Multi-Morbidity and Mortality in Incident CKD

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Burrow N.R., Koyama A.K., Choudhury D., Yu W., Pavkov M.E., Nee R., Cheung A.K., Norris K.C., Yan G.: Age-Related Association between Multimorbidity and Mortality in US Veterans with Incident Chronic Kidney Disease. American Journal of Nephrology DOI 10.1159/000526254

It is well known that prevalent chronic kidney disease (CKD) is associated with excess morbidity and mortality compared to non-CKD. Few studies have examined this association in incident CKD.

Using an electronic health record database, Burrows and colleagues carried out a descriptive analysis of co-morbidity and mortality in a large cohort of nearly exclusively male patients (n = 892,005) receiving care in the US Veterans Administration (VA) facilities between 2004 and 2018. Incident CKD was defined by estimated glomerular filtration rate (eGFR) values only and occurred when the eGFR-creatinine (by the 2009 CKD-EPI equation, including the racial coefficient) fell below 60 mL/min/1.73 m2 for the second time at least 3 months apart, excluding CKD category 4–5. This cohort only included incident categories 3A or 3B. Urine protein excretion was not routinely collected; only 38% of the cohort had proteinuria (albuminuria) testing. Extensive co-morbidity and mortality data were collected. As expected, most subjects were elderly (average age at CKD incidence 72.3 ±9.9 years). Medication use was collected, but apparently not including statins. No data on a control group of non-CKD patients were included.

Multi-morbidity was very common (95% had 2 or more co-morbidities, averaging 4) and cardiovascular disease (CVD) morbidity was associated with high mortality among younger cohort members, while dementia was associated with higher mortality among older members of the cohort. A high burden of co-morbidity was especially indicative of a high mortality risk among the younger members of the cohort. Clearly, co-morbidity is of great concern among an incident CKD group of subjects. The lack of a “control” group without incident CKD is a weakness of this otherwise informative, descriptive study. One can only speculate how the results would have differed if a non-racially adjusted equation for eGFR had been used or if the definition for incident CKD had utilized an age-adapted criterion for eGFR-defined CKD. The lack of a systematic evaluation of albuminuria is a weakness the authors acknowledge. Such under-appreciation of the importance of albuminuria for assessing CVD risk is, unfortunately, common in many primary care settings. Nevertheless, despite its overt weaknesses, this is a useful descriptive study of the many challenges facing the care of patients with incident CKD (at least in American VA facilities).

Quoted Karger Article

Age-Related Association between Multimorbidity and Mortality in US Veterans with Incident Chronic Kidney Disease

Ritximab in Minimal Change and Focal Segmental Glomerulosclerosis Lesions in Adults

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Lan Lan; Lin Yuxin; Yu Binfeng; Wang Yin; Pan Hong; Wang Huijing; Lou Xiaowei; Lang Xiabing; Zhang Qiankun; Jin Lei; Yang Yi; Xiao Liang; Chen Jianghua; Han Fei: Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study. American Journal of Nephrology DOI 10.1159/000535010

A role for rituximab (RTX and other anti-CD19/20 monoclonal antibodies, such as obinutuzumab [1] has been suggested for therapy of steroid-sensitive nephrotic syndrome (SSNS) with a frequently relapsing steroid-dependent (FR/SD) response in patients with apparently primary minimal change (MCL) or focal and sclerosing glomerulosclerosis (FSGS) lesions on kidney biopsy. Most of the studies supporting this suggestion have been carried out in children. 

Lan and colleagues retrospectively collected data on a cohort of young and older adults with these lesions and FR/SD SSNS in 3 centers in China (MCL in 67 and FSGS in 14 patients) treated with RTX. The treatment with RTX was used to induce a remission or to sustain a remission and reduce the intensity of concomitant immunosuppressive therapy and prevent relapses. The pre-RTX relapse rate was 1.71/year and the follow-up was 2 years. Patients received an average dose of RTX of 1.39 ± 0.62 g. B-cell depletion was observed after each infusion. 

Relapses were decreased to 0.04 per year and the post-RTX relapse-free interval was extended to 16.7 ± 8 months. No differences in effectiveness were seen between the two histological groups or between young and older adults. Adverse events were common (17%), mostly infusion reactions. Low serum albumin levels and high CD56+, CD16+ and NK cells in peripheral blood predicted a higher relapse rate. No studies of anti-nephrin autoantibodies were performed. 

The observational study has all of the limitations of a retrospective analysis, and the number of patients with FSGS lesions and the relatively short-term follow-up do not allow for any firm conclusions concerning long-term effectiveness in the FSGS subgroup. Nevertheless, the findings in FR/SD SSNS in the MCL subgroup generally support the suggestion of effectiveness in this subgroup. The lack of any information on anti-nephrin autoantibodies is a significant weakness. It appears that anti-CD19/20 monoclonal antibody therapy (RTX or obinutuzumab) for FR/SD SSNS in both children and adults can materially reduce relapse frequency and limit the intensity of concomitant immunosuppressives (e.g., steroids). Further randomized controlled studies are eagerly awaited. 


  1. Dossier C, Bonneric S, Baudouin V, Kwon T, Prim B, Cambier A, et al. Obinutuzumab in frequently relapsing and steroid-dependent nephrotic syndrome in children. Clin J Am Soc Nephrol. 2023;18:1555–1562.

Quoted Karger Article

Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study

Recurrence of Focal Segmental Glomerulosclerosis (FSGS) in Kidney Allografts

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Gipson Debbie S.; Wang Chia-shi; Salmon Eloise; Gbadegesin Rasheed; Naik Abhijit; Sanna-Cherchi Simone; Fornoni Alessia; Kretzler Matthias; Merscher Sandra; Hoover Paul;  Kidwell Kelley; Saleem Moin; Riella Leonardo;  Holzman Lawrence; Annette Jackson; Opeyemi Olabisi; Paolo Cravedi; Benjamin Solomon Freedman; Himmelfarb Jonathan; Vivarelli Marina; Harder Jennifer; Klein Jon; Burke George; Rheault Michelle; Spino Cathie;  Desmond Hailey E.; Trachtman Howard: FSGS Recurrence Collaboration: Report of a Symposium. Glomerular Diseases DOI 10.1159/000535138

The “primary” form of the focal segmental glomerulosclerosis (FSGS) lesion (commonly associated with the presence of circulating permeability-promoting factors, notably anti-nephrin auto-antibody, among others) frequently (25–40% or higher) recurs in kidney allografts, most commonly early post-transplantation (even immediately upon returning blood circulation to the graft). Such recurrences curtail graft survival. This vexing problem represents a major obstacle to the use of kidney transplantation to restore health to the patients with primary FSGS who develop end-stage kidney disease (ESKD).

Gipson and many expert colleagues report on a virtual Symposium devoted to this topic held on December 14–15, 2021. The intent of the gathering was to summarize the state-of-the-art of this topic with respect to pathogenesis, detection and management in children and adults as well as to suggest a future research agenda that might close some knowledge gaps. Not surprisingly, considerable attention was devoted to the native FSGS disease.

Clinical and pathological risk factors for the development of recurrent FSGS have been described, most notably rapid progression to ESKD of the native kidney disease, co-existent mesangial hypercellularity, the late development of steroid resistance following a period of steroid sensitivity for the native FSGS, and performance of second kidney transplant after the loss of an initial kidney allograft from a recurrence of FSGS. The presence of pre-transplant anti-nephrin auto-antibodies in the recipient seems to predict recurrence of FSGS. The recurrence rate of FSGS can be as high as 90% with the presence of some of these risk factors. Monogenetic forms of FSGS do not recur in the kidney allograft, with a few exceptions. HLA polymorphisms may act to increase or decrease the risk of recurrent FSGS, but this needs more study. APOL1 high-risk alleles (in donor or recipient) are associated with higher risk of graft loss, but do not seem to influence recurrent disease. De novo FSGS, including collapsing nephropathy, is more common in donor kidneys having high-risk APOL1 alleles. The APOLLO study is examining this aspect of FSGS in donors and recipients more carefully.

Circulating “permeability factors” seem to be involved in recurrence, but their precise identification has so far been elusive. Anti-nephrin auto-antibodies are emerging as an important cause of recurrent FSGS, and this phenomenon is under intense study.

Management of recurrent FSGS by combinations of plasma exchange (PLEX) or lipid apheresis and rituximab (or other anti-CD20 monoclonal antibodies) and steroids seems to be effective in about 50% of cases, but PLEX dependence can be observed. Major gaps in treatment of recurrent FSGS currently exist. Anecdotes suggest that ACTH gel or high-dose calcineurin inhibitors can be effective in some cases. Early diagnosis is critical, as any delay in therapy is associated with a poor outcome. Failure of therapy to reduce proteinuria predicts a risk of graft loss.

This niche area of clinical medicine has many knowledge gaps, identified in this summary. A better understanding of the mechanisms involved in the native disease is required to help avoid its development and to successfully treat recurrent FSGS in kidney allografts.

Quoted Karger Article

FSGS Recurrence Collaboration: Report of a Symposium

Monogenic Causes of Steroid-Resistant Nephrotic Syndrome in Children

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Zhang Luyan; Zhao Fei; Ding Guixia; Chen Ying; Zhao Sanlong; Chen Qiuxia; Sha Yugen; Che Ruochen; Huang Songming; Zheng Bixia; Zhang Aihua: Monogenic Causes Identified in 23.68% of Children with Steroid-Resistant Nephrotic Syndrome: A Single-Centre Study. Kidney Diseases DOI 10.1159/000534853

It is very clear that monogenetic diseases commonly underlie the clinical entity known as steroid-resistant nephrotic syndrome (SRNS) in both children and adults. The glomerular lesion associated with this clinical phenotype is focal and segmental glomerulosclerosis (FSGS), but other lesions, including minimal change and membranoproliferative glomerulonephritis, can occasionally be found.

Zhang and co-workers from the Children’s Hospital in Nanjing, China, carried out a descriptive study of a cohort of children with SRNS (n = 101) or FSGS and nephrotic syndrome (n = 11) using whole-exome sequencing with a panel of specific gene mutations (n = 71) known to be causative for nephrotic syndrome.

Causative genetic mutations were found in 24% of the cohort: WT1 (7/27), NPHS1 (3/27), ADCK4 (3/27), ANLN (2/27) and others (12/27), including phenocopy variants. The causative mutation discovery rate was highest in patients with congenital nephrotic syndrome and syndromic nephrotic syndrome. Interestingly, neither NPHS2 nor COLIV alpha mutations were observed, likely because of the young age of the cohort. The ADCK4 gene co-operates with co-enzyme Q10, raising the possibility of supplemental therapy with CoQ10 in such patients.
This study, and others, argues strongly for the routine performance of genetic testing of children with SRNS, and for such testing in congenital nephrotic syndrome and syndromic nephrotic syndrome even before steroid therapy is commenced.

Quoted Karger Article

Monogenic Causes Identified in 23.68% of Children with Steroid-Resistant Nephrotic Syndrome: A Single-Centre Study

CKD in Living Donors: Long-Term Follow-Up

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Haberal Guldehan; Yildirim Tolga; Yilmaz Seref Rahmi; Altun Bulent; Aki Fazil Tuncay; Erdem Yunus; Arici Mustafa: Chronic Kidney Disease Risk in Living Kidney Transplant Donors: A Long-Term Follow-Up Study. Nephron DOI 10.1159/000534397

Chronic kidney disease (as defined by KDIGO-CKD criteria) is fairly common among living kidney donors subjected to uni-nephrectomy, especially in older donors with age-associated decline in pre-transplant GFR. This was originally pointed out by Barri et al. in 2009 [1]. This might contribute to a slight excess of dialysis-requiring ESKD in such donors. 

Haberal and co-workers from Hacettepe University in Ankara, Turkey, have re-examined this issue examining longer-term follow-up of about 71 months in 338 living donors (related and unrelated). The average age at donation was 47 years and all were Caucasian. A few subjects had hypertension pre-donation and the related–unrelated donor frequency is not specified. The eGFR (2009 CKD-EPI eGFR – creatinine) was 102 ± 15 mL/min/1.73 m2 prior to uni-nephrectomy. Thus, the immediate post-uni-nephrectomy eGFR was estimated to be 51 mL/min/1.73 m2. At last follow-up, the eGFR was 77 ± 17 mL/min/1.73 m2, indicating that the usual compensatory increase of eGFR (about 30–35%) following uni-nephrectomy had occurred. Using the KDIGO-CKD definition, only 6 donors developed an eGFR <45 mL/min/1.73 m2, while 41 had an eGFR of 45–59 mL/min/1.73 m2. A total of 12 donors had an eGFR >60 mL/min/1.73 m2 with some mild increase in urinary albumin to creatinine ratio values. No information is given on birth weight of any of the donors, and the original kidney diseases of intra-familial recipients is unknown. Post-donation hypertension was common in the donors, especially if eGFR was 60 mL/min/1.73 m2. Unfortunately, no control group of non-donors was included to evaluate the significance of this finding. 

The results of this study confirm and extend those of Barri et al. [1]. They illustrate that applying the absolute thresholds of an eGFR of <60 mL/min/1.73 m2 to a cohort of living donors of varying age will inevitably lead to an increased “diagnosis” of CKD following uni-nephrectomy, especially in older donors. Whether this “CKD” will progress is highly uncertain, but new onset of hypertension and albuminuria in some living donors is of concern. Evaluation of nephron endowment (birth weight) will be crucial in future studies of “CKD” in living donors.


1. Barri Y, Parker III T, Kaplan B, Glassock R. Primum non nocere: is chronic kidney disease staging appropriate in living kidney transplant donors? Am J Transplant. 2009;9:657–660.

Quoted Karger Article

Chronic Kidney Disease Risk in Living Kidney Transplant Donors: A Long-Term Follow-Up Study

Sarcopenia and Osteoporosis in Kidney Transplant Recipients

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Hori Mayuko; Takahashi Hiroshi; Kondo Chika; Matsuoka Yutaka; Tsujita Makoto; Nishihira Morikuni; Uchida Kazuharu; Takeda; Morozumi Kunio; Maruyama Shoichi: Coexistence of Low Muscle Mass and Osteoporosis as a Predictor of Fragility Fractures in Long-Term Kidney Transplant Recipients. American Journal of Nephrology DOI 10.1159/000534019

Long-term survivors of kidney transplantation suffer from numerous complications. Often, they die due to side effects of immunosuppressive medications. Low bone mineral density (BMD; often equated with “osteoporosis”) and low muscle mass (LMM; “sarcopenia”) are among these complications, frequently attributed to steroid use. 

Hori and co-workers conducted a retrospective observational study in 342 stable kidney transplant (KT) recipients after a median follow-up of about 5 years using DEXA scanning for BMD and bioelectric impedance for LMM.

As expected, low BMD was associated with excess fracture risk. No bone biopsies were performed, so the cause of low BMD was not firmly established. LMM was found in about one-third of subjects and the combination of low BMD and LMM increased the risk of fractures substantially, even after adjustment for many co-morbid factors, perhaps because LMM is a feature of frailty and excess falls. Steroid use, but not dosage, was one of several co-morbidity adjustments.
“Osteo-sarcopenia” in KT appears to be a real phenomenon, with clinically important consequences. An increased risk of fracture associated with “osteo-sarcopenia” is present in this study, but the underlying causes, including cumulative steroid dosage exposure and frailty, remain underexplored and this study cannot inform practitioners how to best attenuate fracture risk in such patients.

Quoted Karger Article

Coexistence of Low Muscle Mass and Osteoporosis as a Predictor of Fragility Fractures in Long-Term Kidney Transplant Recipients

IgA Nephropathy with ANCA Positivity

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Li Wenchao; Chen Ruifan; Chen Wei; Huang Fengxian; Xia Xi: Clinicopathological Features and Outcomes of IgA Nephropathy with Serum Antineutrophil Cytoplasmic Autoantibody Positivity. American Journal of Nephrology DOI 10.1159/000533982

IgA nephropathy (IgAN) is a common glomerular disease that is not infrequently accompanied by superimposed crescentic glomerulonephritis (GN) of varying severity. Extensive crescentic disease (>50% glomerular involvement) with rapidly progressive GN is rather uncommon (<5% in most series). The role of testing for ANCA in patients with IgAN is largely unknown. 

Li and co-workers retrospectively studied 2,864 patients with biopsy-proven IgAN at a single center in China diagnosed between 2007 and 2019. 85% of these cases were primarily tested for anti-myeloperoxidase antibody (about 3% were positive), but only about 50% were tested for ANCA. Only 4 cases had extensive crescentic disease. The clinical/pathologic manifestations were similar in ANCA+ and ANCA– IgAN, except that ANCA+ IgAN had more ANA+, more extra-renal manifestations, and less interstitial inflammation. The rate of ESKD after a follow-up period of 40–48 months was the same in ANCA+ and ANCA– IgAN. All-cause mortality was low (about 1%) in both groups. Discrepancies in the results of ANCA testing by indirect immunofluorescence and chemiluminescent ANCA assays were observed. This was an exclusively Chinese study, so the results may not be applicable to other geographical regions.

In sum, this retrospective single-center study seems to suggest that ANCA+ does not necessarily confer an adverse prognosis, except possibly in males with concomitant ANA+ (a hypothesis requiring further study). It raises questions as to whether a therapeutic approach to lower ANCA levels (e.g., Rituximab, Cyclophosphamide, plasma exchange) would have any beneficial effects, but the design of the study cannot answer these questions.

Quoted Karger Article

Clinicopathological Features and Outcomes of IgA Nephropathy with Serum Antineutrophil Cytoplasmic Autoantibody Positivity

Rituximab in Minimal Change Disease and Primary Focal and Segmental Glomerulosclerosis

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Aslam Ahsan; Koirala Abbal: Review of the Role of Rituximab in the Management of Adult Minimal Change Disease and Immune-Mediated Focal and Segmental Glomerulosclerosis. Glomerular Diseases

It is not presently known if minimal change disease (MCD) and primary focal and segmental glomerulosclerosis (pFSGS) are separate disease entities or part of a continuous spectrum of a single disease. Both are diffuse podocytopathies that have many clinical features in common, but MCD tends to be much more steroid-responsive than pFSGS. Rituximab (RTX) is an emerging therapeutic agent for both disorders, when they are steroid-sensitive, but not when they are steroid-resistant.

Aslam and Koirala provide a comprehensive and current overview of the utility of RTX in MCD/pFSGS. General agreement exists that RTX therapy can diminish the frequency of relapses in both disorders when they are steroid-sensitive and steroid-dependent. Contrariwise, the existing data is not very encouraging for benefits of RTX therapy in steroid-resistant forms of pFSGS or MCD. No convincing data is yet available that supports the use of RTX for therapy of treatment-naïve MCD or pFSGS. Dosing regimens for RTX in steroid-resistant MCD or pFSGS have not yet been adequately explored and the use of second-generation anti-CD20 monoclonal antibodies (Obinutuzumab or Ofatumumab) is largely lacking.

In sum, RTX is a useful addition to the therapeutic toolbox in steroid-sensitive MCD or pFSGS, but this optimism does not apply (yet) to steroid-resistant disease.

Quoted Karger Article

Review of the Role of Rituximab in the Management of Adult Minimal Change Disease and Immune-Mediated Focal and Segmental Glomerulosclerosis

Blood Pressure and Mortality in Dialysis Patients

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Yazdani Babak; Kleber Marcus E.; Delgado Graciela E.; Yücel Gökhan; Asgari Aruscha; Gerken Andreas L.H.; Daschner Clara; Ayasse Niklas; März Winfried;  Wanner Christoph; Krämer Bernhard K.: Blood pressure and Mortality in the 4D Study. Kidney and Blood Pressure Research DOI 10.1159/000533136

The relationship of blood pressure (BP; systolic, diastolic, pulse pressure, mean arterial pressure) in dialysis patients with diabetes is greatly complicated by competing risks and co-morbidities. Many studies failed to show strong predictive power of (pre-dialysis) BP for all-cause (ACM) and cardio-vascular (CVM) mortality.

Yazdani and co-workers retrospectively analyzed the large 4D trial (in Germany) of the effect of lipid control with statins in diabetic hemodialysis patients (n = 1,255) for the impact of BP on ACM and CVM during a follow-up period averaging about 8 months.

The values of systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were not predictive of ACM and CVM, after adjustments for age and sex. However, a U-shaped relationship of pulse pressure was observed for ACM and CVM, with a rough value of 70–80 mm Hg.

In diabetic patients with end-stage kidney disease (ESKD) treated by dialysis, many co-morbid factors contribute to the risks of ACM and CVM, not all of which are captured by BP parameters. The patients included in this study were “prevalent” patients with an average diabetes duration of 18 years and a dialysis duration at the time of enrolment of about 6 months. The follow-up was relatively short (only 8 months).

This study “only” generates a plausible hypothesis that both low and high pulse pressure is a potentially causative factor in generating a higher risk for ACM and CVM in diabetic patients on dialysis. It remains to be shown that better long-term control of pulse pressure would improve the frequency of these outcomes, especially in an incident population of ESKD. Pulse pressure is largely a phenomenon related to dispensability of larger vessels and cardiac stroke volume, both factors that are difficult to influence. Systolic BP is also closely related to the degree of volume overload in patients with ESKD. This in an interesting and valuable addition to the literature on the potential impact of BP parameters on outcomes in diabetic dialysis patients, but the optimal levels needed to assure better outcomes remain uncertain.  

Quoted Karger Article

Blood pressure and Mortality in the 4D Study

Fabry’s Disease and ESKD

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Pahl Madeleine V.; Hou Jean: Fabry Disease Presenting as End-Stage Kidney Disease. Glomerular Diseases DOI 10.1159/000533502

Because of non-specific symptomatology, Fabry’s disease may elude diagnosis during progression of chronic kidney disease (CKD). Many cases may present with end-stage kidney disease (ESKD) of unknown cause. Using a case report as a demonstration of this conundrum, Pahl and Hou discuss strategies for identifying Fabry’s disease as CKD on a timely basis that might add to the prospect of preventing ESKD by early diagnosis and therapy with enzyme replacement.

Neuropathic pain, heat and cold intolerance, hypohidrosis, and episodes of diarrhea or constipation can be clues to the presence of this X-linked deficiency of alpha-galactosidase. Corneal opacities, hearing loss, and angio-keratomas on buttocks, hips, and/or peri-umbilical areas can be very helpful in suspecting the diagnosis. Premature cerebrovascular disease with strokes or transient ischemic attacks can be seen in about 25% of patients with this disease. Cardiac involvement (left ventricular hypertrophy, aortic or mitral valve disease, and arrhythmias) is common. Kidney involvement is seen in 50% of male hemizygous patients, and less in heterozygous female patients, manifesting as proteinuria and progressive loss of glomerular filtration rate. Frank nephrotic syndrome with hypo-albuminemia is infrequently observed. Use of NSAIDs for pain can exacerbate CKD. Genetic testing is diagnostic. Measurement of serum alpha-galactosidase levels is diagnostically useful in males but not females. Early diagnosis with initiation of enzyme replacement can lead to much symptomatic improvement and better outcomes.

Quoted Karger Article

Fabry Disease Presenting as End-Stage Kidney Disease

AKI Biomarkers in ICU Patients

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La Ashley M., Gunning Samantha, Trevino Sharon A., Kunczt Alissa, Forni Lui G., Swamy Varsha, Zarbock Alexander, Groboske Sarah, Leung Edward K.Y., Yeo Kiang-Teck J., Koyner Jay L.: Real-World Use of AKI Biomarkers: A Quality Improvement Project Using Urinary Tissue Inhibitor Metalloprotease-2 and Insulin-Like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7]). American Journal of Nephrology DOI 10.1159/000531641

Novel urinary biomarkers for the early prediction of AKI in newly admitted patients to intensive care units (ICU) have been developed, but the overall clinical utility of these tests and the timing of their use remain uncertain.

La and co-workers carried out a single-center, prospective, observational study of patients admitted to the ICU who were at risk of developing severe AKI (KDIGO Stage 2/3). Treating physicians were allowed to test patients with urinary tissue inhibitor metalloproteinase-2 and insulin-like growth factor binding protein 7 (TIMP-2*IGFBP7) by commercially available point-of-care methods. Historical controls not tested were used as comparators. 

The 7-day progression to severe AKI when TIMP-2*IGFP7 levels were >0.3 was 28% in the prospective cohort and 21% in the historical cohort (p = 0.38), but Stage 1 CKD was present at the time of testing in 67% of the prospective cohort and in 23% of the historical controls (p < 0.001). Patients with elevated TIMP-2*IGFBP7 were more likely to receive a nephrology consult, and early nephrology consultation was associated with better volume control, less severe AKI, and lower dialysis requirement compared to historical controls.

While this study is not conventionally randomized and controlled, it does resemble a “real-life” scenario, at least in reference to a single-center experience. These limitations lead to confounding by unmeasured variables and bias of some relevance. Also, unlike many other reports of the utility of biomarker testing, many of the patients in the prospective cohort already had Stage 1 AKI at the time of testing. With findings of TIMP-2*IGFBP7 of >0.3–2.0 versus <0.3, the overall risk of progression was not greatly different. However, under the “watchful eye” of a nephrology consultant (triggered by a TIMP-2*IGFBP7 >0.3), the outcomes of Stage 1 AKI seemed to be better. One might ask whether a nephrology consult should be regularly recommended for Stage 1 AKI, independent of biomarker testing. More research is needed in patients admitted to the ICU and at risk for AKI (e.g., sepsis, trauma, elderly, etc.) to determine if routine testing for urinary AKI biomarkers adds benefit in terms of outcome in the presence of universal nephrology consultation for stage 1 AKI.  

Quoted Karger Article

Real-World Use of AKI Biomarkers: A Quality Improvement Project Using Urinary Tissue Inhibitor Metalloprotease-2 and Insulin-Like Growth Factor Binding Protein 7 ([TIMP-2]*[IGFBP7])

Calciphylaxis and Bariatric Surgery

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Xia Joyce, Tan Alice J., Biglione Bianca, Cucka Bethany, Ko Lauren, Nguyen Emily D., Khoury Charbel C., Robinson Malcolm K., Nigwekar Sagar U., Kroshinsky Daniela: Nephrogenic Calciphylaxis Arising after Bariatric Surgery: A Case Series. American Journal of Nephrology DOI 10.1159/000531784

Calciphylaxis (Calcific Uremic Arteriopathy, CUA) is an uncommon but devastating and often fatal complication of ESKD and CKD. The “triggers” for the development of CUA are numerous and poorly understood. They include diabetes, obesity, warfarin use, hyperparathyroidism, hypercalcemia and hyperphosphatemia.

In a small case series (n=5) Xia ad colleagues add bariatric surgery for morbid obesity to this list of “triggers” for CUA. Five patients undergoing bariatric surgery, all with ESKD, developed CUA, one of whom died without resolution, despite aggressive therapy. Four had complete resolution, with therapy including IV and intra-lesional injection of sodium thiosulfate. It is possible that enteric oxalate reabsorption contributed to the CUA seen in these cases. Tissue stains for oxalate were not performed.

Although the benefits of bariatric surgery in patients with morbid obesity and ESKD likely outweighed the risks of CUA, careful attention to the multitude of possible “triggers” in these patients seems warranted. Seems like good advice.

Quoted Karger Article

Nephrogenic Calciphylaxis Arising after Bariatric Surgery: A Case Series

Mast Cells and IgA Nephropathy Prognosis

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Wang Shujie, Hu Danni, Li Yue-Qiang, Lei Qing, Liu Liu; He Xiaofeng, Han Min, Pei Guangchang, Zeng Rui, Xu Gang.: High Renal Mast Cell Density Is Associated with Poor Prognosis in Patients with Immunoglobulin A Nephropathy. American Journal of Nephrology DOI 10.1159/000531243

The search for clinical, laboratory, and histological biomarkers useful for predicting outcomes in IgA nephropathy (IgAN) continues at a fairly rapid pace, but actual progress is modest at best. 

Wang and co-workers add to the literature on this interesting topic by examining kidney mast cell density in kidney biopsies showing IgAN. Seventy-six Chinese patients with IgAN (all studied between 2007 and 2010) and followed for an average of 8 years were included. Mast cell density (tryptase + cells) in tubule-interstitium was compared to outcomes of kidney function.

Increased mast cell density, particularly when associated with more severe clinical or histological manifestations, was predictive of poor outcomes in a multi-variate Cox regression model. Mast cell density showed prediction of progression (doubling of serum creatinine) independent of clinical and histological parameters. Only tryptase + cells were counted. Chymase + mast cells were not studied. Increased mast cell density was also associated with more intense C3 deposition in glomeruli.

This is a small series and needs replication in a larger and more geographically diverse population. Whether the finding of increased mast cell density should be utilized to make therapeutic decisions cannot be determined by a study of this design.

Quoted Karger Article

High Renal Mast Cell Density Is Associated with Poor Prognosis in Patients with Immunoglobulin A Nephropathy

Viral-Induced Glomerular Disease

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Deoliveira Margaret, Sikri Hridyesh, Mon-Wei Yu Samuel, Cijiang He John: Viral Glomerulopathy. Glomerular Dis DOI 10.1159/000531434

Viral-induced glomerular disease is a very important part of the spectrum of glomerulonephritis, especially since many of these diseases can now be prevented or treated with viral-specific approaches.

In a well-written review, De Oliveira and co-authors provide an update on this subject emphasizing HIV, SARS-CoV-2, HCV, and HBV. The clinical spectrum of these diseases is constantly changing, particularly HIV. It seems that HIV has a direct pathogenic effect on the kidney, whereas with SARS-CoV-2 the effects on the kidney are largely indirect. The role of kidney biopsy in HIV disease is appropriately recognized. The risks imposed by alleles at the APOL1 locus on both HIV and SARS-CoV-2 infection are detailed. 

The glomerular disease related to HCV and HBV infection has been altered greatly by the availability of effective anti-viral therapy. Vaccination for HBV has drastically reduced the prevalence of HBV infection in many, but not all, countries of the world.

This update is a welcome contribution and is highly recommended for reading.

Quoted Karger Article

Viral Glomerulopathy

CureGN-Diabetes Study

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Mottl Amy K., Bomback Andrew S., Mariani Laura H., Coppock Gaia, Jennette J. Charles, Almaani Salem, Gipson Debbie S., Kelley Sara, Kidd Jason, Laurin Louis-Philippe, Mucha Krzysztof, Oliverio Andrea L., Palmer Matthew, Rizk Dana, Sanghani Neil, Stokes M.Barry, Susztak Katalin, Wadhwani Shikha, Cynthia C.: CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes. Glomerular Diseases DOI 10.1159/000531679

Observational, long-term cohort studies can play an important role for generating testable hypotheses to improve our understanding of kidney disease. Selection of cases to be included in such cohort studies can be an important source of bias, making generalizations to the population questionable. Diabetic kidney disease (CKD in a patient with diabetes) is common in many regions of the world. A large diverse cohort with detailed characterization, including kidney biopsy, and prolonged follow-up would be a valuable contribution to our knowledge.

Mottl and colleagues provide the details of the ongoing CureGN-Diabetes Study which will focus on the impact of type 1 or 2 diabetes on several glomerular disorders (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy); only a small fraction of patients with these disorders will likely have superimposed diabetic nephropathy. The kidney biopsy information will be provided from clinically indicated rather than research biopsies, introducing an element of ascertainment bias in the study as a whole. Kidney biopsies will be analysed by reviewing electronically stored images, rendering a machine learning approach feasible. The overall goal is to better understand how diabetes modifies the pathology and outcomes of these forms of glomerular disease. 

The ever-changing management of diabetes and the intrinsic heterogeneity of the glomerular disorders selected for study will likely prove to be a great challenge for data analysis and interpretation of this cohort study. Only 300 subjects will be enrolled, which may not be sufficient for appropriately stratified analysis. The degree of granularity for the analytical outcomes may be quite limited, but the goals are laudable. Time will tell. Clinicians should be encouraged to contribute patients to the cohort. 

Quoted Karger Article

CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes

Evaluation of Urine Protein Excretion in Lupus Nephritis

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Gutiérrez-Peredo Gabriel B., Montaño-Castellón Iris, Gutiérrez-Peredo Andrea Jimena, Aguilar Ticona Juan P., Montaño-Castellón Fabio, Batista Oliveira Filho José César, Pinto Almeida Antonio Raimundo: Comparison of urinary protein/creatinine ratio as an alternative to 24-hour proteinuria in Lupus Nephritis: TUNARI study. Nephron DOI 10.1159/000531333

The “gold standard” for evaluation of urinary total protein excretion is a timed (preferably 24-hour) collection (uPER). But compliance (inability to accurately collect the specimen) can limit its utility. The comparison (ratio) of the urinary total protein concentration and urinary creatinine concentration (uPCR) in an untimed, random “spot” urine collection is commonly used as an approach to overcome the limitations of uPER, but this adds a degree of variability due to fluctuation of protein and creatinine excretion during the day and night. This variability may limit the utility of uPCR, especially in lupus nephritis.

Gutierrez-Peredo and colleagues address this issue by comparing the performance of uPER (training provided but collections unsupervised) and random “spot” uPCR in 75 patients with lupus nephritis of varying severity under treatment with steroids, immunosuppressants, and RAS inhibitors. 

As is well known, the two tests are well correlated (r2 = 0.59), but the scatter of results was high and tended to increase with higher grades of proteinuria. Interestingly, the median uPER was 1.2 g/24 h and the uPCR was 1.4 g/g. These values suggest systematic under-collection of timed urine or low urine creatinine excretion or both. The predicted and measured 24-hour urine creatinine excretion is not given. While the AUC of the uPCR for prediction of uPER is fairly high (0.92), this statistic is insufficient to judge the clinical utility of uPCR as an estimate of uPER. A test of misclassification errors would have been better. The spread of the values of uPCR relative to uPER tells a story of substantial variability. A compromise of using an aliquot of a presumed 24-hour collection determining the uPCR was not tested. I prefer this latter metric for assessing proteinuria by uPCR, as it avoids much of the variability of the uPCR collected randomly by “spot” urine specimens. 

Quoted Karger Article

Comparison of urinary protein/creatinine ratio as an alternative to 24-hour proteinuria in Lupus Nephritis: TUNARI study

Therapy of Membranous Nephropathy in Advanced CKD

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Ragy O. , Hamilton P. , Pathi A. , Mohamed Ahmed A. A. , Mitra S. , Kanigicherla D. AK. : Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen. Glomerular Diseases DOI  10.1159/000529605

The treatment of membranous nephropathy (MN; PLA2R associated) has improved greatly in recent years, but uncertainties still exist concerning the treatment of such patients who have already advanced to stage 4 chronic kidney disease (CKD) or beyond. Whether therapy with oral (or IV) cyclophosphamide (CYC), rituximab (RTX), or mycophenolate mofetil (MMF) can achieve a reasonable level of remission in patients with MN and advanced CKD is still not well understood. Calcineurin inhibitors are generally contraindicated in such patients because of the fear of nephrotoxicity.

In a small (n = 18) prospective, uncontrolled, open-label study with moderately long-term follow-up (67 months) in patients with MN (67% PLA2R associated) and advanced CKD (eGFR <30 mL/min/1.73 m2), Ragy and colleagues assessed the benefits (complete or partial remission) of a 6-month course of IV CYC (10 mg/kg, monthly X6 for age <70 years and 7.5 mg/kg monthly X6 for age >70 years) plus tapering doses of oral steroids.

At baseline (prior to starting CYC), the mean eGFR was 23ml/min/1.73m2 (IQR = 18–27); serum albumin level was 2.2 g/dL (IQR = 1.8–2.7); UPCR was ≥ 8.4 (IQR = 6.9–16.7); and the median level of anti-PLA2R antibody was 301.5 RU/mL (IQR = 196–2,651). By any criteria, these were all very high-risk patients.

At the end of follow-up, there were 7 complete remissions, 9 partial remissions, and 2 patients failed to develop a remission and progressed to ESKD. The tine to remission did not vary by anti-PLA2R antibody levels. Five patients developed infection, 2 requiring hospitalization. Four cancers were noted (bladder, mesothelioma, colon, and skin). Four patients died (cancer, CVA, and ischemic heart disease). The eGFR increased in those with remission, but not to over 60 mL/min/1.73 m2. Serum albumin levels improved in most patients.

The lack of parallel groups treated with oral CYC, RTX, or MMF precludes any statements regarding superiority of IV CYC over other regimens. Nevertheless, these preliminary results strongly indicate that advanced CKD (stage 4 CKD) is not a reason to declare futility, at least if anti-PLA2R antibody levels remain greatly elevated. The regimen used can be associated with side effects, some serious.

Quoted Karger Article

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen

Kidney Fibrosis Biomarkers in Type 2 Diabetes Treated with Dulaglutide

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Tuttle K. R., Wilson J. M., Lin Y., Hui-Rong Qian H-R, Federica Genovese, Karsdal M. A., Duffin K. L., Botros Fady T.: Indicators of Kidney Fibrosis in Patients with Type 2 Diabetes and Chronic Kidney Disease Treated with Dulaglutide. American Journal of Nephrology DOI 10.1159/000529374

Kidney fibrosis is one of the final common end-points of progressive CKD in both diabetic and non-diabetic patients. But very few studies have attempted to evaluate kidney fibrosis and its progression using potential serum and/or urine biomarkers. This is an important and understudied aspect of CKD progression. 

Tuttle and coworkers studied two fibrosis biomarkers (not necessarily kidney-specific); namely, serum Pro-C6 (a measure of Collagen Type VI production) and urine C3M (a measure of Collagen Type III degradation) in a post-hoc analysis of a therapeutic trial comparing once weekly Dulaglutide (A GLP1R agonist) compared to Insulin Glargine for up to one year in subjects with Type 2 Diabetes and CKD (eGFR >15 and <60ml/min/1.73m2). 

Dulaglutide therapy decreased serum Pro-C6 and increased urine C3M levels compared to insulin glargine. Serum levels of Pro-C6 were negatively correlated. Dulaglutide decreased the rate of eGFR decline compared to Insulin glasgine the change of eGFR over time and the levels of urine C3M were positively correlated with the change in eGFR over time. 

No repeat kidney biopsies were performed to validate changes in kidney fibrosis.  There were no untreated (or metformin treated  only controls.  And as these biomarkers are not kidney specific, extra renal effects are possible. Reverse causality is another possible explanation, as correlation is not proof of causality. Nevertheless, these studies invoke the hypothesis that a GLP1R agonist may lead to a decrease in kidney fibrosis and thereby exert reno-protective effects. Further studies are warranted, especially those involving sequential kidney biopsies and/or non-invasive means of directly assessing the rate of kidney fibrosis. 

Quoted Karger Article

Indicators of Kidney Fibrosis in Patients with Type 2 Diabetes and Chronic Kidney Disease Treated with Dulaglutide


Therapy of Hyperparathyroidism in CKD

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Strugnell S. A., Csomor P., Ashfaq A., Bishop C. W. : Evaluation of Therapies for Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease. Kidney Diseases

The therapy of secondary hyperparathyroidism (SHPTH) in patients with advanced chronic kidney disease (CKD) presenting with 25-hydroxyvitamin D deficiency is not well established. Three approaches are mainly employed; namely, use of extended-release calcifediol (ERC); use of immediate-release, high-dose cholecalciferol (or ergocalciferol) (ICR); use of a combination of paracalcitol (or calcitriol) and low-dose cholecalciferol/ergocalciferol (PLCD). The comparative advantages of these strategies have not been fully evaluated.

Strugnell and co-workers conducted a small randomized trial (n = 62) of these 3 strategies in patients with stage 4 CKD and elevated iPTH and reduced 25-hydroxyvitamin D levels. The trial was short term (8 weeks in duration) and was stopped prematurely due to the impact of the COVID-19 pandemic on recruitment. The primary end-points were the absolute and relative changes in serum total 25-hydroxyvitamin D and iPTH levels.

At baseline, the mean 25-hydroxyvitamin D level was 20.6 ± 6.6 ng/mL and the mean iPTH level was 148 ± 90 pg/mL. The 25-hydroxyvitamin D levels increased with ERC, but not with IRC or PLCD. The iPTH levels decreased with ERC and PLCD, but not with IRC. Hypercalcemia was seen uncommonly only with PLDC, and hyperphosphatemia was seen occasionally with ERC.
Although the small size, short duration, and underpowered nature of this trial limits any firm conclusions, it does appear that ERC has advantages for treatments of patients with advanced CKD and vitamin D deficiency accompanied by SHPTH.

Quoted Karger Article

Evaluation of Therapies for Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease

Prognostic Significance of Persistent Hematuria in IgA Nephropathy

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Huang Z., Zhang J., Chen B., Li D., You X., Zhou Y., Qiu W., Ding X., Chen C.: Clinical Significance of Persistent Hematuria Degrees in Primary IgA Nephropathy: A Propensity Score-Matched Analysis of a 10-Year Follow-Up Cohort. American Journal of Nephrology DOI 10.1159/000529650

Persistent high-grade hematuria is associated with an adverse impact on prognosis in IgA Nephropathy (IgAN), independent of proteinuria according to retrospective observational studies. But this association has not been rigorously examined prospectively, especially in randomized controlled intervention trials, so we are not very well informed on the potential clinical utility of directing management at minimizing hematuria (compared to the volumes of information concerning proteinuria.

Huang and co-workers re-examined this issue in a single-center, retrospective propensity-matched cohort study of 684 patients with biopsy-proven IgA N. The propensity match was performed using age, sex and eGFR, but not proteinuria. High-grade hematuria was defined as ≥ 330 erythrocytes per μL of urine.

These findings are largely confirmatory and may not be generalizable as they were conducted in a single center in China.

Nevertheless, they support the notion that persistent hematuria is an often neglected aspect of prognostication in IgAN. It is not a part of the International IgAN risk tool, perhaps because it is correlated with the morphological aspects of IgAN as assessed by the Oxford-MEST scoring system. The findings indicate that hematuria’s response to intervention is an important finding that should be monitored along with proteinuria and perhaps that hematuria should be examined as an end-point of treatment independent of proteinuria.

This is not an easy task as quantitation of hematuria needs to be performed on-site and is often highly variable from examination to examination. But this, and other studies should heighten awareness concerning the significant prognostic implications of high-grade hematuria on the progression of IgAN.

Quoted Karger Article

Clinical Significance of Persistent Hematuria Degrees in Primary IgA Nephropathy: A Propensity Score-Matched Analysis of a 10-Year Follow-Up Cohort

eGFR Calculations and Obesity

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Domislovic M., Domislovic V., Fucek M., Jelakovic A., Gellineo L., Dika Z., Jelakovic B.: Should the CKD EPI Equation Be Used for Estimation of the Glomerular Filtration Rate in Obese Subjects?. Kidney and Blood Pressure Research DOI 10.1159/000526115

The definition of chronic kidney disease (CKD) using estimated glomerular filtration (eGFR) equations (indexed to a standard body surface area [BSA] of 1.73 m2) has been recognized as problematic in obese subjects for many years. The magnitude of misclassification of CKD in such subjects using indexing by BSA can be quite substantial.

Domislovic and co-workers examined this issue in a random sample of rural-living subjects in Croatia, in which obesity (body mass index [BMI] >30 kg/m2) was rather common (30%). They compared the prevalence of CKD (defined by an absolute single threshold of eGFR-creatinine <60 mL/min/1.73 m2 kg, using the CKD-EPI equation of 2012) in indexed and de-indexed eGFR (applying two different formulas for BSA) in obese and non-obese subjects. In addition, they compared CKD prevalence using an eGFR formula incorporating height and weight (Salazar-Corcoran equation). They also examined the influence of obesity and leanness (BMI 24 kg/m2) on the prevalence of “hyperfiltration,” defined as an eGFR at or greater than the 95th percentile by age decade, and sex. The bias, precision, and accuracy of each eGFR equation according to BMI categories were investigated. Importantly, no measures of true GFR were included in the study.

In confirmation of earlier studies, they found that CKD-EPI eGFR equations indexed to BSA overstated the prevalence of CKD in obese subjects compared to a de-indexed eGFR formula or one using height and weight as variables. Simultaneously, such a BSA-indexed formula understated the prevalence of glomerular hyperfiltration. Opposite results were found for lean subjects. Thus, an indexed eGFR formula is unreliable in about 1/3 of the population. It is recommended that de-indexed eGFR formulas, or ones incorporating height and weight, be used for estimating CKD prevalence in general populations, containing subjects who are obese (BMI >30 kg/m2) or lean (<25 kg/m2). These confirmatory findings in a cohort of a rural-living general population raise questions concerning the reported epidemiology of CKD in the general population using eGFR formulas indexed for BSA, especially when obesity or leanness is common.

Quoted Karger Article

Should the CKD EPI Equation Be Used for Estimation of the Glomerular Filtration Rate in Obese Subjects?

Calcium Deposition in Kidney Biopsy Specimens

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Gaddy A., Schwantes-An T.-H., Moorthi R.N., Phillips C.L., Eadon M.T., Moe S.M.:Incidence and Importance of Calcium Deposition in Kidney Biopsy Specimens. American Journal of Nephrology DOI 10.1159/000525647

Calcium deposition in the kidney parenchyma (using special stains such as the von Kossa stain), also known as dystrophic calcification, is a relatively common finding (about 10%) in native kidney biopsy specimens. The deposits are typically calcium oxalate (CaOx; birefringent on polarized light) or calcium phosphate (CaP; non-birefringent on polarized light) or mixed CaOx/CaP. The prognostic significance of these deposits is not well understood. The von Kossa stain does not directly detect calcium but rather a phosphate complexed with calcium. Pure CaOx does not stain positively with the von Kossa stain (unless the tissue is pre-treated by an oxidant such as H2O2), but mixed CaOx/CaP will be positive [see Pizzalato P, 1964]. Alizarin S staining is required to directly confirm the presence of calcium in deposits.

Gaddy and colleagues sought to better understand the relationship of kidney parenchyma calcium deposition to co-morbidity and prognosis in a retrospective study of 385 patients with calcium deposition in native kidney biopsies (CaOx = 125; CaP = 230; and mixed CaOx/CaP = 30). About 9.8% of all native kidney biopsies showed some evidence of calcium deposition. As expected, CaOx deposits were found more commonly in gastric bypass, malabsorption, or vitamin D intake. Patients with any calcification were older, had more comorbidities and had lower eGFR and a background of prior acute tubular necrosis and acute kidney injury. Importantly, the subjects with any calcification had a slower rate of decline in eGFR perhaps due to the high prevalence of AKI and recovery. This is different than the adverse prognostic implications of calcium deposition in transplant kidney biopsies. It was not possible in this study to examine the differential prognostic implications of CaOx versus CaP deposition. These are intriguing findings. The extreme heterogeneity of dystrophic calcification probably precludes precise determination of its prognostic implication.

Quoted Karger Article

Incidence and Importance of Calcium Deposition in Kidney Biopsy Specimens


Serum Uromodulin Levels in IgA Nephropathy (IgAN): A Biomarker of Injury?

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Tachibana S., Iyoda M., Suzuki T., Kanazawa N., Honda H: Serum Uromodulin Levels Reflect Severity of Clinicopathological Findings in Early Stage IgA Nephropathy. American Journal of Nephrology DOI 10.1159/000525836

Uromodulin (UMOD or Tamm-Horsfall Protein) is synthesized and secreted by the thick ascending limb of the loop of Henle in the kidney. Mutations of the UMOD gene have been linked to autosomal dominant tubule-interstitial disease, hypertension, and chronic kidney disease. The relationship of the serum level of UMOD (sUMOD) to outcomes and histopathological injury in IgA nephropathy (IgAN) is not well studied.

Tachibana and co-workers fill this gap by an interesting study of 108 Japanese patients with IgAN, in whom the sUMOD was measured at the time of kidney biopsy. Kidney injury was assessed by the Japan Histological Grade (HG, I–IV score, including crescents) and by the Oxford-MEST score (not including crescents).

sUMOD was dichotomized into low (≤145 ng/mL; n = 54) and normal-high (>145 ng/mL; n = 54) levels. The low sUMOD group had high body mass index, proteinuria, serum creatinine, and low serum albumin and eGFR. sUMOD was negatively correlated with serum creatinine and positively with eGFR. The low-sUMOD group had higher HG scores and higher values of Oxford-MEST M and T scores. Crescents were not examined. The patients with low sUMOD levels had more progression as assessed by a >30% decline in eGFR during follow-up. Patients with eGFR >60 mL/min/1.73 m2 had greater progression and histological severity. This confirms an earlier study [Zhou J, et al. PLoS One. 2013;8:e71023]. The cause of low sUMOD levels is unknown, but this is a promising new non-invasive serum biomarker that might find utility for stratification purposes in interventional trials.

Quoted Karger Article

Serum Uromodulin Levels Reflect Severity of Clinicopathological Findings in Early Stage IgA Nephropathy

Predictions of Outcomes in IgA Nephropathy

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Ebbestad R., Sanaei Nurmi M., Lundberg S.: Long-Term Outcomes of Patients with IgA Nephropathy Categorized by the International IgAN Risk Prediction Tool and by the Degree of Hematuria at Diagnosis. Nephron DOI 10.1159/000525001

Accurate and reproducible prediction of the long-term (5–10 years) outcomes in individuals or groups of patients with biopsy-proven IgA nephropathy (IgAN) is a very desirable goal. Such prediction helps in treatment decisions and the design of interventional trials. Several well-validated prediction tools are now available, but few have incorporated hematuria as a controlling (or controllable) prognostic variable.

Ebbestad and co-workers attempt to fill this “gap” in a small cohort (n = 95) of Swedish patients with IgAN and a median follow-up of 12.5 years. Particular attention was placed on baseline hematuria defined as >10 erythrocytes per high-power field or a urine dipstick for hemoglobin of 2–3+. No attempt was made to quantify the severity of hematuria at baseline or during follow-up. The primary outcome metric was a 50% or greater decline in eGFR from baseline or ESKD, similar to that used in the IgA Risk Prediction Tool (IgAN-RPT), which was also used in this study.

In total, 2% of the cohort reached the endpoint. 77 of 95 patients had hematuria assessed at baseline. The 5-year risk quartiles were 0.95%, 2.6%, 5.9%, and 23.3%. Very-low and very-high risk primary outcome thresholds were defined as <4% and >11% at 5 years. High prevalence of hematuria (positive tests) was numerically associated with an increased risk of the primary outcome (8.8% vs. 5.7% at 5 years, increasing to 26.2% vs. 6.3% with continued follow-up). However, likely due to the small size of the cohort, these differences were not statistically significant. Unfortunately, the hematuria evaluation at baseline was nonquantitative, and no follow-up observations were made. Treatment with immunosuppression did not differentiate between the low- and high-risk groups, suggesting overtreatment of the low-risk group.

This study is largely confirmatory and not sufficiently powered to examine the influence of hematuria on outcome. Other uncontrolled studies have strongly suggested an adverse effect of continued high-grade hematuria on outcome, independent of other risk biomarkers. Very clearly, the variable of hematuria in risk prediction deserves further study. Standardization of methods to detect and quantify hematuria are greatly needed to foster incorporation of quantitative hematuria assessment into ongoing and future interventional trials of novel agents in IgAN.

Quoted Karger Article

Long-Term Outcomes of Patients with IgA Nephropathy Categorized by the International IgAN Risk Prediction Tool and by the Degree of Hematuria at Diagnosis

Fibrillary Glomerulonephritis and Protein Folding

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Andeen N.K., Kung V.L., Robertson J., Gurley S.B., Avasare R.S., Sitaraman S.: Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response. Glomerular Diseases DOI 10.1159/000525542

Fibrillary glomerulonephritis (FGN) is a rare form of primary glomerular disease defined by the common co-deposition of IgG and DNAJB9 and fibril formation. Its etiology and pathogenesis are unknown. DNAJB9 deposition is a highly sensitive and specific biomarker for FGN. The role of DNAJB9 (a chaperone regulating heat shock protein responding to endoplasmic reticulum stress) in the pathogenesis of the lesion of FGN is largely unknown.

In a very scholarly and well-written review article, Andeen and colleagues from the University of Oregon analyze FGN from the perspective of protein folding with a particular emphasis on DNAJB9. FGN is seen in about 1% of kidney biopsies performed for evaluation of suspected glomerular disease. The IgG deposits are nearly always polyclonal, although rarely they may be monoclonal. The fibrils are typically small (10–20 nm in width). Serological evaluation shows concomitant autoimmunity in up to about 15% of patients (positive FANA or ANCA). Hypocomplementemia is seen in 5% or less. HLA DR7 is found in about 50% of patients. Paraffin immunofluorescence can be required for unmasking of polyclonality of the IgG as frozen immunofluorescence may commonly show light chain monotypism. Rarely, IgG may be absent in the deposits. DNAJB9 is nearly always present in the deposits, and serum levels of DNAJB9 are elevated in 30–50% of patients. No circulating antibody to DNAJB9 has yet been described in FGN. Rarely, AA amyloid may also be DNAJB9 positive. The disease can recur in kidney allografts, but this is usually very delayed and very indolent in its clinical features. Donor-derived FGN has also been described in kidney transplantation.

The authors suggest that misfolded or unfolded proteins may be part of the pathogenesis of the FGN lesions. Such misfolding can unleash a series of molecular and cellular responses covered under the rubric of the “unfolded protein response.” Fibril formation and upregulation of DNAJB9 formation ispart of this cascade of events. Data suggests that DNAJB9 binds to misfolded IgG, but the reverse may also occur. Mutations of the DNAJB9 gene have not yet been found. DNAJB9 deposits are only very rarely seen in other protein misfolding disorders, such as amyloidosis. Studies so far have failed to show upregulation of DNAJB9 in glomeruli, so a post-transcriptional event is likely involved in DNAJB9 deposition seen in FGN.

Collectively, these features suggest that a post-transcriptional defect in DNAJB9 itself is deeply involved in the pathogenesis of FGN. This is perhaps mediated by the “unfolded protein response” to misfolded IgG or DNAJB9 or both. Targeted therapy for FGN will depend upon further unraveling of this complicated cascade. At present, there is no proven effective therapy for FGN, although preliminary, uncontrolled observations suggest a possible beneficial effect of rituximab, which has no known effect on DNAJB9 itself. Stay tuned as this mystery “unfolds.”

Quoted Karger Article

Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response

Interstitial Inflammation as a Prognostic Factor in IgA Nephropathy

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Zhu B., Liu W.-H., Lin Y., Li Q., Yu D.-R., Jiang F., Tang X.-L., Du Y.-Y., Yin J.-Z., Li X.-F., Zhong Y.-Z., Wang W.-R., Sun Y., Zhang M.-J., Gao Y.-C., Yuan C.-Y., Zhu C.-F., Cheng X.-X.: Renal Interstitial Inflammation Predicts Nephropathy Progression in IgA Nephropathy: A Two-Center Cohort Study. American Journal of Nephrology DOI 10.1159/000524585

Prediction of the long-term outcomes in individual patients with IgA nephropathy (IgAN) using pathological parameters has long been a “holy grail” in Nephrology. To be sure, the addition of the Oxford-MEST-C scoring system and the International IgA Nephropathy Prognosis tool (IgAN-PT) have achieved much in improving the prediction of progressive disease. Pathology, when combined with clinical features, especially persistent proteinuria, offers substantial value to outcome prediction, but there is always room for improvement. The role of the extent and severity of renal interstitial inflammation in independent prediction outcome remains uncertain.

Zhu and coworkers sought to clarify the issue of the prognostic value of interstitial inflammation in a two-center retrospective cohort study from China. They included 1,420 patients with IgAN (diagnosed by kidney biopsy between 2003 and 2013) with an average follow-up of 7 years. In a propensity matching sub-study, 181 patients with non-mild interstitial inflammation were compared to 181 patients with moderate to severe interstitial inflammation.

After full adjustments for covariates, a higher level of interstitial inflammation was associated with a faster decline of eGFR. The propensity matching sub-study gave similar results. Incorporating the interstitial inflammation severity into the IgAN-PT improved the capability of this tool to predict outcome. Overall, all the area under the curve analyses of the receiver operating characteristics showed only a modest increase in values from 0.81 to 0.83, but both the Net Reclassification Index and the Integrated Discrimination Index showed improvement when interstitial inflammation was added as a variable. Previously, interstitial inflammation was discarded by the Oxford-MEST-C development group as it was highly correlated with interstitial fibrosis. Perhaps the differences in the findings of this study could be explained by the retrospective nature of the study and the unique Chinese ancestry of the cohort. Nevertheless, this study raises important questions about the utility of adding interstitial inflammation to the list of important predictive factors identified in pathological analysis of kidney biopsies from subjects with IgAN.

Quoted Karger Article

Renal Interstitial Inflammation Predicts Nephropathy Progression in IgA Nephropathy: A Two-Center Cohort Study

COVID Vaccination and Kidney Disease

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Fenoglio R.,Lalloni S., Marchisio M., Oddone V., De Simone E., Del Vecchio G., Sciascia S., Roccatello D.: New Onset Biopsy-Proven Nephropathies after COVID Vaccination. American Journal of Nephrology DOI 10.1159/000523962

The COVID-19 pandemic unleashed a new wave (indeed a torrent) of an old and well-recognized phenomenon; namely, the development of de novo or an exacerbation of underlying kidney disease in subjects receiving vaccinations for prevention of viral or bacterial infectious disease. Administration of any of the vaccines against SARS-CoV-2, the etiologic agent for COVID-19, has been suggested to produce adverse events, including kidney disease, largely based on sporadic case reports or small series. Due to the very widespread use of such vaccines, these adverse events affect only a small minority of subjects receiving these vaccines.

Fenoglio and coworkers conducted a retrospective, time-limited survey of the occurrence of kidney disease following vaccination among hospitalized patients at a single center in Turin, Italy, between April and November 2021. All cases developed kidney disease, either de novo or as a relapse of pre-existing disease (within 3 months of receiving the 1st or 2nd dose of a COVID vaccine). Most (59%) had received the Pfizer BNT162b2 vaccine. Seventeen patients were included out of 123 patients undergoing kidney biopsy during the same interval of time. Seven had nephrotic syndrome, 2 had abnormal urinalyses, and 8 had nephrotic syndrome with progressive kidney function decline. On kidney biopsy, 5 had minimal change disease, 3 had acute tubulointerstitial nephritis (all with acute kidney injury [AKI]), 3 had membranous nephropathy, 2 had IgA nephropathy (IgAN), and one each had membranoproliferative glomerulonephritis, ANCA vasculitis, lupus nephritis, and “tip” lesion focal segmental glomerulosclerosis (FSGS). Eight of the subjects had AKI as the presenting feature. All patients were treated with immunosuppressants (mainly glucocorticoids or rituximab). The age range was 2–82 years. The onset of kidney manifestations ranged from 24 to 89 days after vaccination. There were no African-Americans identified and no cases of collapsing glomerulopathy. De novo disease was seen more frequently after the 2nd dose, while relapsing disease tended to be seen after the 1st dose of vaccine. The mechanism of the adverse events is not known but is thought to be due to augmentation of T- and/or B-cell immune responsiveness. Patients with AKI due to tubulointerstitial nephritis in general recovered, but the long-term Membranous nephropathy (MN) outcomes are not known for those with glomerular disease to short-term follow-up. The actual risk of such adverse events is not well understood due to the lack of information on the number of subjects receiving the vaccines.

This is a valuable contribution as it illustrates the broad spectrum of lesions that can be observed in COVID vaccine-associated nephropathy. Treatment with steroids seems to be effective in AKI with tubulointerstitial nephritis, and immunosuppression might be of value in some cases of de novo or relapsing glomerular disease, but the long-term outcome in these cases is not yet known.

Quoted Karger Article

New Onset Biopsy-Proven Nephropathies after COVID Vaccination

Outcomes in Anti-GBM Disease

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Jia X.-Y., Xu H.-Y., Cui Z., Zhao M.-H.: Predictors of Kidney Outcomes of Anti-Glomerular Basement Membrane Disease in a Large Chinese Cohort. American Journal of Nephrology DOI 10.1159/000512365

Anti-GBM disease poses a serious threat to survival and preservation of kidney function, especially if it is discovered or treated late in its evolution. It is a rare disease (1–3 cases per million per year), so information on outcomes is rather limited.

Jia and colleagues conducted a remarkable, retrospective study of 448 patients with serologically or biopsy-proven anti-GBM disease at a single center in China diagnosed and treated over about a 3-decade period (1991–2020). Of these 448 subjects, 218 underwent a kidney biopsy showing typical linear IgG deposits.

The age of the subjects was 47 ± 19 years. There was a male predominance (1.6 male/female). About one-third had concomitant diffuse alveolar hemorrhage. About 21% had concomitant ANCA positivity. The serum creatinine level at diagnosis was 9.2 ± 5.2 mg/dL, and 83% of the kidney biopsies showed crescents in over 50% of glomeruli. The delay from apparent onset of disease to diagnosis (and presumably treatment) was 1.3 months (interquartile range = 0.9–2.8 months). Plasma exchange (PLEX) was carried out in 56% of patients; 88% received steroids and 67% received cytotoxic agents. The overall renal survival of all patients seen over the 3 decades was only 23%, and the 3-month and 12-month patient mortality was 19% and 31%, respectively. For every 2.3 mg/dL increase in serum creatinine, the risk of kidney failure rose by about 16%.

Over the 30 years covered by this analysis, patient mortality declined (from 37% in 1991–2000 to 2.8% in 2011–2020), but the risk of kidney failure hardly changed at all. The average serum creatinine level at diagnosis was 11.2 mg/dL in 1991–2000 and 9.3 mg/dL in 2011–2020. A serum creatinine level of ≥6.1 mg/dL at diagnosis was highly predictive of eventual dialysis dependency (Sensitivity = 88%; Specificity = 81%). ANCA positivity was predictive of higher mortality but not kidney failure. The use of PLEX was associated with better outcomes. Combined membranous nephropathy and anti-GBM disease increased over the decades.

This detailed analysis of a 3-decade experience in diagnosing and managing anti-GBM disease is a valuable addition to the literature. It is worth pointing out that it applies largely to a subset of patients with anti-GBM disease referred for diagnosis and treatment rather late in the course of the disease. This likely explains the rather poor results in causing remissions without permanent loss of kidney function. It points out again the overriding importance of early recognition and prompt diagnosis (by serology and/or kidney biopsy) and institution of therapy (PLEX, steroids, and cytotoxic agents) for optimizing favorable clinical outcomes.

Quoted Karger Article

Predictors of Kidney Outcomes of Anti-Glomerular Basement Membrane Disease in a Large Chinese Cohort

Definitions of AKI after Cardiac Surgery

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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.

Quoted Karger Article

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

Congenital Heart Disease and Autosomal Dominant Polycystic Kidney Disease

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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).

Quoted Karger Article

Congenital Heart Disease in Adults with Autosomal Dominant Polycystic Kidney Disease