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Miller WL, Grill DE, Qian Q: Intravascular Volume Modulates the Outcomes Predictive Capacity of Clinical Renal Function Biomarkers in Clinically “Euvolemic” Chronic Heart Failure Patients. Kidney Dis DOI 10.1159/000502210
Plasma volume (PV) assessment by clinical means (arterial or venous blood pressure, orthostasis, pulse rate, skin turgor, capillary refilling rate, etc.) is often insensitive and unreliable. Chronic PV expansion in heart failure (HF) and chronic kidney disease (CKD) can be subtle but have important adverse consequences.
Miller and co-workers examined PV expansion by objective and quantitative tools (tracer dilution methods) in 110 adult patients with clinically stable mild-moderate HF with co-existing normo-albuminemic CKD. Substantial PV expansion compared to healthy subjects was evident in 76% of the cohort. Left ventricular ejection fraction ranged from 14–70%, so both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) were represented in the cohort. Estimated glomerular filtration rate (eGFR) ranged from 30–66ml/min/1.73m2 (interquartile range). About 55% of the subjects had sever PV expansion (26%+ above normal PV) and these subjects had much higher NT-proBNP levels.
Not surprisingly, patients with lower eGFR levels had lower event free survival (cardiovascular death or hospitalization), especially in those with concomitant severe PV expansion. Anemia, unrelated to the dilutional effect of PV expansion was also a risk factor. The one-time assessment of PV status and the lack of a separate analysis of HFrEF and HFpEF are weaknesses of the study design, in my opinion.
Nevertheless, several “take-home” messages emerge:
- Subclinical PV expansion is very common in clinically “euvolemic” mild-moderated HF with concomitant CKD
- Standard biomarkers for prediction of cardiovascular risk in such subjects is influenced by the status of the PV
- Quantitative assessment of the degree of PV expansion in such patients may be a useful tool to refine the risk of subsequent risk of cardiovascular events or hospitalization.
Quoted Karger Article
Intravascular Volume Modulates the Outcomes Predictive Capacity of Clinical Renal Function Biomarkers in Clinically “Euvolemic” Chronic Heart Failure Patients
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Mitsides N, Alsehli FMS, Mc Hough D, Shalamanova L, Wilkinson F, Alderdice J, Mitra R, Swiecicka A, Brenchley P, Parker GJM, Alexander MY, Mitra S: Salt and Water Retention Is Associated with Microinflammation and Endothelial Injury in Chronic Kidney Disease. Nephron DOI 10.1159/000502011
Endothelial injury and subclinical inflammation (“micro-inflammation”) are both quite common in CKD and their origins are numerous and diverse. Salt and water retention accompanying CKD with expansion of plasma volume and extra-cellular fluid volume is also a common phenomenon.
Mitsides and co-workers examined the association between these parameters in 23 CKD category 5 patients and 11 healthy controls. Uniquely, tissue [Na+] levels were assessed by MRI, fluid expansion by bio-electrical impedance, and inflammation/endothelial injury by a panel of serum biomarkers.
Tissue [Na+] levels were increased in subcutaneous tissue (but not in muscle) and this correlated with fluid volume expansion. Higher subcutaneous tissue [Na+] were also correlated with increased intracellular adhesion molecule (ICAM), lower E-selectin levels. Higher extra-cellular fluid volume levels were associated with higher IL-6 levels.
While these analyses cannot determine the causal relationship among the measured parameters, they suggest a plausible effect of increased [Na+] retention in CKD and non-osmotic storage in subcutaneous tissue upon inflammation and endothelial injury. The details of this posited relationship require further elucidation, but they heighten interest in [Na+] retention as a factor in the pathogenesis of “uremic” toxicity in advanced CKD. This concept has immediate therapeutic implications that need to be examined in proper randomized clinical trials.
Quoted Karger Article
Salt and Water Retention Is Associated with Microinflammation and Endothelial Injury in Chronic Kidney Disease
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Wong E, Ballew SH, Daya N, Ishigami J, Rebholz CM, Matsushita K, Grams ME, Coresh J: Hospitalization Risk among Older Adults with Chronic Kidney Disease. Am J Nephrol DOI 10.1159/000501539
Chronic kidney disease (CKD) as currently defined is believed to be associated with an increased risk for a variety of adverse events, including shortened life expectancy, end stage kidney disease (ESKD), cardiovascular disease (CVD), and acute kidney injury. All-cause risk for hospitalization is an understudied area of risk associated with CKD, particularly in the older age group which already has a heightened frequency of all-cause hospitalizations.
Wong and co-workers have remedied this deficiency by a very comprehensive observational analysis of hospitalization rates among 4706 older adults (average age 75.7 years) enrolled in the atherosclerosis risk in communities (ARIC) study, 29% of whom had CKD by estimated glomerular filtration rate (eGFR)-creatinine and albumin to creatinine ratio criteria according to the 2013 KDIGO schema. About 70% had an eGFR-creatinine ≥60 ml/min/1.73m2; 20% (G1/G2) had an eGFR creatinine of 45–59ml/min/1.73m2 (G3A) and about 9% had an eGFR creatinine <45ml/min/1.73m2 (G3B, G4/G5). Females exceeded males in all CKD categories, except those <30ml/min/1.73m2. African Americans constituted 21% of the cohort. When classified by eGFR cystatin C about 50% of the cohort were categorized as having CKD; with eGFR creatinine + cystatin C the frequency of CKD was intermediate at about 38%. Using a Reference Group of eGFR creatinine of 60-89ml/min/1.73m2 (G2) without albuminuria (A1), the relative of all-cause hospitalization was increased in a graded fashion from 1.2 (95% CI = 1.1-1.4) in category G3/A1 to 3.3 (95% CI= 2.0-5.5) in category G4/5. Hospitalization rates for CVD were increased in all categories of CKD.
Although CKD was diagnosed more frequently by eGFR cystatin C compared to eGFR creatinine, the pattern of increased relative risk for hospitalization according to CKD category was not appreciably altered. With eGFR creatinine values there was a tendency for an increase in all-cause hospitalization risk when the eGFR increased to >90ml/min/1.73m2 in the presence of abnormal albuminuria. This was less evident when eGFR cystatin C was used for CKD categorization. As expected, co-morbidity (diabetes, CVD, cancer, hypertension) was common in all groups and the prevalence was incrementally increased as eGFR declined and albuminuria increased (except for diabetes).
This study contains a wealth of information concerning the association of CKD category and hospitalization in a carefully characterized and longitudinally followed cohort of older adults with age-related co-morbidity. The effect of eGFR cystatin C on CKD categorization is not unexpected as the non-GFR determinants of serum cystatin C would likely be affected by the co-morbidity present in the cohort. The J-curve seen in eGFR creatinine categorization might have been due to frailty and sarcopenia. It is too bad that a “frailty score” was not included in the analysis. The reference group selected for the relative risk analysis had a rather broad range of eGFR (60-89 ml/min/1.73m2) and included values of GFR that are well above the “normal” values of eGFR for healthy subjects of 75 years of age. Whether this “reference group selection” effect confounded the analysis cannot be determined. About 77% of the C3A/A1 category had no abnormal albuminuria and most had some co-morbidity, including 35% with diabetes. One wonders if the modest risk of increased hospitalization in this category of CKD was due to co-morbidity rather than the CKD itself. It is very hard to disentangle CKD from co-morbidity in an observational analysis of this kind.
All things considered, this is a valuable addition to the literature associating risk of an adverse event (hospitalization in this case) and CKD. It points out that very high risk CKD (eGFR <45 ml/min/1.73m2; G3B/G4) and/or high grade albuminuria (A2) have very high hospitalization rates, often exceeding 500 per 1000 patient years of observation. This is a very tempting target for improved management. Case managers in medical care consortia need to pay attention to this data.
Quoted Karger Article
Hospitalization Risk among Older Adults with Chronic Kidney Disease
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Martinez MG, dos Santos Silva V, do Valle AP, de Oliveira RC, Banin VB, Hokama NK, Martin LC: Association between Sodium Intake and Urinary Fractional Albumin and Immunoglobulin G Excretion in Chronic Nondialytic Renal Disease: A Prospective Longitudinal Study. Nephron DOI 10.1159/000500548
It is generally agreed that the magnitude and composition of proteins excreted in the urine has an important impact on the prognosis of chronic kidney disease (CKD). The influence of concomitant intake and excretion of salt (NaCl) on proteinuria has been incompletely characterized.
A prospective, observational study by Martinez and co-workers addresses this knowledge gap, at least in part. Eighty-four patients with CKD stages 1–4 exhibiting proteinuria of at least 500mg/d were examined at baseline and after 6 months (on stable management and dosing of renin-angiotensin system [RAS] inhibitors). Most (2/3rds) of the patients had diabetes mellitus, hypertensive nephrosclerosis or ischemic kidney disease. Urine albumin and IgG, creatinine and sodium (Na+) excretion were assessed and fractional excretion (FE) of albumin and IgG were calculated. Two groups of approximately equal size were compared: 1) Those with an increase in Na+ excretion over the period of observation (from 139mEq/d to 198mEq/d); 2) Those with a decrease in Na+ excretion over the period of observation (from 196mEq/d to 140mEq/d). The change in FE albumin correlated positively with the change in urinary Na+ excretion (r2= 0.294; p<0.001) as did FE IgG (r2=0.314; p<0.001). Systolic blood pressure also showed a positive correlation with variation in Na+ excretion, but dietary protein intake and glycemia did not.
These findings suggest that intake of NaCl has a material impact on parameter of urine protein excretion. Whether this effect is mediated by changes in systemic arterial pressure or intra-renal hemodynamic or something else (such as micro-inflammation cannot be conclusively analyzed in a study of this design. However, from a practical standpoint it emphasizes that NaCl intake needs to be considered in the interpretation of changes in urinary protein excretion over time in many patients with proteinuric CKD. But additional studies in patients with glomerulonephritis are needed to confirm the findings.
Quoted Karger Article
Association between Sodium Intake and Urinary Fractional Albumin and Immunoglobulin G Excretion in Chronic Nondialytic Renal Disease: A Prospective Longitudinal Study
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Fitzpatrick A, Venugopal K, Scheil W, McDonald SP, Jesudason S: The Spectrum of Adverse Pregnancy Outcomes Based on Kidney Disease Diagnoses: A 20-Year Population Study. Am J Nephrol DOI 10.1159/000499965
Complications of pregnancy (e.g. hypertension, premature birth, intra-uterine growth retardation, urgent C-section, etc.) are generally believed to be associated (in a likely causal manner) with the presence of kidney disease preceding pregnancy.
In a descriptive, retrospective analysis of singleton pregnancies (n=407,580 births) over 20 years (1990–2012) in South Australia, Fitzpatrick and co-workers analysed the frequency and characteristics of kidney disease. Kidney disease was identified in 1392 pregnancies or 0.3% of the total. The presence of kidney disease was associated with an increased risk of pregnancy induced hypertension, urgent C-section, premature birth, low birth weight, prematurity and admissions of the neonate to an Intensive Care Unit. The nature of the underlying kidney disease could only be partially characterized due to data limitations. Vesico-ureteric reflux nephropathy and immunological kidney disease (mainly glomerulonephritis) were particularly associated with adverse maternal/fetal outcomes.
Such population level data is of interest as the findings may guide preventatives measures, such as early recognition and treatment of pre-eclampsia. Interestingly, in this group of subjects, low birth weight was primarily a function of premature delivery, rather than intra-uterine growth retardation. Renal function parameters could not be assessed in this analysis, so chronic kidney disease (CKD) stage could not be determined – a significant weakness. Nevertheless, pregnancy with concomitant kidney disease warrants careful monitoring and attempts to ameliorate the risks of complications.
Quoted Karger Article
The Spectrum of Adverse Pregnancy Outcomes Based on Kidney Disease Diagnoses: A 20-Year Population Study
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McMahon BA, Galligan M, Redahan L, Martin T, Meaney E, Cotter EJ, Murphy N, Hannon C, Doran P, Marsh B, Nichol A, Murray PT: Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study. Am J Nephrol DOI 10.1159/000500231
The use of serum and/or urinary biomarkers for the prediction of the occurrence and/or severity of AKI among hospitalized (mostly intensive care units [ICU]) is of great and growing interest. However, relatively few large, prospective, observational trials have been conducted that examine the specific value of such biomarkers for the risk of AKI.
McMahon and colleagues in the Dublin Acute Biomarker Group Evaluation (DAMAGE) study sought to remedy this knowledge gap. Subjects (n=669) with acute critical illness admitted to an ICU were followed sequentially with a panel of urinary biomarkers (creatinine, cystatin-calbumin, NGAL, KIM-1, alpha and pi GST, L-FABP – not including the Nephrocheck® panel of TIMP-2/IGF-BP7) and for the development and severity of AKI (by KDIGO criteria) over 2 – 7 days and for a 30 day composite outcome of renal replacement therapy (RRT) or death. Of the original cohort, 38% developed AKI within 7 days of ICU admission (41% of whom had stage 3 AKI and 31% met the 30 days composite end-point).
Importantly, no single biomarker was capable of predicting AKI with an area under the curve (AUC) of >0.70. Clinical models alone (APACHE-II, gender, serum creatinine, urine output, BUN) were modestly predictive of AKI and outcomes, particularly for stage 3 AKI, but the biomarkers added no statistically significant improvement of AUC. Combinations of NGAL/albumin seemed to perform best for predicting severe AKI with an AUC of 0.90.
The take home message (for me) is that clinical modelling appears adequate for prediction of AKI and outcomes in a heterogeneous collection of patients with critical illness admitted to an ICU, and that testing of urinary biomarkers adds little (caveat: the FDA approved Nephrocheck® test was not evaluated in this study) to this prediction. Many factors probably account for these disappointing results. Further studies are needed, using broad panels of biomarkers and more homogeneous patient cohorts to explore the potential value of biomarker profiles in ICU patients at high risk of developing AKI.
Quoted Karger Article
Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study
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Comai G, Malvi D, Angeletti A, Vasuri F, Valente S, Ambrosi F, Capelli I, Ravaioli M, Pasquinelli G, D’Errico A, Fornoni A, La Manna G: Histological evidence of diabetic kidney disease precede clinical diagnosis. Am J Nephrol DOI 10.1159/000500353
The microscopical anatomy of subjects with diabetes but exhibiting normal urinalyses and kidney function is largely unknown, as kidney biopsies are not presently indicated in these circumstances.
Comai and co-workers sought to remedy this deficiency by taking advantage of pre-implantation kidney biopsies of deceased donors with diabetes (mostly type 2) and protein excretion of <30mg/dL and eGFR >60ml/min/1.73m2 kidneys in the context of kidney transplantation. A total of 35 kidney biopsies from patients with diabetes (mean age 69.7 years, all white) were evaluated by light and electron microscopy. The mean urine protein-to-creatinine ratio (UPCR) was about 12mg/gm and the average eGFR was about 68ml/min/1.73m2. Hypertension was present in 69% and 22% were treated with renin-angiotensin system (RAS) inhibitors. No patient had diabetic retinopathy. Three had no evidence of diabetic kidney disease; 3 had stage 1; 22 had stage 2a; 3 had stage 2b, 4 had stage 3, and 0 had stage 4 diabetic kidney disease (assessed by the system of Tervaert, et al. , Tervaert TW et al. JASN, 2010). Additional histological parameters of glomerulosclerosis, tubular atrophy interstitial fibrosis, and vascular damage were assessed by the Karpinski score (Karpinski J, Transplantation, 1999).
These findings represent a good snapshot of renal histology of subjects with diabetes and normal renal function. The presence of hyper-filtration in the donors could not be excluded because no measured GFR were performed. The assessment of proteinuria did not include albuminuria to creatinine ratios. There was no comparison group of similarly aged non-diabetic donors so the significance of the Karpinski scores is very uncertain.
Despite these weaknesses, this study and other autopsy based descriptive analysis strongly support the notion that diabetes-related pathology precedes the development of overt clinical signs, such as proteinuria or reduced GFR. Whether this study justifies the broader application of kidney biopsy to foster earlier treatment of clinically lanthanic, diabetes-related lesion, as suggested by the authors, remains to be seen.
Quoted Karger Article
Histological evidence of diabetic kidney disease precede clinical diagnosis
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Cebeci E, Ekinci I, Gursu M, Coskun C, Karadag S, Uzun S, Behlul A, Senel TE, Kazancioglu R, Ozturk S: Podocyte Injury in Autosomal Dominant Polycystic Kidney Disease. Nephron DOI: 10.1159.000499741
Autosomal dominant polycystic kidney diseases (ADPKD) is generally regarded as a prototypical hereditary tubulo-interstitial kidney disease.
Glomerular alterations have received little attention.
Cebeci and colleagues help to fill this gap in information by conducting an observational (non-biopsy) study of urinary biomarkers of podocyte injury, specifically podocin (P) and podocalyxin (PC), in patients with ADPKD and healthy controls. They found increased excretion of P and PC (measured as urine concentration indexed to creatinine in ng/mg) in ADPKD compared to controls, especially in the presence of decreased eGFR or proteinuria. As expected about 2/3rds of the ADPKD were hypertensive. The P and PC levels correlated with urine protein creatinine ratio (UPCR) but not with hypertension or its treatment.
These findings suggest ongoing glomerular (podocyte) injury in ADPKD, but do not answer question about this injurious process to the rate of decline in eGFR in ADPKD. The pathological process in ADPKD include slow decline in the nephron population and compensatory hypertrophy in residual, spared nephrons. This compensation may exact consequences, like mechanical-stress induced podocyte injury. Thus, in a sense, these findings were predictable. Whether monitoring of podocyte injury by urinary P or PC will be useful as a prognostic tool, like total kidney volume by MRI, in ADPKD cannot be answered by a study of this design. Longitudinal studies would be required, but such an analysis might be reasonable going forward.
Quoted Karger Article
Podocyte Injury in Autosomal Dominant Polycystic Kidney Disease
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Kapoian T, Khalil S, O’Mara NB, Brink DM, Daugirdas JT: Modeled Daily Ingested, Absorbed and Bound Phosphorus: New Measures of Mineral Balance in Hemodialysis Patients. Am J Nephrol 2019;49:368–376
Control of pre-dialysis (and inter-dialysis) serum phosphorous levels (P) is regarded as a desirable, but challenging, goal in dialytic care of ESKD patients. The level of P in the serum is governed by a complex interplay of a series of processes; namely, dietary P intake and its GI absorption, the distribution of P among the body fluid spaces (including bone), and its removal by the gut, kidney and by dialysis in ESRD patients.
Kapoian and colleagues exploit urea and P kinetic modeling as a novel way to determine and quantify some of these components in hemodialysis (HD) patients, specifically dietary P intake (DPI) and daily absorbed + bound P (DABP), utilizing values for P equivalent binder dosage (EBD).
The modelled DIP was about 12.8mg/kg/d and varied according to body weight (BW) and protein catabolic rate (PCR). The DPI/PCR was about 17.4 for men and 20.1 in women. Not bound and unabsorbed P was about 20% of total DPI, while DABP was about 80% of DPI. Patients took on average about 4.8gms/d of EBD. The kinetic data revealed that a high DPI/PCR, DAPB/PCR, or DIP/BW ratio indicated either a diet rich in soluble, readily absorbed P additives or to non-adherence to prescribed EBD, especially in anuric HD patients (without residual renal function). The nature of food intake (i.e. vegetable/fruit vs animal protein) was not systematically evaluated. This may be important as the P contained in phytates present in vegetables and fruits are poorly absorbed [1].
The strength of this novel study is that it uses commonly accessible data to construct the modeling programs. Furthermore, it generates parameters that can be useful for detection of non-compliance or excessive consumption of P via foods containing high quantities of added soluble P. It seems mainly applicable to anuric HD patients, and those with substantial residual renal function may require different approaches to kinetic modeling.
References
1. Palmer BF, Clegg DJ: Cardiovascular benefits of a diet enriched with fruits and vegetables. Am J Nephrol 2019; 49:435-437
Quoted Karger Article
Modeled Daily Ingested, Absorbed and Bound Phosphorus: New Measures of Mineral Balance in Hemodialysis Patients
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Dieter BP, Daratha KB, McPherson SM, Short R, Alicic RZ, Tuttle KR: Association of Acute Kidney Injury with Cardiovascular Events and Death in Systolic Blood Pressure Intervention Trial. Am J Nephrol 2019;49:359–367
The landmark SPRINT trial [1] of intensive vs standard anti-hypertensive therapy in older, non-diabetic subjects at a high-risk of cardiovascular disease (CVD) demonstrated an overall clear-cut benefit in terms of avoidance of CVD events and all-cause mortality when the systolic arterial blood pressure (SBP) was reduced to 120mmHg or less. However, the cost of these benefits was an increase in acute kidney injury (AKI) events to about double in the intensive SBP group (4.4%) compared to the standard SBP group (2.6%). Whether these AKI events have long term sequelae remains an open question.
Dieter and colleagues addressed this issue by conducting a post-hoc analysis of the SPRINT data. Hypotensive episodes and AKI were frequently observed in the intrusive SBP group. In addition, there was an increased frequency of a decline in eGFR from baseline of >30% in the intensive SBP group, even after adjusting for clinical risk factors. Among patients with chronic kidney disease (CKD) at baseline the intensive SBP group did not experience any slowing of progression.
Importantly, the risk of developing a CVD event or all cause mortal event was higher in those subjects experiencing an episode of AKI, even after adjustment for co-variates, although the magnitude of this risk was attenuated by such an adjustment. Thus, the theoretical advantages of a lower blood pressure in preventing CVD events or death was entirely lost in association with the development of AKI. Fortunately. AKI was rather uncommon in the intensive SBP group (4.4%), and the development of AKI did not abrogate the overall beneficial effects seen in the SPRINT trial as a whole.
This analysis is hypothesis-generating rather than a proof that the AKI events are causally related to the enhanced risk of CVD events and death. But when combined with other observational data, this analysis creates a clear conundrum: namely, is the lowering of SBP to 120mmHg or less and the attendant increase in risk of AKI worthwhile? The episodes of AKI are usually minor and reversible, and we still do not understand the mechanisms underlying a connection between a brief episode of AKI and a longer term enhancement of CVD risk. In addition, we do not have very precise tools to predict which patients are more likely to exhibit AKI when SBP is reduced to around 120mmHg. In an accompanying Editorial, Thomas and Schold stressed the need for vigilance in trying to avoid AKI when initiating therapy for hypertension whenever possible, and to encourage appropriate close monitoring of patients during intensive blood pressure control. [2] The SPRINT trial was conducted in subjects without diabetes but who were at a high risk of CVD. Do these findings also apply to individuals (mainly younger) who are at much lower risk of CVD? These are important questions, yet to be answered. The US Hypertension guidelines, drawing extensively from the SPRINT trial, adopted a goal of <130mmHg for SBP in management of hypertensive patients, and we do not know whether this intermediate goal between intensive and standard approaches to therapy will minimize the risks of AKI and simultaneously optimize the benefits of blood pressure control on CVD events. Stay tuned! This is an evolving story and some answers may be forthcoming in the not too distant future.
References
1. SPRINT Research Group, Wright et al., A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015;373:2103–2116
2. Thomas G, Schold JD, Blood Pressure Control, Acute Kidney Injury, and Cardiovascular Events: Separating the Chaff from the Wheat. Am J Nephrol 2019;49:356–358
Quoted Karger Article
Association of Acute Kidney Injury with Cardiovascular Events and Death in Systolic Blood Pressure Intervention Trial
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Rivera M, Tamariz L, Suarez M, Contreras G: Modifying Effect of Statins on Fatal Outcomes in Chronic Kidney Disease Patients in the Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis. Am J Nephrol 2019;49:297–306
Both blood pressure control (with antihypertensive agents) and lowering low density lipoprotein (LDL) cholesterol levels (with statins) are widely regarded as cornerstones of prevention of cardiovascular disease (CVD) related morbidity and mortality in patients with non-dialysis requiring CKD, as shown by the SPRINT and SHARP trials. The interaction of these two interventions on outcomes has not been well studied.
Rivera and colleagues conducted a post-hoc analysis of the SPRINT data in order to examine the impact on fatal outcomes and CVD events of combinations of statin use and low blood pressure targets in 2646 subjects with CKD (1343 taking statins and 1273 not taking statins, 19 unknown). Quite remarkably, the hazard ratio (HR) CVD mortality was dramatically decreased in patients taking a statin and assigned to the intensive blood pressure lowering group (fully adjusted HR= 0.29). No such reduction of CVD mortality risk was seen in the non-statin group.
As this is a post-hoc analysis, a causal interpretation of these findings is not possible (as emphasized in an accompanying Editorial by Tu and Agarwal). Nevertheless, this interaction raises important issues concerning the combined use of statins and low blood pressure targets in prevention of mortality (and morbidity) from CVD in patients with non-dialysis requiring CVD. For example, how robust is the interaction as the severity of CVD worsens? What are the optimal goals for both blood pressure and LDL cholesterol to achieve optimum outcomes? Is the interaction seen to the same degree in diabetic and non-diabetic subjects?
It is also of interest to note that neither intervention may have an equivalent impact on the rate of progression of chronic kidney disease (CKD) to end-stage kidney disease (ESKD). Most older patients with progressive CKD die of CVD before reaching ESRD. Therefore the net population effect will be to reduce mortality for CVD and paradoxically increase the incidence rate of treatment requiring ESRD. Certainly, extended patient survival is a laudable and desirable outcome, but unless progression of CKD can be halted or slowed, the overall impact of combined statin and lower blood pressure targets may be to increase, not decrease the societal burden of ESRD and its treatment. What is needed is an interventional strategy that both retards CKD progression and reduces CVD morbidity and mortality, simultaneously.
Quoted Karger Article
Modifying Effect of Statins on Fatal Outcomes in Chronic Kidney Disease Patients in the Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis
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Anyanwagu U, Donnelly R, Idris I: Individual and Combined Relationship between Reduced eGFR and/or Increased Urinary Albumin Excretion Rate with Mortality Risk among Insulin-Treated Patients with Type 2 Diabetes in Routine Practice. Kidney Dis 2019;5:91–99
A decrease in glomerular filtration rate (GFR), and an increase in albuminuria are both recognized potential risk factors for cardiovascular disease (CVD) and all-cause mortality (ACM) in both diabetic and non-diabetic subjects. The extent to which these parameters are independent of traditional risk factors (like obesity, hypertension, hyper-lipidemia, smoking, and age) remains controversial. The risks associated with these parameters are not well understood in subjects with type 2 diabetes (T2DM) receiving insulin for management of hyperglycemia.
Anyanwagu and co-workers examined this issue by an observational cohort study enabled by a probe of a large administrative database involving UK primary care practices. Patients with T2DM receiving insulin at baseline (n=18, 227). Four non-overlapping groups were assembled based on entry criteria: group 1- eGFR <60ml/min/1.73m2, and urinary albumin:creatinine ratio (uACR) of >300mg/gm; group 2- eGFR <60ml/min/1.73m2 and uACR <300mg/gm; group 3- eGFR > 60ml/min/1.73m2 and uACR >300mg/gm; group 4- eGFR >60ml/min/1.73m2 and uACR <300mg/gm. The primary end-point examined was ACM with secondary end-points of CVD mortality and morbidity. Using group 1 as the comparator, group 2 had a hazard ratio (HR) for ACM of 0.94 (CI=0.79–1.12); group 3 had a HR for ACM of 0.80 (CI=0.68–0.96; group 4 had a HR for ACM of 0.72 (CI=0.59–0.87). The impact of the intensity of blood pressure control and statin use could not be evaluated. Sodium-glucose transport protein 2 (SGLT2) inhibitors were used in only 0.5% of the subjects studied and the means glycated haemoglobin (HbA1c) at entry was 8.7%, 63% were obese, and 14% were smokers. High uACR was the major driver of adverse outcomes. The combination of low eGFR and high uACR was independently associated with an increased risk for CVD events, even after adjustment for all measured other risk factors. Very clearly, subjects with T2DM treated with insulin and having lower GFR and higher uACR are at the greatest risk for morbidity and mortality. These are the patients who should receive aggressive treatment directed at blood pressure, glycemia, lipidemia, obesity, and smoking. It is possible that newer non-insulin agents, like SGLT2 inhibitors, may alter the landscape for prevention of CVD and CKD in this group of vulnerable patients.
Quoted Karger Article
Individual and Combined Relationship between Reduced eGFR and/or Increased Urinary Albumin Excretion Rate with Mortality Risk among Insulin-Treated Patients with Type 2 Diabetes in Routine Practice
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Roetker NS, Peng Y, Ashfaq A, Gilbertson DT, Wetmore JB: Adherence to Kidney Disease: Improving Global Outcomes Mineral and Bone Guidelines for Monitoring Biochemical Parameters. Am J Nephrol 2019;49:225–232
In 2018, KDIGO updated its clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorders (CKD–MBD). Recommendations and suggestions for monitoring the biochemical disturbances that characterize CKD-MBD were explicitly stated, although the evidence that universal adoption of these guidelines would directly lead to improved patient-centered outcomes was weak or entirely lacking. Nevertheless, these guidelines acquired a “standard-of-care” status in the nephrology community. Compliance to these guidelines has been disappointingly low in small cohort studies.
Using a Medicare administrative data base consisting of claims for Parts A, B and D coverage for 2007–2015 (a period preceding the latest KDIGO guidelines), Roetker and co-workers analyzed the CKD-MBD laboratory testing of iPTH, calcium, phosphorus, alkaline phosphatase, and 25–OH vitamin D in 799,300 Medicare enrollees with CKD, based on International Classification of Diseases (ICD) diagnosis (80 % with stage 3, 17 % with stage 4, and 3 % with stage 5 [non-dialysis] CKD). Approximately ½ of the subjects had diabetes, 90 % had hypertension, and the mean ages were 74–78 years.
Less than ½ of the subjects received any testing for iPTH or 25-OH vitamin D. Testing that was included in comprehensive biochemical profiling (calcium alkaline phosphatase) were performed much more frequently, averaging 88 – 95 %. Older age was associated with less testing and prior nephrology care was associated with increased testing for iPTH and phosphorus levels. The presence of co-morbidity had no consistent relationship with testing character or frequency, with a few exceptions. Given these findings from a very large cohort of Medicare enrollees, it seems likely that secondary hyperparathyroidism and hyperphosphatemia are “underdiagnosed” in CKD, at least in this cohort.
Whether this “deficiency” is contributing to avoidable mortality or morbidity remains very uncertain and cannot be studied in an analysis of this design. A major limitation of the Roetker et al. study is that it can only examine the frequency of testing, not whether abnormal test findings leading to an action of some sort were found. This study does highlight a low compliance to KDIGO CKD-MBD guidelines in aggregate among older adults with “CKD”. This raises questions regarding the accuracy of CKD diagnosis in the older individual (since the glomerular filtration rate [GFR] based diagnostic criteria are not age-adapted). It also poses issues concerning the presence of skepticism or nihilism in the application of guidelines to testing strategies employed by primary care physicians. It is also possible that some degree of lack of awareness of the details of current guidelines contributed to the disturbing findings. Even if an association between compliance to guideline suggestions/recommendations and better patient outcomes existed, it might simply represent the effect of compliance itself on outcomes rather than to any salubrious impact of the guidelines themselves. The gap between CKD-MBD guidelines and direct benefits to patients is large and deserving of much more study, in my opinion.
Quoted Karger Article
Adherence to Kidney Disease: Improving Global Outcomes Mineral and Bone Guidelines for Monitoring Biochemical Parameters
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Anyanwagu U, Donnelly R, Idris I: Albuminuria Regression and All-cause Mortality among Insulin-Treated Patients with Type 2 Diabetes: Analysis of a Large UK Primary Care Cohort. Am J Nephrol 2019;49:146–155
Overt albuminuria (Urine Albumin-to-Creatinine Ratio (UACR) > 300 mg/gm) is a well established biomarker for progression of CKD, all-cause mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Regression of UACR towards normoalbuminuria translates to a lower likelihood of reaching ESRD, but the impact of a regression of albuminuria on mortality is uncertain, especially in insulin-treated subjects with T2DM. Insulin therapy can have proatherogenic activities and promote obesity in T2DM.
Anyanwagu and colleagues studied a large cohort (n = 11,074) of T2DM and overt nephropathy. All treated with insulin in a primary care setting, by employing an administrative database accumulated between 2007 – 2014 in the United Kingdom. The cohort was followed for 5 years and divided into those showing regression of albuminuria (UACR < 300 mg/gm) and those with persistence or worsening albuminuria (> 300 mg/gm; non-regressors). The overall cohort was age 62 years, eGFR of 60 ml/min/1.73m2 at baseline and a HbA1c equal to 8 %.
The 5 years survival was reduced from 95 % to 91 % in the non-regressor population and both all-cause mortality and major atherosclerotic cardiovascular events (mainly strokes) were lower in the regressor population. There was no difference in non-fatal myocardial infarction between the two regression groups. The regression of albuminuria was a result of better glycemic control and / or blood pressure control. Only 14 % of the cohort showed a regression in albuminuria.
This study has numerous weaknesses, including residual confounding, one-time measurement of UACR at baseline, and lack of detail concerning blood pressure (BP) measurements and treatment, a common problem when administrative databases are used in epidemiologic investigations. Nevertheless, the study suggests that regression of albuminuria per se should be regarded as a goal in management of T2DM. The impact of insulin treatment could not be examined as all subjects were treated with insulin. These data also suggest that treatment of subjects with T2DM with agents that aggravate albuminuria might be harmful.
Quoted Karger Article
Albuminuria Regression and All-cause Mortality among Insulin-Treated Patients with Type 2 Diabetes: Analysis of a Large UK Primary Care Cohort
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Daubresse M, Alexander GC, Crews D, Segev DL, McAdams-DeMarco MA: Trends in Opioid Prescribing Among Hemodialysis Patients, 2007–2014. Am J Nephrol 2019;49:20–31
The “opioid epidemic” in the USA is widely reported in many media sources, but data concerning trends in opioid use among patients with specific diseases, other than cancer, is rather sparse.
Daubresse and co-workers have remedied this deficit, in part, by examining opioid use in a longitudinal cohort study of 484,745 patients receiving hemodialysis (HD) therapy in the USA between 2007 and 2014. Opioid use in such patients is quite common — in 2007 62.4 % of patients received one or more opioid prescriptions. However, the rate of opioid prescriptions for HD patients decreased to 53.7 % after a peak in 2010. Opioid use was higher in non-Hispanics and lower-income persons. Not surprisingly, opioid use was more common in HD patients than in the general US population, but the decline in opioid use by HD patients over time outstripped that of the general US population. Chronic pain, of various types and origins, is common among HD patients, but it appears that policies to curb the use of opiates for pain relief are having an effect in both the general US population and in HD patients. Groups with highest opioid use in HD are patients aged 36 – 57 years, women, black, non-Hispanic, disabled, diabetic, and located in specific regions of the US. These data might be used to target educational programs to further curtail the inappropriate use of opioids. The market withdrawal of fentanyl in 2011 probably had an effect on opioid use.
The “opioid epidemic” probably extends to HD patients but it seems to be subsiding, at least in some groups of patients. But much more remains to be done to minimize the apparent over-utilization of these addictive agents in HD patients. Non-opioid pain relievers (e.g. non-steroidal anti-inflammatory agents with analgesic properties) might be under-utilized but this was not the focus of this analysis.
Quoted Karger Article
Trends in Opioid Prescribing Among Hemodialysis Patients, 2007–2014
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Bossola M, Di Stasio E, Monteburini T, Parodi E, Ippoliti F, Cenerelli S, Santarelli S, Nebiolo PE, Sirolli V, Bonomini M, Antocicco M, Zuccalà G, Laudisio A: Recovery Time after Hemodialysis Is Inversely Associated with the Ultrafiltration Rate. doi.org/10.1159/000492919
Patients with ESRD undergoing renal replacement therapy (averaging about 4 hours each) frequently complain of fatigue, sluggishness, weakness and other constitutional symptoms during the immediate post-dialysis treatment period, usually lasting one to several hours. The dialysis recovery time (DRT) is variable and the determinants of this subjective symptom complex is an under-studied area.
Bossola and colleagues carried out an observational study to better define the correlations of DRT with patient characteristics and intra-dialytic parameters in 210 prevalent hemodialysis patients. They used a patient completed survey instrument to determine the per-patient DRT, but it is unclear how many times this survey was completed on a per-patient basis during the conduct of the study, nor is the timing of administration of the survey instrument clearly defined. The overall aim was to determine the relationship between ultra-filtration rate (UFR) and DRT.
The median DRT was 180 minutes (60 – 240 minutes) and 45 % of the patients had DRT ≥ the median value. Frail patients with limitations in daily living activities had a shorter DRT and those with a lower UFR had had a longer DRT. Thus, DRT was inversely related to UFR. Dialysate Na+ concentration, Kt/V and dialysate temperature were not associated with DRT. Changes in serum K+ concentration during and after dialysis was not studied. Prior studies have suggested a “U” shaped relationship between DRT and UFR. The design of this study precludes any mechanistic connection between UFR and DRT. These findings do not mean that UFR should be intentionally increased to reduce DRT, but they do illustrate the complex relationships between the subjective complaints of patients following dialysis and what is done to them during the dialysis session itself.
Quoted Karger Article
Recovery Time after Hemodialysis Is Inversely Associated with the Ultrafiltration Rate
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Brunelli SM, Cohen DE, Marlowe G, Van Wyck D: The Impact of Midodrine on Outcomes in Patients with Intradialytic Hypotension. Am J Nephrol 2018;48:381–388
Hypotension occurring during hemodialysis treatment sessions is a common and vexing problem. It can often be traced to excessive or to rapid ultrafiltration with inadequate or delayed refilling of the intra-vascular volume, sometimes compounded by anti-hypertensive drug use. But, some patients develop symptomatic intradialytic hypotension (IDH) despite relatively normal volume status and in the absence of anti-hypertensive drug use. Such patients frequently are given midodrine (*off-label), an alpha-1 adrenergic receptor agonist, having both veno- and arteriolo- constrictive properties, in an attempt to alleviate IDH and its symptoms. Small, short term trials have generally supported a beneficial effect of midodrine for these indications, but each has had deficiencies in study design, so the evidence for safety and efficacy of midodrine for IDH is weak.
Brunelli and co-workers sought to evaluate the role of midodrine in IDH in a large, retrospective observational matched cohort study involving 1043 midodrine treated patients and 2033 controls. Midodrine use was associated with higher mortality, cardiovascular and all-cause hospitalization rates, even after adjustment for co-variates. This association might have been due to a bias introduced by indications for the use of midodrine.
Importantly, blood pressure (BP) changes during dialysis were initially similar in the two groups, but over time BP fell to a bigger extent in midodrine treated patients despite comparable ultra-filtration rates.
Taken together, and considering the limitations of the study design, these findings raise doubts about the overall efficacy (and safety) of midodrine treatment of IDH. Nonetheless, patient-specific reporting of symptoms were not routinely collected. So, this study is primarily hypothesis-generating. A well designed, adequately powered, long-term randomized, placebo-controlled, double blinded clinical trial embedded with patient self-reported data on symptoms is still required to establish a clear and convincing role for midodrine treatment of IDH.
Quoted Karger Article
The Impact of Midodrine on Outcomes in Patients with Intradialytic Hypotension
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Qu Z, Zhang M, Cui Z, Wang J, Wang M, Zhang Y, Wang F, Wang X, Meng L, Cheng X, Liu G, Zhao M: Antibodies against M-Type Phospholipase A2 Receptor May Predict Treatment Response and Outcome in Membranous Nephropathy. Am J Nephrol 2018;48:438–446
The pathological “pattern-of-injury” designated as membranous nephropathy (MN) is pathogenetically heterogeneous. Among those subjects with this lesion of MN who have apparently primary rather than secondary MN, about 65 – 80 % (depending on the assay used and geographical location of the patient) have a pathogenesis linked to formation of auto-antibodies to the PLA2R antigen. This impact of the presence or absence of anti-PLA2R antibody (and the levels of antibody in the circulation) on outcomes of apparently primary MN have been the subject of intense study in recent years. In general, these studies have strongly suggested that measurement of these auto-antibodies contribute materially to management decisions and prediction of outcomes of PLA2R associated MN, but many uncertainties remain unresolved.
Zhang and co-workers retrospectively examined a large Chinese cohort of patients with apparent primary MN (n = 359), among whom 65 % has anti-PLA2R antibody by an IFA assay and 56 % had anti-PLA2R antibody by an ELISA assay (using a cut-off of 20 RU/ml as positive). Positive antibody levels by ELISA were positively correlated with the magnitude of proteinuria at diagnosis, and failure of antibody levels to become negative (with or without treatment) were highly correlated with no clinical remission (in a smaller cohort of 57 subjects followed serially). Fourteen of 125 patients with negative anti-PLA2R antibody by IFA had positive PLA2R antigen despotism in glomeruli b renal biopsy. None of the PLA2R negative patients in the cohort (n = 125) had anti-THSD7A antibodies or THSD7A antigen deposition. Patients with high levels of anti-PLA2R antibody or PLA2R antigen in glomeruli had higher levels of proteinuria than those with negative studies. A total of 254 patients in the entire cohort (n = 359) were treated with immunosuppressive agents (with or without steroids), and 208 (58 % of the total cohort) achieved a clinical remission (75 with a complete remission, and 133 with a partial remission). Spontaneous remissions occurred in patients with low or absent anti-PLA2R antibody. No remission was correlated with higher levels of anti-PLA2R antibody (by ELISA), higher levels of proteinuria and lower serum albumin levels.
Of the 359 patients in the entire cohort (248 positive for anti-PLA2R antibody, and 111 with negative PLA2R antibody) 12 reached end-stage renal disease (ESRD) and 67 developed a 50 % decline of estimated glomerular filtration rate (eGFR) from baseline during follow-up (total 22 %). Older age, higher levels of anti-PLA2R antibody were associated with a poor renal outcome. With therapy the anti-PLA2R antibody became negative in 80 % of patients, and a lack of a decline in antibody levels was highly correlated with a poor renal outcome. Relapses were infrequent (5/57 patients) and were associated with persistence of anti-PLA2R antibody following treatment.
In summary, this retrospective analysis of a large cohort of Chinese subjects with apparent primary MN adds important new information and specifically adds new knowledge about the impact of assessing anti-PLA2R antibody status for predicting outcomes. Nevertheless, prospectively acquired data form validation studies are still needed.
In an accompanying editorial, Jack FM Wetzels of Nijmegen, The Netherlands, adds a note of caution for the interpretation of this study. First, the ELISA anti-PLA2R antibody assay is not very sensitive. Only 81 % of patients with PLA2R antigen hyper-expression in glomeruli + IFA positive anti-PLA2R antibody (the gold standard for defining a PLA2R associated form of MN) were positive for anti-PLA2R by ELSA (using a cut-off of 20 RU/ml) – a 19 % “false negative” rate. 91 % of patients who were IFA positive also had PLA2R antigen hype-expression in glomeruli. Second, using a definition of < 20 RU/ml (ELISA) as PLA2R-negative introduces a bias since some patients with a true PLA2R associated pathogenesis can have very low antibody levels. Third, the study included patients previously treated with immunosuppressive agents, so the results may not apply to treatment- naïve subjects with MN. Fourth, patients with non-nephrotic proteinuria were included in the analysis which may have introduced a bias in the findings. The main interest is in nephrotic patients with MN as these are the patients requiring treatment, and who may have the poorest outcomes. Finally, the response to treatment of anti-PLA2R antibody positive MN may depend on the levels of antibody (by ELISA) present at diagnosis. The modality employed in treatment may have differential efficacy depending on the levels of anti-PLA2R antibody (see Van de Logt et al. Kidney Int 2018; 87:1263-1264) and the issue concerning responses to treatment of MN by different modalities in anti-PLA2R antibody positive and negative patients with apparent primary MN is still unsettled.
Despite these caveats the study by the Chinese group of investigators has revealed some new insights into the relationships between serology and outcome in MN, and has raised some interesting questions for future studies.
Quoted Karger Article
Antibodies against M-Type Phospholipase A2 Receptor May Predict Treatment Response and Outcome in Membranous Nephropathy
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Ko GJ, Obi Y, Soohoo M, Chang T, Choi SJ, Kovesdy CP, Streja E, Rhee CM, Kalantar-Zadeh K: No Survival Benefit in Octogenarians and Nonagenarians with Extended Hemodialysis Treatment Time. Am J Nephrol 2018;48:389–398
The elderly continue to be a growing segment of patients with end-stage renal disease (ESRD) who are treated by dialysis. As expected, they have a mortality rate largely because of the concomitant burden of comorbidity. The impact of treatment modality and especially treatment session time with hemodialysis (HD) on mortality risk remains uncertain.
Ko and colleagues conducted an observational retrospective study of 112,026 incident HD patients, all 80 years or older at the inception of dialysis treatment (usually thrice weekly) starting between 2007 and 2011. All-cause mortality (ACM) adjusted for 10 co-morbidity factors, and for nutrition-inflammatory parameters, was the outcome of interest. Interestingly, despite many clinical recommendations to the contrary, elderly patients (≥ 80 years of age) tended to have the shortest treatment session times (median = 211 minutes) during the first 91 days after initiation of treatment. Longer treatment times were associated with better survival in those under 80 years of age, but not in those of age 80 years or more. Very short treatment times (< 210 minutes) were associated with increased mortality risk at all ages. Treatment times ≥ 240 minutes were associated with a trend toward higher mortality risk in the elderly (HR = 1.10; 95 % CI = 0.99 – 1.20 reference group 210 – 239 minutes) but the clinical significance of this observation is highly uncertain.
As this study is purely associative in character, no inferences can be made with high confidence that the observed impact of treatment times on mortality are causally related. The crude mortality rates for the entire all ages cohort was 135 deaths per 1000 treatment years. The lowest HR for mortality was seen with a treatment time of 210 – 240 minutes in the age 80 year plus group. The strength of this study lies in the large number of nationally representative patients included in the cohort. An attempt was made to correct for the impact of multiple comorbidities. The association of trend for a worsening mortality risk with extended treatment time (≥ 240 minutes) is an interesting finding, but it might be attributed to a reverse causality phenomenon. In addition, the mortality risk augmentation by short dialysis treatment times (≤ 210 minutes) regardless of age, is a finding that deserves much attention. This observation suggests that a minimum treatment session length (? > 210 minutes) should be recommended for most patients starting dialysis, regardless of age. A value of 240 minutes for the optimal treatment starting length seems advisable for most patients under 80 years of age. The optimal range of treatment session times for those starting dialysis over 80 years of age is deserving of further investigation by prospectively designed interventional trials.
Quoted Karger Article
No Survival Benefit in Octogenarians and Nonagenarians with Extended Hemodialysis Treatment Time
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Kanic V, Kompara G, Suran D, Ekart R, Bevc S, Hojs R: Impact of KDIGO-Defined Acute Kidney Injury on Mortality after Percutaneous Coronary Intervention for Acute Myocardial Infarction. Cardiorenal Med 2018;8:332–339
Acute kidney injury (AKI), defined by rapid and often transient changes in serum creatinine concentration (with or without oliguria), is a common problem, especially in older hospitalized patients undergoing various surgical procedures, including coronary interventions for acute myocardial infarction (AMI). The impact of such episodes of AKI on subsequent mortality is a poorly understood issue, of great contemporary interest.
Kanic and colleagues have narrowed the knowledge gaps in this arena by conducting a retrospective, observational study of 5859 patients with an AMI who underwent percutaneous coronary intervention, of whom 499 (8.5 %) developed AKI (mild stage 1 in 73 %). The end-point examined was all-cause mortality after a median 4.2 years of follow-up. Models were constructed using logistic regression with adjustment of variables different among the groups at baseline.
The adjusted hazard ratio (HR) for cumulative mortality was 2.09 (95 % CI = 1.80 – 2.43) for all stages of AKI and was highest (HR – 6.30 – 95 % CI = 4.69 – 8.48) for stage 3 AKI. But even mild AKI (stage 1) was associated with two-fold increase in mortality risk. Several variables seemed to predict a higher risk of AKI and mortality. Unfortunately, the specific causes of death were not recorded and data on mediations were not collected. A study using propensity matched cohort would have been a better design for answering the questions posed. As with all such observational studies residual confounding could have impacted the results, and causal inferences cannot be made with much confidence.
Nevertheless, this and other studies seem to indicate that even a mild (and usually transient) increase in serum creatinine levels have a “legacy-like” effect lasting several years leading to enhanced mortality risk. The exact mechanism responsible for this apparent association remains obscure and needs further study. It will be important to validate this observation by prospective studies, and to identify possible interventions that might blunt or eliminate this apparent effect of AKI on mortality risk.
Quoted Karger Article
Impact of KDIGO-Defined Acute Kidney Injury on Mortality after Percutaneous Coronary Intervention for Acute Myocardial Infarction
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Furlano M, Loscos I, Martí T, Bullich G, Ayasreh N, Rius A, Roca L, Ballarín J, Ars E, Torra R: Autosomal Dominant Polycystic Kidney Disease: Clinical Assessment of Rapid Progression. Am J Nephrol 2018;48:308–317
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a progressive form of Chronic Kidney Disease (CKD), although there is extensive variability in the progression rate even among families with a presumed identical genetic mutation. This complicates the choice of treatment modalities as Tolvaptan, a vasopressin V2 receptor antagonist, is only approved for treatment of a “rapidly progressive” (RP) phenotype of ADPKD. Several “decision-making” algorithms are available for early identification of “rapid progessors” (eGFR decline of ≥ 5ml/min/1.73m2/year or > 2.5ml/min/1.73m2/year over 5 years) so that Tolvaptan therapy can be appropriately applied.
Furlano and colleagues asses the ERA-EDTA Working Group (WG) algorithm using an expanded definition that included both age and baseline eGFR parameters in a cross-sectional analysis with an 18 month time-frame.
A total of 305 subjects with ADPKD were examined, 73 of whom were eligible for assessment of “rapidly progressive“ definition using:
- Historical eGFR decline
- Historical Total Kidney Volume (TKV) growth (by MRI)
- Changes in kidney length (by ultrasound)
- Age / height adjusted TKV (Mayo Clinic)
- PKD1 / PKD2 mutation analysis can substitute for gender, blood pressure and kidney enlargement (PROPKD criteria)
- A family history of end-stage renal disease (ESRD) due to ADPKD at age < 58 years
A total of 48 patients met the criteria for RP (15.7 % of the overall cohort), 33 % of those 18 – 50 years of age who had a baseline eGFR of > 45 ml/min/1.73m2. In patients ages 18 – 55 years of age with a baseline eGFR of > 25 and < 45 ml/min/1,73m2 the overall proportion of patients with RP rose to 27 % and a further increase in treatment eligibility was observed for patients with a well preserved initial eGFR if serial imaging tools are taken into account.
This study clearly illustrates how selection criteria influence the percentage of subjects with ADPKD with presumed RP. With the most conservative approach (ERA-EDTA WG) about 1:6 patients will become eligible for Tolvaptan treatment. With expanded criteria, using age and baseline eGFR, the percentage eligibility can rise to about 1:4 patients.
These expanded criteria need additional external validation, as the decision to initiate Tolvaptan therapy in ADPK is one having major consequences.
Quoted Karger Article
Autosomal Dominant Polycystic Kidney Disease: Clinical Assessment of Rapid Progression
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Tsai M-H, Hsu C-Y, Lin M-Y, Yen M-F, Chen H-H, Chiu Y-H, Hwang S-J: Incidence, Prevalence, and Duration of Chronic Kidney Disease in Taiwan: Results from a Community-Based Screening Program of 106,094 Individuals. Nephron 10.1159/000491708
The rate of progression of CKD from one KDIGO defined category (”stage”) to subsequent “stages” (called “dwell time”(DT)) is commonly variable, pending in large part on the specific disease characteristics of the patient population examined (e.g. slow in most patients with ADPKD and often rapid in crescentic glomerulonephritis). Few epidemiological studies have attempted to address this feature of CKD using large data-sets and population cohorts.
Tsai and co-workers examined the “dwell time” in a Taiwanese adult population of CKD Category 3 – 5 (defined by eGFR < 60 ml/min/1.73m2 by the CKD-EPI eGFR equation, without dialysis) over 10 years (from 1999-2009). Dipstick proteinuria was also evaluated. The “dwell time” was represented by the ratio of prevalence to incidence of CKD at various intervals of time for the categories of CKD examined. A short DT was equal to: 1) Premature death; 2) Starting dialysis for ESRD or an aberrant increase in CKD incidence. A total of 106,964 participants were examined (average age 47 years). The overall prevalence of CKD (any category) in this cohort was 15.4 %; 9.6 % in category 3 – 5 CKD, 60 % of whom were women and 5 % diabetic. The overall incidence of CKD category 3 – 5 was 16.89/1000 patients years. Except for diabetes, the cause of CKD was not specified in any patient.
The overall DT for CKD 3 – 5 was 5.35 years (95 % CI = 5.12-5.57). The calculated value for DT was shorter in younger men than in older women and in those with diabetes and metabolic syndrome. The absence of disease diagnosis and a more quantitative approach to the role of proteinuria in determining DT are major weakness of this study. The data do provide some gross descriptive data of progression of CKD but much more “granularity” of the data will be required to translate the findings into meaningful actions to impact the rates of progression and to prolong the DT.
Quoted Karger Article
Incidence, Prevalence, and Duration of Chronic Kidney Disease in Taiwan: Results from a Community-Based Screening Program of 106,094 Individuals
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Garza-Mayers AC, Shah R, Sykes DB, Nigwekar SU, Kroshinsky D: The Successful Use of Apixaban in Dialysis Patients with Calciphylaxis Who Require Anticoagulation: A Retrospective Analysis. Am J Nephrol 2018;48:168–171
Calciphylaxis is a serious, potentially life-threatening complication of ESRD that may be precipitated (or aggravated) by vitamin K antagonists (such as warfarin) used for necessary anticoagulation. Alternative non-warfarin anti-coagulation strategies are now available by use of oral direct factor Xa antagonism (apixaban or rivaroxaban), but the effect on employing these new strategies in patients with ESRD and calciphylaxis is unknown.
Shah and co-workers conducted a chart review of the use of apixaban in ESRD (dialysis treated) in patients with new onset calciphylaxis previously receiving warfarin for deep vein thrombosis (DVT) or non-valvular atrial fibrillation (AFib) under the care of physicians at the Massachusetts General Hospital or the Brigham and Women’s Hospital in Boston between 2011 and 2017. 41 patients were identified that had both calciphylaxis and apixaban therapy, 20 of whom were on dialysis therapy for ESRD. Apixaban was given for approved indications of DVT or non-valvular AFib. 18 patients showed “improvement” of the calciphylaxis during apixaban use and the one-year mortality was 20 %. 2 patients experienced further progression of calciphylaxis while receiving apixaban and died within 30 days. 4 of the 20 patients (20 %) experienced bleeding complications, 3 of whom required blood transfusions.
This small uncontrolled experience is modestly encouraging, but needs confirmation. Nevertheless, a 90 % improvement in calciphylaxis and a 20 % serious bleeding rate suggests a favorable benefit to risk relationship.
Quoted Karger Article
The Successful Use of Apixaban in Dialysis Patients with Calciphylaxis Who Require Anticoagulation: A Retrospective Analysis
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Ikenoue T, Koike K, Fukuma S, Ogata S, Iseki K, Fukuhara S: Salt Intake and All-Cause Mortality in Hemodialysis Patients. Am J Nephrol 2018;48:87–95
The relationships between sodium chlorid (NaCl) intake and clinical outcomes in hemodialysis patients (such as mortality rates) are difficult to study and controversial. Urinary NaCl excretion rate, a valid method to estimate daily consumption of NaCl in subjects with normal renal function, cannot be used in subjects with advanced chronic kidney disease (CKD) receiving hemodialysis (HD; especially in anuric subjects).
Ikenoue and colleagues conducted a retrospective, registry-based (hypothesis generating) study in 88,116 Japanese prevalent HD patients in order to determine the association of estimated (not measured) NaCl intake with all cause (cancer excluded) and cardiovascular disease (CVD) mortality. NaCl intake was estimated from intra-dialytic weight loss as a surrogate for inter-dialytic weight gain. The follow-up for determining the selected outcomes was only one year. About 34 % of the patients included in the study had missing data. The data points were imputed in the study design in these patients.
Surprisingly, at least to me, estimated NaCl intake in the low range (< 6 gm NaCl/d) was associated with the highest all-cause mortality (ACM), even after adjustment for multiple confounding variables, except for smoking. The lowest risk for ACM was observed at a NaCl intake of 9 gm/d. There was a “hint” of a “U” shaped curve for ACM but not CVD mortality in the comparisons with estimated NaCl intake.
While rigorous in design and analysis, this study cannot implicate low NaCl intake as a causal factor in enhancement of ACM or CVD mortality rates. In addition, the follow-up times for calculation of event rates were quite short (only one year). Furthermore, as this was a registry-based study, it was not possible to validate the accuracy of the NaCl intake estimates by use of intra-dialytic weight loss. The exclusively Japanese character of this study limits its application to other populations. The high “missing” data points are also of concern.
While current guidelines concerning ideal NaCl intake for HD patients suggest values of < 6 gm/d no interventional controlled studies have demonstrated that these values are optimal. This study, despite its flaws, provides some weak but tantalizing evidence that low NaCl intake may be harmful. But, I would suspend judgement on this conclusion until interventional trials are executed using direct measurement of NaCl intake (by dietary history recall) comparing longer term outcomes with high and low NaCl intake. This would not be an easy study to conduct, due to effect of varying NaCl intake on inter-dialytic weight gain and the need for aggressive ultrafiltration during dialysis session. But at least it might shed some light on the validity of using inter-dialytic weight loss as an estimate of NaCl intake, which is at the core of this hypothesis generating study.
Quoted Karger Article
Salt Intake and All-Cause Mortality in Hemodialysis Patients
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Zhou H, Yang M, Jiang Z, Ding J, Di J, Cui L: Renal Hypoxia: An Important Prognostic Marker in Patients with Chronic Kidney Disease. Am J Nephrol 2018;48:46–55
An adaptation of magnetic resonance imaging (MRI) technology has made it possible to non-invasively asses the state of blood oxygenation in renal tissue (tissue deoxyhemoglobin concentration or R2*), also called BOLD-MRI.
Zhou and colleagues studied 60 patients with various forms of CKD (mostly diabetes-related and glomerulonephritis) by BOLD-MRI in a prospective observational design. Both cortical (CR2*) and medullary (MR2*) oxygenation levels were assessed separately. A Kaplan-Meier analysis showed that the lowest CR2* levels (better oxygenation, lower deoxyhemoglobin) predicted a favorable outcome determined by an end-point of a 30 % or more decline in GFRe from baseline GFR or ESRD, after a median follow-up of 3.2 years. The association of high CR2* (poorer oxygenation) with unfavorable outcomes persisted after adjustment for possible confounding variables (age, gender, diabetes, proteinuria, but not therapy). The level of CR2*, but not that of MR2*, were reasonably reproducible. The study did not examine whether interventions designed to enhance tissue oxygenation improved outcomes, so these findings are primarily correlative and not causal in nature. This study is largely confirmatory of other studies [1]. Nevertheless, this is a promising new beginning for an old avenue of research highlighting a possible important role of tissue hypoxia in progression of CKD. Whether high deoxygenation of renal cortical tissue is modifiable biomarker of CKD progression must await further studies. An adaptive increase in oxygen consumption of hypertrophied residual nephrons in the face of constant or decreasing supply of oxygen is a distinct possible explanation for these findings.
References
1. Pruijm M et al., Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease. Kidney Int. 2018 Apr;93(4):932-940
Quoted Karger Article
Renal Hypoxia Detected by Blood Oxygen Level-Dependent-MRI: A Prognostic Marker in Chronic Kidney Disease?
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Song JJ, Lee KB, Hyun YY, Kim H: Trace Albumin in the Urine Dipstick Test is Associated with Coronary Artery Calcification in Korean Adults. Nephron 10.1159/000490954
Albuminuria, even in the high normal range (> 10 and < 30 mg/d), is associated with the presence or development of cardiovascular disease (CVD), including atherosclerotic CVD. Whether this association is directly causal or reverse causal is not known. Coronary artery calcification (CAC) is believed to be a useful non-traditional predictor of CVD, although this is debated [1].
Song and co-workers conducted an observational, cross-sectional study of 46,002 Korean adults, all without known prior CVD, in whom both CAC scoring and urine dipstick for albuminuria were performed (the latter only once; randomly). Three groups were analyzed: group I – negative for albuminuria; group II – trace for albuminuria; group III – positive (1 – 4+) for albuminuria. An abnormal CAC score was defined as > 100 units.
The % with an abnormal CAC score were 2.0 % in group I, 2.8 % in Group II and 4.9 % in group III. The odds ratios for an abnormal CAC score were 1.72 (CI = 1.10 – 2.41) for group III and 1.34 (CI = 1.07 – 1.64) for group II using group I as the reference, in a “fully adjusted” model. The association of low-grade albuminuria with elevated CAC scores could be due to common risk factors, or due to low-grade underlying inflammation and endothelial dysfunction. Whether the use of trace albuminuria by dipstick will be a useful simple screening test for the presence of underlying CAC is unknown. The use of a single urine test in this study is a weakness as it is well known that single urine testing for albuminuria has a high false-positive rate.
References
1. Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Kemper AR, Kubik M, Landefeld CS, Mangione CM, Silverstein M, Simon MA, Tseng CW, Wong JB: Risk Assessment for Cardiovascular Disease with Nontraditional Risk Factors: US Preventive Services Task Force Recommendation Statement. JAMA 2018; 320:272-280
Quoted Karger Article
Trace Albumin in the Urine Dipstick Test is Associated with Coronary Artery Calcification in Korean Adults
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Kraut J & Madias N: Re-Evaluation of Total CO2 Concentration in Apparently Healthy Younger Adults. Am J Nephrol 2018;48:15–20
Surprisingly, the normal limits of venous serum total CO2 (tCO2; a surrogate for serum HCO3- concentration) in adults are not well established.
Kraut and Madias set out to correct this deficiency by examining the tCO2 levels of venous serum in 28,480 apparently normal young adults (ages 18 – 40 years; mean age = 28.9 ± 5.1 years). 91 % of the values fell between 23 – 30 mmol/l – a span of only 8 mmol/l between high and low normal values. Many clinical laboratories report a wider range of values with lower limits of 18 – 25 mmol/l and upper limit of normal of 26 – 35 mmol/l. Interestingly, in this study there was a small but consistent gender difference in the normal values for serum tCO2; slightly higher values in males than females (about a 1.6 mmol/l difference on average). Pre-menopausal females may experience greater alveolar ventilation than males due to the effects of progesterone. One might expect these gender differences to disappear after menopause and to be aggravated with pregnancy. The influence of diet (e.g. vegan vs omnivore) could not be assessed in this study, but one might expect somewhat higher levels of tCO2 in vegans.
The main message of this paper is that when venous serum tCO2 levels are < 23 or > 30 mmol/l, an arterial blood gas measurement should be undertaken to define the nature of the acid-base disturbance, unless the cause and mechanism of the abnormality is obvious.
Quoted Karger Article
Re-Evaluation of Total CO2 Concentration in Apparently Healthy Younger Adults
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Gaspari F, Thakar S, Carrara F, Perna A, Trillini M, Aparicio MC, Diadei O, Ferrari S, Cannata A, Stucchi N, Ruggenenti P, Remuzzi G, Perico N: Safety of Iohexol Administration to Measure Glomerular Filtration Rate in Different Patient Populations: A 25-Year Experience. Nephron 10.1159/000489898
The current estimating equations for glomerular filtration rate (GFR) exhibit consistent inaccuracies (bias and precision) and as a result from time-to-time a measurement of GFR (mGFR) is both necessary and appropriate. The classic, “gold standard” urinary inulin clearance method, pioneered by Homer Smith more than 80 years ago, is too cumbersome for routine clinical use and as a result, various simpler methods of assessing mGFR have evolved. The plasma disappearances of non-radioactive, non-ionic iohexol has been very widely used for this purpose. This method entails multiple collections of venous blood after a single bolus infusion of iohexol. As iohexol contains iodine, concerns have arisen regarding safety and hypersensitivity reactions.
Gaspari and co-workers from Bergamo, Italy, have had extensive experience in using iohexol plasma disappearance as a means of obtaining a mGFR for over 25 years entailing over 15,000 procedures. They are in a very good position to examine these postulated safety concerns. In a detailed survey of their experience, they found an overall rate of iohexol related adverse events to be 0.0066 % or 6.6 / 100,000 procedures. Thus, the safety of the procedure is verified. Other issues remain. Iohexol plasma disappearance requires multiple blood samples (2 – 5) over several hours (even greater numbers in patients with impaired kidney function) rendering the procedure somewhat labor intensive. Although it is more accurate than eGFR in many circumstances, the iohexol plasma disappearance provides mGFR values that are not in perfect agreement with “gold standard” urinary inulin clearance method (for details see [1,2] ), but these variations are of doubtful clinical significance. Hopefully, simpler, cost-effective and accurate methods of assessing mGFR on a routine clinical basis will evolve in the not too distant future [3]. But it is quite clear that the answer to the Question posed by short essay is that iohexol plasma disappearance is a quite safe procedure.
References
1. Delanaye P, Ebert N, Melsom T, Gaspari F, Mariat C, Cavalier E, Björk J, Christensson A, Nyman U, Porrini E, Remuzzi G, Ruggenenti P, Schaeffner E, Soveri I, Sterner G, Eriksen BO, Bäck SE. Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 1: How to measure glomerular filtration rate with iohexol? Clin Kidney J. 2016 Oct;9(5):682-99
2. Delanaye P, Melsom T, Ebert N, Bäck SE, Mariat C, Cavalier E, Björk J, Christensson A, Nyman U, Porrini E, Remuzzi G, Ruggenenti P, Schaeffner E, Soveri I, Sterner G, Eriksen BO, Gaspari F. Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 2: Why to measure glomerular filtration rate with iohexol? Clin Kidney J. 2016 Oct;9(5):700-4
3. Wang E, Meier DJ, Sandoval RM, Von Hendy-Willson VE, Pressler BM, Bunch RM, Alloosh M, Sturek MS, Schwartz GJ, Molitoris BA. A portable fiberoptic ratiometric fluorescence analyzer provides rapid point-of-care determination of glomerular filtration rate in large animals. Kidney Int. 2012 Jan;81(1):112-7
Quoted Karger Article
Safety of Iohexol Administration to Measure Glomerular Filtration Rate in Different Patient Populations: A 25-Year Experience
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Fujisaki K, Tanaka S, Taniguchi M, Matsukuma Y, Masutani K, Hirakata H, Kitazono T, Tsuruya K: Study on Dialysis Session Length and Mortality in Maintenance Hemodialysis Patients: The Q-Cohort Study. Nephron 10.1159/000489680
The dialysis treatment session length (DSL) in conventional thrice weekly hemodialysis therapy has been long suspected to contribute importantly to the “adequacy” of therapy for end stage renal disease (ESRD) independent of dose of therapy (spKt/V urea). However, the independent impact of DSL on patient centered outcomes (such as survival and hospitalization rates) has been difficult to quantify by randomized trials. Nevertheless, short DSL (less than 3 – 4 hours) has been suspected to represent “inadequate” treatment, especially in those patients with high inter-dialytic weight gain mandating high intra-dialytic ultrafiltration rates (often exceeding 13 ml/kg/hour), frequently observed in oliguric subjects with little residual renal function.
Upon this background of uncertainty, Fujisaki and co-workers report on a prospective, propensity-matched cohort study (“Q Cohort Study”) conducted in Japan between 2006 and 2010 examining the risk factor of DSL and its association with all-cause mortality (ACM) in conventional thrice weekly hemodialysis. They studied 3486 prevalent hemodialysis patients (average age 64 years, dialysis vintage 7.7 years) followed for 4 years. In a propensity match sub-cohort (n = 1934), a DSL of 4.1 hours was compared to a DSL of 5.1 hours. Subjects with DSL of 5 hours or more had a slightly higher spKt/V urea of 1.6 ± 0.3 versus 1.5 ± 0.3 for those with a DSL of < 5 hours. Unfortunately, no data is available on residual renal function so the study may be biased by treatment indication as this was not a randomized trial. Nevertheless, in a propensity-matched, fully adjusted analysis the hazard rate (HR) for ACM was 22 % lower in the long-DSL cohort (p = 0.12). The impact of long-DSL was more pronounced in the very elderly (> 80 years) and not significant in subjects younger than 80 years. It needs to be emphasized that this is a study of DSL in prevalent but not incident hemodialysis patients. In addition, only ACM not cardiovascular mortality was examined. Earlier studies have largely supported the concept that short DSL (< 4 hours) with conventional thrice weekly treatment sessions can be associated with an increased risk of mortality when applied in incident patients, especially with low values for residual renal function or oliguria. But randomized clinical trials, usually with DSA of < 4.5 hours, have generally failed to demonstrate beneficial effects of longer DSL, but some of these studies may have been underpowered to show such effects or have confounding variables affecting interpretation. It does seem fairly clear that short-DSL obligate higher intra-dialytic ultrafiltration rates that can have a deleterious effect on long term survival.
While supplying mostly moderately weak evidence, this study does support the notion that longer DSL is better (at least for the elderly prevalent dialysis patient. But more well-powered randomized trials in subjects with minimal residual renal function are still needed to determine the optimal DSL in thrice weekly conventional hemodialysis, both in incident and prevalent patients of varying age and dialysis vintage. In the meantime, in my opinion, any DSL of < 4 hours with a thrice weekly schedule of treatments should not be regarded as “adequate” in a patient with ESRD and minimal residual renal function, independent of spKt/V.
Quoted Karger Article
Study on Dialysis Session Length and Mortality in Maintenance Hemodialysis Patients: The Q-Cohort Study
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Bikbov B, Perico N, Remuzzi G: Disparities in Chronic Kidney Disease Prevalence among Males and Females in 195 Countries: Analysis of the Global Burden of Disease 2016 Study. Nephron 10.1159/000489897
The presence of CKD in adults (mostly older) is a common global problem, although the precise incidence and prevalence of CKD, the changes in frequency over-time and its variation between and within countries, ancestries and genders remain a matter of controversy. The Global Burden of Disease (GBD) Study has provided much useful information on the epidemiology of this important socio-medial issue.
Bikbov and colleagues have added to our knowledge of this issue by conducting a systematic review, including unpublished studies, in order to examine CKD prevalence rates in 195 countries, using 6 categories of CKD, largely based on the KDIGO schema of estimated glomerular filtration rate (eGFR) and albuminuria, including those subjects receiving renal replacement therapy (RRT; dialysis, or renal transplantation). In this study emphasis was placed on disparities between countries that are resource rich or poor and upon gender based differences in epidemiology of CKD, so defined. Impaired kidney function (IKF) is a term introduced by the GBD to encompass the 6 subgroups of CKD, defined by eGFR and/or albuminuria.
According to this study, the global prevalence of IKF (in adults) was 753 M in 2016, or about 1 in 9 adults (≈ 120,000 pmp). The male (M) / female (F) ratio was 0.80 (different from the general population M : F ratio = 1.01). Abnormal albuminuria with preserved GFR accounted for 467 M of 753 M (62 %) while a GFR of 45 – 59 ml/min/1,73m2 accounted for 243 M of 753 M (32 %). Patients with RRT accounted for only 3.7 M of 753 M (0.5 %). Interestingly, the M : F ratio was 1.31 among those with RRT. Thus, a great gender disparity exists for both pre end-stage renal disease (ESRD) and ESRD with RRT, but in completely opposite directions. The RRT prevalence also varied considerably between countries. In 38 of 195 countries the dialysis RRT prevalence rate was < 20 pmp and in 52 of 195 countries the renal transplantation RRT prevalence rate was 0 – 10 pmp. The M : F ratio for both CKD and RRT varied widely between counties and gross domestic product (GDP) but the M : F ratio for CKD showed no correlation with GDP. However, the dialysis / renal transplantation prevalence ratio was sensitive to GDP in both M and F, implying an important socio-economic impact on access to transplantation.
The interpretation of these findings is complex. Many of the studies identifying CKD used only one determination of eGFR or albuminuria, so an overestimation (of about 30 %) for the prevalence of pre-ESRD due to “false positives” is very likely. While part of the gender disparity of the pre-ESRD CKD prevalence can be attributed to the use of a single (non-gender or age stratified) GFR (< 60 ml/min/1.73m2) for defining CKD, the observation that CKD defined by albuminuria alone (again not gender stratified) is higher in women indicates that the arbitrary selection of GFR thresholds for defining CKD is not the whole explanation for the observed gender disparities in CKD prevalence. If abnormal proteinuria in women is linked to fetal dysmaturity and consequent nephron under-development, it is possible that this might play a role in inter-generational transfer of CKD risk and prevalence.
The higher prevalence of RRT in males is commonly observed but its explanation remains poorly understood. It could bed due to a greater propensity for CKD to progress to ESRD in males compared to females. Perhaps women are being excluded from RRT for other reasons in low-GDP countries, but similar M : F ratios (> 1.1) are observed for RRT in high-GDP countries. Gender inequalities of access to renal transplantation are implied by very high M : F ratios for functioning renal transplants in some countries.
The global gender disparity issues in CKD epidemiology are very complex and multi-factorial, but are deserving of careful study and rigorous analysis in order to identify causative factors.
Quoted Karger Article
Disparities in Chronic Kidney Disease Prevalence among Males and Females in 195 Countries: Analysis of the Global Burden of Disease 2016 Study
