) at baseline to 88.4 ml/min per 1.73 m(2) at 24 months. Of 18 patients who completed 24-month follow-up, 4 are in complete remission, 12 are in partial remission, 1 has a limited response, and 1 patient relapsed. Serum RTX levels were similar to those obtained with two doses of RTX. CONCLUSIONS Four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. Baseline quantification of lymphocyte subpopulations did not predict response to RTX therapy.

Kidney Stones Associate with Increased Risk for Myocardial Infarction

Kidney stones are a risk factor for chronic kidney disease (CKD), which, in turn, is a risk factor for myocardial infarction (MI). The objective of this study was to determine whether kidney stones associate with an increased risk for MI. We matched 4564 stone formers (1984 through 2003) on age and gender with 10,860 control subjects among residents in Olmsted County, Minnesota. We identified incident MI by diagnostic codes and validated events by chart review through 2006. We used diagnostic codes to determine incidence of kidney stones and presence of comorbidities (CKD, hypertension, diabetes, obesity, dyslipidemia, gout, alcohol dependence, and tobacco use). During a mean of 9 years of follow-up, stone formers had a 38% (95% confidence interval 7 to 77%) increased risk for MI, which remained at 31% (95% confidence interval 2% to 69%) after adjustment for CKD and other comorbidities. In conclusion, kidney stone formers are at increased risk for MI, and this risk is independent of CKD and other risk factors.

Fat malabsorption and increased intestinal oxalate absorption are common after Roux-en-Y gastric bypass surgery.

BACKGROUND Hyperoxaluria and increased calcium oxalate stone formation occur after Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity. The etiology of this hyperoxaluria is unknown. We hypothesized that after bariatric surgery, intestinal hyperabsorption of oxalate contributes to increases in plasma oxalate and urinary calcium oxalate supersaturation. METHODS We prospectively examined oxalate metabolism in 11 morbidly obese subjects before and 6 and 12 months after RYGB (n = 9) and biliopancreatic diversion-duodenal switch (BPD-DS) (n = 2). We measured 24-hour urinary supersaturations for calcium oxalate, apatite, brushite, uric acid, and sodium urate; fasting plasma oxalate; 72-hour fecal fat; and increases in urine oxalate following an oral oxalate load. RESULTS Six and 12 months after RYGB, plasma oxalate and urine calcium oxalate supersaturation increased significantly compared with similar measurements obtained before surgery (all P ≤ .02). Fecal fat excretion at 6 and 12 months was increased (P = .026 and .055, 0 vs 6 and 12 months). An increase in urine oxalate excretion after an oral dose of oxalate was observed at 6 and 12 months (all P ≤ .02). Therefore, after bariatric surgery, increases in fecal fat excretion, urinary oxalate excretion after an oral oxalate load, plasma oxalate, and urinary calcium oxalate supersaturation values were observed. CONCLUSION Enteric hyperoxaluria is often present in patients after the operations of RYGB and BPD-DS that utilize an element of intestinal malabsorption as a mechanism for weight loss.

Somatostatin analog therapy for severe polycystic liver disease: results after 2 years

BACKGROUND We showed in a randomized double-blinded placebo-controlled clinical trial that octreotide long-acting repeatable depot.® (OctLAR(®)) for 12 months reduces kidney and liver growth in autosomal dominant polycystic kidney patients with severe polycystic liver disease (PLD) and liver growth in patients with severe isolated PLD. We have now completed an open-label extension for one additional year to assess safety and clinical benefits of continued use of OctLAR for 2 years (O → O) and examined drug effect in the placebo group who crossed over to OctLAR in Year 2 (P → O). METHODS The primary end point was change in total liver volume (TLV) measured by magnetic resonance imaging (MRI); secondary end points were changes in total kidney volume (TKV) measured by MRI, glomerular filtration rate (GFR), quality of life (QOL), safety, vital signs and laboratory parameters. RESULTS Forty-one of 42 patients received OctLAR (n = 28) or placebo (n = 14) in Year 1 and received OctLAR in Year 2 (maximum dose 40 mg). Patients originally randomized to placebo (P → O) showed substantial reduction in TLV after treatment with OctLAR in Year 2 (Δ% -7.66 ± 9.69%, P = 0.011). The initial reduction of TLV in the OctLAR group (O → O) was maintained for 2 years (Δ% -5.96 ± 8.90%), although did not change significantly during Year 2 (Δ% -0.77 ± 6.82%). OctLAR inhibited renal enlargement during Year 1 (Δ% +0.42 ± 7.61%) in the (O → O) group and during Year 2 (Δ% -0.41 ± 9.45%) in the (P → O) group, but not throughout Year 2 (Δ% +6.49 ± 7.08%) in the (O → O) group. Using pooled analyses of all individuals who received OctLAR for 12 months, i.e. in Year 1 for O → O patients and Year 2 for P → O patients, average reduction in TLV was -6.08 ± 7.58% (P = 0.001) compared to net growth of 0.9 ± 8.35% in the original placebo group. OctLAR-treated individuals continued to experience improvements in QOL in Year 2, although overall physical and mental improvements were not significant during Year 2 compared to Year 1. Changes in GFR were similar in both groups. CONCLUSION Over 2 years, OctLAR significantly reduced the rate of increase in TLV and possibly the rate of increase in TKV.

Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calcium oxalate supersaturation

We examined the effect of a controlled diet and two probiotic preparations on urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, in patients with mild hyperoxaluria. Patients were randomized to a placebo, a probiotic, or a synbiotic preparation. This tested whether these probiotic preparations can increase oxalate metabolism in the intestine and/or decrease oxalate absorption from the gut. Patients were maintained on a controlled diet to remove the confounding variable of differing oxalate intake from food. Urinary oxalate excretion and calcium oxalate supersaturation on the controlled diet were significantly lower compared with baseline on a free-choice diet. Neither study preparation reduced urinary oxalate excretion nor calcium oxalate supersaturation. Fecal lactobacilli colony counts increased on both preparations, whereas enterococcal and yeast colony counts were increased on the synbiotic. Total urine volume and the excretion of oxalate and calcium were all strong independent determinants of urinary calcium oxalate supersaturation. Hence, dietary oxalate restriction reduced urinary oxalate excretion, but the tested probiotics did not influence urinary oxalate levels in patients on a restricted oxalate diet. However, this study suggests that dietary oxalate restriction is useful for kidney stone prevention.

Risk factors for CKD in persons with kidney stones: a case-control study in Olmsted County, Minnesota.

BACKGROUND Kidney stones are associated with increased risk of chronic kidney disease (CKD); however, risk factors in the general community are poorly defined. STUDY DESIGN A nested case-control study was performed in residents of Olmsted County, MN, who presented with a kidney stone at the Mayo Clinic in 1980-1994 to contrast patients with kidney stones who developed CKD with a group that did not. SETTING & PARTICIPANTS Participants were selected from the Rochester Epidemiology Project, an electronic linkage system among health care providers in Olmsted County, MN. Cases were identified by diagnostic code for CKD and confirmed to have an estimated glomerular filtration rate < 60 mL/min/1.73 m(2). Controls were matched 2:1 to cases for age, sex, date of first kidney stone, and length of medical record. PREDICTOR Charts were abstracted to characterize stone disease, hypertension, diabetes, obesity, tobacco use, ileal conduit, symptomatic stones, type and number of stones, urinary tract infections, number and type of surgical procedures, and medical therapy. OUTCOMES & MEASUREMENTS Kidney stone patients with CKD were compared with matched stone patients without CKD. RESULTS There were 53 cases and 106 controls with a mean age of 57 years at first stone event and 59% men. In kidney stone patients, cases with CKD were significantly more likely (P < 0.05) than controls to have had a history of diabetes (41.5% vs 17.0%), hypertension (71.7% vs 49.1%), frequent urinary tract infections (22.6% vs 6.6%), struvite stones (7.5% vs 0%), and allopurinol use (32.1% vs 4.7%) based on univariate analysis. LIMITATIONS Potential limitations include limited statistical power to detect associations, incomplete data from 24-hour urine studies, and that stone composition was not always available. CONCLUSION As in the general population, hypertension and diabetes are associated with increased risk of CKD in patients with kidney stones. However, other unique predictors were identified in patients with kidney stones that increased the possibility of CKD. Further studies are warranted to elucidate the nature of these associations.

Prevalence of Renal Artery and Kidney Abnormalities by Computed Tomography among Healthy Adults

BACKGROUND AND OBJECTIVES Management of incidental renal artery and kidney abnormalities in patients undergoing computed tomography scans is a clinical challenge because their frequency in healthy subjects has not been precisely estimated. Therefore, the prevalence and management of these abnormalities were determined among a large cohort of potential kidney donors undergoing protocol evaluations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients at the Mayo Clinic who underwent computed tomographic angiography and urography as part of their kidney donor evaluation between 2000 and 2008 were identified. Radiographic reports were abstracted for abnormalities of the renal arteries and kidneys. The prevalence of radiographic abnormalities was stratified by age and gender, and the effect on approval for kidney donation was determined. RESULTS Among 1957 potential kidney donors, the mean +/- SD age was 43 +/- 12 years, and 58% were women. The most common abnormalities were kidney stones (11%), focal scarring (3.6%), fibromuscular dysplasia (2.8%), and other renal artery narrowing or atherosclerosis (5.3%). Fibromuscular dysplasia, focal scarring, parenchymal atrophy, and upper tract dilation were more common in women. Renal artery narrowing, focal scarring, and indeterminate masses increased with age. Overall, 25% of potential donors had at least one abnormality. However, these incidental radiographic abnormalities contributed to exclusion from donation in only 6.7% of potential donors. CONCLUSIONS Incidental radiographic abnormalities of the renal arteries and kidneys are common. The majority of imaging findings are not perceived to be harmful enough to prevent kidney donation, but future studies are needed to determine their clinical relevance.