Obesity-Related Glomerulopathy: Clinical Management.

Obesity-related glomerulopathy (ORG) and other obesity-associated kidney diseases pose a major challenge to the treating nephrologist. We review the benefits of weight loss and optimal management of ORG and kidney disease in the setting of obesity. Therapeutic strategies in ORG were limited mainly in the past to weight loss through lifestyle interventions and bariatric surgery, antihypertensive treatment, and renin-angiotensin-aldosterone system blockade. Current approaches to obtain the desired weight loss include novel pharmacologic therapies that have been approved for the treatment of diabetes while offering kidney protection, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1-receptor agonists. This review focuses on the nephroprotective role of the renin-angiotensin-aldosterone system blockade and of these new pharmacologic agents, and on the renal effects of bariatric surgery in chronic kidney disease.

Familial Mediterranean Fever Is Associated With Increased Mortality After Kidney Transplantation-A 19 Years' Single Center Experience.

BACKGROUND: Current data regarding the outcome of kidney transplantation in patients with familial Mediterranean fever (FMF) who reach end-stage renal disease (ESRD) due to reactive amyloidosis A (AA) are scarce and inconclusive. METHODS: The outcomes of 20 patients with FMF and biopsy-proven AA amyloidosis that were transplanted between 1995 and 2014 were compared with 82 control patients (32 with diabetes mellitus and 50 with nondiabetic kidney disease). Major outcome data included overall patient and graft survivals. RESULTS: During a mean overall follow-up of 116.6 ± 67.5 months 11 patients (55%) with FMF died versus 26 patients (31%) in the control group. Median time of death for patients with FMF was 61 months (range, 16-81) after transplantation. Estimated 5-year, 10-year, and actuarial 15-year overall patients survival rates were 73%, 45%, and 39%, respectively, for patients with FMF, versus 84%, 68% and 63%, respectively, for the control group (P = 0.028). FMF was associated with more than twofold increased risk for death after transplantation, and with a threefold increased risk for hospitalization because of infections during the first year. Infections and cardiovascular disease were the cause of death in the majority of patients with FMF. Overall graft survival was similar between the groups. Recurrence of AA amyloidosis was diagnosed in 2 patients during the first year after transplantation. CONCLUSIONS: FMF is associated with increased risk of mortality after kidney transplantation.

The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation.

PURPOSE: Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time. METHODS: We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis. RESULTS: Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5-134.3), respectively, for cancer diagnosed more than 3 years after transplantation. CONCLUSION: Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.

Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.

The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.

Cytomegalovirus-negative kidney transplant recipients are at an increased risk for malignancy after kidney transplantation.

BACKGROUND: The effect of cytomegalovirus (CMV) serology status on malignancy risk in kidney transplanted patients is not clear yet. METHODS: In a nested case-control study, CMV serology status was compared between patients with a malignancy and 2:1 matched control patients without a malignancy. In a cohort study, the hazard of malignancy was compared between patients that were CMV-negative but had a CMV-positive donor and other patients, using Cox analysis. RESULTS: Fifty-two of 599 patients transplanted in our center between 2001 and 2014 developed a malignancy. Nine (17.3%) of the 52 patients that developed cancer were CMV-negative but had a-CMV-positive donor compared with 6 (5.8%) of the 104 matched control patients (odd ratio 3.42, 95% confidence interval [CI] 1.15-10.2, P=.021). By univariate Cox model, there was a trend toward increased cancer risk in CMV-negative patients with a positive donor (hazard ratio [HR] 1.95, 95% CI 0.95-4.0, P=.07), but after adjusting for multiple covariates, CMV-negative status was significantly associated with increased risk of cancer (HR 2.55, 95% CI 1.23-5.26; P=.012). CONCLUSIONS: CMV-negative patients that had a CMV-positive donor were found to have a higher risk of malignancy after kidney transplantation.

Changes in inflammatory markers during a hemodialysis session and their relation to vascular access type.

PURPOSE: In an attempt to better understand the relationship between vascular access and inflammation we assessed the effect of vascular access on inflammatory markers changes during hemodialysis (HD) session. METHODS: Fifty HD patients were included: 23 patients with central venous catheters (CVC) and 27 patients with arteriovenous fistulas (AVF). Blood samples for high sensitivity C-reactive protein (hsCRP), Interleukin 6 (IL-6), and Tumor Necrosis Factor α (TNF α) were collected before and after HD session. The outcome was the change in the inflammatory markers during the dialysis. RESULTS: Predialysis hsCRP levels were high in 70% of patients, without differences between the groups. Predialysis values were also similar in the two groups for IL-6 and TNF α. There was no increase in hsCRP values following HD and no difference between the change from baseline values in the CVC and AVF groups (-0.01±0.09 mg/dL and -0.01±0.13 mg/dL, respectively [P=.95]). IL-6 values increased during the HD session in the AVF group and non-significantly decreased in the CVC group. The change from baseline values was statistically significantly greater in the AVF group compared to the CVC group (0.76±1.44 ng/mL and -0.52±1.66 ng/mL, respectively, P=.006). TNF α values were significantly decreased in the CVC group and were not changed in the AVF group. The decrease from baseline values was not different between the groups. CONCLUSIONS: Chronic inflammation is present in most HD patients. No increase in pro-inflammatory parameters was seen after a HD session in patients treated via CVC or AVF.

Inhibition of mitochondrial function reduces DNA repair in human mononuclear cells.

BACKGROUND: Mitochondria provide ATP and Ca(2+) needed for DNA repair, but also produce reactive oxygen species (ROS), which may damage DNA. AIM: To investigate the effect of mitochondrial function inhibition on DNA repair. METHOD: Five mitochondrial inhibitors acting at various sites of electron transport were studied. Human peripheral blood mononuclear cells, spontaneous and H(2)O(2)-induced DNA repair, as well as %-double-stranded-DNA, were measured. RESULTS: All mitochondrial inhibitors suppressed spontaneous and H(2)O(2)-induced DNA repair. However, their effect on %-double-stranded-DNA differed, which is partly related to ROS suppression. CONCLUSION: Mitochondrial inhibition may enhance efficacy and reduce toxicity of radiation and cytotoxic drugs therapy.

Acute phosphate nephropathy-an emerging threat.

BACKGROUND: Acute phosphate nephropathy (APN) is a clinicopathological entity causing renal failure, after ingestion of oral sodium phosphate solution (OSPS). Approximately 25 cases have been described, but OSPS is still widely used. This study reports a further 5 cases and discusses the ever-growing significance of APN. METHODS: Five cases of APN were included, 3 retrospectively whereas 2 were diagnosed prospectively. In all, use of OSPS was established, and other causes of nephrocalcinosis were excluded. RESULTS: Average age was 67.4 +/- 7.0 years, with a female preponderance (4:1). All patients had hypertension. Baseline serum creatinine: 0.7 to 1.2 mg/dL (creatinine clearance: 52 to 77 mL/min). Time from colonoscopy to presentation was 56 +/- 36 days. Serum creatinine levels at presentation: 1.4 to 3.6 mg/dL. Time from colonoscopy to renal biopsy was 123 +/- 88 days. Urinalysis showed minimal proteinuria, leucocyturia, and hematuria. One patient had renal glucosuria. All patients were anemic (hemoglobin 8.8-11.4 gr/dL). Serum calcium and phosphate were normal. One required hemodialysis. Mean follow-up was 36 +/- 17 months. Serum creatinine levels at end of follow-up were 1.3 to 3.1 mg/dL. Renal function did not recover completely in any patient. Four required long-term erythropoietin treatment. The prominent histopathological findings were calcium-phosphate tubular depositions (100%), interstitial fibrosis (80%), hypertensive changes (80%), and acute tubular degenerative and regenerative changes (60%). CONCLUSIONS: APN is a serious, irreversible renal complication of OSPS. It is probably under-recognized. Risk factors include female gender, older age, hypertension, and renal failure, although it may occur with preexisting normal renal function.

Effect of hemodialysis on the thickness of vocal folds: a possible explanation for postdialysis hoarseness.

BACKGROUND: Determining the dry weight of chronically hemodialysed patients is a common problem. Patients on intermittent hemodialysis often experience transient hoarseness at the end of dialysis. The vocal folds may be affected by the hydration state. AIM: To test the hypothesis that postdialysis hoarseness may be related to changes in the thickness of the vocal folds. METHODS: Twenty-five stable chronic hemodialysis patients underwent endoscopic nasopharyngeal laryngoscopy before and after dialysis. Pictures of the vocal folds were taken and the folds were measured using computer software. Eighteen vocal folds from 16 patients were technically adequate for analysis. The change in the width/length ratio of the vocal folds (W/L) was used as a measurement of the folds' thickness. RESULTS: W/L decreased from 0.175 +/- 0.011 before dialysis to 0.152 +/- 0.009 after dialysis (p < 0.01, mean reduction 10.9 +/- 3.8%). Patients' weight decreased by 4.7 +/- 0.3% (p < 0.0001), systolic blood pressure decreased by 15.0 +/- 3.1% (p < 0.001), diastolic blood pressure decreased by 13.0 +/- 3.6% (p < 0.01), and mean blood pressure decreased by 14.1 +/- 3.1% (p < 0.001). Sixty percent of the patients had postdialysis hoarseness, and in 72% of the patients a decrease in the vocal folds' thickness was observed. CONCLUSIONS: Chronic hemodialysis patients may experience transient postdialysis hoarseness, and a decrease in the vocal folds' thickness. The latter may result from dehydration.

Non-occlusive mesenteric ischemia in chronically dialyzed patients: a disease with multiple risk factors.

BACKGROUND: Non-occlusive mesenteric ischemia (NOMI) can be a fatal complication in dialysis patients. Intradialytic hypotension is usually the precipitating factor. The occurrence of 16 cases in 5 years (1998-2002), compared with only 4 in previous years, led us to investigate other risk factors contributing to NOMI. A control group of stable hemodialysis patients was used for comparison. RESULTS: 20 patients were studied: 17 diagnosed surgically, and 3 clinically. The mean age was 70.8 +/- 1.8 years, and the male:female ratio 7:13. Nineteen patients were on hemodialysis. Clinically overt atherosclerosis was present in 17 patients. Preceding dialysis-associated hypotension was identified in all patients studied and access thrombosis in 6 patients. In all patients, abdominal pain was the presenting symptom. Initial abdominal examination was unimpressive in 16 patients. The hemoconcentration, leukocytosis and metabolic acidosis were the most prominent laboratory findings. 5/11 abdominal sonograms showed intestinal pathology. 2/3 angiographies were diagnostic. Three patients responded to early fluid challenge and did not require surgery. Pathology was related to the area of the superior mesenteric artery in all 15 patients operated. Twelve (60%) patients died from the event. The 1-year mortality rate was 17/20 patients (85%). Possible contributing factors, other than dialysis-associated hypotension, included: high-dose recombinant human erythropoietin (rhEPO) therapy (179 +/- 35 vs. 116 +/- 10 U/kg/week in the control group, p < 0.05); metastatic calcifications (abdominal aorta 14/14, aortic valve 11/18; medial calcification of mesenteric arteries in 2/11 pathology specimens); digoxin, and hypoalbuminemia. CONCLUSIONS: The increased incidence of NOMI in dialysis patients may be related to overly aggressive rhEPO therapy and the unsuspected presence of mesenteric arterial medial calcifications. Identification of patients at risk, prevention of intradialytic hypotension and a controlled increase in dry weight may help to reduce the incidence of NOMI in chronically dialyzed patients.

Spontaneous DNA repair in human peripheral blood mononuclear cells.

DNA molecules are constantly damaged during mitosis and by oxygen-free radicals produced by either cellular metabolism or by external factors. Populations at risk include patients with cancer-prone disease, patients under enhanced oxidative stress, and those treated with immunosuppressive/cytotoxic therapy. The DNA repair process is crucial in maintaining the genomal DNA integrity. The aim of this study was to evaluate spontaneous DNA repair capacity of peripheral blood mononuclear cells (PBMC) from normal blood donors. PBMC DNA repair ability represents DNA repair by other tissues as well. It is shown in the present study that in vitro incorporation of [3H]thymidine in non-stimulated PBMC expresses the ability of the cells to repair DNA damage. This method was validated by double-stranded DNA measurements. Both catalase and Fe2+ increased DNA repair, the former by preventing re-breakage of newly repaired DNA and the latter by introducing additional DNA damage, which enhanced DNA repair. Better understanding of DNA repair processes will enable to minimize DNA damage induced by oxidative stress.

Electrolyte disorders following oral sodium phosphate administration for bowel cleansing in elderly patients.

BACKGROUND: Oral sodium phosphate is currently used for colon preparation prior to colonoscopy or barium enema. Sodium phosphate induces hyperphosphatemia, hypocalcemia, and hypokalemia. Elderly patients are at an increased risk for phosphate intoxication due to decreased glomerular filtration rate, medication use, and systemic and gastrointestinal diseases. We investigated these electrolyte disorders and their correlation with creatinine clearance, coexistent diseases, medications, and functional status. METHODS: Thirty-six hospitalized patients were included in the study. On day 1, patients were administered 2 doses of oral sodium phosphate. Venous blood samples for electrolyte determination were obtained at 7 AM on days 1, 2 (the procedure day), and 3. Urine samples were obtained from 10 patients. RESULTS: An increase in serum phosphorus level was correlated with a decreased creatinine clearance (R = -0.52; P =.001). Hypocalcemia and hypokalemia were present in 21 (58%) and 20 (56%) patients, respectively. Patients with a serum potassium concentration of 3.5 mEq/L or less on day 2 had a lower serum potassium concentration on day 1 vs those with a serum potassium concentration greater than 3.5 mEq/L on day 2 (P =.03). Five (dependent patients) had a serum potassium concentration of 3 mEq/L or less and 2 had severe diarrhea, necessitating treatment. There were more demented patients with hypokalemia compared with normokalemic patients (P<.05). Urinary fractional excretion of phosphorus tripled on day 2 (P =.01). Potassium and sodium fractional excretion remained unchanged. CONCLUSIONS: Sodium phosphate induces serious electrolyte abnormalities in the elderly. The frequency and severity of hypokalemia is due to intestinal potassium loss associated with inadequate renal potassium conservation and is apparently more prevalent in frail patients. Assessment of serum electrolytes, phosphorus, and calcium prior to sodium phosphate preparation is advised, and in selected patients, postprocedural assessment and correction may be required.

Using the automated biopsy gun with real-time ultrasound for native renal biopsy.

BACKGROUND: The use of an automated biopsy system for renal biopsy has recently gained popularity, but its safety in single functioning kidneys is unclear. OBJECTIVE: To report our experience with the automated system for closed renal biopsy during a 5 year period. METHODS: Eighty-five patients underwent percutaneous native renal biopsy with the automated biopsy gun (16G needle) under real-time ultrasound. They were chronologically divided into two groups: 41 patients (group A), using an older ultrasound machine; and 44 patients (group B), using a newer ultrasound machine. Nine patients biopsied with a manual 14G Tru-cut needle served as the control (group C). RESULTS: The number of "attempted" passes at the kidney was 4.0 +/- 0.1 in group B, 4.7 +/- 0.3 in group A (P < 0.05 vs. group B), and 5.8 +/- 0.5 in group C (P < 0.01 vs. group B). The number of successful passes did not differ (3.3 +/- 0.1, 3.3 +/- 0.1, 3.1 +/- 0.2). The ratio of "attempted/successful" was 1.28 +/- 0.07 in group B, 1.95 +/- 0.38 in A, and 1.90 +/- 0.21 in C (P < 0.01 vs. B). The number of glomeruli obtained was similar in the three groups. Adequate tissue was obtained in 95%, 98%, and 100%, respectively. Hemoglobin decreased by 4.3 +/- 1.1% in group B, 6.9 +/- 1.3% in group A, and 11.3 +/- 1.8% in group C (P < 0.05 vs. B). Perinephric/subcapsular hematoma occurred in 5 patients (11.4%) in group A (2 taking aspirin), in 2 patients (4.9%) in group B, and in none in group C. The necessity for blood transfusion post-biopsy was similar in all groups. Four of five patients with single functioning kidneys (one in group A and four in group B) had uneventful biopsies, and adequate tissue was obtained in three. CONCLUSIONS: The use of the automated biopsy gun is effective, safe and has a low rate of major complications. It may be used safely in single functioning kidneys.

DNA repair in mononuclear cells: role of serine/threonine phosphatases.

Treatment with cyclosporin A (CsA) in kidney-transplant recipients is associated with reduced DNA repair and enhanced cancer incidence. CsA is an inhibitor of the serine/threonine phosphatase calcineurin, also termed PP2B, which is a Ca(2+)/calmodulin-dependent phosphatase. In this study we sought to elucidate the role of calcineurin in DNA repair using CsA and tacrolimus; examine whether UV-induced DNA repair is associated with dephosphorylation; and investigate whether phosphatases other than calcineurin are active in DNA repair, in light of the fact that calcineurin inhibition only partially suppressed DNA repair. Peripheral blood mononuclear cells from healthy donors were used. In vitro, we assayed UV-induced DNA repair by measuring the incorporation of tritiated thymidine in UV-irradiated cells. We gauged phosphatase activity indirectly by measuring free inorganic phosphate (Pi) excreted into the medium. The phosphatase assay was performed under the same conditions and in parallel to the DNA-repair assay. Tacrolimus, like CsA, inhibited DNA repair in a dose-dependent fashion. DNA repair was associated with production of Pi, which correlated with the number of cells performing DNA repair. Phosphatase activity increased after UV irradiation. DNA repair correlated directly with phosphatase activity, whereas CsA reduced both DNA repair and Pi production. Inhibition of calmodulin by trifluoperazine and W7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide] reduced DNA repair in part. We investigated the role of the Ca(2+)-independent phosphatases PP1 and PP2A using specific inhibitors. Calyculin A, which inhibits both phosphatases, reduced DNA repair. Endothall, a PP2A inhibitor, had no effect on DNA repair. Okadaic acid, which is mostly a PP2A inhibitor but also a weak inhibitor of PP1, reduced DNA repair only slightly. We suggest that DNA repair is mediated by way of Ca(2+)-dependent and Ca(2+)-independent pathways, with calcineurin and PP1 being the respective phosphatases involved in each pathway.

Effect of increased dialysate volume on peritoneal surface area among peritoneal dialysis patients.

Large dialysate volumes are often required to increase solute clearance for peritoneal dialysis patients. The resulting increase in solute clearance might be attributable to an increased plasma-to-dialysate concentration gradient and/or to an increased effective peritoneal surface area. One of the factors affecting the latter is the peritoneal surface area in contact with dialysate (PSA-CD). The aim of this study was to estimate the change in PSA-CD after a 50% increase in the instilled dialysate volume for patients undergoing peritoneal dialysis. PSA-CD was estimated by using a method applying stereologic techniques to computed tomographic (CT) scans of the peritoneal space. The peritoneal cavity of 10 peritoneal dialysis patients was filled with a solution containing dialysate, half-isotonic saline solution, and contrast medium. Peritoneal function tests and CT scanning of the abdomen were performed twice for each patient (with an interval of 1 wk), after instillation of a 2- or 3-L solution. Scanning of thin helical CT sections was performed, and 36 random sections of the abdomen were obtained after reconstruction. A grid was superimposed on the sections. The surface area was estimated by using stereologic methods. After instillation of the 2-L solution, the volume of the peritoneal solution at the time of CT scanning was 2.32 +/- 0.05 L. The PSA-CD was 0.57 +/- 0.03 m(2), ranging from 0.41 to 0.76 m(2). The use of the 3-L solution increased the peritoneal volume by 46 +/- 2%. PSA-CD increased by 18 +/- 2.3% to 0.67 +/- 0.04 m(2) (range, 0.49 to 0.84 m(2); P < 0.01). Creatinine mass transfer increased from 112 +/- 10 mg to 142 +/- 11 mg (P < 0.0001). The slope of the change of the plasma-to-dialysate creatinine concentration gradient with time decreased from -2.26 +/- 0.23 x 10(-2) to -1.97 +/- 0.16 x 10(-2) (P = 0.01). K(BD-0) (permeability-surface area product or mass area transfer coefficient at time 0 of the dwell) increased from 10.6 +/- 0.7 to 13.6 +/- 1.2 ml/min (P < 0.02). These data demonstrate that increasing the instilled dialysate volume by 50% for peritoneal dialysis patients results in significant increases in the PSA-CD and K(BD).