Pathological characteristics of light chain crystalline podocytopathy.

Monoclonal immunoglobulin light chain (LC) crystalline inclusions within podocytes are rare, poorly characterized entities. To provide more insight, we now present the first clinicopathologic series of LC crystalline podocytopathy (LCCP) encompassing 25 patients (68% male, median age 56 years). Most (80%) patients presented with proteinuria and chronic kidney disease, with nephrotic syndrome in 28%. Crystalline keratopathy and Fanconi syndrome were present in 22% and 10%, respectively. The hematologic condition was monoclonal gammopathy of renal significance (MGRS) in 55% and multiple myeloma in 45%. The serum monoclonal immunoglobulin was IgG κappa in 86%. Histologically, 60% exhibited focal segmental glomerulosclerosis (FSGS), often collapsing. Ultrastructurally, podocyte LC crystals were numerous with variable effacement of foot processes. Crystals were also present in proximal tubular cells as light chain proximal tubulopathy (LCPT) in 80% and in interstitial histiocytes in 36%. Significantly, frozen-section immunofluorescence failed to reveal the LC composition of crystals in 88%, requiring paraffin-immunofluorescence or immunohistochemistry, with identification of kappa LC in 87%. The LC variable region gene segment, determined by mass spectrometry of glomeruli or bone marrow plasma cell sequencing, was IGKV1-33 in four and IGKV3-20 in one. Among 21 patients who received anti-plasma cell-directed chemotherapy, 50% achieved a kidney response, which depended on a deep hematologic response. After a median follow-up of 36 months, 26% progressed to kidney failure and 17% died. The mean kidney failure-free survival was 57.6 months and was worse in those with FSGS. In sum, LCCP is rare, mostly associates with IgG κappa MGRS, and frequently has concurrent LCPT, although Fanconi syndrome is uncommon. Paraffin-immunofluorescence and electron microscopy are essential to prevent misdiagnosis as primary FSGS since kidney survival depends on early diagnosis and subsequent clone-directed therapy.

Assessment of renal outcome following therapy in monoclonal immunoglobulin deposition disease: Emphasizing the need for a consensus approach.

Monoclonal immunoglobulin deposition disease (MIDD), often associated with plasma cell dyscrasias, predominantly affects the kidneys. In this disease, hematologic response (HR) to treatment can be reliably assessed by International Myeloma Working Group (IMWG) consensus criteria, while uniform criteria for assessing renal response are lacking. We report a retrospective analysis of renal outcomes among 34 patients with MIDD. With most patients treated with bortezomib and autologous stem cell transplantation, 26 of 28 (94%) achieved very good partial HR or better. We demonstrate that both IMWG (based on estimated glomerular filtration rate, eGFR) and amyloid (based on proteinuria) criteria are needed to capture renal response: among 28 evaluable patients, 6 (21%) had isolated proteinuria, while 13 (46%) had isolated decreased eGFR. Using both criteria, which were concordant in patients with both decreased eGFR and proteinuria, 22 of 28 patients (79%) achieved a renal response, including 2 of 7 discontinuing dialyses. All 6 patients (100%) with isolated proteinuria and 7 of 13 (54%) with isolated decreased eGFR achieved renal response, suggesting that isolated proteinuria is an early manifestation of MIDD associated with reversible renal damage. Baseline eGFR predicted renal response (p = .02 by quartile) and survival (p = .02), while HR (CR vs. non-CR) did not, probably because of high HR rate. With a median follow-up of 110 months, the median overall survival was 136 months (95% CI: 79-NR) and median renal survival had not been reached. Prospective studies using uniform renal response criteria are needed to optimize the management of MIDD.

The characteristics of seronegative and seropositive non-hepatitis-associated cryoglobulinemic glomerulonephritis.

The clinicopathologic characteristics and long-term outcome of non-hepatitis-associated cryoglobulinemic glomerulonephritis (CryoGN) are not well-defined and cases with undetectable serum cryoglobulin (seronegative CryoGN) have not been investigated. To resolve this, we retrospectively identified 81 patients with biopsy-proven non-hepatitis CryoGN, including 22 with seronegative CryoGN. The median age was 61 years and 76% presented with nephritic syndrome. A hematologic condition was found in 89% of patients, including monoclonal gammopathy of renal significance (65%) and symptomatic lymphoproliferative disorder (35%). In the seropositive group, 56% had type II, 29% type I, and 8% type III cryoglobulin. Extrarenal manifestations, mostly of skin, were present in 64% and were significantly less common in seronegative CryoGN. Glomerular deposits by immunofluorescence were IgM dominant (84%) and polytypic (70%) in the seropositive group, whereas 52% of seronegative cases had monotypic deposits (i.e., type I cryoglobulin). Ultrastructurally, the deposits were organized in 77% of cases. Substructure appearance significantly differed according to the type of CryoGN, forming most commonly short cylindrical structures in type II and other organized substructures in type I CryoGN. Most patients were treated with clone-directed therapy. On follow up (median 33 months), 77% had partial or complete remission, 10% reached kidney failure and 14% died. Predictors of kidney failure on univariate analysis were AKIN stage 3, positive rheumatoid factor and biclonal gammopathy at diagnosis. We conclude that most CryoGN cases (types I and II) are due to a hematologic condition and are associated with favorable outcome after clone-directed therapy. Seronegative CryoGN accounts for about a quarter of cases and is mostly a kidney-limited disease. Thus, further investigations are needed to unravel the pathophysiology of seronegative CryoGN.

Incidence and Risk Factors for Acute and Chronic Kidney Injury after Adult Cord Blood Transplantation.

Although cord blood transplantation (CBT) extends allograft access, patient comorbidities, chemoradiation, and nephrotoxic medications all contribute to acute kidney injury (AKI) risk. We analyzed AKI in adult myeloablative CBT recipients who underwent transplantation from 2006 to 2017 for hematologic malignancies using cyclosporine A (CSA)/mycophenolate mofetil immunosuppression. Maximum grades of AKI were calculated using Kidney Disease: Improving Global Outcomes (grade 1, 1.5 to <2-fold; grade 2, 2 to <3-fold; or grade 3, ≥3-fold over baseline) definitions. In total, 153 patients (median 51 years [range, 23-65], 114/153 [75%] acute leukemia, 27/153 [18%] African, 88/153 [58%] cytomegalovirus seropositive, median age-adjusted hematopoietic cell comorbidity index 3 [range, 0-9], median pretransplant albumin 4.0 g/dL [range, 2.6-5.2]) underwent transplantation. The day 100 cumulative incidence of grade 1-3 AKI was 83% (95% confidence interval [CI], 77%-89%) (predominantly grade 2, median onset 40 days, range 0 to 96), and grade 2-3 AKI incidence was 54% (95% CI, 46%-62%) (median onset 43 days, range 0 to 96). Mean CSA level preceding AKI onset was high (360 ng/mL, target range 300-350). In multivariate analysis, African ancestry, addition of haploidentical CD34+ cells, low day -7 albumin, critical illness/intensive care admission, and nephrotoxic drug exposure (predominantly CSA and/or foscarnet) were associated with AKI. In a day 100 landmark analysis, 6% of patients with no prior AKI had chronic kidney disease (CKD) at 2 years versus 43% with prior grade 1 and 38% with prior grade 2-3 AKI (overall P= .02). Adult CBT recipients are at significant AKI risk, and AKI is associated with increased risk of CKD. Prevention strategies, early recognition, and prompt intervention are critical to mitigate kidney injury.

The sensitivity and specificity of the routine kidney biopsy immunofluorescence panel are inferior to diagnosing renal immunoglobulin-derived amyloidosis by mass spectrometry.

Immunoglobulin light chain amyloidosis is the most frequent type of renal amyloidosis in the United States, accounting for 81% of cases. Accurate typing is crucial for early diagnosis and treatment of immunoglobulin-derived amyloidosis and to avoid treating other amyloidoses with potentially toxic chemotherapy. Immunofluorescence is the first step to type renal immunoglobulin-derived amyloidosis but the performance characteristics of this method are largely unknown. Here, we establish the sensitivity and specificity of immunofluorescence for diagnosing immunoglobulin-derived amyloidosis in patients whose amyloid typing was performed by the current gold standard of laser microdissection/mass spectrometry. Renal biopsy pathology reports originating from several institutions with a diagnosis of amyloidosis and which had amyloid typing by laser microdissection/mass spectrometry performed at our center were reviewed. Reported immunofluorescence staining for kappa or lambda of 2+ or more, with weak or no staining for the other light chain was considered positive for light chain amyloidosis by immunofluorescence. Based on microdissection/mass spectrometry results, of the 170 cases reviewed, 104 cases were typed as immunoglobulin-derived amyloidosis and 66 were typed as non-immunoglobulin-derived amyloidosis. Immunofluorescence sensitivity for diagnosing immunoglobulin-derived amyloidosis was 84.6%. The remaining 16 cases could not be diagnosed by immunofluorescence due to reported weak staining for all antigens or reported lack of preferential staining for one antigen. Immunofluorescence specificity was 92.4%. Five cases, all amyloid A amyloidosis, were misdiagnosed as immunoglobulin-derived amyloidosis by immunofluorescence. Immunofluorescence failed to accurately differentiate immunoglobulin-derived from non-immunoglobulin-derived amyloidosis in 12.3% of cases of renal amyloidosis. Relying on immunofluorescence alone for determining immunoglobulin-derived vs. non-immunoglobulin-derived amyloidosis may lead to misdiagnosis. Thus, immunofluorescence has inferior sensitivity and specificity compared with laser microdissection/mass spectrometry in the typing of immunoglobulin-derived amyloidosis.

Corticosteroid therapy alone for the treatment of C3 glomerulonephritis in association with monoclonal gammopathy
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INTRODUCTION: C3 glomerulonephritis (C3GN) is a form of proliferative glomerulonephritis characterized by dominant glomerular C3 deposition. There is currently no consensus guideline on therapy for this disease. Experience with corticosteroids alone is scant in C3GN. We report the experience of treating patients with C3GN in association with monoclonal gammopathy with corticosteroid at a single center. MATERIALS AND METHODS: Corticosteroid therapy alone was used to treat 6 patients with C3GN who were also found to have monoclonal gammopathy at the time of presentation. RESULTS: Median age of this cohort was 65 years. Median estimated glomerular filtration rate (eGFR) by MDRD equation was 31.6 mL/min/1.73m2 at presentation. After a median duration of follow-up of 23.5 months, all patients showed improvement in proteinuria: median proteinuria reduced from 2.3 to 0.5 g/d. Four of 6 patients showed improvement in kidney function. One patient who had required renal replacement therapy recovered renal function. Median eGFR at follow-up was 38.7 mL/min/1.73m2. DISCUSSION: In patients with C3GN in association with monoclonal gammopathy, corticosteroid therapy alone may be a viable treatment option. Work-up should be done to exclude a hematologic neoplasm and inherited complement abnormalities before proceeding to corticosteroid therapy.
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Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is an oncologic emergency due to massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Clinical presentation is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. Acute kidney injury due to tumor lysis is potentiated by the precipitation of uric acid and calcium phosphate as well as renal vasoconstriction. Early recognition of tumor lysis can help prevent cardiac arrhythmias, seizures, and death. Management includes intravenous hydration to maintain urine flow, medications targeting hyperuricemia including rasburicase and allopurinol and in severe cases renal replacement therapy may be required.

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND AND OBJECTIVES: AKI is a major complication of allogeneic hematopoietic stem cell transplantation, increasing risk of nonrelapse mortality. AKI etiology is often ambiguous due to heterogeneity of conditioning/graft versus host disease regimens. To date, graft versus host disease and calcineurin inhibitor effects on AKI are not well defined. We aimed to describe AKI and assess pre-/post-hematopoietic transplant risk factors in a large recent cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a single-center, retrospective study of 616 allogeneic hematopoietic cell transplant recipients from 2014 to 2017. We defined AKI and CKD based on Kidney Disease Improving Global Outcomes (KDIGO) criteria and estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration equation. We assessed AKI pre-/post-hematopoietic transplant risk factors using cause-specific Cox regression and association of AKI with CKD outcomes using chi-squared test. AKI was treated as a time-dependent variable in relation to nonrelapse mortality. RESULTS: Incidence of AKI by day 100 was 64%. Exposure to tacrolimus and other nephrotoxins conferred a higher risk of AKI, but tacrolimus levels were not associated with severity. Reduced-intensity conditioning carried higher AKI risk compared with myeloablative conditioning. Most stage 3 AKIs were due to ischemic acute tubular necrosis and calcineurin inhibitor nephrotoxicity. KRT was initiated in 21 out of 616 patients (3%); of these 21 patients, nine (43%) recovered and five (24%) survived to hospital discharge. T cell-depleted transplants, higher baseline serum albumin, and non-Hispanic ethnicity were associated with lower risk of AKI. CKD developed in 21% (73 of 345) of patients after 12 months. Nonrelapse mortality was higher in those with AKI (hazard ratio, 2.77; 95% confidence interval, 1.8 to 4.27). CONCLUSIONS: AKI post-hematopoietic cell transplant remains a major concern. Risk of AKI was higher with exposure to calcineurin inhibitors. T cell-depleted hematopoietic cell transplants and higher serum albumin had lower risk of AKI. Of the patients requiring KRT, 43% recovered kidney function. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN19801220.mp3.

Serum free light chain level at diagnosis in myeloma cast nephropathy-a multicentre study.

Myeloma cast nephropathy (MCN) is a common cause of severe renal impairment in multiple myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002-2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107-114600). Serum creatinine was 535 µmol/L (range 168-2993) and eGFR 7 ml/min/1.73 m2 (range 1-34). Six patients (5.8%) had an FLC level <1500 mg/L, which is the International Myeloma Working Group threshold for MCN and two patients were below the International Kidney and Monoclonal Gammopathy working group threshold of 500 mg/L; one was hypercalcaemic, and one had high-normal serum calcium level and had received a non-steroidal anti-inflammatory agent. Sixty-nine (67%) patients required haemodialysis treatment of whom 36 (52.1%) recovered independent renal function. Sixty-six (64%) patients died with a median OS of 2.5 years (95% CI 1.8-3.3). A landmark analysis revealed that independence from dialysis was associated with improved survival at 3-months (P = 0.003), 6-months (P = 0.035) and 9-months (P = 0.014); there was no survival benefit observed beyond 12 months (P = 0.146). Serum FLC level at diagnosis was neither associated with renal function recovery nor with OS. This is the largest reported cohort of patients with biopsy-confirmed MCN and prospectively measured serum FLC levels. These results indicate that a serum monoclonal FLC > 500 mg/L should be considered the threshold level associated with the development of MCN.

Myeloma light chain cast nephropathy, a review.

Multiple Myeloma is a plasma cell proliferative disorder that commonly involves the kidney. Renal impairment is a serious complication during the course of the disease that is associated with increased morbidity and mortality. Light chain cast nephropathy is the predominant pattern of renal injury in Multiple Myeloma. This review article focuses on the pathophysiology and diagnostic approach of myeloma cast nephropathy. The management of precipitating factors as well as anti-plasma cell treatment modalities in the context of renal impairment are also discussed.

Quality of life of caregivers and patients on peritoneal dialysis.

Peritoneal dialysis is the archetypal home-based therapy and is often favoured by patients. However, as patients with end-stage renal failure become more elderly, with more co-morbidity, their dependence on carers to provide physical, emotional and logistical support increases. The effect of this chronic burden has not been systematically studied. We have prospectively studied patients with end-stage renal failure starting peritoneal dialysis and their carers over a 1-year period. We selected a cohort of caregivers that are actively involved with the care of their partners' dialysis. Quality of Life (QoL) assessed by SF-36 questionnaires showed the patients and carers had impairment of QoL at the start of dialysis. As expected, the baseline QoL Physical Component Scores highly correlated with co-morbidity and assessment of functional capacity. Scores of all QoL domains improved after 1 year and this reached statistical significance for social functioning for both patients and carers. When we compared carers of highly dependent patients (required to perform daily dialysis) with carers of less dependent patients, we noted that the former had a statistically significant worsening of their mental health but other parameters were not different. We have shown that despite increasing the burden for caregivers, with careful selection, education and support, we did not adversely impact on the QoL of carers whilst there was some evidence of improvement, especially in social functioning. This gives reassurance that establishing dependent patients on PD is compatible with a holistic approach to the patients and their families.

The Effect of Renin-angiotensin System Inhibitors on Kidney Allograft Survival: A Systematic Review and Meta-analysis.

BACKGROUND: The use of renin-angiotensin system (RAS) inhibitors in patients with chronic kidney disease, and especially in diabetic kidney disease, has been shown to provide renoprotective effects and slow progression to end-stage renal disease. However, this protective effect in kidney transplant patient populations is unclear. AIM: The objective of this systematic review and meta-analysis was to evaluate the effect of RAS inhibitors on kidney allograft survival. MATERIALS AND METHODS: A literature search for randomized controlled trials (RCTs) was performed from inception through February 2016. Studies that reported relative risks or hazard ratios comparing the risks of renal graft loss in renal transplant recipients who received RAS inhibitors vs. controls were included. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. RESULTS: Five studies (3 RCTs and 2 cohort studies) with 20024 kidney transplant patients were included in the meta-analysis. Pooled RR of allograft failure in recipients who received RAS inhibitors was 0.73 (95% CI: 0.45-1.21). When meta-analysis was limited only to RCTs, the pooled RR of allograft failure in patients using RAS inhibitors was 0.59 (95%: CI 0.20-1.69). The risk for mortality (RR: 1.13 [95% CI: 0.62-2.07]) in patients using RAS inhibitors compared to controls was not significantly reduced. CONCLUSION: This meta-analysis demonstrated insignificant reduced risks of renal graft loss among renal transplant recipients who received RAS inhibitors. Future studies assessing the potential benefits of RAS inhibitors on allograft survival in specific kidney transplant patient populations are needed.

Incidence of kidney stones in kidney transplant recipients: A systematic review and meta-analysis.

AIM: To evaluate the incidence and characteristics of kidney stones in kidney transplant recipients. METHODS: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from the inception of the databases through March 2016. Studies assessing the incidence of kidney stones in kidney transplant recipients were included. We applied a random-effects model to estimate the incidence of kidney stones. RESULTS: Twenty one studies with 64416 kidney transplant patients were included in the analyses to assess the incidence of kidney stones after kidney transplantation. The estimated incidence of kidney stones was 1.0% (95%CI: 0.6%-1.4%). The mean duration to diagnosis of kidney stones after kidney transplantation was 28 ± 22 mo. The mean age of patients with kidney stones was 42 ± 7 years. Within reported studies, approximately 50% of kidney transplant recipients with kidney stones were males. 67% of kidney stones were calcium-based stones (30% mixed CaOx/CaP, 27%CaOx and 10%CaP), followed by struvite stones (20%) and uric acid stones (13%). CONCLUSION: The estimated incidence of kidney stones in patients after kidney transplantation is 1.0%. Although calcium based stones are the most common kidney stones after transplantation, struvite stones (also known as "infection stones") are not uncommon in kidney transplant recipients. These findings may impact the prevention and clinical management of kidney stones after kidney transplantation.

The effects of napping on the risk of hypertension: a systematic review and meta-analysis.

OBJECTIVE: The risk of hypertension in adults who regularly take a nap is controversial. The objective of this meta-analysis was to assess the associations between napping and hypertension. METHODS: A literature search was performed using MEDLINE, EMbase and The Cochrane Database of Systematic Reviews from inception through October, 2015. Studies that reported relative risks, odd ratios or hazard ratios comparing the risk of hypertension in individuals who regularly take nap were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Nine observational studies with 112,267 individuals were included in the analysis to assess the risk of hypertension in nappers. The pooled RR of hypertension in nappers was 1.13 with 95% CI (0.98 to 1.30). When meta-analysis was limited only to studies assessing the risk of hypertension in daytime nappers, the pooled RR of hypertension was 1.19 with 95% CI (1.06 to 1.35). The data on association between nighttime napping in individuals who work night shift and hypertension were limited, only one observational study reported reduced risk of hypertension in nighttime nappers with odds ratio of 0.79 with 95% CI (0.63 to 1.00). CONCLUSIONS: Our meta-analysis demonstrates a significant association between daytime napping and hypertension. Future study is needed to assess the potential benefits of HTN screening for daytime nappers.