A diet containing cod backbone proteins attenuated the development of mesangial sclerosis and tubular dysfunction in male obese BTBR ob/ob mice.

PURPOSE: The obese black and tan, brachyuric (BTBR) ob/ob mouse spontaneously develops features comparable to human diabetic nephropathy. The primary aim of the present study was to investigate if a diet containing fish proteins would attenuate or delay the development of glomerular hypertrophy (glomerulomegaly), mesangial sclerosis and albuminuria in obese BTBR ob/ob mice. METHODS: Obese BTBR.CgLepob/WiscJ male mice were fed diets containing 25% of protein from Atlantic cod backbones and 75% of protein from casein (Cod-BB group), or casein as the sole protein source (control group). Kidneys were analysed morphologically, and markers for renal dysfunction were analysed biochemically in urine and serum. RESULTS: The Cod-BB diet attenuated the development of mesangial sclerosis (P 0.040) without affecting the development of glomerular hypertrophy and albuminuria. The urine concentration of cystatin C (relative to creatinine) was lower in mice fed the Cod-BB diet (P 0.0044). CONCLUSION: A diet containing cod backbone protein powder attenuated the development of mesangial sclerosis and tubular dysfunction in obese BTBR ob/ob mice, but did not prevent the development of glomerular hypertrophy and albuminuria in these mice.

Pathological and clinical characteristics of late-onset oligomeganephronia based on a histomorphometric study.

BACKGROUND: Late-onset oligomeganephronia (OMN) is a rare chronic kidney disease and has no quantitative criteria for diagnosis yet. The current study aimed to explore its clinicopathological features by histomorphometric analysis. METHODS: We retrospectively re-reviewed all patients with enlarged and sparse glomeruli by light microscopy at Peking University First Hospital from 2012 to 2021, excluding those with any factor known to contribute to similar changes. Age- and sex-matched patients with thin basement membrane nephropathy were selected as control to establish the cut-off values for glomerulomegaly and rarity. Late-onset OMN cases were then confirmed and the clinicopathological characteristics were summarized. RESULTS: Mean diameter and density of cortical glomeruli in control was 156.53 ± 27.50 µm and 4.07 ± 0.63 /mm2, giving a lower limit of 211.53 µm for glomerulomegaly and an upper of 2.81 /mm2 for rarity. Seven adults of three females and four males were finally diagnosed as late-onset OMN with a mean age of 26.57 years. They showed mild to moderate proteinuria and/or renal dysfunction at biopsy with the mean proteinuria, serum creatinine (Scr) level, and estimated glomerular filtration rate of 0.50 g/d (0.10-0.95 g/d), 140.9 µmol/L (95.1-227.1 µmol/L), and 58.7 mL/min/1.73m2 (21.3-98.0 mL/min/1.73m2), respectively. Four patients (57.1%) had normal Scr at diagnosis. Six patients with available data showed renal tubular injury with increased urinary microalbumin in all, elevated N-acetyl-ß-glucosaminidase in two, and elevated α1 microglobulin in five. Kidney size was normal or slightly reduced. The mean density and glomerular diameter of the seven cases was 0.86 mm2 (0.55-1.41 /mm2) and 229.73 µm (211.88-260.66 µm). Segmental glomerular sclerosis was observed in six (85.7%) with four (66.7%) of perihilar type. Proximal tubule dilation was observed in all, focal to diffuse, lining with enlarged epithelial cells. The mean foot process width was 634.02 nm, wider than 472.54 nm of the control (P = 0.0002). CONCLUSION: Late-onset OMN should be considered a special entity with relatively slow clinical progress characterized by hypertrophy of the sparsely distributed nephron.

Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race.

BACKGROUND: African Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis. METHODS: Stereological disector/fractionator estimates of glomerular number (N(glom)) and average glomerular volume (V(glom)) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with V(glom) by age, race, gender, body mass index (BMI) and blood pressure. RESULTS: African Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). N(glom) was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased V(glom) with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased V(glom) (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased V(glom) was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of V(glom) was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased. CONCLUSIONS: Glomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on V(glom) and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

Obesity-related glomerulopathy and the nephron complement.

Obesity-related glomerulopathy (ORG) is a secondary form of glomerular disease that can occur in individuals with obesity. However, the absolute risk for an obese individual to develop progressive renal deterioration is low. Therefore, obesity alone appears to be insufficient to develop such severe renal injury, and there are likely other factors that contribute to the development of this entity. The glomerular hyperfiltration found in patients with ORG has been postulated to lead to structural abnormalities in glomeruli, such as glomerulomegaly and focal segmental glomerular sclerosis, in a manner analogous to that described in patients with reduced renal mass. In fact, recent studies suggest that a reduction in nephron mass is implicated in patients with ORG and synergistically contributes to the development of this renal complication together with obesity-induced changes in renal hemodynamics.

The Fatty Kidney and Beyond: A Silent Epidemic.

As the prevalence of obesity rises in the United States, so does the incidence of obesity-related kidney disease. Obesity itself is an independent risk factor for chronic kidney disease where the pathophysiology is complex, involving altered hemodynamics, renin-angiotensin-aldosterone system overactivation, and adipokines leading to inflammation and fibrosis. Obesity-related kidney disease comprises both obesity-related glomerulopathy and fatty kidney disease. Obesity-related glomerulopathy is a consequence of glomerular hyperfiltration and often presents clinically with subnephrotic proteinuria and pathologically with glomerulomegaly with or without focal glomerulosclerosis. Fatty kidney disease is the effect of renal ectopic fat contributing to chronic kidney disease. Whether the renal ectopic fat is a distinct clinical entity or a pathologic mechanism contributing to obesity-related glomerulopathy, the treatment paradigm of weight and proteinuria reduction remains the same. We present the pathophysiology behind obesity-related kidney disease, clinical outcomes, and treatment strategies, which include lifestyle interventions, use of renin-angiotensin-aldosterone system inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, and bariatric surgery. With old and novel therapeutics, we are attempting to stave off the silent epidemic that obesity-related kidney disease is becoming.

Baseline High Blood Pressure is Associated with Clinico-Pathologic Findings and Later Renal Progression in Chronic Glomerulonephritis.

BACKGROUND: Several factors had been suggested to contribute to the development of hypertension in chronic glomerulonephritis (GN). This study was conducted to find the association of baseline blood pressure (BP) with pathophysiologic findings and later renal progression in chronic GN. METHODS: Clinico-pathological findings including serum creatinine (Cr), proteinuria, pathological findings, and urinary Na excretion were analyzed in a total of 233 patients with IgA nephropathy from The Kyung-Hee Cohort of GN. Glomerular surface area (GSA) was measured by imaging analysis and urine angiotensinogen (AGT) concentrations by human ELISA kits. RESULTS: Systolic BP was ≥130mmHg in 124 patients (53%). Systolic BP was negatively correlated with follow-up eGFR (r=-0.32, p<0.0001) and positively serum uric acid concentrations, while it had no significant relationships with initial serum Cr and eGFR. As compared with patients with systolic BP<130 mmHg, those with ≥130 mmHg were older and showed higher serum Cr, proteinuria, 24 hr urinary Na excretion, mean GSA, and T-I fibrosis, lower follow-up eGFR, and steeper decline in slope of eGFR. The results in patients with normal serum Cr concentrations were comparable to those in whole group. Systolic BP was positively correlated with age, baseline and follow-up proteinuria, serum uric acid concentrations and IgM deposit and negatively with follow-up eGFR. In subgroup analysis, systolic BP was also positively correlated with mean GSA and urinary AGT concentrations. CONCLUSION: This study showed that baseline systolic BP is related to urinary Na excretion, glomerulomegaly, T-I fibrosis and later renal progression in patients with IgA nephropathy.

Ultrasound Imaging of the Renal Parenchyma of Premature Neonates for the Assessment of Renal Growth and Glomerulomegaly.

Evidence is increasingly showing that prematurity results in chronic kidney disease. We hypothesized that we could use ultrasound imaging to measure and monitor the growth of the renal parenchyma in premature neonates. We conducted a prospective, case-control study to compare renal parenchymal growth between neonates born prematurely and term neonates. The study patients underwent ultrasound assessment at 32 wk postmenstrual age (PMA) and 37 wk PMA. Term neonates (gestation >37 completed wk) admitted to the neonatal unit with minor neonatal conditions were recruited into the control group. Complete data sets were available in 91 premature neonates and during the same period, 56 term neonates were recruited as the control. The median birth weight (preterm babies) was 930 g (780-1220 g), and the mean gestational age was 27.0 wk (2.1 wk). Total renal volume (TRV) increased from 14.6 (4.3) cm3 to 20.5 (5.3) cm3 from 32 to 37 wk PMA. During the same period, the total renal parenchyma (TRP) thickness increased from 1.6 (0.3) cm to 1.8 (0.3) cm. At 37 wk PMA, ex-premature neonates have a significantly smaller total renal volume (20.5 [5.3] versus 25.9 [6.4] cm3; p < 0.001) and total renal parenchyma thickness (1.8 [0.3] versus 2.0 [0.2] cm; p = 0.015) compared with term (control) neonates. However, premature neonates at 37 wk PMA have a larger TRP:TRV ratio compared with term neonates (0.09 [0.02] versus 0.0 8 [0.02] cm-2; p < 0.001). Reduced nephron endowment as a result of prematurity may cause the remaining nephrons to undergo compensatory glomerulomegaly and we postulate this is the reason for the observed differences. Ultrasound imaging of the renal parenchyma shows promise in assessing the effects of prematurity on the developing kidney.

Glomerulomegaly in lupus nephritis: a prognostic marker for renal outcomes.

AIM: Glomerulomegaly refers to the abnormal enlargement of glomeruli and is associated with an increased risk of progressive chronic kidney disease (CKD). However, it has rarely been investigated in lupus nephritis (LN). We therefore assessed glomerulomegaly as a prognostic factor for renal pathology. METHOD: Patients with class III or IV LN were retrospectively recruited and divided into two groups according to complete renal response (CR) at 3 years after the initiation of induction therapy. Baseline clinical and renal pathological findings were compared to identify prognostic factors, and patients were followed for up to 10 years to assess long-term renal outcomes. RESULTS: Nineteen patients with and 19 without CR on 3-year follow-up were analyzed. Long-term disease duration and high levels of proteinuria were frequently observed in patients without CR (P = 0.03 and P = 0.01, respectively) at baseline compared to those with CR. On renal pathological analysis, a significantly higher proportion of patients without CR had enlarged glomeruli than those with CR (P = 0.03) in analysis of segmentally or minimally affected glomeruli. On 10-year follow-up, a higher proportion of patients without enlarged glomeruli maintained CR compared to those with enlarged glomeruli (P = 0.004). Further, glomerular area and disease duration were significantly correlated (P = 0.04). CONCLUSIONS: Enlarged segmentally or minimally affected glomeruli at diagnosis of LN might predict a worse renal prognosis at 3 years after induction therapy. Mechanical glomerular injury might influence clinical outcomes.

Manifestation of renal disease in obesity: pathophysiology of obesity-related dysfunction of the kidney.

Albuminuria in individuals whose body mass index exceeds 40 kg/m(2) is associated with the presence of large glomeruli, thickened basement membrane and epithelial cellular (podocyte) distortion. Obstructive sleep apnea magnifies glomerular injury as well, probably through a vasoconstrictive mechanism. Insulin resistance from excess fatty acids is exacerbated by decreased secretion of high molecular weight adiponectin from adipose cells in the obese state. Adiponectin potentiates insulin in its post-receptor signaling resulting in glucose oxidation in mitochondria. Recent studies of podocyte physiology have concentrated on the structural and functional requirements that prevent glomerular albumin leakage. The architecture of the podocyte involves nephrin and podocin, proteins that cooperate to keep slit pores between foot processes competent to retain albumin. Insulin and adiponectin are necessary for high-energy phosphate generation. When fatty acids bind to albumin, the toxicity to proximal renal tubules is magnified. Albumin and fatty acids are elevated in urine of individuals with obesity related nephrotic syndrome. Fatty acid accumulation and resistin inhibit insulin and adiponectin. Study of cytokines produced by adipose tissue (adiponectin and leptin) and macrophages (resistin) has led to a better understanding of the relationship between weight and hypertension. Leptin, is presumably secreted after food intake to inhibit the midbrain/hypothalamic appetite centers. Resistance to leptin results in excess signaling to hypothalamic sympathetics leading to hypertension. Demonstration of the existence of a cerebral receptor mutation provide evidence for a role in hypertension of a central nervous reflex arc in humans. Further understanding of obesity-related renal dysfunction has been accomplished recently using experimental models. Rapid weight loss following bariatric surgery may reverse renal pathology of obesity with restoration of normal blood pressure.