Farsad Afshinnia

Urine Podocyte mRNAs, Proteinuria, and Progression in Human Glomerular Diseases

Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P<0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P<0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimal-change disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology.

Evaluation of characteristics, associations and clinical course of isolated spontaneous renal artery dissection

BACKGROUND Spontaneous renal artery dissection (SRAD) is a rare entity of unknown etiology. We aimed to study the clinical course and outcomes and compare the characteristics of patients with SRAD with those of the general population. METHODS All cases of isolated renal artery dissection diagnosed at the University of Michigan Hospitals between January 2000 and July 2012 were identified by the ICD-9 code. Cases were matched by age, gender and race with individuals from the 2009-2010 National Health and Nutrition Examination Survey (NHANES). Characteristics and awareness of comorbid conditions were compared. Information about the clinical course after diagnosis was retrieved from the case group to ascertain their outcomes. RESULTS Overall, 17 patients with SRAD with a mean age of 38.6 years (SD = 8.3) were identified. Eleven patients were male and 14 were white. The most common presenting symptom was excruciating sudden-onset flank pain ipsilateral to the site of dissection. Fibromuscular dysplasia, Ehlers-Danlos and polyarteritis nodosa were present in 4, 4 and 1 patients, respectively. After adjusting in a multivariable model, the case group was more likely to report history of hypertension, cancer and connective tissue disorders (P < 0.001), and less likely to have obesity (BMI ≥30 kg/m(2)) compared with the general population. Supportive medical treatment, endovascular intervention and surgery were required in 8, 5 and 4 cases, respectively. After discharge from the hospital, hypertension was adequately controlled in all the patients but one. CONCLUSION SRAD may be part of a syndrome having multi-organ involvement. With appropriate medical or surgical management, long-term clinical outcome appears favorable.

Podocyte Depletion in Thin GBM and Alport Syndrome

The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2–17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman’s capsule) were present at 30–50% podocyte depletion, and FSGS was progressively present above 50% podocyte depletion. eGFR did not change measurably until >70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.

The Effect of Different Dialysate Magnesium Concentrations on QTc Dispersion in Hemodialysis Patients

Background: Electrolyte changes during dialysis affect corrected QT (QTc) and QTc dispersion (QTcd), a surrogate marker of arrhythmogenicity. The impact of magnesium on QTcd is not clear. Methods: Twenty-two stable patients on maintenance hemodialysis were enrolled in this study. Each underwent two consecutive hemodialysis sessions at least 2 days apart, the first against normal magnesium dialysate (with magnesium at 1.8 mg/dL) followed by a low magnesium dialysate (with magnesium at 0.6 mg/dL). Pre- and post-dialysis weights, blood pressure, electrolytes, and 12-lead surface EKG were recorded. The QT interval and the QTcd were calculated before and after dialysis in both sessions. Results: Of 22 patients, 16 were female. The mean age ± SD was 53.7 ± 18.0 years. The mean change of QTcd (pre- vs. post-dialysis) was 9.5 ms (p = 0.120) and 9.3 ms (p = 0.145) in low and normal magnesium groups, respectively. Using univariate analysis, there was a statistically significant decrease in the mean blood pressure, weight, potassium, magnesium, and QTc interval post-dialysis (compared to pre-dialysis) in both groups (p ≤ 0.049). Post-dialysis concentrations of sodium and calcium were unchanged (compared to pre-dialysis) but bicarbonate increased with both dialysate groups (p < 0.001). The mean change of QTcd was not significant pre- versus post-dialysis by univariate analysis in either group. Multiple linear regression analysis adjusting for pertinent factors did not change the results in either of the two groups. Conclusion: Using a low magnesium dialysate bath in hemodynamically stable hemodialysis patients without preexisting advanced cardiac disease does not significantly impact QTcd.

Lipidomic Signature of Progression of Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort

Introduction Human studies report conflicting results on the predictive power of serum lipids on the progression of chronic kidney disease. We aimed to systematically identify the lipids that predict progression to end-stage kidney disease. Methods From the Chronic Renal Insufficiency Cohort, 79 patients with chronic kidney disease stages 2 to 3 who progressed to end-stage kidney disease over 6 years of follow-up were selected and frequency matched by age, sex, race, and diabetes with 121 nonprogressors with less than 25% decline in estimated glomerular filtration rate during the follow-up. The patients were randomly divided into training and test sets. We applied liquid chromatography-mass spectrometry-based lipidomics on visit year 1 samples. Results We identified 510 lipids, of which the top 10 coincided with false discovery threshold of 0.058 in the training set. From the top 10 lipids, the abundance of diacylglycerols and cholesteryl esters was lower, but that of phosphatidic acid 44:4 and monoacylglycerol 16:0 was significantly higher in progressors. Using logistic regression models, a multimarker panel consisting of diacylglycerols and monoacylglycerol independently predicted progression. The c-statistic of the multimarker panel added to the base model consisting of estimated glomerular filtration rate and urine protein-to-creatinine ratio as compared with that of the base model was 0.92 (95% confidence interval: 0.88–0.97) and 0.83 (95% confidence interval: 0.76–0.90, P < 0.01), respectively, an observation that was validated in the test subset. Discussion We conclude that a distinct panel of lipids may improve prediction of progression of chronic kidney disease beyond estimated glomerular filtration rate and urine protein-to-creatinine ratio when added to the base model.

Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD

Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of β-oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD. Among participants, 110 were men (51.4%), 64 were black (29.9%), and 150 were white (70.1%), and the mean (SD) age was 60 (16) years old. We measured plasma lipids and acylcarnitines using liquid chromatography-mass spectrometry. Overall, we identified 330 different lipids across 17 different classes. Compared with earlier stages, stage 5 CKD associated with a higher abundance of saturated C16-C20 free fatty acids (FFAs) and long polyunsaturated complex lipids. Long-chain-to-intermediate-chain acylcarnitine ratio, a marker of efficiency of β-oxidation, exhibited a graded decrease from stage 2 to 5 CKD (P<0.001). Additionally, multiple linear regression revealed that the long-chain-to-intermediate-chain acylcarnitine ratio inversely associated with polyunsaturated long complex lipid subclasses and the C16-C20 FFAs but directly associated with short complex lipids with fewer double bonds. We conclude that increased abundance of saturated C16-C20 FFAs coupled with impaired β-oxidation of FFAs and inverse partitioning into complex lipids may be mechanisms underpinning lipid metabolism changes that typify advancing CKD.

Quantitative podocyte parameters predict human native kidney and allograft half-lives

BACKGROUND Kidney function decreases with age. A potential mechanistic explanation for kidney and allograft half-life has evolved through the realization that linear reduction in glomerular podocyte density could drive progressive glomerulosclerosis to impact both native kidney and allograft half-lives. METHODS Predictions from podometrics (quantitation of podocyte parameters) were tested using independent pathologic, functional, and outcome data for native kidneys and allografts derived from published reports and large registries. RESULTS With age, native kidneys exponentially develop glomerulosclerosis, reduced renal function, and end-stage kidney disease, projecting a finite average kidney life span. The slope of allograft failure rate versus age parallels that of reduction in podocyte density versus age. Quantitative modeling projects allograft half-life at any donor age, and rate of podocyte detachment parallels the observed allograft loss rate. CONCLUSION Native kidneys are designed to have a limited average life span of about 100-140 years. Allografts undergo an accelerated aging-like process that accounts for their unexpectedly short half-life (about 15 years), the observation that older donor age is associated with shorter allograft half-life, and the fact that long-term allograft survival has not substantially improved. Podometrics provides potential readouts for these processes, thereby offering new approaches for monitoring and intervention. FUNDING National Institutes of Health.

Focal segmental glomerulosclerosis in association with neurofibromatosis type 1: a case report and proposed molecular pathways.

A 42-year-old Caucasian female with history of neurofibromatosis type 1 presented with nephrotic range proteinuria and focal segmental glomerulosclerosis (FSGS). On final dose of lisinopril 20 mg/day, protein–creatinine ratio declined to 0.33 within 10 months. We propose the hypothesis that development of FSGS in NF1 may be mediated by activation of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways secondary to up-regulation of ras proteins due to deficient neurofibromin. Since mTOR signaling pathway is partially mediated through angiotensin-II activation, angiotensin-converting enzyme (ACE) inhibition may serve as an effective initial treatment beyond anti-proteinuric properties of ACE-inhibitors.

Association of Hypoalbuminemia With Osteoporosis: Analysis of the National Health and Nutrition Examination Survey

CONTEXT The association of hypoalbuminemia with osteoporosis in human studies is controversial. OBJECTIVE We tested the independent association between hypoalbuminemia and osteoporosis in a national dataset. DESIGN This is a cross-sectional observation. SETTING AND PARTICIPANTS Participants are individuals selected from the National Health and Nutrition Examination Survey (NHANES) with available clinical, laboratory, and densitometry data from the 2005-2010 and 2013-2014 cycles. EXPOSURE Exposure is hypoalbuminemia defined as serum albumin <3.5 g/dL. MAIN OUTCOME MEASURE Osteoporosis is defined as bone mineral density of ≤2.5 SD below the mean peak bone mass of young, healthy adults. Analysis took into account the hidden variance and the weighting methodology pertinent to analysis of NHANES. RESULTS Overall, 15 539 individuals were included. The mean age was 48.6 years (SE = 0.27). Fifty percent of the individuals were male, and 10.2% were of the black race. There was a graded decrease in the rate of osteoporosis from 15.2% at albumin <3.5 g/dL to 2.6% at albumin >4 g/dL (P = .007) at the femoral neck and from 11.0 to 1.4% at total femur (P = .009). In a fully adjusted model, the odds of osteoporosis with hypoalbuminemia were 5.37-fold (95% confidence interval [CI], 1.43 to 20.20; P = .014) at the femoral neck, 12.46-fold (95% CI, 3.24 to 48.01; P < .001) at total femur, and 4.59-fold (95% CI, 1.49 to 14.16; P = .025) at the lumbar spine higher as compared to albumin >4 mg/dL. CONCLUSION In the NHANES dataset, we report an independent association of osteoporosis with hypoalbuminemia at different anatomical sites.

Effect of ionized serum calcium on outcomes in acute kidney injury needing renal replacement therapy: secondary analysis of the acute renal failure trial network study

Abstract Background: Hypocalcemia is very common in critically ill patients. While the effect of ionized calcium (iCa) on outcome is not well understood, manipulation of iCa in critically ill patients is a common practice. We analyzed all-cause mortality and several secondary outcomes in patients with acute kidney injury (AKI) by categories of serum iCa among participants in the Acute Renal Failure Trial Network (ATN) Study. Methods: This is a post hoc secondary analysis of the ATN Study which was not preplanned in the original trial. Risk of mortality and renal recovery by categories of iCa were compared using multiple fixed and adjusted time-varying Cox regression models. Multiple linear regression models were used to explore the impact of baseline iCa on days free from ICU and hospital. Results: A total of 685 patients were included in the analysis. Mean age was 60 (SD = 15) years. There were 502 male patients (73.3%). Sixty-day all-cause mortality was 57.0%, 54.8%, and 54.4%, in patients with an iCa <1, 1–1.14, and ≥1.15 mmol/L, respectively (p = 0.87). Mean of days free from ICU or hospital in all patients and the 28-day renal recovery in survivors to Day 28 were not significantly different by categories of iCa. The hazard for death in a fully adjusted time-varying Cox regression survival model was 1.7 (95% CI: 1.3–2.4) comparing iCa <1 to iCa ≥ 1.15 mmol/L. No outcome was different for levels of iCa > 1 mmol/L. Conclusion: Severe hypocalcemia with iCa < 1 mmol/L independently predicted mortality in patients with AKI needing renal replacement therapy.