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Misaki T, Naka S, Wato K, Hatakeyama R, Nagasawa Y, Ito S, Inaba H, Nomura R, Matsumoto-Nakano M, Nakano K: Campylobacter Rectus in the Oral Cavity Correlates with Proteinuria in Immunoglobulin A Nephropathy Patiens. Nephron 2018;139:143–149
It is generally accepted that systemic inflammatory processes can enhance or induce proteinuria, especially in subjects with pre-existing glomerular disorders. However, much less is known about the impact of localized inflammatory disorders, especially those of a bacterial nature, on the permselectivity properties in glomerular diseases.
Misaki and colleagues sought to help fill this knowledge gap by studying the bacterial flora of the mouth (using salivary fluid samples and polymerase chain reaction (PCR) techniques) in 117 patients with IgA nephropathy (lgAN) and 56 healthy controls. Campylobacter rectus and treponema denticola were considered representative of bacteria associated with periodontitis, and streptococcus mutans as bacteria associated with dental caries. Campylobacter rectus, especially when combined with streptococcus mutans, was positively associated with an increased risk of having proteinuria > 0.5gms/d in the patients with IgAN (see table 1). About 44 % of IgAN patients and 27 % of healthy controls had demonstrable campylobacter rectus in saliva. Streptococcus mutans demonstration alone did not show any effect on urinary protein excretion levels. There were no correlations between campylobacter rectus demonstration and renal pathology.
This study is primarily hypothesis generating as correlation is not equivalent to causation. It is unfortunate that no measures of systemic inflammation, such as serum Interleukin 6 or C-reactive protein levels, were included in the study. As the authors note, it is possible that reverse causality is operative (e.g. IgAN predisposes to gingivitis and/or caries). Also, the disease specificity of the observations were not examined. The study needs confirmation and extension into a broader array of proteinuric renal diseases. Nevertheless, it raises the interesting possibility that aggressive treatment of the oral and dental lesion induced by these bacteria might lower the prevalence of proteinuria and thus have salutary effects on the long-term progression of disease.
Table 1: Association between urinary protein levels >0.5 g/gCr and C. rectus and cnm-positive S. mutans (From Nephron 2018;139:143–149)
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Campylobacter Rectus in the Oral Cavity Correlates with Proteinuria in Immunoglobulin A Nephropathy Patiens
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Major R W, Shepherd D, Brunskill N J: Reclassification of Chronic Kidney Disease Stage, Eligibility for Cystatin-C and Its Associated Costs in a UK Primary Care Cohort. Nephron 2018;139:39–46
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines recommend confirmatory testing for estimated glomerular filtration rate (eGFR) using cystatin C or cystatin C + creatinine eGFR formulas when eGFR is between 45 and 59 ml/min/1.73m2 (CKD category 3A), when proteinuria is absent (category A1), or when no co-morbid diseases (such as diabetes) is present that might explain the presence of CKD. If the eGFR is < 60ml/min/1.73m2 with one or the other of the “confirmatory” tests, then CKD may be diagnosed. The utility and cost-effectiveness of these recommendations have not been well studied, especially in a primary care practice situation largely involving older adults. The prevalence of category G3a without abnormal proteinuria (CKD G3a/A1) is likely to be affected by the type of eGFR equation (Modification of Diet in Renal Disease (MDRD) vs CKD-EPI creatinine vs other equations) in such a population.
Major and co-workers in the United Kingdom sought to remedy this gap in knowledge by conducting a study in 353,256 adult patients (over 18 years of age) enrolled in 49 primary care practices. Initially, a total of 21,544 individuals (6.1 %) had at least two eGFR values (MDRD equation) < 60ml/min/1.73m2 three months apart, of which 10,031 (46.6 %) had CKD category G3a/A1. As expected, patients identified as having CKD were older adults (average age 75 years), predominantly female (61 %), and 22 % had diabetes. Reclassification of the patients using the CKD-EPI equation reduced the number of subjects with category G3a/A1 CKD from 10,031 to 8762 (about -12 %) and increased the number categorized with more severe CKD (category G3b/A1) from 2213 to 3095 (about 40 %). See Table:
Classification of CKD at the study’s baseline by MDRD, CKD-EPI and proteinuria stage and reclassification of CKD stages between MDRD and CKD-EP (from Nephron 2018;139:39–46)
Thus, use of CKD-EPI-creatinine actually decreases “eligibility” of patients for confirmatory cystatin C eGFR testing by virtue of its effect of worsening the CKD severity category in those originally defined as having CKD by the MDRD eGFR equation. But since the cohort was originally constructed by inclusion of only those subjects with any CKD by eGFR criteria using MDRD values, the overall impact of using a CKD-EPI creatinine equation for assessment of CKD could not be evaluated, but suggests the possibility that more patients will be classified as having CKD, by KDIGO criteria, if a CKD-EPI creatinine equation is used as the “classifier” in an elderly cohort of patients being seen in primary care practice. It is generally agreed that the prevalence of CKD (by KDIGO criteria) in the elderly highly depends on the formula used to estimate GFR. No formulas for eGFR other than CKD-EPI creatinine or MDRD were examined in this study. Applying these data to the entire UK adult population (51.3 million in 2015, all ages > 18 years) it was estimated about 1.27 million subjects (2.5 %) would be eligible for “confirmatory” cystatin C eGFR determinations (fewer using CKD-EPI creatinine compared to MDRD). When visits and primary care consultation costs were included in addition to the serum cystatin C determination cost a total of 67.5 million Euros (USD 81 million) would be required for implementation of a serum cystatin C confirmation program if 100 % of adults in the UK were screened for CKD using eGFR MDRD or CKD-EPI creatinine determinations. Comparable costs in the USA are unknown but might approximate USD 500 million.
This study provides no insights into the cost-benefit relationships of confirmatory cystatin C eGFR testing in the G3a/A1 CKD population, but raises some serious issues about its application in defined populations, about selection of the optimum GFR formulas for determining eligibility for such confirmational testing, and the need for additional “refinement” of the eligibility criteria if such confirmatory testing is deemed to have clinical utility.
Quoted Karger Article
Reclassification of Chronic Kidney Disease Stage, Eligibility for Cystatin-C and Its Associated Costs in a UK Primary Care Cohort
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Iwashita Y, Ohya M, Yashiro M, Sonou T, Kawakami K, Nakashima Y, Yano T, Iwashita Y, Mima T, Negi S, Kubo K, Tomoda K, Odamaki T, Shigematsu T: Dietary Changes Involving Bifidobacterium Longum and Other Nutrients Delay CKD Progression. Am J Nephrol 2018;47:325–332
The intestinal microbiome has become a facet of human biology that is attracting great interest, including among investigators in the field of kidney disease. In CKD, “uremic” toxins may be elaborated by the action of intestinal microbiota on dietary constituents (dysbiosis). Altering the composition of the bacterial flora of the intestine may have therapeutic potential, but this is a very challenging area of clinical investigation.
Iwashita and co-workers conducted an experimental study of gut microbiota in 5/6th nephrectomized rats and sham-operated controls. Combined treatment (for 8 weeks) with pre-biotics (glutamine, fiber and oligosaccharides) and probiotics (bifidobacterium longum), or “synbiotic” therapy (also called GFOB diets) were examined. Gut microbiota as assessed by stool DNA analysis was altered in the nephrectomized rats compared to controls and the synbiotic diets tended to reverse these abnormalities. Indoxyl sulfate levels in the serum were reduced by the synbiotic treatment. Serum creatinine, inorganic phosphate, calcium, iPTH but not FGF23 levels were lower in the synbiotic treated nephrectomized rats compared to controls. Tubulo-interstitial injury was modestly less in the synbiotic treated nephrectomized rats compared to controls. See Figure:
Tubulointerstitial injury. a Histological images of tubulointerstitial injury by PAS staining and (b) tubulointerstitial injury score in each group. Nx and diet effects were significantly different when analyzed using 2-way ANOVA. Scale bars: 50 μm. PAS, periodic acid–Schiff; Sham, sham-operated; Nx, nephrectomy; CON, control; ANOVA, analysis of variance. (From: Am J Nephrol 2018;47:325-332)
These preliminary findings provide some encouragement for pursuit of similar studies in humans with CKD, but whether the mechanism(s) of the demonstrated beneficial effects are actually due to the induced changes in gut microbiota cannot be determined. Pair-feeding, estimations of total nitrogen intake and excretion, and blood pressure alterations were not examined in the experimental design. Much more work is required to see if this “synbiotic” therapeutic approach to modify the course of CKD in human is valid. This preliminary study is novel and interesting, but incomplete.
Quoted Karger Article
Dietary Changes Involving Bifidobacterium Longum and Other Nutrients Delay CKD Progression
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Kamran H, Kupferstein E, Sharma N, Singh G, Sowers JR, Whaley-Connell A, Yacoub M, Marmur JD, Salifu MO, McFarlane SI: Revascularization versus Medical Management of Coronary Artery Disease in Prerenal Transplant Patients: A Meta-Analysis. Cardiorenal Med 2018;8:192–198
The optimal management of ischemic coronary artery disease in patients with end-stage renal disease (ESRD) awaiting renal transplantation remains a conundrum. Avoidance of a cardiovascular (CV) death following renal transplantation with an otherwise successful grafting is a laudable goal. The decision as to whether medical management or a revascularization procedure (such as coronary artery bypass surgery (CABG) or percutaneous angioplasty with stenting) is the optimum choice in patients with ESRD awaiting renal transplantation is still controversial area. An individualized (personalized) approach is probably best, but such guidance is often clouded by numerous variables.
Karman and colleagues attempted to illuminate this arena of uncertainty by conducting a systemic review and meta-analysis of 6 studies involving 598 patients in which outcomes following transplantation could be compared between medical management alone and coronary revascularization (not specified as to surgical or angioplasty). Only 5 of the 6 studies selected contained post-transplant outcomes. The hazard rate for the primary composite outcome of major cardiovascular event (including death) were not different for medical management versus revascularization (HR= 1.42; 95% CI= 0.89–0.26) but the heterogeneity of the included studies was high (see Figure 1). Due to the small number of subjects the analysis could not be stratified for the degrees of coronary artery disease (number of vessels involved), the presence or absence of diabetes, the compliance to medical management, or the type of revascularization. These are significant limitations of the analysis.
Figure 1: Forrest plot showing odds of having cardiovascular mortality among patients with coronary artery disease receiving standard medical therapy (MM) versus revascularization (REV), post renal transplantation. (From Cardiorenal Med 2018;8:192–198)
Nevertheless, this study suggests that medical management alone does not confer a great disadvantage compared to revascularization for the post-transplant course of patient with ESRD. Clearly, additional large prospective trials are needed to clarify the optimum management strategy in patients with ESRD and overt coronary artery disease.
Quoted Karger Article
Revascularization versus Medical Management of Coronary Artery Disease in Prerenal Transplant Patients: A Meta-Analysis
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Yu X, Cai J, Jiao X, Zhang S, Liu H, Ding X: Response Predictors to Calcineurin Inhibitors in Patients with Primary Membranous Nephropathy.Am J Nephrol 2018;47:266–274
The ability to reliably and accurately predict the response to treatment of glomerular disease with specific regimens would be a great advance. Factors such as renal function, scarring on renal biopsy analysis, urine protein composition, and genetic background (for focal segmental glomerulosclerosis [FSGS]) are already used for this purpose, but an easily accessible serum biomarker with high predictive capability would be a practice altering development.
Yu and co-workers have attempted to fill this gap by conducting a novel pilot study in calcineurin-inhibitors (CNI) treated patients with presumed primary membranous nephropathy (PMN) followed for at least 12 months for a remission (complete or partial) or no remissions. About 90% of the patients were anti-phospholipase A2 receptor (anti-PLA2R) antibody positive by ELISA. Since all patients with PMN studied were treated with a CNI it is not possible to determine how many of the observed remissions were “spontaneous” or whether the predication based on one or more biomarkers also applies to other treatment regimens (such as rituximab or cyclophosphamide) or whether the findings are specific only to CNI treatment. These are serious limitations of the study.
Using nano-HPLC-MS technology they were able to identify several differentially expressed serum biomarkers predictive of remission or no remission following CNI therapy. The leading candidate was serum amyloid A1 protein (SAA-1) – a well-known acute phase reactant synthesised in the liver in response to interleukin-6. Decreased levels of SAA-1 were found in non-responsive patients compared to those with a complete remission. The area-under-the-urve of a receiver operating characteristic analysis (AUROC) was 0.91 for SAA-1, 0.93 for anti-PLA2R, and 0.96 for the combination of SAA-1 and anti-PLA2R, indicating an additive effect when two biomarkers were combined, but also showing that SAA1 and anti-PLA2R are comparable for prediction of remission in CNI treated subjects with PMN (see Figure 1). However, it must be recognized that the initial response to CNI in PMN is very high, so long as the treatment is continued, but relapses very commonly develop when the treatment is discontinued and as stated above, the study design cannot discern the outcomes in terms of treatment induced or a spontaneous remission. It is possible that CNI exhibited their effects on remission locally by altering podocyte biology rather that promoting an immunological remission of PMN. The high relapse rate after stopping CNI in PMN attests to this possibility. Interestingly SAA-1 serum levels correlate inversely with anti-PLA2R antibody levels in PMN.
Despite its weaknesses, this study is of interest as it provides a glimpse of how a personalized approach to treatment of PMN may evolve in the future. Perhaps a panel of highly validated serum / urine biomarkers will be utilized to predict responses to specific regimens of therapy, this allowing for treatment to be tailored to individual patients with PMN. Anti-PLA2R antibody levels are already widely accepted as one such biomarker [1], but assessing anti-PLA2R antibody levels do not help much (yet) in deciding which one of several treatment regimens (CNI, Rituximab, Cyclophosphamide, other) are best suited to the individual patient, except that low anti-PLA2R titers predict a spontaneous remission and no immediate need for any specific treatment at all [1]. The study of Yu et al. does not contribute much to this aspect of individualized treatment of PMN. Also, CNIs are not the first choice for treatment of PMN, except perhaps in China, so the generalization of the findings of this novel and preliminary study to the universe of PMN is limited. Nevertheless, studies of this type are likely to increase in frequency over time and may eventually lead to a change in practice.
References
1. De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A Proposal for a Serology-Based Approach to Membranous Nephropathy. J Am Soc Nephrol. 2017 ;28:421-430. J Am Soc Nephrol. 2017 ;28:421-430.
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Response Predictors to Calcineurin Inhibitors in Patients with Primary Membranous Nephropathy
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Schrauben SJ, Negoianu D, Costa C, Cohen RM, Goldfarb S, Fuchs BD, Berns JS: Accuracy of Acid-Base Diagnoses Using the Central Venous Blood Gas in the Medical Intensive Care Unit. Nephron. 2018 doi: 10.1159/000488501
Disturbances of acid-base homeostasis very commonly complicate critical illnesses. Arterial blood gases (ABG) combined with assessment of serum electrolytes (especially the anion gap and delta bicarbonate) are traditionally used to determine the nature of these disturbances.
Schrauben and colleagues studied an alternative approach, using venous blood gas (VBG) analyses employing blood obtained from a central venous catheter in 23 critically ill patients in a medical intensive care unit, 55% of whom were vaso-pressor dependent. The average anion gap was 9mmol/L and 70% has acute kidney injury of whom 25% required dialysis.
Venous blood gas showed an excellent sensitivity compared to with ABG for metabolic acidosis and alkalosis and respiratory acidosis but lesser sensitivity for respiratory alkalosis. The specificity for any acidosis, respiratory or metabolic, was 58%. This agreement between VBG and ABG was very good for acidosis, but less satisfactory for alkalosis, particularly respiratory alkalosis (see Table 1). While these data suggest cautious use of VBG as a substitute for ABG in diagnosis of acid-base disorders in critically ill patients, the performance of such VBG-based diagnostic approaches have inherent weaknesses which must be understood. Arterial blood gas determinations remain as the “gold-standard” for diagnosis of acid-base disorders, but VBG can be utilized as a non-invasive substitute for ABG, as they have high sensitivity for detecting and classifying acidosis, but are less valuable for detecting respiratory alkalosis.
Table 1: Percent agreement of central VBG-based diagnosis compared to ABG-based diagnosis
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Accuracy of Acid-Base Diagnoses Using the Central Venous Blood Gas in the Medical Intensive Care Unit
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Chan CT, Kaysen GA, Beck GJ, Li M, Lo J, Rocco MV, Kliger AS: Changes in Biomarker Profile and Left Ventricular Hypertrophy Regression: Results from the Frequent Hemodialysis Network Trials: Am J Nephrol 2018;47:208–217
Left ventricular hypertrophy (LVH) is common in chronic kidney disease (CKD) and in end-stage renal disease (ESRD) treated by dialysis. The failure of LVH to regress or its progression can be associated with a high risk of mortality, especially that due to sudden cardiac death. The Frequent Hemodialysis Network (FHN) trials of daily or nocturnal hemodialysis (HD) have suggested that these forms of dialysis have the potential to benefit LVH compared to conventional HD. Better control of fluid volume status and blood pressure (BP) have been suggested to explain these findings, but the mechanisms involved remain not well understood.
Chan and co-workers have conducted a post-hoc analysis of the FHN trials to see if biomarkers can predict the changes in LVH in dialysis treated ESRD. Of 243 subjects with complete data, the LVH regressed in 77, progressed in 45 and neither regressed or progressed in 121. Regression LVH was highly associated with more frequent HD and lower levels of systolic and diastolic BP. In addition, serum Klotho levels increased and tissue inhibitor of metalloproteinase-2 (TIMP-2) decreased in association with regression of LVH. Changes in LVH were inversely associated with changes in serum Klotho levels (see Figure 1). Fibroblast Growth Factor 23 (FGF23) and serum phosphorous levels were not consistently associated with regression of LVH, although these levels tended to increase among repressors and decrease in progressors. Serum B-natriuretic peptide levels (a marker of volume status) declined in association with LVH regression. The differences in serum aldosterone levels (after adjustment for serum potassium and BP) did not differ in regressors compared to progressors. Copeptin levels tended to increase in progressors and decline in regressors.
Figure 1: Association between changes in Klotho and changes in left ventricular mass (LVM) (r = –0.24, p = 0.014; red circles denote regressors, blue circles denote progressors). From Am J Nephrol 2018;47:208–217
Although this study is largely exploratory and hypothesis-generating, it does point in a new direction for future examination of the mechanisms underlying the benefits of more-frequent HD in control of the lethal consequences of LVH in ESRD. The FGF23 studies are interesting since this bone-derived hormone has been suggested to play a role in LVH of ESRD.
The findings concerning Klotho and TIMP-2 are novel and deserve further exploration as they support a role for extracellular matrix homeostasis in LVH of ESRD and may give rise to new therapeutic opportunities.
Quoted Karger Article
Changes in Biomarker Profile and Left Ventricular Hypertrophy Regression: Results from the Frequent Hemodialysis Network Trials
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Hou JH, Zhu HX, Zhou ML, Le WB, Zeng CH, Liang SS, Xu F, Liang DD, Shao SJ, Liu Y, Liu ZH: Changes in the Spectrum of Kidney Diseases: An Analysis of 40,759 Biopsy-Proven Cases from 2003 to 2014 in China. Kidney Dis 2018;4:10–19
In a very remarkable retrospective “registry-based” study, Hou and colleagues examined the changes in the spectrum of kidney disease derived from careful study of 40,759 native kidney biopsies performed in the Jinling Hospital in Nanjing located in the Jiangsu Province of the People’s Republic of China (population about 12 million, in 2017) between the years 2003-2014. This translates into an approximate renal biopsy rate of about 280 per million persons per year (pmppy) (if the population denominator is a reasonable approximation of the catchment area). If this approximation is valid, then this may be one of the highest renal biopsy rates in the world. By comparison, the estimated (native) renal biopsy rate in the USA (in 2017, including both adults and children) was about 200 pmppy. Only subjects >14 years of age and biopsies with >10 glomeruli were included in the Chinese analysis.
Between 2003 and 2014 the frequency of a biopsy diagnosis of membranous nephropathy (MN) about doubled, diabetic nephropathy (DN) nearly doubled, and monoclonal immunoglobulin deposition disease tripled. In part, these findings might be attributed to a gradual increase in the average age (by about 5 years) of biopsied patients over the periods of 2003-2014. The proportion of subjects biopsied who were over 60 years of age about doubled over this period of time. IgA nephropathy (IgAN) remained as the commonest primary form of glomerulonephritis (GN) but showed a slow decrease in relative frequency over time. The frequency of IgAN peaked at about age 35 years. Focal and segmental glomerulosclerosis (FSGS) was an uncommon diagnosis (only 7.3% of primary glomerular disease). Lupus nephritis (33%) and DN (21%) accounted for 54% of all secondary glomerular diseases. As expected, the finding of DN steadily increased with age of the patients (see figure 1).
Figure 1: Temporal trends of the renal biopsy frequencies of kidney diseases subtypes, 2003-2014. a Frequencies of primary glomerulonephritis subtypes. Percent of all primary glomerulonephritis categories. b Frequencies of secondary glomerulonephritis subtypes. Percent of all secondary glomerulonephritis categories. c Frequencies of tubulointerstitial disease subtypes. Percent of all tubulointerstitial disease categories. d Frequencies of hereditary renal disease subtypes. Percent of all hereditary renal disease categories. From Kidney Dis 2018;4:10–19
These data are likely influenced to some degree by changes in the indications for renal biopsy, a variable that is very difficult to examine in a registry-based data base. Common diseases, like IgAN, increase in frequency in direct proportion to the biopsy rate in the community as a whole. So one cannot assume that the secular changes in biopsy diagnoses reflect a true change in the prevalence of disease. The marked changes in the frequency of MN observed in China are unexplained but might have some connection to environmental factors such as air pollution [1, 2]. The paucity of FSGS as a diagnosis of primary glomerular disease is of great interest, but the lack of differentiation into primary (idiopathic) and genetic forms of this lesion, limit any interpretation.
Nevertheless, large scale epidemiological studies by renal biopsy registries continue to generate some interesting hypotheses concerning etiology of these diseases and have great potential from a public health perspective. Linkage of renal biopsy registries to gene banking programs will likely be of immense value going forward.
References
1. Tang L, Yao J, Kong X, Sun Q, Wang Z, Zhang Y, Wang P, Liu Y, Li W, Cui M, Zhen J, Xu D: Increasing prevalence of membranous nephropathy in patients with primary glomerular diseases: A cross-sectional study in China. Nephrology (Carlton). 2017; 22:168-173
2. Xu X, Wang G, Chen N, Lu T, Nie S, Xu G, Zhang P, Luo Y, Wang Y, Wang X, Schwartz J, Geng J, Hou FF: Long-Term Exposure to Air Pollution and Increased Risk of Membranous Nephropathy in China. J Am Soc Nephrol 2016; 22: 3739-3746
Quoted Karger Article
Changes in the Spectrum of Kidney Diseases: An Analysis of 40,759 Biopsy-Proven Cases from 2003 to 2014 in China
