Mariam P. Alexander

Kidney Pathological Changes in Metabolic Syndrome: A Cross- sectional Study

BACKGROUND The worldwide prevalence of metabolic syndrome is increasing and has been associated with chronic kidney disease. Kidney pathological findings in patients with metabolic syndrome have not been well described, as was explored in this study. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS We retrospectively screened clinical information for 146 patients who underwent elective nephrectomy for renal cell carcinoma between January 2005 and March 2007 at Brigham and Womens Hospital, Boston, MA. Twelve patients with metabolic syndrome were identified. Twelve age- and sex-matched patients who did not have any of the criteria for metabolic syndrome were used as controls. PREDICTOR Presence of metabolic syndrome defined by using Adult Treatment Panel III criteria. OUTCOMES Histological characteristics in each group, decrease in kidney function at 1-year follow-up. MEASUREMENTS Two pathologists blinded to the clinical diagnosis independently evaluated nephrectomy specimens using Banff criteria to objectively assess histological characteristics. RESULTS Baseline characteristics were similar between the 2 groups. On histopathologic examination, patients with metabolic syndrome compared with controls had a greater prevalence of tubular atrophy (P = 0.006), interstitial fibrosis (P = 0.001), and arterial sclerosis (P = 0.001), suggesting microvascular disease. Patients with metabolic syndrome had greater global (P = 0.04) and segmental glomerulosclerosis (P = 0.05). Glomerular volume and cross-sectional surface area were not different. The combined end point of tubular atrophy greater than 5%, interstitial fibrosis greater than 5%, and presence of arterial sclerosis was more prevalent in patients with metabolic syndrome (P = 0.003; odds ratio, 33; confidence interval, 2.9 to 374.3) than controls. After 1 year, estimated glomerular filtration rate was significantly lower in patients with metabolic syndrome compared with controls (P = 0.03). LIMITATIONS Small sample size, retrospective design. CONCLUSIONS We report a high prevalence of microvascular disease in patients with metabolic syndrome. There was a steeper decrease in kidney function over time in patients with metabolic syndrome, suggesting limited renal reserve. Aggressive screening and management may be warranted in patients with metabolic syndrome to protect kidney function.

The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging

Nephron number may be an important determinant of kidney health but has been difficult to study in living humans. We evaluated 1638 living kidney donors at Mayo Clinic (MN and AZ sites) and Cleveland Clinic. We obtained cortical volumes of both kidneys from predonation computed tomography scans. At the time of kidney transplant, we obtained and analyzed the sections of a biopsy specimen of the cortex to determine the density of both nonsclerotic and globally sclerotic glomeruli; the total number of glomeruli was estimated from cortical volume×glomerular density. Donors 18-29 years old had a mean 990,661 nonsclerotic glomeruli and 16,614 globally sclerotic glomeruli per kidney, which progressively decreased to 520,410 nonsclerotic glomeruli per kidney and increased to 141,714 globally sclerotic glomeruli per kidney in donors 70-75 years old. Between the youngest and oldest age groups, the number of nonsclerotic glomeruli decreased by 48%, whereas cortical volume decreased by only 16% and the proportion of globally sclerotic glomeruli on biopsy increased by only 15%. Clinical characteristics that independently associated with fewer nonsclerotic glomeruli were older age, shorter height, family history of ESRD, higher serum uric acid level, and lower measured GFR. The incomplete representation of nephron loss with aging by either increased glomerulosclerosis or by cortical volume decline is consistent with atrophy and reabsorption of globally sclerotic glomeruli and hypertrophy of remaining nephrons. In conclusion, lower nephron number in healthy adults associates with characteristics reflective of both lower nephron endowment at birth and subsequent loss of nephrons.

Nephron Hypertrophy and Glomerulosclerosis and Their Association with Kidney Function and Risk Factors among Living Kidney Donors

BACKGROUND AND OBJECTIVES The relationship of kidney function and CKD risk factors to structural changes in the renal parenchyma of normal adults is unclear. This study assessed whether nephron hypertrophy and nephrosclerosis had similar or different associations with kidney function and risk factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS From 1999 to 2009, 1395 living kidney donors had a core needle biopsy of their donated kidney during transplant surgery. The mean nonsclerotic glomerular volume and glomerular density (globally sclerotic and nonsclerotic) were estimated using the Weibel and Gomez stereologic methods. All tubules were counted in 1 cm(2) of cortex to determine a mean profile tubular area. Nephron hypertrophy was identified by larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density. Nephrosclerosis was identified by higher globally sclerotic glomerular density. RESULTS The mean (± SD) age was 44 ± 12 years, 24-hour urine albumin excretion was 5 ± 7 mg, measured GFR was 103 ± 17 ml/min per 1.73 m(2), uric acid was 5.2 ± 1.4 mg/dl, and body mass index was 28 ± 5 kg/m(2). Of the study participants, 43% were men, 11% had hypertension, and 52% had a family history of ESRD. Larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density were correlated. Male sex, higher 24-hour urine albumin excretion, family history of ESRD, and higher body mass index were independently associated with each of these measures of nephron hypertrophy. Higher uric acid, higher GFR, and older age were also independently associated with some of these measures of nephron hypertrophy. Hypertension was not independently associated with measures of nephron hypertrophy. However, hypertension and older age were independently associated with higher globally sclerotic glomerular density. CONCLUSIONS Nephron hypertrophy and nephrosclerosis are structural characteristics in normal adults that relate differently to clinical characteristics and may reflect kidney function and risk factors via separate but inter-related pathways.

Patients with ACTN4 Mutations Demonstrate Distinctive Features of Glomerular Injury

Mutations in ACTN4, the gene encoding the actin-binding protein alpha-actinin-4, are a cause of familial FSGS. We examined kidney biopsies from patients with ACTN4 mutations to characterize systematically the histopathology of kidney damage in these patients and to determine whether distinctive morphologic changes are associated with mutations in this gene. The changes observed with light microscopy were typical of FSGS and were morphologically heterogeneous, similar to other inherited podocytopathies. The ultrastructural characteristics, however, were distinctive: Most notably, the presence of cytoplasmic electron-dense aggregates in podocytes. Indirect immunofluorescence using antibodies to a conserved domain of alpha-actinin-4 (present in both wild-type and mutant proteins) revealed a segmental and irregular granular staining pattern in the capillary walls of preserved glomeruli of ACTN4 mutants, whereas preserved glomeruli of patients with other podocyte diseases retained a global linear staining pattern for alpha-actinin-4. These characteristics resemble features observed in mouse models of this disease and may aid in the identification of patients and families who harbor ACTN4 mutations.

A case of familial kidney disease

L.N. was born in 1981 in the Los Angeles area, where she continues to live. As a child, she had a history of seizures but was otherwise healthy. Proteinuria was noted at 15 yr of age. Quantification of urine protein and blood chemistries from that time are not known. She underwent kidney biopsy at age 16. Light microscopic examination of the biopsy revealed global or segmental glomerulosclerosis involving 10 of 12 glomeruli (Figure 1). Moderate atrophy involving 60% of the tubulointerstitial compartment was also apparent, and the arteries and arterioles exhibited mild subintimal sclerosis. Immunofluorescence microscopy showed segmentally prominent IgM and C3 deposition in the glomerular tufts but no IgA or IgG. Electron microscopy showed extensive effacement of glomerular visceral epithelial cell (podocyte) foot processes, along with other podocyte degenerative changes, including microvillous degeneration and cell swelling (Figure 1). There were no significant abnormalities of the glomerular basement membranes, and electron-dense deposits were not observed in the mesangium or along the peripheral capillary loops. Figure 1. (A) Photomicrograph of periodic acid-Schiff–stained biopsy from patient L.N. showing global and segmental glomerulosclerosis, moderate tubular atrophy, and arteries and arterioles with mild subintimal sclerosis. (B) Higher power photomicrograph showing segmental glomerulosclerosis

Acute phosphate nephropathy

Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USACASE PRESENTATIONA 60-year-old white Latino female with a clinical diagnosisof diabetes mellitus (diagnosed in 1993) and hypertensionwas referred to the chronic kidney disease clinic atBrigham and Women’s Hospital for the evaluation of acutekidney injury; serum creatinine had increased from abaseline of 0.9 to 1.5mg/dl in a 11-week period. She wasasymptomatic at the time of presentation. Her pastmedical history included a total abdominal hysterectomywith bilateral salpingo oophorectomy and uppervaginectomy for high-grade squamous intraepitheliallesion of the cervix, 11 weeks prior to presentation. Threeweeks prior to presentation (8 weeks after surgery) andwithin a week of each other, she was evaluated for twoconsecutive episodes of acute onset of chest pain withpulmonary edema in the setting of severe hypertension.Both episodes had blood pressures in excess of190–200mmHg systolic that resolved with intravenousdiuretics. Cardiovascular workup revealed no evidence ofischemic heart disease. Additionally, renal evaluationincluded magnetic resonance angiography with andwithout gadolinium, which did not reveal renal arterystenosis. However, serum creatinine peaked at 1.9 mg/dlimmediately after surgical procedure and remainedelevated at 1.5mg/dl throughout the course of her currentpresentation (corresponding to a glomerular filtration rateof 33ml/min per 1.73m

DnaJ heat shock protein family B member 9 is a novel biomarker for fibrillary GN

Fibrillary GN (FGN) is a rare primary glomerular disease. Histologic and histochemical features of FGN overlap with those of other glomerular diseases, and no unique histologic biomarkers for diagnosing FGN have been identified. We analyzed the proteomic content of glomeruli in patient biopsy specimens and detected DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) as the fourth most abundant protein in FGN glomeruli. Compared with amyloidosis glomeruli, FGN glomeruli exhibited a >6-fold overexpression of DNAJB9 protein. Sanger sequencing and protein sequence coverage maps showed that the DNAJB9 protein deposited in FGN glomeruli did not have any major sequence or structural alterations. Notably, we detected DNAJB9 in all patients with FGN but not in healthy glomeruli or in 19 types of non-FGN glomerular diseases. We also observed the codeposition of DNAJB9 and Ig-γ Overall, these findings indicate that DNAJB9 is an FGN marker with 100% sensitivity and 100% specificity. The magnitude and specificity of DNAJB9 overabundance in FGN also suggests that this protein has a role in FGN pathogenesis. With this evidence, we propose that DNAJB9 is a strong biomarker for rapid diagnosis of FGN in renal biopsy specimens.

De novo multifocal renal cell carcinoma in the renal allograft

A 30-year-old Caucasian male on chronic hemodialysis presents with a 4-day history of right flank pain accompanied by fever, nausea, and anorexia. On physical examination, he had a heart rate of 100 beats per minute and a blood pressure of 147/95 mm Hg. The abdomen was soft. There was no tenderness or guarding over the allograft, and lymph nodes were not enlarged. His remaining examination was unremarkable. Blood and urine cultures were negative. The patient had undergone ultrasonographic examination of the allograft every year since 1998 with evidence of simple cysts in the parenchyma (Figure la) and a persistent fluid collection adjacent to the lower pole representing a lymphocele. A CT scan of the abdomen showed two sub-centimeter low-density lesions within the enlarged right transplanted kidney, suspicious for an infectious or neoplastic process. A persistent and stable right lower quadrant lymphocele was also present. Aspiration of the lymphocele yielded sterile fluid without evidence of infection. A transplant nephrectomy was performed.