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Yaqub S., Hashmi S., Kazmi M.K., Aziz Ali A., Dawood T., Sharif H.: A Comparison of AKIN, KDIGO, and RIFLE Definitions to Diagnose Acute Kidney Injury and Predict the Outcomes after Cardiac Surgery in a South Asian Cohort. Cardiorenal Medicine DOI 10.1159/000523828
Various definitions of acute kidney injury (AKI) are in common use, globally. But comparisons of the utility of these definitions for AKI following cardiac surgery have come to differing conclusions.
Yaqub and co-workers have conducted a single-center retrospective review of the receiver operating characteristics of the Acute Kidney Injury Network (AKIN), Kidney Disease Improving Global Outcomes (KDIGO), and the Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) in 1,508 subjects undergoing coronary artery bypass surgery during 2015–2019 in South Pakistan. Only changes in serum creatinine were used in applying the definition.
AKI by any definition or stage was found postoperatively in 59% of the subjects – 34% by AKIN, 35% by KDIGO, and 58% by RIFLE. AKIN Stage 2 was found in 8.9%, KDIGO Stage 2 in 10.1%, and RIFLE injury in 13.5% of the subjects. Stage 3 AKI was uncommon by any definition (about 2–3%). RIFLE identified risk in more patients than Stage 1 in either AKIN or KDIGO. Any AKI, regardless of definition or stage, was associated with an increase in 30-day mortality rate, and the RIFLE criterion was superior to both AKIN or KDIGO in the prediction of 30-day mortality rate.
This analysis gives useful insights into the utility of various criteria for the definition of AKI. The question remains if this is generalizable to other settings and other forms of cardiac surgery. The reproducibility of the diagnostic criteria was not studied. It is noteworthy that AKI Stage 3 (AKIN/KDIGO) or loss (RIFLE) was very uncommon in this cohort of subjects.
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A Comparison of AKIN, KDIGO, and RIFLE Definitions to Diagnose Acute Kidney Injury and Predict the Outcomes after Cardiac Surgery in a South Asian Cohort
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Chedid M, Hanna C, Zaatari G, Mkhaimer Y, Reddy P, Rangel L, Zubidat D, Kaidbay D.H.N, Irazabal M.V, Connolly H.M, Senum S.R, Madsen C.D, Hogan M.C, Zoghby Z, Harris P.C, Torres V.E, Johnson J.N, Chebib F.T: Congenital Heart Disease in Adults with Autosomal Dominant Polycystic Kidney Disease. Am J Nephrol DOI 10.1159/000522377
The optimum dosage and preparation of renin-angiotensin system inhibitors (RASi) for slowing the progression of progressive proteinuric CKD remains somewhat uncertain, although it is generally appreciated that these agents exert their beneficial effects lately via lowering of systemic arterial and intra-glomerular capillary blood pressure. Both of these effects play a role in lowering the magnitude of proteinuria, and thus the rate of progression.
Suehiro and co-workers examined the relative effects of azilsartan and candesartan (both angiotensin receptor blockers; ARBs) on proteinuria and systemic arterial pressure in 111 patients with CKD (14% with diabetic kidney disease, 53% with chronic glomerulonephritis, and 28% with “hypertensive” nephropathy). The baseline proteinuria (urine protein to creatinine ratio; UPCR) was 1.8 ± 1.8 g/gCr and the eGFR was 42 ± 20 mL/min/1.73 m2. The average baseline blood pressure was 131/71 mm Hg. The dosage was 20 mg/day for azilsartan and 6 mg/day for candesartan. The trial was a randomized, cross-over design and the follow-up was 3 months. The primary endpoint was the percentage change in UPCR from baseline. Sodium chloride intake was not controlled.
At the end of study, the mean percentage change in UPCR was +6.1% in the azilsartan group and +25.8% in the candesartan group. Adverse events were similar. Average systolic blood declined at the end of the study in the azilsartan group and increased in the candesartan group. The change in UPCR was correlated with the decline in systemic arterial blood pressure.
This study confirms the generally well-known superior efficacy of azilsartan for blood pressure control, but only one dose (20 mg/day) was compared to one dose (6 mg/day) of candesartan. In the absence of a dose ranging study it is unknown whether the effects of higher doses of either agent would confirm this superiority of azilsartan over the entire range of commonly used dosages. Also, the lack of controlling for sodium chloride intake is a confounder in this study. The benefits on proteinuria track with the systemic anti-hypertensive effects, so it is unknown whether the superior anti-proteinuric effects of azilsartan are due to a systemic or an intra-renal effect (or both). The short duration of the study precluded any conclusions concerning beneficial effects on CKD progression. Nevertheless, this study does indicate that azilsartan might be the preferred agent for achieving blood pressure control and reducing proteinuria in patients with “generic” CKD. Larger and longer studies will be required to confirm this hypothesis and the beneficial effects may differ between the categories of CKD defined by etiology (particularly diabetic vs. glomerulo-nephritic CKD).
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Congenital Heart Disease in Adults with Autosomal Dominant Polycystic Kidney Disease
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Soohoo M, Obi Y, Rivara M.B, Adams S.V, Lau W.L, Rhee C.M, Kovesdy C.P, Kalantar-Zadeh K, Arah O.A, Mehrotra R, Streja E: Comparative Effectiveness of Dialysis Modality on Laboratory Parameters of Mineral Metabolism. Am J Nephrol DOI 10.1159/000521508
The comparative effectiveness of various modalities of dialysis in patients with kidney failure has long been controversial, in large part due to the paucity of long-term randomized clinical trials. Soohoo and coworkers sought to examine the laboratory biomarkers of chronic kidney disease-metabolic bone disease (CKD-MBD) in a large cohort of patients receiving a variety of dialysis modalities, using an administrative database accumulated between 2002 and 2011. The analysis was conducted by inverse-weighted marginal structural modelling.
Using conventional thrice weekly in-center hemodialysis as the comparator, patients with nocturnal in-center hemodialysis had lower PTH and phosphate levels, whereas patients undergoing peritoneal or home hemodialysis had higher levels of PTH but lower levels of phosphate. Serum calcium and alkaline phosphatase levels showed no systematic differences that were modality dependent.
This study was focused on laboratory parameters commonly used as biomarkers for CKD-MBD. As such, no data is provided concerning important outcome measures, such as mortality, fractures, and hospitalization. In addition, dietary measures, timing of blood sampling, and vitamin D status were not included. Only phosphate binder and oral/IV vitamin D use were analyzed.
This study is primarily hypothesis generating and is likely confounded by many unmeasured variables. Whether it indicates that modality selection is an important and independent determinant in the risk of developing CKD-MBD remains uncertain, but is deserving of further study.
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Comparative Effectiveness of Dialysis Modality on Laboratory Parameters of Mineral Metabolism
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Friedrich A.C, Linz P, Nagel A, Rosenhauer D, Horn S, Schiffer M, Uder M, Kopp C, Dahlmann A: Hemodialysis Patients with Cardiovascular Disease Reveal Increased Tissue Na+ Deposition. Kidney and Blood Pressure Research DOI 10.1159/520821
Sodium balance in patients with kidney failure treated by dialysis is highly variable and incompletely understood, in pathophysiological terms. Sodium excess is linked both to hypertension and cardiovascular disease (CVD), particularly heart failure. Some of the excess sodium retained in CKD is stored in skin (and muscle), non-osmotically. The role of this storage of retained sodium in the pathogenesis of CVD remains uncertain.
Friedrich and colleagues examined this issue in an observational study of hemodialysis patients with (n=23) and without (n=29) overt CVD. 23Na- MRI at 3.0 Tesla was used to quantify the sodium content of skin and muscle before and after a dialysis treatment session. Body fluid distribution parameters were examined by bioimpedance spectroscopy.
Skin and muscle sodium content was increased in those with overt CVD, bur extracellular water levels were similar in both groups. Those patients with high skin or muscle sodium content had higher levels of inflammatory markers (Il-6) than those without such increased levels of sodium in skin or muscle. The causal pathways responsible for these associations could not be determined due to the study design, but the findings support the hypothesis that skin/muscle (non-osmotic) storage of sodium in CKD is somehow involved in the pathogenesis of CVD.
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Hemodialysis Patients with Cardiovascular Disease Reveal Increased Tissue Na+ Deposition
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Parasyri M, Brandström P, Uusimaa J, Ostergaard E, Hikmat O, Isohanni P, Naess K, de Coo I.F.M, Nascimento Osorio A, Nuutinen M, Lindberg C, Bindoff L.A, Tulinius M, Darin N, Sofou K: Renal Phenotype in Mitochondrial Diseases: A Multicenter Study. Kidney Diseases DOI 10.1159/000521148
Disorders of mitochondria (MT), often due to mutations of the MT genome, are uncommon and usually present in infancy or childhood. The kidney aspects of these disorders are quite varied.
Parasyri and coworkers conducted a, multi-institutional retrospective cohort study (m=36) using data collected by the European Consortium of the Mitochondrial Clinical Research Network (MCRN). The median age of onset was 2 years (range pre-natal to 67 years). Kidney manifestations were the first sign of MT disease in about 20% of the subjects. Anemia, hearing impairment, epilepsy and multi-organ involvement was common. Fanconi syndrome was present in about 15% of the subjects. Acute kidney injury was the presenting feature in about 20% and chronic kidney disease in about 75% of patients. About 10% 0f the cases had MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke –like Episodes). Interestingly Cystatin C eGFR was more accurate measure than eGFR creatinine in these cases.
The study provides wealth of information concerning the diagnosis and prognosis of these rare diseases.
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Renal Phenotype in Mitochondrial Diseases: A Multicenter Study
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Zuo Y, Cavalcante L.B, Smelser J.M, Sanghani N, Dwyer J.P, Lewis J.B, Fogo A.B: Anti-Phospholipase A2 Receptor in Nonlupus Patients with Membranous Nephropathy and Crescents. Glomerular Diseases DOI 10.1159/000520641
Primary membranous nephropathy (pMN) (that form not associated with systemic disease, like SLE) can occasionally present with or develop super-imposed crescentic glomerulonephritis (GN), along with rapidly progressive deterioration of kidney function. The pathogenesis underlying this uncommon event can often be linked to the appearance of ANCA-associated vasculitis (AAV) or anti-GBM (aGBM) disease, but the role of anti-PLA2R antibodies in this subset of pMN is largely unknown.
Zuo and co-workers retrospectively analyzed a cohort of 16 cases of pMN (5 females and 11 males) who had developed crescentic GN, with particular attention to their PLA2R status, using PLA2R staining of biopsy material, compared to ANCA and anti-GBM antibody pathogenesis.
The mean age was 61 years, average proteinuria at presentation 4.97 g/day, and initial serum creatinine was 4.68 mg/dL. Two patients (13%) had anti-GBM disease; 9 (of 11 tested) (56%) had ANCA; and 5 had neither ANCA nor anti-GBM or were unknown. Five of the 16 patients were PLA2R antigen positive (none of the anti-GBM cases were positive for PLA2R antigen). The crescentic disease and pMN were discovered concurrently in 14 cases, and crescentic disease followed pMN in 2 cases. Overall, 78% of the patients with concurrent pMN and crescentic GN were either ANCA or anti-GBM positive and 69% were PLA2R antigen negative.
A retrospective study of such a small cohort cannot uncover the discrete pathogenic links between PLA2R and crescentic glomerular disease in pMN. But the findings indicate that complicating crescentic disease in pMN (regardless of PLA2R status) is commonly due to well-defined auto-immune processes. Whether this is due to a common underlying genetically determined predisposition (for example due to HLA specificities on chromosome 6) or due to release of auto-antigenic epitopes from damaged podocytes or GBM, or both, remains uncertain.
Quoted Karger Article
Anti-Phospholipase A2 Receptor in Nonlupus Patients with Membranous Nephropathy and Crescents
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Villacorta J., Martinez-Valenzuela L., Martin-Capon I., Bordignon-Draibe J.: Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Toward an Individualized Approach. Nephron DOI 10.1159/000520727
Individualized (precision) therapy of ANCA-associated vasculitis (AAV) is a goal that will likely improve long-term outcomes of this very pathogenically heterogenous and clinically variable disorder. Genetics, environment, and serology contribute to the spectrum of clinical presentations and course of the group of disorders covered under the generic heading of AAV. They are presently divided into anti-proteinase 3 (aPR3) and anti-myeloperoxidase (aMPO) antibody subsets. A fraction (about 20%) will have concomitant anti-GBM, and rarely both aPR3 and aMPO may coexist. A major question is whether the approach to treatment is the same regardless of the phenotype or whether an opportunity exists to individualize therapy based on clinical, pathologic, genetic, or serological sub-categorization to improve outcomes (precision medicine).
Villacorta and colleagues address this question with a scholarly review of AAV and conclude that serological biomarkers (aPR3 and aMPO) can be used effectively to construct individually specific regimens of immunosuppressive/anti-inflammatory therapy (mainly focused on avoidance of relapse). Whether genetic analysis, novel biomarkers (urinary CD163, MCP1), complement activation profile, or deep morphologic phenotyping will allow even more refinement of individualized treatment of AAV remains uncertain. The role of biomarkers to help determine the potential efficacy of plasma exchange (PLEX) also remains uncertain. Clearly, patients with concomitant AAV and aGBM require very specific approaches to therapy, which frequently involve timely use of PLEX.
Overall, this report is a valuable and quite contemporary addition to the literature on this complex topic. Some might claim that a “multi-omic” analysis of AAV might provide an even more thorough sub-categorization and a standardized precision medicine approach to management of all patients with AAV, but I think that this goal is presently elusive.
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Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Toward an Individualized Approach
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Kavanagh C.R., Zanoni F., Leal R., Jain N.G., Stack M.N., Vasilescu E.-R., Serban G., Shaut C., Kamal J., Kudose S., Martinho A., Alves R., Santoriello D., Canetta P.A., Cohen D., Radhakrishnan J., Appel G.B., Stokes M.B., Markowitz G.S., D’Agati V.D., Kiryluk K., Andeen N.K., Batal I.: Clinical Predictors and Prognosis of Recurrent IgA Nephropathy in the Kidney Allograft. Glomerular Disease DOI 10.1159/000519834
It is well known that IgA nephropathy (IgAN) in a recipient of a kidney allograft (or isograft) has high propensity to redevelop in the kidney graft. This recurrence is believed to disadvantage the kidney graft in terms of long-term functional survival in the recipient.
Kavanagh and coworkers sought to determine predictive and prognostic factors for such recurrent IgAN. They examined cohorts (two from the USA and one from Europe) consisting of 282 patients with IgAN receiving kidney allografts. After a follow-up of 92 months (median), 80 patients (28%) had developed a recurrence of IgAN and 202 were free of recurrence after a follow-up of 74 months (median). Recurrence of IgAN was detected on clinical grounds and a transplant biopsy (n = 73) or according to protocol (non-clinical) transplant biopsy findings (n = 7).
Ninety percent were first kidney transplants, and 47% were deceased donor transplants. Fifty percent of patients received induction therapy, and 41% received steroid-free regimens of immunosuppression. Recurrences were discovered at a median of 43 months post-transplantation (range 13–121 months).
Recurrences developed more frequently in younger recipients, better HLA matching, lower use of induction therapy, and possibly in association with the frequency of HLA-DQ05 in recipients. Higher HLA matching frequency only had an impact on recurrence in living related donor kidneys. Steroid-free immunosuppressive therapy had no impact on recurrence rates. HLA matching was not independently associated with protection from recurrent IgAN, and individual HLA antigen in donor or recipient did not affect overall IgAN recurrence rates.
Recurrent IgAN was associated with poorer long-term graft survival. Treatment of recurrent IgAN was highly variable and not determined by a pre-defined protocol. High-dose steroids were used in 45% of those with a recurrence. Allograft failure was associated with a long post-transplant interval (no surprise), a higher serum creatinine level, greater magnitude of proteinuria, concomitant acute rejection episodes, and higher Oxford-MEST scores.
While this observational study is largely confirmatory, the studies on the impact of HLA matching and steroid-free immunosuppression are valuable additions to our understanding of how to best predict recurrence risk. Treatment of IgAN recurrence remains highly uncertain, and the design of this study precludes making any statement on efficacy of any particular regimen.
Quoted Karger Article
Clinical Predictors and Prognosis of Recurrent IgA Nephropathy in the Kidney Allograft.
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Tantisattamo E., Reddy U.G., Ichii H.d,Ferrey A.J., Dafoe D.C., Ioannou N., Xie J., Pitman T.R., Hendricks E., Eguchi N., Kalantar-Zadeh K.: Is It Time to Utilize Genetic Testing for Living Kidney Donor Evaluation? Nephron DOI 10.1159/000520150
Living related or unrelated (altruistic) donor kidney transplantation is practically universally applied as an option for therapy of kidney failure, often as a preemptive procedure to avoid the need for dialysis. Such living donor transplantation may be the only option in countries where access to deceased donor transplants is severely limited. The Hippocratic principle of Primum non Nocere (“first do no harm”) applies to such situations and rigorous pre-donation evaluation is required to ensure that the potential donor is fully healthy and does not possess any factor that might increase the short- or long-term risks of elective removal of one healthy kidney. Pre-transplant kidney biopsy and/or genetic testing of the donor is not commonly part of this donor evaluation process, except in limited circumstances.
Tantisattamo and colleagues raise the issue of pre-donation genetic testing in a single case of autosomal dominant Alport syndrome discovered in a live donor by whole exome sequencing. The patient was an adopted white woman, without any knowledge of birth weight, who wished to altruistically donate her kidney to an unrelated friend. The donor evaluation was normal except for history of gestational diabetes and pre-eclampsia in one pregnancy. She was not obese. In addition, the endogenous 24-hour urinary creatinine clearance (Ccr) was 156 mL/min/1.73 m2 and the urine albumin excretion rate (AER) was 65 mg/day, both abnormal. Repeat values were 110 mL/min/1.73 m2 and 24 mg/day for Ccr and AER, respectively, 3.5 months after instruction to decrease dietary protein intake from a high value of 1.4 g/kg/day. Interestingly, dietary protein intake did not appreciably change during this interval. Hematuria was not observed during the evaluation, and blood pressure was normal. A creatinine-cystatin C eGFR was not performed. There were no hearing or ocular abnormalities found and the children were apparently normal.
She was approved for donation and underwent a uni-nephrectomy without complications. Three weeks after donation, she was found to have albuminuria (100 mg/dL) by qualitative testing and non-visible hematuria. Further follow-up over 12–18 months showed fluctuating albuminuria (UACR = 318–507 mg/g), a serum creatinine of about 0.8–0.9 mg/dL, and a Ccr of 76 mL/min/1.73 m2. Hematuria was intermittent. The recipient had stable kidney function and low-grade albuminuria.
A whole exome sequencing panel investigation (RenaSight; Natera) revealed a heterozygous, likely pathogenic, mutation in the COL4A3 gene (c.2083G>A; pGly695Arg) compatible with an autosomal dominant Alport syndrome.
While quite uncommon, this case suggests that a heightened awareness of possible genetic kidney disease is appropriate when family history data is inaccessible (such as in adopted donors) and when clues to a possible underlying kidney disease are present (hyperfiltration-induced albuminuria), as in this case. As the cost of genetic screening falls, such testing might be incorporated into the routine evaluation of donors, with the Primum non Nocere doctrine in mind. We already recognize the importance of screening for APOL-1 risk alleles in donors of West African ancestry, especially when a history of low birth weight is present. A very thought-provoking case presentation.
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Is It Time to Utilize Genetic Testing for Living Kidney Donor Evaluation?
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Decaux GT: Low Creatininuria due to Hyponatremia Is Reversible in Many Patients. Nephron DOI 10.1159/000519049
Low urinary creatinine excretion (hypocreatininuria) and low serum creatinine are often observed in euvolemic hyponatremia (due to the syndrome of inappropriate anti-diuretic hormone release; SIADH). This is presumably due to sarcopenia accompanying the state of chronic SIADH. This pathophysiological state is also often accompanied by low solute excretion, which can magnify the effect of a urinary dilution defect on water retention.
In a very nice study, Decaux elaborated on the clinical and biochemical process underlying hypocreatininuria and low solute excretion accompanying acute and chronic euvolemic hyponatremia. Urinary creatinine excretion and solute excretion were measured in patients with hyponatremia early and late, before and after the correction of hyponatremia. This was compared to similar data in normal volunteers with hyponatremia induced by dDAVP administration.
Patients with chronic hyponatremia (>1 month) had marked hypocreatininuria and this reversed after prolonged correction of hyponatremia. Solute excretion followed a similar path. Normal individual with induced acute hyponatremia did not show a reduction in creatinine excretion.
These studies suggest that the changes in creatinine and solute excretion that accompany chronic euvolemic hyponatremia (SIADH) are likely the consequence of muscle loss (sarcopenia) perhaps related to a sedentary lifestyle. They are quite reversible phenomena. Acute hyponatremia has no such effect and the reduction in creatinine excretion is delayed by months after the onset of chronic hyponatremia. The administration or oral urea for treatment of chronic euvolemic hyponatremia (SIADH) confounds the interpretation of the changes in solute excretion.
This very nice study, simple in design and execution, provides a good explanation for the finding of low creatinine excretion in chronic euvolemic hyponatremia.
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Low Creatininuria due to Hyponatremia Is Reversible in Many Patients
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Yeaman M.R: Immunosuppression in Glomerular Diseases: Implications for SARS-CoV-2 Vaccines and COVID-19. Glomerular Diseases DOI 10.1159/000519182
Patients with chronic glomerulonephritis (GN) often have underlying immunological abnormalities that can be further altered by concomitant immunosuppressive (IS) therapy. In the era of the COVID-19 pandemic these changes can impact the ability of COVID vaccines to impart protective immunity, influence susceptibility to SARS-CoV-2 infection, and influence the natural clinical evolution of COVID-19.
In a very scholarly, comprehensive, and well-written review, Dr. Yeaman has summarized these issues in a very useful and understandable fashion. It is difficult to do justice to this elegant presentation in only a few short words. Physicians caring for patients with GN who are also receiving IS agents and who are concerned about COVID-19 infections or COVID vaccine administration should read this review in the original form. The effects of uremia itself, steroids, alkylating agents, anti-metabolites, calcineurin inhibitors, mTOR inhibitors, and CD38 monoclonal antibodies are discussed. Strategies to optimize the safety and effectiveness of COVID-19-preventative measures in patients with GN receiving IS treatment are also stressed. Altogether, a timely and highly relevant contemporary review of a subject of immense global importance.
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Immunosuppression in Glomerular Diseases: Implications for SARS-CoV-2 Vaccines and COVID-19
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Deleersnijder D, Van Craenenbroeck A.H,Sprangers B: Deconvolution of Focal Segmental Glomerulosclerosis Pathophysiology Using Transcriptomics Techniques. Glomerular Diseases Research DOI 10.1159/000518404
The lesion of FSGS can be due to many quite different pathogenic mechanisms. Sorting out the correct disease diagnosis can be a difficult challenge in individual cases and requires a careful systematic clinico-pathologic approach [1]. It has long been hoped that sophisticated molecular approaches using molecular analysis of kidney tissue, serum, or urine might ultimately lead to an accurate differentiation of the various causes of the FSGS, and also provide new insight into pathogenic pathways fostering the development of disease-specific treatment regimens, i.e., personalized medicine.
Deleersnijder and colleagues provide a very scholarly, well-written, comprehensive, and up-to-date review of the utility of cellular and tissue transcriptomics in devolving the lesion of FSGS into its discrete disease-specific fingerprints. Much has been accomplished and the future seems bright, but proof of the principle still needs much work before it can be considered clinically mainstream technology. Single cell or single nucleus transcriptomics seems to be the direction of future research. Reverse transcription-polymerase chain reaction and in situ hybridization seem to have limited applicability since only a few of the thousands of genes expressed can be studied. Microarray technology has the great advantage of high throughput, and fingerprints of many differentially expressed genes can be simultaneously analyzed. Microarray technology has already identified a number of target genes in FSGS lesions (such as those operating in the mTOR system), but this has not yet been translated into differential diagnosis or treatment regimens for the FSGA group of diseases. Nevertheless, tissue transcriptomics shows great promise in defining a treatment responsive compared to a treatment unresponsive subset of primary FSGS. Prognostic scoring systems based on transcriptomics have begun to evolve from such studies. Bulk RNA sequencing methods are less biased and show great utility in identifying small non-coding RNAs that regulate gene expression at the post-translational level (such as miR-21-5p that has been implicated in the generation of renal fibrosis). We have just scratched the surface of this complex but very important disease pathway.
Single cell and single nuclear RNA sequencing obviate some of the disadvantages of bulk RNA sequencing. The use of microfluidic technologies to separate single cells from mechanically or enzymatically disrupted whole tissue has been transformative. Many challenges exist in applying single cell or nucleus RNA sequencing to the deconvolution of a lesion of FSGS. Poor recovery of podocytes in single cell preparations is a weakness – one that might be overcome by using urine as a source of “viable but detached” podocytes in FSGS. Single cell technology is much more revealing in studies of kidney endothelial cell biology and tubule-interstitial changes in disease. Nevertheless, the field of “single-cell- omics” is moving rapidly and may yet be a “goldmine” of new information concerning patterns of pathogenesis in FSGS. A clean and unequivocal differentiation of primary, secondary, and genetic forms of the FSGS lesion is an ultimate goal, but final common pathways of pathogenesis that are shared among the diagnostic categories cannot be ignored. Progress in either arena will likely lead to new targets of treatment.
However, proper and careful clinico-pathologic analysis of FSGS cases studied by new omics approaches will still be a mandatory requirement of the analytic design.
References
1. De Vriese AS, Wetzels JF, Glassock RJ, Sethi S, Fervenza FC. Therapeutic trials in adult FSGS: lessons learned and the road forward. Nat Rev Nephrol. 2021 Sep;17(9):619–30.
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Deconvolution of Focal Segmental Glomerulosclerosis Pathophysiology Using Transcriptomics Techniques
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Shiroshita A, Oda Y, Takenouchi S, Hagino N, Kataoka Y: Accuracy of Anti-GBM Antibodies in Diagnosing Anti-Glomerular Basement Membrane Disease: A Systematic Review and Meta-Analysis. American Journal of Nephrology DOI 10.1159/000518362
Laboratory testing for anti-GBM antibodies has been available (for research or clinical care) for many decades. Yet standardization across laboratories is virtually non-existent and uncertainty remains concerning the overall accuracy of the multiple assays that are used. Western blot assays are the “gold standard” but have very limited availability. Turn-around time is very important in clinical utility.
In a very scholarly and comprehensive systematic review and meta-analysis of six studies involving 1,691 patients and 11 different anti-GBM assays, Shiroshita and colleagues have helped to clarify uncertainties concerning the accuracy of anti-GBM assays. Overall, the sensitivity and specificity of these assays were 93% (95% CI 84–97) and 95% (95% CI 94–99). However, an assessment of the overall quality of the reports was low, due to design features and the possibility of bias. The ELISA methods using the COLIV alpha 3 NC domain as the substrate were the most frequently used test (55%). Not surprisingly “false negative” tests were encountered (using immunofluorescence microscopy [IF] of linear IgG deposits as the defining finding of anti-GBM disease) up to about 16%. False positive tests were less common. The lack of standardization of “cut-off” values distinguishing “positive” from “negative” results was apparent. Misclassifications may have occurred since not all of the included studies employed a “gold standard” of IF on kidney biopsy. Nevertheless, the high specificity of ELISA anti-GBM means that a diagnosis of anti-GBM disease can be based on serology alone, especially in cases with a high a priori probability of anti-GBM disease. On the other hand, the lower sensitivity of anti-GBM antibody assays, including ELISA, suggests the need for multiple testing, such as indirect immunofluorescence assays, when ELISA is negative, especially when a high a priori probability of anti-GBM antibody disease is present. The inclusion of cases of “atypical anti-GBM disease” will only accentuate the possibility of “false negative” results for anti-GBM disease. This issue was not specifically addressed in the meta-analysis.
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Accuracy of Anti-GBM Antibodies in Diagnosing Anti-Glomerular Basement Membrane Disease: A Systematic Review and Meta-Analysis
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Shi Y, Tian H,Wang Y, Shen Y, Zhu Q, Ding F: Improved Dialysis Removal of Protein-Bound Uraemic Toxins with a Combined Displacement and Adsorption Technique. Blood Purification DOI 10.1159/000518065
Protein-bound uremic solutes are very inefficiently removed by standard dialytic techniques. Adding adsorption or displacement measures might enhance removal of these toxins.
In an in vitro and uremic rat model, Shi et al. analyzed the impact of an adsorptive strategy (adding bovine serum albumin [BSA] to the dialysate), a displacement strategy (infusing a fatty acid mixture to the pre-filter bold), and a combination of the two strategies on removal of protein-bound solutes (PBS; e.g., para-cresol sulfate, indoxyl sulfate, etc.).
The addition of BSA to the dialysate had a minimal effect on PBS removal. The combination of adsorptive and displacement strategies had the greatest impact on PBS removal rates. However, all of the studies were short-term in nature, so the safety and side-effects could not be evaluated. Only one type of displacement method (lipid emulsion infusion) was studied. The preliminary data are intriguing, but whether the absorptive/displacement strategies will ever reach clinical utility is highly uncertain.
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Improved Dialysis Removal of Protein-Bound Uraemic Toxins with a Combined Displacement and Adsorption Technique
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O’Brien Z, Finnis M, Gallagher M, Bellomo R: Hyperoncotic Albumin Solution in Continuous Renal Replacement Therapy Patients. Blood Purification DOI 10.1159/000517957
A beneficial role for the use of infusions of human serum albumin (iso-oncotic [4%] or hyper-oncotic [20%]) during the management of acute kinder injury (AKI) with continuous renal replacement therapy (CRRT) has been difficult to establish, and the differential impact of iso-oncotic and hyper-oncotic albumin infusions is unknown.
In a post hoc analysis of data generated by the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial of CRRT in AKI, O’Brien et al. evaluated the clinical impact of iso-oncotic and hyper-oncotic serum albumin infusions, or their combinations.
About 51% of the 1,508 subjects enrolled in the RENAL trial received serum albumin infusions: 45% as 4%, 20% as 20%, and 35% as a combination of both 4% and 20% human serum albumin. The characteristics of the subjects receiving human serum albumin infusions were not the same as those who did not – the subjects receiving human serum albumin infusions were generally much sicker. Using a Cox proportional hazard analysis, exposure to 20% human serum albumin infusions was not associated with worse outcomes (90-day mortality or longer recovery time). Administration of 20% human serum albumin was associated with better volume control (less fluid retention). While this post hoc analysis is largely hypothesis generating, it does suggest that hyper-oncotic albumin infusions during CRRT for AKI is not harmful. A randomized clinical trial will be required to establish a clinical role for human serum albumin infusion in terms of efficacy in patients receiving CRRT for severe AKI.
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Hyperoncotic Albumin Solution in Continuous Renal Replacement Therapy Patients
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Radin M, Miraglia P, Barinotti A, Fenoglio R, Roccatello D, Sciascia S: Prognostic and Diagnostic Values of Novel Serum and Urine Biomarkers in Lupus Nephritis: A Systematic Review. American Journal of Nephrology DOI 10.1159/000517852
The role and value of novel serum and/or urinary biomarkers in the diagnosis and prognosis evaluation of lupus nephritis continues to be highly uncertain.
This is largely due to the paucity of randomized clinical trials and/or the lack of comparison with standard clinically recommended parameters. An extensive literature has accumulated (mainly observational and retrospective) concerning the utility of such novel biomarkers. Only a few have shown much promise, but none have yet been validated in a prospective controlled clinical trial.
In a systematic review of the published data (between 2015 and 2020), involving 8,872 patients with lupus nephritis, Radin et al. attempted to evaluate the current status of novel urinary and/or serum biomarkers in lupus nephritis. They excluded from consideration those biomarkers (like serum creatinine, proteinuria, anti-nuclear antibodies, or serum complement assays) that have already been incorporated into guideline recommendations.
This analysis, not unexpectedly, revealed a great deal of heterogeneity in subject enrollment and in analytic approaches. No randomized clinical trials were included. A few novel biomarkers showed some promise (MCP-1, VCAM-1, urinary adiponectin, KIM-1). Inconsistencies in the utility of many of the studied biomarkers rendered their value suspect. The role of assays for factors acting on B-cells was limited and uncertain.
This field is rather stagnant, and much work needs to be done before any novel biomarker can be elevated to routine clinical use as standard-of-care. In my opinion, none can yet be used to augment a precision-medicine approach to lupus nephritis. The conclusions of the authors of this detailed systematic review support this viewpoint.
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Prognostic and Diagnostic Values of Novel Serum and Urine Biomarkers in Lupus Nephritis: A Systematic Review
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Seshan SV, Salvatore SP: Recurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy. Glomerular Diseases DOI 10.1159/000517259
A recurrence of the original disease that affected the native kidney in the allografts (or isografts) of patients undergoing kidney transplantation is a common problem that has a significant impact on both short- and long-term graft survival. Recognition of these disease recurrences, especially glomerulonephritis, requires biopsy of the transplanted kidney and meticulous study of the tissue by light, immunofluorescence, and electron microscopy (EM). The added value of EM for identification of the pathogenic processes involved in recurrent glomerulonephritis has been elegantly analyzed by Dr. Surya Seshan, an experienced and knowledgeable nephron-pathologist. EM has particular utility in defining a recurrence of primary (permeability factor-related) FSGS, immune complex-mediated MPGN, C3 glomerulonephritis/dense deposit disease, fibrillary glomerulonephritis, monoclonal deposition diseases (such as amyloidosis), and diabetic nephropathy. EM is of somewhat less utility in defining recurrences of thrombotic microangiopathy, membranous nephropathy, IgA nephropathy, lupus nephritis, anti-GBM disease, ANCA vasculitis, and proliferative glomerulonephritis with mononclonal Ig deposition.
Nevertheless, this well-written and illustrated compendium of EM findings in post-transplant recurrent disease is an excellent resource and provides a broad overview of the morphological features of recurrent disease. It is worth reading and viewing in its original form.
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Recurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy
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Li Z, Li N: Epigenetic Modification Drives Acute Kidney Injury-to-Chronic Kidney Disease Progression. Nephron DOI 10.1159/000517073
Little doubt exists that a variable fraction of patients with acute kidney injury (AKI; defined by the creatinine-based KDIGO criteria) can eventually develop new-onset chronic kidney disease (CKD; again defined by KDIGO criteria), even when no (recognizable) underlying kidney disease preceded the episode of AKI. This evolution depends highly on the cause of the AKI: urinary tract obstruction, acute renal ischemia, nephrotoxins, thrombotic microangiopathy, inflammatory interstitial nephritis, vasculitis or glomerulonephritis. Hypoxia of renal parenchyma can lead to tubular injury and apoptosis, capillary rarefaction, and maladaptive repair, and renal fibrosis is a common end result.
The role of epigenetics, via DNA methylation/demethylation, histone modification, chromosomal re-configuration, and transcriptomic or translational activity, is likely important for the AKI to CKD transition. Reductions in peri-tubular capillary density, apoptosis, and stimulation of pro-fibrotic (myo-fibroblast-dependent) processes (MCP-1, TGF-β, CTGF mediated) seem to be a common final pathway.
Li and Li comprehensively review the role and mechanisms for epigenetic modifications in the AKI to CKD transition. Histone modification (methylation/acetylation) and chromatin remodeling has been established as mechanistically involved in the AKI to CKD transition in animal models. Preliminary data suggest that interventions directed to these epigenetic pathways may have salutary effects. Similarly, DNA methylation/demethylation seems to play crucial roles, acting via genes for such entities, including klotho, erythropoetin, and GTPase-activating proteins. Furthermore, non-coding RNA (mainly microRNA) and/or long non-coding RNA also likely play key roles in promoting fibrosis in the AKI to CKD transition.
These findings open up new avenues for mitigating the AKI to CKD evolution, but translation from animal models to human disease will be both challenging and difficult. Many obstacles must be overcome before epigenetic modification becomes a practical intervention in the AKI to CKD transition, not the least of which is the extreme heterogeneity of the pathogenesis of AKI, as presently defined. Subjects with AKI at highest and lowest risk for a clinically significant AKI to CKD transition will have to be prospectively characterized, using both serum and urine biomarkers and biopsy-determined morphology. This will be an arduous task, in my opinion. The well-written and comprehensive review by Li and Li provides a glimpse at a road map for the future, and engenders cautious optimism that the AKI to CKD transition may be beneficially modifiable in the not too distant future.
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Epigenetic Modification Drives Acute Kidney Injury-to-Chronic Kidney Disease Progression
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Yamashita M, Lin MY, Hou J, Ren KYM, Haas M: The Continuing Need for Electron Microscopy in Examination of Medical Renal Biopsies: Examples in Practice. Glomerular Diseases DOI 10.1159/000516831
Transmission electron microscopy (TEM) is often performed as a routine part of the pathologic examination of native kidney biopsies and also kidney transplant biopsies. However, this evaluative method is not generally available in many countries of the world and tissue specimen limitations may impact upon the ability to perform TEM in every case. Thus, it is important to understand the degree to which an accurate diagnosis of kidney disease is impaired when TEM is lacking.
Yamashita and coworkers have addressed this conundrum by describing 6 examples where TEM played a vital and irreplaceable role in determining an accurate diagnosis in a kidney biopsy. Minimal change disease, early membranous nephropathy, Alport syndrome, infection-related glomerulonephritis, immunotactoid glomerulonephritis, and collagen III glomerulopathy were the chosen examples. In each case the TEM findings were essential in making a correct diagnosis.
While this case-oriented paper makes a very good point, many other examples of the crucial value of TEM could have been included, such as the evaluation of the degree of foot process effacement in lesion of FSGS, the detection of “footprint” deposits pathognomonic of lupus nephritis, and the characteristic lesions by TEM in certain genetic diseases. Perhaps in the future the need for TEM studies will be diminished; for example, by expanded use of serum biomarkers such as DNAJB9 (for fibrillary GN) and panels of anti-podocyte antibodies for study of serum and immunofluorescence microscopy in membranous nephropathy. For the present, the recommendation to collect appropriately preserved specimens for future TEM in all cases of native and transplant kidney biopsies is good advice, when the prospect of immediate TEM is not feasible.
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The Continuing Need for Electron Microscopy in Examination of Medical Renal Biopsies: Examples in Practice
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Zamami R, Kohagura K, Kinjyo K, Nakamura T, Kinjo T, Yamazato M, Ishida A, Ohya Y: The Association between Glomerular Diameter and Secondary Focal Segmental Glomerulosclerosis in Chronic Kidney Disease. Kidney and Blood Pressure Research DOI 10.1159/000515528
Disease-related loss of nephrons (but not normal aging-related loss of nephrons) is commonly associated with the enlargement (hypertrophy) of residual, less-damaged glomeruli. Comorbid conditions such as obesity or diabetes can also result in glomerular hypertrophy. However, the relationships between such hypertrophy and specific glomerular lesions (such as FSGS) have not been systematically evaluated.
Zamami and coworkers investigated the association between glomerular diameter (as a measure of glomerular hypertrophy) in 77 patients undergoing kidney biopsy with “non-primary” FSGS lesions on kidney biopsy, also excluding those with active proliferative or crescentic glomerulonephritis. The presence of glomerular hypertrophy correlated with FSGS lesions. The optimal threshold for predicting the presence of FSGS lesions was a glomerular diameter of >224 μm, independent of other confounding features.
Of course, a study of this design does not prove causality of the glomerular enlargement and the development of FSGS lesions; however, such a connection is plausible. Glomerular density (the number of glomeruli per centimeter of section) does not correlate with glomerular diameter, but the total nephron number per kidney was not quantified in this study. A high glomerular diameter is linked to progressive CKD. This study indicates that glomerulomegaly is a feature of secondary FGSS lesions and, when present, indicates an unfavorable prognosis.
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The Association between Glomerular Diameter and Secondary Focal Segmental Glomerulosclerosis in Chronic Kidney Disease
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Bhatt GC, Das RR, Satapathy A: Early versus Late Initiation of Renal Replacement Therapy: Have We Reached the Consensus? An Updated Meta-Analysis. Nephron DOI 10.1159/000515129
The added patient-centered benefit of early versus late initiation of hemodialysis (HD) therapy for patients with severe AKI has been widely debated for many years without a clear resolution, largely due to the extreme heterogeneity of the etiology of AKI and difficulties in predicting its natural history at the time of diagnosis using conventional KDIGO-based criteria. However, recent trials have strongly suggested that early (pre-symptomatic) initiation of HD has no measurable benefit, results in unnecessary use of HD, and might, in fact, lead to harm due to unavoidable effects of HD.
Bhatt and coworkers have evaluated the current state-of-the-art concerning the timing of HD initiation in AKI in a systematic review and meta-analysis of 14 published randomized controlled trials involving 5,234 patients with AKI between 1997 and 2020.
The pooled estimates of differences between early and late initiation of HD for AKI showed no difference in multiple analyses, including 30- and 90-day mortality and length of hospital or ICU stay. Dialysis dependence at 90 days was increased in those with early HD initiation. Hypotension and hypophosphatemia were increased in the early HD cohorts, as were healthcare resource utilizations.
Delaying HD initiation in patients meeting the definition of AKI accompanied by close monitoring and use of clinical and laboratory indications (e.g., volume overload, acidosis, hyperkalemia) for the timing of dialysis initiation should be the default position.
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Early versus Late Initiation of Renal Replacement Therapy: Have We Reached the Consensus? An Updated Meta-Analysis
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See EJ, Polkinghorne KR, Toussaint ND, Bailey M, Johnson DW, Bellomo R: Epidemiology and Outcomes of Acute Kidney Diseases: A Comparative Analysis. American Journal of Nephrology DOI 10.1159/000515231
It is now generally recognized that the generic disorder designated as acute kidney disease (AKD) by KDIGO is a manifestation of many individual diseases that do not meet the criteria established for either chronic kidney disease (CKD) or acute kidney injury (AKI). The diagnosis of AKD and CKD are mutually exclusive, but AKI is regarded as a subset of AKD. Both AKD and AKI can evolve over time to CKD. The epidemiology and natural history of subjects with AKD need better characterization.
This deficiency has, in part, been remedied by a large retrospective population-wide cohort study of AKD (with or without AKI) in 62,977 patients admitted to an academic medical center in Melbourne, Australia between 2012 and 2016. All of the included patients had a baseline eGFR of >60 mL/min/1.73 m2 and survived for at least 30 days. Using conventional KDIGO diagnostic criteria (using serum creatinine measurements, 906 patients [1.4%] had AKD with AKI, 485 patients [0.7%] had AKD without AKI, and 3,921 patients [6.2%] had AKI alone; stage 1, 76%; stage 2, 18%; stage 3, 7%). The risk factors for AKD and the occurrence of major adverse kidney events (MAKE) – de novo non-dialysis CKD, kidney failure and death – were examined during follow-up in 36,118 patients.
AKD with or without AKI was associated with a substantially higher risk of MAKE, driven largely by transition to CKD, especially in the first 3 months of observation. This is the first of many large epidemiologic studies that will more precisely define the burden and outcomes for AKD, in a fashion that has so successfully been undertaken for AKI and CKD. Many questions remain regarding how to best harmonize the definitions and prognostic factors involved in AKD, AKI, and CKD. The involvement of KDIGO and the International Society of Nephrology in this process augurs a favorable outcome with global implications [1]. Stay tuned…
References
1. KDIGO. Consensus conference on harmonizing acute and chronic kidney disease definition and classification. August, 2020. ISN Academy Webinar on Harmonizing AKD; March 26, 2021.
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Epidemiology and Outcomes of Acute Kidney Diseases: A Comparative Analysis
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Miao J, Sy-Go JPT, Issa M, Jenad H, Manohar S, Zoghby Z, Kashani KB, Gregoire JR: Ultrasonographic Assessment of Extravascular Lung Water in Hospitalized Patients Requiring Hemodialysis: A Prospective Observational Study. Cardiorenal Medicine DOI 10.1159/000516474
Evaluation of fluid overload in patients requiring hemodialysis for ESKD or AKI can be unreliable. Bedside assessment of lung water (B lines, TBLN) or inferior vena cava diameter (IVCD) with ultrasound are both of growing interest, especially as point-of-care handheld ultrasound devices are now readily available.
Miao and colleagues compared handheld ultrasound devices to standard portable ultrasound for the assessment of TBLN and IVCD in 54 hospitalized patients requiring hemodialysis (35 with ESKD and 19 with AKI). These measurements were made before and after each dialysis session.
The two methods were not different for measuring TBLN or IVCD, but the correlations were higher for TBLN (r = 0.92) than for IVCD (r = 0.51). Evaluation of fluid volume by physical examination was unreliable. The value for TBLN decreased post-dialysis, whereas the value for IVCD did not.
This study has significant value as it suggests that handheld ultrasound devices are as reliable as standard portable ultrasound devices in evaluating extracellular lung water in hospitalized subjects undergoing hemodialysis for ESKD or AKI. Assessing IVCD seems less reliable. This is a small study and relatively few subjects had severe volume overload. It needs to be confirmed in a larger cohort, including both in- and outpatients, with a broader range of fluid volume expansion.
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Ultrasonographic Assessment of Extravascular Lung Water in Hospitalized Patients Requiring Hemodialysis: A Prospective Observational Study
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Miyata K, Zhang S, Chan J: The Rationale and Evidence for SGLT2 Inhibitors as a Treatment for Nondiabetic Glomerular Disease. Glomerular Diseases DOI 10.1159/000513659
The report of the benefits of dapagliflozin on the progression of CKD in patients with non-diabetic kidney disease by Heerspink et al. [1] in late 2020 was a “blockbuster”. It will likely have an enormous practice-changing impact on clinical nephrology just as earlier reports of the benefits of SGLT2 inhibitors on heart failure in non-diabetic subjects had on the practice of clinical cardiology. The biologic effects of SGLT2 inhibitors are pleiotropic and the process is underway to elucidate the fine details of the mechanism(s) for these clinical effects.
Miyata and colleagues provide a masterful overview of current knowledge concerning the biology of SGLT2 inhibition in non-diabetic kidney disease. The main target of SGLT2 inhibitors is SGLT2 expressed in proximal tubules of the nephron. The expression is upregulated in diabetes, but not consistently in many proteinuric non-diabetic kidney diseases, such as IgA nephropathy. Nevertheless, SGLT2 inhibitors, as a class, seem to be effective in reducing the rate of progression of these diseases. SGLT2 inhibitors decrease intra-glomerular capillary pressure likely due to afferent arteriolar constriction. The lower intra-glomerular pressure initially reduces GFR modestly and has a long-term reno-protective action, similar to renin-angiotensin system (RAS) inhibitors that also reduce intra-glomerular capillary pressure mainly by efferent arteriolar relaxation. Thus, the effects of SGLT2 inhibitors are additive to RAS inhibition. This effect of SGLT2 inhibitors may be linked to the inhibition of proximal nephron sodium reabsorption and activation of tubule-glomerular feedback mediated by local adenosine release, but other factors may be in play, such as reduced cardiac elaboration of atrial natriuretic factors, secondary to diuresis and reduction of expanded circulatory volume.
SGLT2 inhibitors have a weak and inconsistent effect on lowering blood pressure (about a –2 to –3 mm Hg systolic), which is unlikely to explain the reno-protective actions. Improved control of blood glucose levels in diabetics is modest at best, and would not explain the reno-protective action in non-diabetic subjects. SGLT2 inhibitors also have anti-inflammatory, hypouricemic, and anti-fibrotic effects. Evidence is also accruing that SGLTR2 inhibitors may have direct modifying effects on endothelial, mesangial, and visceral epithelial cell components of glomeruli. So far, studies of SGLT2 inhibitors in non-diabetic kidney disease have excluded patients with lupus nephritis, autosomal dominant polycystic kidney disease, and vasculitis, and have enrolled too few patients with primary glomerular disease and nephrotic syndrome (such as membranous nephropathy) to be sure of the reno-protective actions in these patients. The reno-protective actions of SGLKT2 inhibitors do extend to patients with IgA nephropathy. So far, most studies have used SGLT2 inhibitors in combination with RAS inhibition, so we know very little about SGLT2 inhibitor monotherapy. Side effects are generally tolerable, with genital mycotic infection the main issue.
Clearly SGLT2 inhibitors have launched a new era of therapy in CKD. The comprehensive review by Miyata et al. is a good place to start for learning more about this very important class of reno- (and cardio-)protective agents. Bon voyage!!
References
1. Heerspink HJ, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.
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The Rationale and Evidence for SGLT2 Inhibitors as a Treatment for Nondiabetic Glomerular Disease
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Bonani M, Seeger H, Weber N, Lorenzen JM, Wüthrich RP, Kistler AD: Safety of Kidney Biopsy when Performed as an Outpatient Procedure. Kidney and Blood Pressure Research DOI 10.1159/000515439
For many decades elective percutaneous kidney biopsy in the prone position was uniformly performed during a short hospital stay, so that patients could be carefully monitored for adverse events. More recently, this procedure has been performed on an entirely outpatient basis, in patients deemed to be at low risk for such events. The actual biopsy procedure details and the required skills of the individual physician (nephrologist or interventional radiologist) performing the procedure are not different in the two settings (inpatient or outpatient). The overall comparative safety of kidney biopsy performed on inpatients or outpatients largely devolves around the risk factors for adverse events in the patients subjected to the procedure and the extent of post-biopsy monitoring. Transplant kidney biopsies generally have a lower risk of adverse events than kidney biopsies performed in native kidneys, regardless of the site.
Bonani and colleagues studied a cohort of kidney biopsies performed at a single center in native kidneys and kidney transplants on inpatients (n = 514; 233 native/281 transplant) or outpatients (n = 1,506; 430 native/1,076 transplant) between 2015 and 2019. All percutaneous biopsies were performed/supervised by 1 of 2 physicians (nephrologists) using a standardized protocol using ultrasound guidance and 16-G needles incorporated into semi-automated devices. The outpatients were monitored for adverse events for 4 h and were discharged if no macroscopic hematuria was observed or post-procedure US showed no “significant” bleeding (hematoma formation).
Major bleeding events occurred in 3.6 and 4.3% of native or transplant kidney biopsies, respectively, conducted at an inpatient site. Major bleeding events occurred in 0.7 and 1.1% of native or transplant kidney biopsies conducted at an outpatient site. No fatalities occurred. High-risk patients (amyloidosis, liver cirrhosis, bleeding disorder, inability to temporarily interrupt anti-platelet therapy, platelet counts <80,000/μL, hemoglobin <7 g/dL, BP >160/110 mm Hg) were preferentially biopsied at an inpatient site. Eighty-seven percent of the adverse bleeding events found in the outpatient biopsy cohort occurred during the 4-h observation period. Routine post-biopsy kidney ultrasound had no effect on management.
While this is a single-center, retrospective study, it involved a well-designed protocol as well as very experienced biopsy proceduralists. It supports the notion that in carefully selected patients a percutaneous kidney biopsy can be performed with reasonable safety on an outpatient basis with an observation period as short as 4 h. Routine post-biopsy ultrasound contributes nothing of a material nature to management.
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Safety of Kidney Biopsy when Performed as an Outpatient Procedure
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Ali H, Mohamed M, Sharma A, Fulop T, Halawa A: Outcomes of Interleukin-2 Receptor Antagonist Induction Therapy in Standard-Risk Renal Transplant Recipients Maintained on Tacrolimus: A Systematic Review and Meta-Analysis. American Journal of Nephrology DOI 10.1159/000514454
The short-term benefits (1–3 years) attending the routine use of induction adjuvant therapy with interleukin-2 (IL-2) receptor antagonists (basiliximab or daclizumab) in standard-risk kidney allograft recipients treated with conventional tacrolimus/mycophenolate mofetil/corticosteroid regimens is uncertain.
Ali and coworkers addressed this issue by conducting a systematic review and meta-analysis of reported prospective randomized clinical trials examining the effects of IL-2 receptor antagonists in standard-risk allograft recipients treated with tacrolimus-based regimens. Two groups were analyzed: (a) the same dose of tacrolimus in both arms of the trial (n = 2,886); (b) IL-2 receptor antagonists + low-dose tacrolimus versus no IL-2 receptor antagonists and high-dose tacrolimus (n = 669). No benefits for the “hard” endpoints of graft or patient survival were seen for IL-2 receptor antagonism use at 1 year of follow-up.
This analysis represents an important addition to the literature on pharmacotherapy for the prevention of allograft rejection leading to early graft loss. The analysis was carried out with rigorous attention to recommendations for such systematic reviews. The subjects examined were “standard risk” and the results may not apply to “high-risk” patients, such as sensitized patients or second kidney allografts. The dearth of Black recipients prevented any analysis of ancestry-related factors in determining outcomes. The short-term nature of the analyses prevented examination of other clinically important differences that are delayed, such as malignancy risk, chronic allograft nephropathy, and calcineurin inhibitor-associated nephrotoxicity. Nevertheless, it does appear that there are no compelling short-term advantages of use of adjuvant IL-2 receptor antagonism in patients receiving tacrolimus-based conventional post-transplant immunosuppression. It is unclear whether a slightly better eGFR at 1 year in the group B subjects receiving IL-2 receptor induction therapy and low-dose tacrolimus will be predictive of better long-term outcomes. No transplant kidney biopsy data were included in this analysis. This needs to be corrected by future studies as morphology in early transplant kidney biopsies may predict longer-term graft outcomes. However, the analysis suggests that omission of the use of IL-2 receptor antagonism might be considered in “standard-risk” patients when tacrolimus-based regimens are employed for the prevention of kidney allograft rejection.
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Outcomes of Interleukin-2 Receptor Antagonist Induction Therapy in Standard-Risk Renal Transplant Recipients Maintained on Tacrolimus: A Systematic Review and Meta-Analysis
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Shah P, Brady T, Meyers K, O’Shaughnessy M, Gibson K, Srivastava T, Zee J, Cattran D, Tuttle K, Gadegbeku C, Glenn D, Derebail V, Smith A, Wang C, Gillespie B, Bitzer M, Sethna C: Association of Obesity with Cardiovascular Risk Factors and Kidney Disease Outcomes in Primary Proteinuric Glomerulopathies. Nephron DOI 10.1159/000513869
Obesity is a well-established modifiable risk factor for cardiovascular disease (CVD) in the general population. However, the role of obesity for CVD risk is not well studied in subjects with proteinuric primary glomerular disease.
Shah and colleagues utilized an extensive prospectively collected database including 541 subjects with proteinuric primary glomerular disease (mainly minimal change disease, membranous nephropathy, and focal segmental glomerulosclerosis lesions) from the Nephrotic Syndrome Study Network (NEPTUNE) in order to study associations of CVD risk factors and obesity in adults and children with glomerular disease. In adults, obesity (as assessed by BMI) was associated with hypertension and dyslipidemia and a lower likelihood of achieving a complete remission with treatment for the underlying disease. In children there was an association of obesity with hypertension but not dyslipidemia, but a lower likelihood of reaching complete remission was seen with obesity, similar to adults. Satin use was not recorded. No long-term CVD outcomes were analyzed due to the short follow-up, which averaged about 3 years.
The association of obesity with a lower likelihood of achieving a complete remission is novel but not explained. Many possibilities are discussed, but causality cannot be proven in an observational study of this nature. The use of BMI to determine “obesity” in edematous subjects is problematical but the authors make an attempt to separate weight gain from sodium retention and true adiposity. In a companion article in the same issue, Sandino et al. [1] provided an excellent overview of obesity-related glomerulopathy (ORG) which is worth reading. It seems doubtful to me that the existence of ORG confounded the study by Shah et al., although a few patients with a focal segmental glomerulosclerosis lesion might have had ORG.
Overall the study by Shah et al. highlights the possible effects of concomitant obesity on risk for CVD and poor outcomes in proteinuric primary glomerular disease, but the lack of long-term follow-up makes this connection a weak one, requiring additional studies for confirmation.
References
1. Sandino J, et al. Which patients with obesity are at risk for kidney disease? Nephron. 2021, in press.
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Association of Obesity with Cardiovascular Risk Factors and Kidney Disease Outcomes in Primary Proteinuric Glomerulopathies
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Floris M, Lepori N, Angioi A, Cabiddu G, Piras D, Loi V, Swaminathan S, Rosner M, Pani A: Chronic Kidney Disease of Undetermined Etiology around the World. Kidney and Blood Pressure Research DOI 10.1159/000513014
Chronic kidney disease of undetermined etiology (CKDu) is endemic in several parts of the world, especially among agricultural workers exposed to high ambient temperatures, episodic dehydration, and uric acid-crystalluria and nephrotoxins (such as agricultural pesticides). The “disease” is very likely heterogeneous in etiology. Whether it can be positively defined by its pathological features is controversial, but alterations seen in mitochondria by electron microscopy suggest a nephrotoxic basis in many cases. The dominant picture is a chronic, progressive tubule-interstitial nephritis. It is a common cause of kidney failure in the affected regions.
Floris and colleagues from Sardinia and the USA provide a very well-written, comprehensive and up-to-date review of the epidemiology, ethnography, susceptibility (genetic and environmental), possible causes/pathogenesis, clinical and histologic features, pathways for prevention, and needed further research. They advance a hypothesis that CKDu is caused by an interaction between geography-specific risk factors and the influence of protective factors. The clustering of cases in Mexico, Meso-America, Tunisia, Egypt, Uddanam (India), and Sri Lanka strongly suggest an environmental cause (– heat, dehydration, pesticides?) which may vary from country to country. The review is worth reading for those who want to learn more about this intriguing “disease.”
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Chronic Kidney Disease of Undetermined Etiology around the World
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Chemouny JM, Bobot M, Sannier A, Maisons V, Jourde-Chiche N, Ferriere E, Joly D, Vigneau C, Rioux-Leclercq N, Barba C, Daniel L, Halimi J-M, Vrtovsnik F: Kidney Biopsy in Type 2 Diabetes: A Multicenter Cross-Sectional Study. American Journal of Nephrology DOI 10.1159/000514259
The role of kidney biopsy in patients with type 2 diabetes mellitus (T2DM) is constantly being re-examined. It is very clear that a fraction of patients with T2DM presenting with clinical features of CKD (diabetic kidney disease; DKD) do not have the classical findings of diabetic nephropathy (DN; a pathological diagnosis) but rather have one or the other of a myriad of non-diabetic kidney disease (NDKD) or both DN and NDKD simultaneously. Clinical differentiation of these possibilities is difficult. Thus, when NDKD is suspected, a kidney biopsy is indicated as it might change the prognosis or treatment. Kidney biopsy findings in patients with DKD therefore differ according to the indications for performing the biopsy in the first place.
Chemouny and colleagues from France report on a multi-institutional, cross-sectional study of 463 kidney biopsies in patients with T2DM. The indications for kidney biopsy fell into 7 categories: (1) recent onset of nephrotic syndrome; (2) low or rapidly declining eGFR; (3) rapid increase in proteinuria; (4) short duration of T2DM; (5) presence of hematuria; (6) absence of retinopathy, and (7) any other clinical/laboratory clue suggesting NDKD. Overall, NDKD was found in 40% of the kidney biopsies.
NDKD was found in kidney biopsies performed for indications 1, 2, 3, and 7 in 40, 24, 7, and 54% of the subjects. No kidney biopsy showed NDKD when performed for indications 4, 5, and 6. Logistic regression suggested that an eGFR <15 mL/min/1.73 m2, urine protein:creatinine ratio <300 mg/mmol, hematuria, HBA1c of <7%, and T2DM of <5 years duration were predictive of NDKD, independent of the indication used to perform the kidney biopsy. These findings suggest that rapid progression of kidney impairment or proteinuria are major clues to the presence of NDKD and that the presence of hematuria or the absence of retinopathy are not very useful in determining the likelihood of finding NDKD in a kidney biopsy in a patient with DKD. This issue was also recently examined by Sanghavi et al. [1] in 399 kidney biopsies in patients with DKD in a single-center study in Seattle, WA, USA. They found that retinopathy and more severe proteinuria were indicative of DN while signs of acute kidney injury were more compatible with NDKD.
Clinical differentiation of DN from NDKD in patients with DKD and T2DM remains an inexact science. Biomarkers specific for NDKD would be very helpful to add precision to what is now a very sophisticated guessing game with a few emerging rules. Because of the implications for prognosis and treatment it is probably wise to err on the side of kidney biopsy when doubt exists.
References
1. Sanghavi SF, et al. Histopathologic and clinical features in patients with diabetes and kidney disease. Kidney360. 2020;1:1217–25.
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Kidney Biopsy in Type 2 Diabetes: A Multicenter Cross-Sectional Study
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Chen Y, Huang S, Chen T, Liang D, Yang J, Zeng C, Li X, Xie G, Liu Z: Machine Learning for Prediction and Risk Stratification of Lupus Nephritis Renal Flare. American Journal of Nephrology DOI 10.1159/000513566
Flare-ups (relapses) of lupus nephritis (LN) are common and when frequent represent a major factor contributing to a poor long-term outcome. Predicting and stratifying risk for such renal flares are very important factors that must be taken into consideration for optimal management of LN. Hopefully, such abilities will lead to better treatment and improved outcomes.
Chen and co-workers utilized machine learning protocols to develop a risk-score prediction model by analyzing derivation (n = 1,186) and internal validation (n = 508) cohorts of Chinese patients with biopsy-proven LN who had achieved a remission (complete or partial) following immunosuppressive therapy. Lupus renal flares were common in both cohorts (about 39%).
A 6-variable renal flare prediction model was developed and validated. These variables included: partial remission, endocapillary hypercellularity at baseline, age, serum albumin level, anti-dsDNA antibody level, and serum C3 at the time of remission. The C-statistic for the model prediction was about 0.82 (95% CI = 0.77–0.86).
While this study still needs independent external validation and may be affected by ancestry, the nature of therapy used to induce and maintain remission, and other factors, it remains a “proof-of-principle” for the value of machine learning systems in providing a more quantitative and personalized approach to renal flare risk prediction and stratification. It might lead to better outcomes if externally validated and applied to patients with LN who obtain a remission following immunosuppressive therapy.
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Machine Learning for Prediction and Risk Stratification of Lupus Nephritis Renal Flare
