The latest medical research on Nephrology

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Sodium Bicarbonate Supplementation and Urinary TGF-β1 in Nonacidotic Diabetic Kidney Disease: A Randomized, Controlled Trial.

Clinical Journal of the American

In early-phase studies of individuals with hypertensive CKD and normal serum total CO2, sodium bicarbonate reduced urinary TGF-β1 levels and preserved kidney function. The effect of sodium bicarbonate on kidney fibrosis and injury markers in individuals with diabetic kidney disease and normal serum total CO2 is unknown.

We conducted a randomized, double-blinded, placebo-controlled study in 74 United States veterans with type 1 or 2 diabetes mellitus, eGFR of 15-89 ml/min per 1.73 m2, urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and serum total CO2 of 22-28 meq/L. Participants received oral sodium bicarbonate (0.5 meq/kg lean body wt per day; n=35) or placebo (n=39) for 6 months. The primary outcome was change in urinary TGF-β1-to-creatinine from baseline to months 3 and 6. Secondary outcomes included changes in urinary kidney injury molecule-1 (KIM-1)-to-creatinine, fibronectin-to-creatinine, neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine, and UACR from baseline to months 3 and 6.

Key baseline characteristics were age 72±8 years, eGFR of 51±18 ml/min per 1.73 m2, and serum total CO2 of 24±2 meq/L. Sodium bicarbonate treatment increased mean total CO2 by 1.2 (95% confidence interval [95% CI], 0.3 to 2.1) meq/L, increased urinary pH by 0.6 (95% CI, 0.5 to 0.8), and decreased urinary ammonium excretion by 5 (95% CI, 0 to 11) meq/d and urinary titratable acid excretion by 11 (95% CI, 5 to 18) meq/d. Sodium bicarbonate did not significantly change urinary TGF-β1/creatinine (difference in change, 13%, 95% CI, -10% to 40%; change within the sodium bicarbonate group, 8%, 95% CI, -10% to 28%; change within the placebo group, -4%, 95% CI, -19% to 13%). Similarly, no significant effect on KIM-1-to-creatinine (difference in change, -10%, 95% CI, -38% to 31%), fibronectin-to-creatinine (8%, 95% CI, -15% to 37%), NGAL-to-creatinine (-33%, 95% CI, -56% to 4%), or UACR (1%, 95% CI, -25% to 36%) was observed.

In nonacidotic diabetic kidney disease, sodium bicarbonate did not significantly reduce urinary TGF-β1, KIM-1, fibronectin, NGAL, or UACR over 6 months.

Recurrence of FSGS after Kidney Transplantation in Adults.

Clinical Journal of the American

FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients.

The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors.

Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival.

Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.

Reproducibility of Deceased Donor Kidney Procurement Biopsies.

Clinical Journal of the American

Unfavorable histology on procurement biopsies is the most common reason for deceased donor kidney discard. We sought to assess the reproducibility of procurement biopsy findings.

We compiled a continuous cohort of deceased donor kidneys transplanted at our institution from 1/1/2006 to 12/31/2016 that had at least one procurement biopsy performed, and excluded cases with missing biopsy reports and those used in multiorgan transplants. Suboptimal histology was defined as the presence of advanced sclerosis in greater than or equal to one biopsy compartment (glomeruli, tubules/interstitium, vessels). We calculated κ coefficients to assess agreement in optimal versus suboptimal classification between sequential biopsy reports for kidneys that underwent multiple procurement biopsies and used time-to-event analysis to evaluate the association between first versus second biopsies and patient and allograft survival.

Of the 1011 kidneys included in our cohort, 606 (60%) had multiple procurement biopsies; 98% had first biopsy performed at another organ procurement organization and their second biopsy performed locally. Categorical agreement was highest for vascular disease (κ=0.17) followed by interstitial fibrosis and tubular atrophy (κ=0.12) and glomerulosclerosis (κ=0.12). Overall histologic agreement (optimal versus suboptimal) was κ=0.15. First biopsy histology had no association with allograft survival in unadjusted or adjusted analyses. However, second biopsy optimal histology was associated with a higher probability of death-censored allograft survival, even after adjusting for donor and recipient factors (adjusted hazard ratio, 0.50; 95% confidence interval, 0.34 to 0.75; P=0.001).

Deceased donor kidneys that underwent multiple procurement biopsies often displayed substantial differences in histologic categorization in sequential biopsies, and there was no association between first biopsy findings and post-transplant outcomes.

Effects of alcohol consumption on copeptin levels and sodium-water homeostasis.

American Journal of

Alcohol consumption influences the sodium-water homeostasis. However, the effect of alcohol on vasopressin levels is controversial. The aim of this...

Early Response of the Parathyroid Gland to Withdrawal of a Calcimimetic Compound in Uremic Rats.

American Journal of

Little is known about changes in parathyroid cells when calcimimetics are withdrawn. We examined the response of parathyroid glands to withdrawal o...

Inhibition of PDE4/PDE4B improves renal function and ameliorates inflammation in cisplatin-induced acute kidney injury.

American Journal of

Nephrotoxicity is a known clinical complication of cisplatin that limits the use of this potent antitumour drug. Cyclic nucleotide phosphodiesteras...

Association of Sleep Apnea with Mortality in Patients with Advanced Kidney Disease.

Clinical Journal of the American

In the general population, sleep disorders are associated with mortality. However, such evidence in patients with CKD and ESKD is limited and shows conflicting results. Our aim was to examine the association of sleep apnea with mortality among patients with CKD and ESKD.

In this prospective cohort study, 180 patients (88 with CKD stage 4 or 5, 92 with ESKD) underwent in-home polysomnography, and sleep apnea measures such as apnea hypopnea index (AHI) and nocturnal hypoxemia were obtained. Mortality data were obtained from the National Death Index. Cox proportional hazard models were used for survival analysis.

Among the 180 patients (mean age 54 years, 37% women, 39% with diabetes, 49% CKD with mean eGFR 18±7 ml/min per 1.73 m2), 71% had sleep apnea (AHI>5) and 23% had severe sleep apnea (AHI>30). Median AHI was 13 (range, 4-29) and was not significantly different in patients with advanced CKD or ESKD. Over a median follow-up of 9 years, there were 84 (47%) deaths. AHI was not significantly associated with mortality after adjusting for age, sex, race, diabetes, body mass index, CKD/ESKD status, and kidney transplant status (AHI>30: hazard ratio [HR], 1.5; 95% confidence interval [95% CI], 0.6 to 4.0; AHI >15 to 30: HR, 2.3; 95% CI, 0.9 to 5.9; AHI >5 to 15: HR, 2.1; 95% CI, 0.8 to 5.4, compared with AHI≤5). Higher proportion of sleep time with oxygen saturation <90% and lower mean oxygen saturation were significantly associated with higher mortality in adjusted analysis (HR, 1.4; 95% CI, 1.1 to 1.7; P=0.007 for every 15% higher proportion, and HR, 1.6; 95% CI, 1.2 to 2.1; P=0.003 for every 2% lower saturation, respectively). Sleep duration, sleep efficiency, or periodic limb movement index were not associated with mortality.

Hypoxemia-based measures of sleep apnea are significantly associated with increased risk of death among advanced CKD and ESKD.

Randomized, Controlled Trial of Tacrolimus and Prednisolone Monotherapy for Adults with De Novo Minimal Change Disease: A Multicenter, Randomized, Controlled Trial.

Clinical Journal of the American

Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease.

This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function.

There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], -11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, -8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, -17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22 [73%] for tacrolimus cohorts) for patients in each group who achieved complete remission (P=0.99), or in the time from complete remission to relapse.

Tacrolimus monotherapy can be effective alternative treatment for patients wishing to avoid steroid therapy for minimal change disease.

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Klotho supplementation ameliorates blood pressure and renal function in DBA/2-pcy mice, a model of polycystic kidney disease.

American Journal of

Klotho interacts with various membrane proteins such as receptors for transforming growth factor (TGF) β and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed.

Recombinant human klotho protein (10 μg/kg/day) or a vehicle was administered daily by subcutaneous injection to 6-week-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 months, the mice were killed, and the kidneys were harvested for analysis.

Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-prostaglandin F2α excretion (p<0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expressions of superoxide dismutase (SOD), klotho itself (p<0.05). Klotho supplementation attenuated renal expressions of TGFβ and collagen I, and diminished renal abundance of Twist, phosphorylated Akt, and mTOR (p<0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys (p<0.05).

Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mTOR signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

Mediterranean Style Diet and Kidney Function Loss in Kidney Transplant Recipients.

Clinical Journal of the American

Despite improvement of short-term graft survival over recent years, long-term graft survival after kidney transplantation has not improved. Studies in the general population suggest the Mediterranean diet benefits kidney function preservation. We investigated whether adherence to the Mediterranean diet is associated with kidney outcomes in kidney transplant recipients.

We included 632 adult kidney transplant recipients with a functioning graft for ≥1 year. Dietary intake was inquired using a 177-item validated food frequency questionnaire. Adherence to the Mediterranean diet was assessed using a nine-point Mediterranean Diet Score. Primary end point of the study was graft failure and secondary end points included kidney function decline (doubling of serum creatinine or graft failure) and graft loss (graft failure or death with a functioning graft). Cox regression analyses were used to prospectively study the associations of the Mediterranean Diet Score with study end points.

During median follow-up of 5.4 (interquartile range, 4.9-6.0) years, 76 participants developed graft failure, 119 developed kidney function decline, and 181 developed graft loss. The Mediterranean Diet Score was inversely associated with all study end points (graft failure: hazard ratio [HR], 0.68; 95% confidence interval [95% CI], 0.50 to 0.91; kidney function decline: HR, 0.68; 95% CI, 0.55 to 0.85; and graft loss: HR, 0.74; 95% CI, 0.63 to 0.88 per two-point increase in Mediterranean Diet Score) independent of potential confounders. We identified 24-hour urinary protein excretion and time since transplantation to be an effect modifier, with stronger inverse associations between the Mediterranean Diet Score and kidney outcomes observed in participants with higher urinary protein excretion and participants transplanted more recently.

Adherence to the Mediterranean diet is associated with better kidney function outcomes in kidney transplant recipients.

Cyclophosphamide-Induced Cystitis Results in NLRP3-Mediated Inflammation in the Hippocampus and Symptoms of Depression in Rats.

American Journal of

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depressio...

Racial and Ethnic Variations in Mortality Rates for Patients Undergoing Maintenance Dialysis Treated in US Territories Compared with the US 50 States.

Clinical Journal of the American

In the United States mortality rates for patients treated with dialysis differ by racial and/or ethnic (racial/ethnic) group. Mortality outcomes for patients undergoing maintenance dialysis in the United States territories may differ from patients in the United States 50 states.

This retrospective cohort study of using US Renal Data System data included 1,547,438 adults with no prior transplantation and first dialysis treatment between April 1, 1995 and September 28, 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) of death for the territories versus 50 states for each racial/ethnic group using the whole cohort and covariate-matched samples. Covariates included demographics, year of dialysis initiation, cause of kidney failure, comorbid conditions, dialysis modality, and many others.

Of 22,828 patients treated in the territories (American Samoa, Guam, Puerto Rico, Virgin Islands), 321 were white, 666 were black, 20,299 were Hispanic, and 1542 were Asian. Of 1,524,610 patients in the 50 states, 838,736 were white, 444,066 were black, 182,994 were Hispanic, and 58,814 were Asian. The crude mortality rate (deaths per 100 patient-years) was lower for whites in the territories than the 50 states (14 and 29, respectively), similar for blacks (18 and 17, respectively), higher for Hispanics (27 and 16, respectively), and higher for Asians (22 and 15). In matched analyses, greater risks of death remained for Hispanics (HR, 1.65; 95% confidence interval, 1.60 to 1.70; P<0.001) and Asians (HR, 2.01; 95% confidence interval, 1.78 to 2.27; P<0.001) living in the territories versus their matched 50 states counterparts. There were no significant differences in mortality among white or black patients in the territories versus the 50 states.

Mortality rates for patients undergoing dialysis in the United States territories differ substantially by race/ethnicity compared with the 50 states. After matched analyses for comparable age and risk factors, mortality risk no longer differed for whites or blacks, but remained much greater for territory-dwelling Hispanics and Asians.