Among African-Americans, genome wide association revealed a strong correlation between the G1 and G2 alleles of APOL1 (apolipoproteinL1, also called trypanolytic factor) and kidney diseases including ...focal and segmental glomerulosclerosis, HIV-associated nephropathy and hypertensive nephrosclerosis. In the prevailing hypothesis, heterozygous APOL1 G1 and G2 alleles increase resistance against Trypanosoma that cause African sleeping sickness, resulting in positive selection of these alleles, but when homozygous the G1 and G2 alleles predispose to glomerulosclerosis. While efforts are underway to screen patients for G1 and G2 alleles and to better understand "APOL1 glomerulopathy," no data prove that these APOL1 sequence variants cause glomerulosclerosis. G1 and G2 correlate best with glomerulosclerosis as recessive alleles, which suggests a loss of function mutation for which proof of causality is commonly tested with homozygous null alleles. This test cannot be performed in rodents as the APOL gene cluster evolved only in primates. However, there is a homozygous APOL1 null human being who lives in a village in rural India. This individual and his family offer a unique opportunity to test causality between APOL1 null alleles and glomerulosclerosis.
We obtained clinical data, blood and urine from this APOL1 null patient and 50 related villagers. Based on measurements of blood pressure, BUN, creatinine, albuminuria, genotyping and immunoblotting, this APOL1 null individual does not have glomerulosclerosis, nor do his relatives who carry APOL1 null alleles.
This small study cannot provide definitive conclusions but the absence of glomerulosclerosis in this unique population is consistent with the possibility that African-American glomerulosclerosis is caused, not by loss of APOL1 function, but by other mechanisms including a subtle gain of function or by the "genetic hitchhiking" of deleterious mutations in a gene linked to APOL1 G1 and G2.
We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition ...to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9(flox) alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p>0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p<0.05 or less). In contrast, we found that PodΔMyh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that PodΔMyh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes.
Erythropoiesis-stimulating agents (ESAs) are commonly used for the treatment of anemia due to chronic kidney disease (CKD) and end stage renal disease (ESRD). Patients often lack an understanding of ...the potential risks and benefits of ESAs, despite government mandated education on this topic. Decision aids are tools commonly used to discuss important information in health care settings. To address this knowledge gap, we designed this study to evaluate the effectiveness of a novel ESA decision aid at promoting informed shared decision making (ISDM) between patients and providers related to ESA use for CKD- and ESRD-related anemia.
Using the principles of informed shared decision making theory, we designed and piloted an ESA decision aid intended to increase CKD and ESRD patient understanding of the potential risks and benefits of ESAs. Informed by the findings during development, the ESA decision aid was modified and finalized for testing. We will perform a randomized clinical trial to assess if administration of the ESA decision aid improves patient understanding of the risks and benefits of ESA use compared to control patients receiving standard care. Participants with either CKD or ESRD and who are receiving ESAs will be eligible for participation. The primary outcome is patients' score on the Patient Anemia Knowledge in Kidney Disease (PAKKD) survey assessed at enrollment and 3 months after. Secondary outcomes include decisional conflict related to ESAs, and patient satisfaction with provider communication.
The Anemia Risk Communication for patients with Kidney Disease (ARC-KD) study will assess the effectiveness of a novel ESA decision aid to improve patient understanding of ESA use to manage CKD- and ESRD-related anemia. This decision aid is the first resource targeted to improve patient understanding of anemia management in the kidney health context. With the increasing options available for anemia management, this will serve as an important foundation to evolve in the future to optimize anemia-related shared decision making.
ClinicalTrials.gov, number NCT01992926 . Registered 11/14/2013.
In chronic kidney disease (CKD), dietary acid may promote metabolic acidosis and insulin resistance, which in turn may contribute to adverse clinical health outcomes. We examined associations between ...dietary acid load, serum bicarbonate, and insulin sensitivity in CKD.
In a cross-sectional study, we collected 3-day prospective food diaries to quantify dietary acid load as net endogenous acid production (NEAP, the nonvolatile acid load produced by the diet's acid balance) and potential renal acid load (PRAL). We measured urine net acid excretion (NAE) in 24-hour urine samples. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp.
Forty-two patients with CKD Stages 3 to 5 attending nephrology clinics in the Pacific Northwest and 21 control subjects (estimated glomerular filtration rate eGFR ≥ 60 mL/minute/1.73 m(2)).
Serum bicarbonate and insulin sensitivity (SIclamp).
Mean age was 60.8 ± 13.6 years, and 54% of participants were men. Mean eGFR and serum bicarbonate concentrations were 34.4 ± 13.1 mL/minute/1.73 m(2) and 24.1 ± 2.9 mEq/L for participants with CKD and 88.6 ± 14.5 mL/minute/1.73 m(2) and 26.3 ± 1.8 mEq/L for control subjects, respectively. Mean NEAP, PRAL, and NAE were 58.2 ± 24.3, 9.7 ± 18.4, and 32.1 ± 19.8 mEq/day, respectively. Considering all participants, dietary acid load was significantly, inversely associated with serum bicarbonate, adjusting for age, gender, race, eGFR, body mass index, and diuretic use: -1.2 mEq/L per standard deviation (SD) NEAP (95% confidence interval CI -1.8 to -0.6, P < .0001); -0.9 mEq/L bicarbonate per SD PRAL (95% CI -1.5 to -0.4, P = .0005); -0.7 mEq/L bicarbonate per SD NAE (95% CI -1.2 to -0.1, P = .01). These associations were similar in participants with and without CKD. However, neither NEAP and PRAL nor NAE was significantly associated with SIclamp. Serum bicarbonate was also not significantly associated with SIclamp.
In CKD, dietary acid load is associated with serum bicarbonate, suggesting that acidosis may be improved by dietary changes, but not with insulin sensitivity.
Objective
To examine the degree of insulin resistance at different stages of chronic kidney disease (CKD) including patients on CHD.
Methods
217 non‐diabetic subjects participated in this study. ...Fasting blood samples were taken to examine concentrations of glucose and insulin. Homeostasis model assessment of insulin resistance (HOMA) was used to calculate insulin resistance in all subjects.
Results
Insulin and HOMA were significantly different between groups overall (p < 0.001 for both). There was no statistical significant difference between CKD stages while the CHD group was significantly different from each of the other groups for insulin and HOMA.
Conclusion
This study shows that insulin resistance increases significantly after initiation of hemodialysis. While there is a trend towards worsening insulin resistance with progression of kidney disease this did not reach a statistical significance.
The authors present an infant with left ventricular and mitral valve thrombi diagnosed by cross-sectional echocardiography. Thrombosis was due to acquired transient protein C deficiency, which was ...caused by impaired liver function due to sepsis. Because the thombi were very large and mobile, urgent surgery was performed. Eight weeks later, the patient's protein C level returned to normal ranges. The authors suggest that in all cases with intracardiac thrombosis, protein C deficiency should be investigated.
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