Oral Sodium Bicarbonate Reduces Proximal Renal Tubular Peptide Catabolism,Ammoniogenesis, and Tubular Damage in Renal Patients

Oral sodium bicarbonate (NaHCO₃) is widely used to treat acidosis in patients with renal failure. However, no data are available in man on the effects on proximal renal tubular protein catabolism or markers of tubular injury. We have developed methods to allow such studies, and both increased tubular catabolism of ^99mTc-labelled aprotinin (Apr^*), as well as tubular damage were found in association with increased ammonia (NH₃) excretion in patients with nephrotic range proteinuria.

We now examine the effects of reducing renal ammoniogenesis, without altering proteinuria, using oral NaHCO₃ in 11 patients with mild/moderate renal impairment and proteinuria. Renal tubular catabolism of Apr^* was measured before and after NaHCO₃ by renal imaging (Kidney uptake, K % of dose) and urinary excretion of free ^99mTcO₄ (metabolism, Met % of dose/h) over 26 h. Fractional degradation (Frac) was calculated from Met/K (/h). Fresh urine was also analyzed for NH₃ excretion every fortnight from 6/52 before treatment. Total urinary N-acetyl-β-D-glucoseaminidase (NAG) and the more tubulo-specific NAG “A2” were measured. ⁵¹CrEDTA clearance and 99mTc- MAG 3 TER were also assessed.

After NaHCO₃ Met over 26 h was significantly reduced (from 1.3 ± 0.2 % of dose/h to 0.9 ± 0.1 % dose/hrp <0.005), as was Frac of Apr^* (from 0.06 ±. 006/h to 0.04 ± 0.005/hrp <0.003). NH₃ excretion also fell significantly (from 0.9 ± 0.2 mmol/h to 0.2 ± 0.05 mmol/hp <0.007), as did both total urinary NAG (from 169 μmol/24 h, 74-642 μmol/24 h to 79 μmol/ 24 h, 37-393 μmol/24 hp <0.01), and the NAG ‘A2’ isoenzyme (from 81.5 μmol/24 h, 20–472 μmol/24 h to 35.0 μmol/24 h, 6–388 μmol/24 hp <0.001). Proteinuria remained unaltered, and there was no change in blood pressure nor in glomerular haemodynamics. Oral NaHCO₃ may thus pro-tect the proximal renal tubule and help delay renal disease progression.     

Renal tubular peptide catabolism in chronic vascular rejection

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolism and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2+/-3.3 mL/min/1.73 m2), proteinuria (6.1+/-1.5 g/24 h) and biopsy proven CR. Lisinopril (10-40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80MBq), was measured before and after Lisinopril by gamma-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-beta-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8+/-2.2 to 3.4+/-1.9 g/24 h, p<0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5+/-0.05 to 0.3+/-0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04+/-0.009 to 0.02+/-0.005/h, p<0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1+/-0.7 to 17.4+/-0.8 mmol/L, p < 0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044-3816) to 1008 (76-2147) micromol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.     

Treatment of Proteinuria with Lercanidipine Associated with Renin-Angiotensin Axis-Blocking Drugs

Objective. Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers. Design and Methods. The study included 68 proteinuric (> 500 mg/day) patients (age 63.1 ± 12.9 years, 69.1% males and 30.9 females). All patients were receiving ACE inhibitors (51.4%) or angiotensin II receptor blockers (48.6%) therapy but had higher blood pressure than recommended for proteinuric patients (<130/80 mmHg). Patients were clinically evaluated one, three, and six months after starting treatment with lercanidipine (20 mg/day). Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment. Creatinine clearance was measured using 24 h urine collection. Results. BP significantly decreases from 152 ± 15/86 ± 11 mmHg to 135 ± 12/77 ± 10 mmHg at six months of follow-up (p < 0.001). After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5%, and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Plasmatic creatinine did not change nor did creatinine clearance. Plasmatic cholesterol also decreased from 210 ± 48 to 192 ± 34 mg/dL (p < 0.001), as did plasma triglycerides (from 151 ± 77 to 134 ± 72 mg/dL, p = 0.022). Basal proteinuria was 1.63 ± 1.34 g/day; it was significantly (p < 0.001) reduced by 23% at the first month, 37% at three months, and 33% at the last visit. Conclusions. Lercanidipine at 20 mg dose, associated to renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction.     

Blood pressure load,proteinuria and renal function in pre-hypertensive children

It is as yet unclear whether blood pressure load (BPL) can affect renal function in pre-hypertensive children. We have studied 250 children, with a mean age of 9.12 ± 3.28 years, with the aim of assessing if pre-hypertension in children can indeed affect renal function. The study cohort consisted of 146 children with pre-hypertension (group P) and a control group of 104 children with normal blood pressure (group C). All children were tested for orthostatic proteinuria, an exclusion criterion, glomerular filtration rate (GFR), and proteinuria, and ambulatory blood pressure monitoring was performed. Based on the BPL, group P was further subdivided into group P1 (BPL ≤ 40%, low BPL) and group P2 (BPL > 40%, high BPL). We found that GFR was reduced in pre-hypertensive children (90.74 ± 48.69 vs. 110.32 ± 20.30 ml/min per 1.73 m², p < 0.0001) and that proteinuria was increased (145.36 ± 110.91 vs. 66.84 ± 42.94 mg/m² per 24 h; p < 0.0001). However, mean values were still within normal limits. A comparison of the group with high BPL and that with low BPL revealed that the former had relatively reduced GFR (79.15 ± 42.04 vs. 96.78 ± 51.20 ml/min per 1.73 m²; p < 0.006) and increased proteinuria (198.29 ± 142.17 vs. 118.31 ± 80.07 mg/m² per 24 h; p < 0.036). In comparison to the reference values of the normal population, the GFR was reduced and proteinuria was increased in the group with high BPL. Based on our results, pre-hypertension in children with high BPL seems to be associated with reduced GFR and increased proteinuria. A reasonable doubt remains that the patients with higher proteinuria and larger reduction of GFR may harbor an as yet unknown subclinical renal condition responsible for the onset of pre-hypertension. Therefore, children with even mildly elevated BP are at risk of developing renal damage and should change their lifestyle to prevent further increases in BP.     

Prevalence and Risk Factors of Myocardial Remodeling in Hemodialysis Patients

Background. Left ventricular hypertrophy (LVH) is an independent risk factor for morbidity/mortality in patients with end stage renal disease (ESRD). Our study aimed to identify prevalence as well as independent risk factors that contribute to the development of LV geometric remodeling in our HD patients. Methods. The left ventricles of 116 HD patients were classified echocardiographically into four different geometric patterns on the basis of LV mass and relative wall thickness. Furthermore, we measured inferior vena cava (IVC) diameter and its collapsibility index (CI) by echocardiography. Finally, we modeled a stepwise multiple regression analysis to determine the predictors of LV geometry.?Results. Our study provides evidence that HD patients had a prevalence of abnormal LV geometry in 92% and LVH in 81%. We found all four geometric models of LV. Most dominant were eccentric LVH. Concentric LVH was observed in 37, normal geometry (NG) in 9, and concentric remodeling (CR) in 13 of HD patients. Mean arterial blood pressure was significantly higher in the cLVH group (95 ± 10 mmHg) than in the NG and CR groups (81.6 ± 12.3 and 80 ± 11.8, respectively, p < 0.001). The cLVH and eCLVH groups had significantly lower mean hemoglobin (10.3 ± 1.4g/dL and 10.6 ± 1g/dL, respectively) compared with the NG group (11.9 ± 1.4g/dL), p < 0.001. Furthermore, interdialytic weight gain (kg) was significantly higher in eCLVH group (3.13 ± 0.8) than in NG group (2.3 ± 1.1), p < 0.001. Mean IVC index of the eLVH group (10.83 ± 2.07 mm/m²) was significantly higher than corresponding indexes of NG (10.83 ± 2.07 mm/m²), CR (8.31 ± 1.32 mm/m²) and cLVH (8.12 ± 2.06 mm/m²) groups (p < 0.001 for each comparisons). Conclusion. Mean arterial pressure, hemoglobin, IVC index, and interdialytic weight gain were found to be independent predictors of LV geometry (R² = 0.147; p < 0.001) in HD patients.     

Differences in new-onset IgA nephropathy between young adults and the elderly

Background: The goal of this study was to define the clinical and histological differences in new-onset IgA nephropathy between young adults and the elderly. Methods: We retrospectively examined renal biopsy findings, clinical features at presentation and outcomes in 82 young adults (mean age 30.3 ± 10.2 years) and 17 elderly patients (mean age 71.9 ± 4.5 years) with IgA nephropathy whose renal biopsies were taken within 1 year from the onset of renal manifestations. Results: The elderly group more frequently had hypertension (p < 0.001), acute renal failure (p < 0.001), and nephrotic range proteinuria (p = 0.001) at presentation than the young adults group. On histology, a higher percentage of globally sclerotic glomeruli (p < 0.001) was present in the elderly group. In patients presenting with acute renal failure, the elderly group more frequently had an intercurrent disease (p = 0.02), mostly infection, and a higher mortality rate (p = 0.033). On histology, the young adults group had a higher percentage of glomeruli affected by crescents (p = 0.027); in contrast, the elderly group more commonly had acute tubular injury (p = 0.02). Conclusions: The elderly patients affected by IgA nephropathy had more severe renal manifestations at presentation (acute renal failure in 52.9% and nephrotic syndrome in 41.2% of patients). In cases of acute renal failure, the elderly patients had more predominant tubular rather than glomerular injury. Moreover, the considerable mortality rate (44.4%) might be associated with the intercurrent disease, mostly infection, which was more commonly present in the elderly patients.     

Histological Features of Acute Tubular Necrosis in Native Kidneys and Long-Term Renal Function

There are few studies on the relationship between the morphology of acute tubular necrosis (ATN) in native kidneys and late functional recovery. Eighteen patients with acute renal failure (ARF) who had undergone renal biopsy were studied. All had the histological diagnosis of ATN and were followed for at least six months. Clinical characteristics of ARF were analyzed, and histological features were semi-quantitatively evaluated (tubular atrophy, interstitial inflammatory infiltrate, interstitial fibrosis, and ATN). According to the maximal GFR achieved during the follow-up, patients were divided into two groups: complete recovery (GFR ≥ 90 mL/min/1.73 m²) and partial recovery (GFR < 90 mL/min/1.73 m²). Only 39% of the patients achieved complete recovery. Patients with partial recovery achieved their maximal GFR (63 ± 9 mL/min/1.73 m²) 37 ± 14 months after ARF, a period of time similar to those patients with complete recovery (i.e., 54 ± 22 months). Patients with partial recovery had more severe ARF: oliguria was more frequent (90 versus 17%, p < 0.01), and they had higher peak creatinine (13.85 ± 1.12 versus 8.95 ± 1.30 mg/dL, p = 0.01), and longer hospitalization (45 ± 7 versus 20 ± 4 days, p = 0.03). No single histological parameter was associated with partial recovery, but the sum of all was when expressed as an injury index [4.00 (2.73–5.45) versus 2.00 (1.25–3.31), p < 0.05]. In conclusion, among patients with atypical ATN course, those with more severe ARF and tubule-interstitial lesions are more prone to partial recovery.     

Could urinary kidney injury molecule-1 be a good marker in subclinical acute kidney injury in mild to moderate COVID-19 infection?

Purpose

To evaluate urinary kidney injury molecule-1 (uKIM-1), which is a proximal tubule injury biomarker in subclinical acute kidney injury (AKI) that may occur in COVID-19 infection.

Methods

The study included proteinuric (n?=?30) and non-proteinuric (n?=?30) patients diagnosed with mild/moderate COVID-19 infection between March and September 2020 and healthy individuals as a control group (n?=?20). The uKIM-1, serum creatinine, cystatin C, spot urine protein, creatinine, and albumin levels of the patients were evaluated again after an average of 21 days.

Results

The median (interquartile range) uKIM-1 level at the time of presentation was 246 (141–347) pg/mL in the proteinuric group, 83 (29–217) pg/mL in the non-proteinuric group, and 55 (21–123) pg/mL in the control group and significantly high in the proteinuric group than the others (p?<?0.001). Creatinine and cystatin C were significantly higher in the proteinuric group than in the group without proteinuria, but none of the patients met the KDIGO-AKI criteria. uKIM-1 had a positive correlation with PCR, non-albumin proteinuria, creatinine, cystatin C, CRP, fibrinogen, LDH, and ferritin, and a negative correlation with eGFR and albumin (p?<?0.05). In the multivariate regression analysis, non-albumin proteinuria (p?=?0.048) and BUN (p?=?0.034) were identified as independent factors predicting a high uKIM-1 level. After 21?±?4 days, proteinuria regressed to normal levels in 20 (67%) patients in the proteinuric group. In addition, the uKIM-1 level, albuminuria, non-albumin proteinuria, and CRP significantly decreased.

Conclusions

Our findings support that the kidney is one of the target organs of the COVID-19 and it may cause proximal tubule injury even in patients that do not present with AKI or critical/severe COVID-19 infection.

     

Prednisolone Co-Administered with Losartan Confers Renoprotection in Patients with IgA Nephropathy

Background.Treatment options for progressive IgA nephropathy are limited. Methods. We performed a small, randomized controlled trial to evaluate the effects of prednisolone (PSL, 30 mg/dL, gradually tapered to 5 mg/dL over two years) plus 50 mg/day of losartan (LST, an angiotensin II receptor blocker) or PSL alone on IgA nephropathy. We separated 38 patients (age, 33 ± 11 years; creatinine clearance, 103 ± 31 mL/min; proteinuria, 1.6 ± 0.5 g/day) into two groups that were treated with either PSL plus LST or PSL alone, and compared the proteinuria and creatinine clearance after two years. Baseline and histopathological data did not significantly differ between the two groups. Results. Two years of treatment in both groups significantly decreased proteinuria compared with baseline, and PSL plus LST (from 1.6 ± 0.6 to 0.3 ± 0.1 g/day, p < 0.05) was more effective than PSL alone (from 1.6 ± 0.3 to 0.5 ± 0.1 g/day, p < 0.05). Creatinine clearance in both groups was similar at the start of study but significantly differed at the end of the study (PSL plus LST, 104.3 ± 36.4 to 100.4 ± 38.9 mL/min; PSL alone, 103.4 ± 28.5 to 84.8 ± 34.3 mL/min, p < 0.05). Conclusions. Combined therapy with PSL plus LST appears to be more effective than PSL alone in reducing proteinuria and protecting renal function in patients with IgA nephropathy.     

Comparison of oral steroids with tonsillectomy plus steroid pulse therapy in patients with IgA nephropathy

Background

Treatment of IgA nephropathy (IgAN) in Japan has recently changed, from oral prednisolone (oPSL) to tonsillectomy plus steroid pulse (TSP) therapy. However, a few studies have compared their efficacy and safety.

Methods

IgAN patients diagnosed in our institution between 1991 and 2013, treated with TSP or oPSL, aged ≥16 years, with ≥1 g/day proteinuria, and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m², and no other renal disease were selected. Baseline clinical and histological findings, clinical outcomes, and adverse events were compared. Clinical remission (CR) was defined as <0.3 g/day proteinuria and <5 urinary red blood cells per high-powered field.

Results

Sixty-six patients were identified; after propensity score adjustment, 26 patients were selected in each group. CR rates were significantly higher at 12 (30.8 % vs. 3.9 %), 36 (47.3 % vs. 7.9 %), and 72 (57.8 % vs. 20.1 %) months (p < 0.01), and the renal survival rate, defined as the development of a 25 % reduction from baseline eGFR, was significantly higher at 12 (96.2 % vs. 69.2 %), 36 (96.2 % vs. 61.5 %), and 72 (96.2 % vs. 41.0 %) months in the TSP than the oPSL group (p < 0.001). Multivariate analysis showed that TSP was the only independent factor associated with CR (hazard ratio, 3.58; 95 % confidence interval, 1.32–10.91, p = 0.01). The number of patients with adverse events was significant lower in TSP group than in oPSL group (11.5 % vs. 34.6 %, p = 0.04).

Conclusions

CR rates are higher; protection of renal function and prevention from adverse events were superior with TSP than with oPSL in patients with IgAN and moderate-to-severe proteinuria.

     

Effect of Two‐Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non‐Obese Younger Adults: A Randomized Clinical Trial

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two‐hundred eighteen non‐obese (body mass index [BMI] 25.1 ± 1.7 kg/m²), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone‐active hormones, nutrient intake, and physical activity. Body weight (–7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (–5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat‐free mass (–2.2 ± 0.2 versus –0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001). Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (–0.013 ± 0.003 versus 0.007 ± 0.004 g/cm²; p < 0.001), total hip (–0.017 ± 0.002 versus 0.001 ± 0.003 g/cm²; p < 0.001), and femoral neck (–0.015 ± 0.003 versus –0.005 ± 0.004 g/cm²; p = 0.03). Changes in bone markers were greater at 12 months for C‐telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001), tartrate‐resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004), and bone‐specific alkaline phosphatase (BSAP) (–1.4 ± 0.4 versus –0.3 ± 0.5 U/L; p = 0.047) but not procollagen type 1 N‐propeptide; at 24 months, only BSAP differed between groups (–1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001). The CR group had larger increases in 25‐hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF‐1 levels did not differ between groups. The CR group also had lower levels of physical activity. Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ～31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long‐term studies are needed to determine if CR‐induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise. © 2015 American Society for Bone and Mineral Research.     

A retrospective analysis of kidney function and risk factors by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in elderly Chinese patients

Abstract

Chronic kidney disease accounts for much of the increased mortality, especially in the elder population. The prevalence of this disease is expected to increase significantly as the society ages. Our aim was to evaluate the kidney function and risk factors of reduced renal function among elderly Chinese patients. This study retrospectively collected clinical data from a total of 1062 inpatients aged 65 years or over. Estimated glomerular filtration rate (eGFR) was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Renal function and risk factors were also analyzed. For all 1062 subjects, the mean eGFR was 71.0?±?24.8?mL/min/1.73?m², and the incidence rates of reduced renal function, proteinuria, hematuria and leukocyturia were 31.1%, 11.8%, 6.6% and 8.7%, respectively. The eGFR values were 83.4?±?28.4, 72.2?±?22.9, 67.8?±?24.3 and 58.8?±?29.1?mL/min/1.73?m² in the groups of 60–69, 70–79, 80–89 and ≥90 years age group (F?=?15.101, p?=?0.000), respectively; while the incidences of reduced renal function were 12.8%, 27.0%, 37.8% and 51.7% (χ²?=?36.143, p?=?0.000). Binary logistic regression analysis showed that hyperuricemia (OR?=?4.62, p?=?0.000), proteinuria (OR?=?3.96, p?=?0.000), urinary tumor (OR?=?2.92, p?=?0.015), anemia (OR?=?2.45, p?=?0.000), stroke (OR?=?1.96, p?=?0.000), hypertension (OR?=?1.83, p?=?0.006), renal cyst (OR?=?1.64, p?=?0.018), female (OR?=?1.54, p?=?0.015), coronary artery disease (OR?=?1.53, p?=?0.008) and age (OR?=?1.05, p?=?0.000) were the risk factors of reduced renal function. In conclusion, eGFR values decreased by age, while the incidence of reduced renal function, proteinuria, hematuria and leukocyturia increased with age. Treatment and control of comorbidities may slow the decline of renal function in elderly patients.     

Urinary angiotensinogen levels in relation to renal involvement of Henoch-Schonlein purpura in children

Aim: To investigate whether urinary angiotensinogen (UAGT) levels are correlated with renal involvement of Henoch‐Schonlein purpura (HSP) in children, and to explore whether UAGT has any relation to the severity of HSP. Methods: The study sample consisted of 107 patients (50 boys and 57 girls, 6.68 ± 2.41 years) with clinical diagnosis of HSP. A 24 h urine sample was collected before treatment. UAGT levels were measured in patients with HSP in the acute and convalescent phases by enzyme linked immunosorbent assay. Results: Urinary angiotensinogen/urinary concentration of creatinine levels were significantly higher in proteinuric HSP in the acute phase and the convalescent phase (32.02 ± 3.95 and 25.31 ± 4.11 µg/g) compared with those with HSP without renal involvement (17.26 ± 2.60 and 15.14 ± 3.81 µg/g) and those with hematuric HSP (19.70 ± 2.21 and 17.28 ± 3.62 µg/g) (P < 0.0001 and P < 0.01, respectively). Using matched urine samples from the same patients, UAGT/urinary concentration of creatinine (UCr) levels of proteinuric HSP patients were significantly lower in the convalescent phase (25.31 ± 4.11 µg/g, P < 0.01) than in the acute phase (32.02 ± 3.95 µg/g). UAGT/UCr levels showed positive correlation with 24 h urine protein or serum creatinine in both hematuric HSP and proteinuric HSP groups during the acute phase (P < 0.05). Conclusions: Urinary angiotensinogen levels were remarkably high in the acute phase in the patients with proteinuric HSP, suggesting increased UAGT may indicate a series of functional changes in the kidney and it may be used as a potential biomarker of severity of HSP to monitor the progression of HSP with renal involvement.     

Does graft mass impact on pediatric kidney transplant outcomes?

Background

The aim of this study is to assess the evolution of renal size and function in pediatric transplant patients according to the graft mass/recipient size ratio.

Methods

Fifty pediatric renal transplant recipients were followed over 2 years. Grafts were weighed, and three different graft mass/m² ratios were determined: (1) low graft mass (58 g/m², range?31–57 g/m²), (2) median (142 g/m², range?59–141 g/m²) and high (267 g/m², range?143–353 g/m²). Patients underwent repeated ultrasound Doppler scans and repeated measurements of estimated glomerular filtration rate (eGFR; 1 week and 1, 6, 12 and 24 months), urinary retinol-binding protein (RBP) and proteinuria (1 week and 6, 12 and 24 months).

Results

The volume of renal tissue increased by 12?±?5.6 cm³ at 24 months (p?=?0.035) in the low graft mass and decreased by ?14?±?7 cm³ (p?=?0.046) in the high graft mass. The eGFR increased when either low (30?±?5 ml/min/1.73 m², p?<?0.001) or median (19?±?4 ml/min/1.73 m², p?<?0.001) graft mass was transplanted but remained stable when high graft mass was transplanted. The resistive index (RI) presented a significant decrease throughout early follow-up in the transplants involving low and median graft mass, whereas a slight rise was observed in those involving high graft mass. A significant difference was apparent 6 months post-transplant. Transplants of low and median graft mass were associated with an initial higher urinary RBP. No significant differences in proteinuria were detected.

Conclusions

Small kidneys undergo increases in volume and function without escalation of either proteinuria or urinary RBP, characterizing an adequate adaptation to the recipient. Children receiving larger kidneys present a reduction in volume, stable GFR and higher RI at 6 months.     

Increased Urinary Excretion of Monocyte Chemoattractant Protein-1 in Proteinuric Renal Diseases

Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is produced mainly by tubular epithelial cells in kidney and contributes to renal interstitial inflammation and fibrosis. More recently, we have demonstrated that urinary MCP-1 excretion is increased in proportion to the degree of albuminuria (proteinuria) and positively correlated with urinary N-acetylglucosaminidase (NAG) levels in type 2 diabetic patients. Based on these findings, we have suggested that heavy proteinuria, itself, probably aggravates renal tubular damage and accelerates the disease progression in diabetic nephropathy by increasing the MCP-1 expression in renal tubuli. In the present study, to evaluate whether urinary MCP-1 excretion is increased in the proteinuric states not only in diabetic nephropathy but also in other renal diseases, we examined urinary MCP-1 levels in IgA nephropathy patients with macroalbuminuria (IgAN group; n = 6), and compared the results with the data obtained from type 2 diabetic patients with overt diabetic nephropathy (DN group; n = 23) and those without diabetic nephropathy (non-DN group; n = 27). Urinary MCP-1 excretion levels in non-DN, DN, IgAN groups were 157.2 (52.8–378.5), 346.1 (147.0–1276.7), and 274.4 (162.2–994.5) ng/g creatinine, median (range), respectively. Expectedly, urinary MCP-1 and NAG excretion levels in DN and IgAN groups were significantly elevated as compared with non-DN group. Therefore, we suggest that MCP-1 expression in renal tubuli is enhanced in proteinuric states, irrespective of the types of renal disease, and that increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states.     

URINARY THYMIDINE GLYCOL AS A BIOMARKER FOR OXIDATIVE STRESS AFTER KIDNEY TRANSPLANTATION

Reactive oxygen species are generated during ischemia-reperfusion tissue injury. Oxidation of thymidine by hydroxyl radicals (HO^˙) causes formation of 5,6-dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol excreted in urine can be used as a biomarker of oxidative DNA damage. The aim of this study was to investigate the oxidative DNA damage in patients showing immediate allograft function after kidney transplantation, and to find out whether this damage correlates with glomerular and tubular lesions.

Time dependent changes in urinary excretion rates of thymidine glycol, but also of total protein, albumin, low molecular weight (α₁-microglobulin, β₂-microglobulin) and high molecular weight proteins (transferrin, IgG, α₂-macroglobulin) were analyzed quantitatively and by polyacrylamide-gel electrophoresis in six patients. Urinary thymidine glycol was determined by a fluorimetric assay in combination with affinity chromatography and HPLC.

After kidney transplantation the urinary excretion rate of thymidine glycol increased gradually reaching a maximum within the first 48 hours (16.56 ± 11.3 nmol/mmol creatinine, ref. 4.3 ± 0.97). Severe proteinuria with an excretion rate of up to 7.2 g/mmol creatinine was observed and declined within the first 24 hours of allograft function (0.35 ± 0.26 g/mmol creatinine). The gel-electrophoretic pattern showed a nonselective glomerular and tubular proteinuria. The initial nonselective glomerular proteinuria disappeared within 48 hours, changing to a mild selective glomerular proteinuria. In this period (12–48 hours) higher levels of thymidine glycol excretion were observed, when compared to the initial posttransplant phase (13.66 ± 9.76 vs. 4.31 ± 3.61 nmol/mmol creatinine; p < 0.05).

An increased excretion of thymidine glycol is seen after kidney transplantation and is explained by the ischemia-reperfusion induced oxidative DNA damage in the kidney. In the second phase higher levels of excretion were observed parallel to the change from a nonselective to a selective glomerular and tubular proteinuria. An explanation may be sought in the repair process of DNA in the glomerular and tubular epithelial cells, appearing simultaneously with functional recovery.     

Phenotypic Characteristics of Bone in Carbonic Anhydrase II-Deficient Mice

Carbonic anhydrase II (CAII)-deficient mice were created to study the syndrome of CAII deficiency in humans including osteopetrosis, renal tubular acidosis, and cerebral calcification. Although CAII mice have renal tubular acidosis, studies that analyzed only cortical bones found no changes characteristic of osteopetrosis. Consistent with previous studies, the tibiae of CAII-deficient mice were significantly smaller than those of wild-type (WT) mice (28.7 ± 0.9 vs. 43.6 ± 3.7 mg; p < 0.005), and the normalized cortical bone volume of CAII-deficient mice (79.3 ± 2.2%) was within 5% of that of WT mice (82.7 ± 2.3%; p < 0.05), however, metaphyseal widening of the tibial plateau was noted in CAII-deficient mice, consistent with osteopetrosis. In contrast to cortical bone, trabecular bone volume demonstrated a nearly 50% increase in CAII-deficient mice (22.9 ± 3.5% in CAII, compared to 15.3 ± 1.6% in WT; p < 0.001). In addition, histomorphometry demonstrated that bone formation rate was decreased by 68% in cortical bone (4.77 ± 1.65 μm³/μm²/day in WT vs. 2.07 ± 1.71 μm³/μm²/day in CAII mice; p < 0.05) and 55% in trabecular bone (0.617 ± 0.230 μm³/μm²/day in WT vs. 0.272 ± 0.114 μm³/μm²/day in CAII mice; p < 0.05) in CAII-deficient mice. The number of osteoclasts was significantly increased (67%) in CAII-deficient mice, while osteoblast number was not different from that in WT mice. The metaphyseal widening and changes in the trabecular bone are consistent with osteopetrosis, making the CAII-deficient mouse a valuable model of human disease.     

Vesicoureteric Reflux and Reflux Nephropathy as Seen at a Tertiary Care Adult Nephrology Service in India—An Analysis of 86 Patients

Clinical features and risk factors for renal failure in patients with reflux nephropathy (RN) as seen in an adult nephrology service are likely to be different than those seen in a pediatric service. There are only a few studies on adults with vesicoureteric reflux (VUR) and RN and data on RN as seen in developing countries is still evolving. Retrospective analysis of records of patients diagnosed to have VUR by conventional micturating cystourethrogram over a 13 year period, as seen in the adult nephrology services of this tertiary care hospital in north India was carried out. Results are presented as mean ± 2 SD. Unpaired t-test was used to compare means, chi-square test to define associations, and logistic regression analysis was done to define risk factors. Out of 86 patients diagnosed to have VUR, 69 (80.2%) were males and 22 (25.6%) were children. The mean age at presentation was 24.3 ± 14.5 years and at onset of symptoms was 19.6 ± 14.8 years. Sixty-nine (80.2%) patients had chronic renal failure (CRF) at presentation, including 33 (38.4%) patients who already had end stage renal failure (ESRF) at presentation in whom reflux was diagnosed during routine pretransplant evaluation and these constituted 5.5% of all ESRF patients. The clinical features at presentation were hypertension in 51 (59.3%), recurrent urinary tract infection (UTI) in 31 (36.1%), history of stones in 7 (8.1%), and gross hematuria in 4 (4.7%). Patients with history of recurrent UTI were more likely to be females (p<0.01) and to present without renal failure (p<0.05). Proteinuria >1 g/day was significantly associated (p<0.02) with hypertension at presentation. Patients who presented with renal failure were more likely to be males (p<0.05), not to have history of recurrent UTI (p<0.05), have proteinuria >1 g/day (p < 0.02) and higher grades (grades IV and V) of reflux (p<0.05). On logistic regression analysis, higher age of onset (odds ratio 4.6, p<0.03), proteinuria >1 g/day (odds ratio 3.8, p<0.05), and male gender (odds ratio 3.5, p<0.05) were significant risk factors for presentation for the first time with renal failure. The clinical features and course of VUR and RN as seen in India are different from those reported from elsewhere. The vast majority of patients in India are males and almost two thirds do not have a past history of UTI. Renal failure is present in more than three fourths of patients when a diagnosis of reflux is made and one third of all patients present with ESRD. Patients with a prior history of UTI are more commonly females and are less likely to have renal failure at presentation. Higher age of onset of symptoms, proteinuria >1 g/day and male gender were risk factors for the development of renal failure. It is likely that these asymptomatic patients remain undetected during childhood, presenting late only after having incurred severe renal damage.     

Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure

Neutral endopeptidase (NEP: EC 3.4.24.11) is involved in the degradation of peptides such as atrial natriuretic peptide, angiotensin II (AngII), and endothelin-1 (ET-1). In this study we propose that NEP inhibition provides protection in glycerol-induced acute renal failure (ARF). Renal vascular responses were evaluated in ARF rats where ARF was induced by injecting 50% glycerol in candoxatril, a NEP inhibitor (30 mg/kg, orally; for 3 weeks) pretreated rats. AngII and U46619 (a TxA₂ mimetic) vasoconstriction was increased (2- to 4-fold) in ARF while ET-1 vasoconstriction was surprisingly reduced (23 ± 3%; p < 0.05). In ARF, candoxatril paradoxically enhanced ET-1 response (60 ± 20%; p < 0.05) but reduced AngII vasoconstriction (51 ± 11%; p < 0.05) without affecting U46619 response. However, candoxatril treatment was without effect on plasma ET-1 and TxB₂ levels in ARF. Candoxatril reduced plasma AngII by 34 ± 4% (p < 0.05) in ARF which was ～3.5-fold higher compared to control. Candoxatril doubled the nitrite excretion in control but was without effect on proteinuria or nitrite excretion in ARF. Candoxatril enhanced Na⁺ and creatinine excretion in ARF by 73 ± 9% and 33 ± 2%, respectively. These results suggest that NEP inhibition may confer protection in glycerol-induced ARF by stimulating renal function but without a consistent effect on renal production and renal vascular responses to endogenous vasoconstrictors.     

Significance of tonsillectomy combined with steroid pulse therapy for IgA nephropathy with mild proteinuria

Background

Medical intervention for patients with IgA nephropathy and mild proteinuria (<1.0 g/day) is controversial, and the effectiveness of tonsillectomy plus steroid pulse therapy (TSP) for such patients remains obscure.

Methods

Among 323 patients in our multicenter cohort study, 79 who had mild proteinuria (0.4–1.0 g/day) at diagnosis were eligible to participate in this study. We compared the clinicopathological findings at diagnosis, a decline in renal function defined as a 50 or 100 % increase in serum creatinine (sCr) and clinical remission (CR) defined as the disappearance of hematuria and proteinuria (<0.3 g/day) among groups given TSP (n = 46), steroid therapy (ST) (n = 9), and non-ST (n = 24). Factors contributing to CR were also evaluated using multivariate analysis.

Results

Background factors at diagnosis including age, ratio (%) of patients with hypertension, sCr, proteinuria, and histological severity did not significantly differ among the groups. Only two patients each in the TSP (4.3 %) and non-ST (8.3 %) groups achieved a 50 % increase in sCr during a mean follow–up period of 4.7 years. At the final observation, 71.7, 44.4, and 41.7 % of patients in the TSP, ST, and non-ST groups, respectively, achieved CR (p = 0.032). Cox proportional hazards models revealed that TSP led to CR more effectively than non-TSP by a factor of about threefold (hazard ratio, 2.74; p = 0.008).

Conclusion

TSP therapy has potential for inducing CR in patients with IgAN and mild proteinuria (<1.0 g/day).