Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.

BACKGROUND: The timing of renal replacement therapy (RRT) for severe acute kidney injury is highly debated when no life-threatening complications are present. We assessed whether a strategy of delayed versus early RRT initiation affects 28-day survival in critically ill adults with severe acute kidney injury. METHODS: In this systematic review and individual patient data meta-analysis, we searched MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials for randomised trials published from April 1, 2008, to Dec 20, 2019, that compared delayed and early RRT initiation strategies in patients with severe acute kidney injury. Trials were eligible for inclusion if they included critically ill patients aged 18 years or older with acute kidney injury (defined as a Kidney Disease: Improving Global Outcomes [KDIGO] acute kidney injury stage 2 or 3, or, where KDIGO was unavailable, a renal Sequential Organ Failure Assessment score of 3 or higher). We contacted the principal investigator of each eligible trial to request individual patient data. From the included trials, any patients without acute kidney injury or who were not randomly allocated were not included in the individual patient data meta-analysis. The primary outcome was all-cause mortality at day 28 after randomisation. This study is registered with PROSPERO (CRD42019125025). FINDINGS: Among the 1031 studies identified, one study that met the eligibility criteria was excluded because the recruitment period was not recent enough, and ten (including 2143 patients) were included in the analysis. Individual patient data were available for nine studies (2083 patients), from which 1879 patients had severe acute kidney injury and were randomly allocated: 946 (50%) to the delayed RRT group and 933 (50%) to the early RRT group. 390 (42%) of 929 patients allocated to the delayed RRT group and who had available data did not receive RRT. The proportion of patients who died by day 28 did not significantly differ between the delayed RRT group (366 [44%] of 837) and the early RRT group (355 [43%] of 827; risk ratio 1·01 [95% CI 0·91 to 1·13], p=0·80), corresponding to an overall risk difference of 0·01 (95% CI -0·04 to 0·06). There was no heterogeneity across studies (I2=0%; τ2=0), and most studies had a low risk of bias. INTERPRETATION: The timing of RRT initiation does not affect survival in critically ill patients with severe acute kidney injury in the absence of urgent indications for RRT. Delaying RRT initiation, with close patient monitoring, might lead to a reduced use of RRT, thereby saving health resources. FUNDING: None.

Recovery of kidney function after AKI because of COVID-19 in kidney transplant recipients.

Evidence on the evolution of graft function in kidney transplant recipients recovering from coronavirus disease-2019 (COVID-19) is lacking. This multicenter observational study evaluated the short-term clinical outcomes in recipients with acute kidney injury (AKI) secondary to COVID-19. Out of 452 recipients following up at five centers, 50 had AKI secondary to COVID-19. 42 recipients with at least 3-month follow-up were included. Median follow-up was 5.23 months [IQR 4.09-6.99]. Severe COVID-19 was seen in 21 (50%), and 12 (28.6%) had KDIGO stage 3 AKI. Complete recovery of graft function at 3 months was seen in 17 (40.5%) patients. Worsening of proteinuria was seen in 15 (37.5%) patients, and 4 (9.5%) patients had new onset proteinuria. Graft failure was seen in 6 (14.3%) patients. Kidney biopsy revealed acute tubular injury (9/11 patients), thrombotic microangiopathy (2/11), acute cellular rejection (2/11), and chronic active antibody-mediated rejection (3/11). Patients with incomplete recovery were likely to have lower eGFR and proteinuria at baseline, historical allograft rejection, higher admission SOFA score, orthostatic hypotension, and KDIGO stage 3 AKI. Baseline proteinuria and the presence of orthostatic hypotension independently predicted incomplete graft recovery. This shows that graft recovery may remain incomplete after AKI secondary to COVID-19.

Symptom Management among Patients with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) experience high symptom burden, both physical and psychological, that is underrecognized and undertreated. The high symptom burden significantly impacts the quality of life for patients and their families. This review enumerates the various physical and psychological symptoms that patients with CKD often experience and guides in the management of these symptoms. This review follows the recommended international guidelines and has been tailored to suit the Indian context.

Adipokine interactions promote the pathogenesis of systemic lupus erythematosus.

BACKGROUND: Adipokines are chemical mediators released from adipose tissue involved in regulation of appetite, insulin sensitivity, immune system and inflammatory responses. Adipokines contributes to low grade inflammatory response in autoimmune disease like Systemic Lupus Erythematosus (SLE) but the pathophysiology is yet not clear. The aim of this study is to understand role of adipokine interactions in SLE disease pathogenesis. METHODS: Sixty newly diagnosed treatment naïve SLE patients fulfilling the ACR criteria and forty age-sex matched healthy subjects were enrolled in thiscase-control study. Disease activity in SLE patients was evaluated using SELENA-SLEDAI. Array of adipokines, C1q circulating immune complexes (C1q-CIC), anti-C1q, anti-ribososmal P0 (anti-RibP0) and anti-mitochondrial antibodies (AMA) levels were detected by ELISA. Antinuclear antibodies (ANA) and anti-dsDNA autoantibodieswere detected by Indirect Immunofluorescence (IIF), while antigen specificities were detected by Immunoassay blot. Serum levels of C3 and C4 complement factors were assessed by nephlometer. RESULTS: Statistically significant elevation in progranulin, adipsin and resistin levels was seen among SLE patients when compared to healthy controls (p < 0.0001). Leptin and omentin levels were significantly reduced in SLE patients (p < 0.0001). There was no statistically significant difference in serum adiponectin, chemerin and visfatin levels when these two groups were compared (p > 0.05). Adiponectin, adipsin and resistin levels were elevated in SLE patients with renal manifestations (p < 0.05). Reduced leptin levels were significantly associated with presence of renal manifestations (p < 0.05). Adiponectin levels positively correlated with disease activity (r = 0.294, p = 0.027) whereas negatively correlated with C3 levels (r = -0.439, p = 0.0007). A positive correlation was observed between hypocomplementemia and leptin levels (p < 0.05). Leptin levels were negatively correlated with disease activity, anti-dsDNA, C1q-CIC and anti-C1q levels (p < 0.05). A significant positive correlation was observed between progranulin levels and anti-ribosomal P0 antibodies (r = 0.499, p < 0.0001). CONCLUSION: Adipokines levels and associated clinical manifestations suggest involvement of adipokines in disease pathogenesis of SLE. SLE disease activity and complement components may suggest regulatory effect of adipokines (adiponectin and leptin) on disease pathogenesis. Further studies on adipokines in SLE patients with renal manifestations may propose them as prognostic markers in renal damage. TRIAL REGISTRATION: NA.

Subcutaneous hyalohyphomycosis caused by Fusarium in a kidney transplant recipient.

Fusarium is a filamentous opportunistic pathogenic fungus responsible for superficial as well as invasive infection in immunocompromized hosts. Net state of immunosuppression and cytomegalovirus (CMV) infection appear to predispose to this disease which is life-threatening when disseminated. Though infections with Fusarium have been widely described in hematological malignancies and hematopoietic stem cell transplant cases, they have been reported to be rare in solid organ transplant recipients, are often localized and carry a favorable prognosis. We here describe a rare case of subcutaneous non-invasive infection with Fusarium in a renal allograft recipient two and half years after transplantation. Patient had a previous history of CMV infection along with multiple other recurrent co-infections. Diagnosis was based on culture of tissue specimens yielding Fusarium species. The infection had a protracted course with persistence of lesions after treatment with voriconazole alone, requiring a combination of complete surgical excision and therapy with the anti-fungal drug.

Acquired disorders of phosphaturia: Beyond tumor-induced osteomalacia.

Phosphate is an integral part of human cellular structure and function. Though most recognised disorders of phosphaturia are genetic in origin, phosphate loss due to acquired conditions is commonly encountered in clinical practice. Acquired hypophosphatemia is most commonly due to renal phosphate wasting and can produce significant morbidity. It also heralds future kidney damage, and continued exposure can lead to progressive kidney injury and potentially renal failure. These conditions are a diverse group of disorders with common shared mechanisms causing loss of phosphate in the urine. Renal phosphate loss can occur as an isolated entity or as a part of generalised proximal tubular dysfunction, i.e., Fanconi's syndrome. An insight into the pathophysiological mechanisms of acquired phosphaturia can help clinicians monitor their patients better and avoid potential harms.

Multifocal Burkholderia cepacia Infection in Postrenal Transplantation Fever : Role of 18 F-FDG PET/CT in Treatment Optimization.

ABSTRACT: Nosocomial Burkholderia cepacia infection in the clinical setting of postrenal transplantation pyrexia of unknown origin and the role of 18 F-FDG PET/CT in treatment optimization in such situation is presented in this report. The consequence of fastidious infection by nosocomial colonizing organisms like B. cepacia can be catastrophic in immunocompromised postrenal transplant individuals causing severe urinary tract infection. In the presented case, following 2 weeks of IV antibiotics, the patient didn't show clinical response, and FDG PET scan recognized multifocal infective sites early, likely representing immune reconstitution inflammatory syndrome and timely appropriate and optimal treatment salvaged the renal graft.

Acute oxalate nephropathy: exploring the role of excess dietary oxalate intake.

Acute oxalate nephropathy is a rare but important cause of severe acute kidney injury. We report here two cases presenting as unexplained AKI which were confirmed histologically to be due to acute oxalate nephropathy. Dietary oxalate or its precursor vitamin C was the cause of oxalate exposure in both of these cases. While one patient recovered, another continued to need dialysis and succumbed to underlying metastatic cancer. This cause should be suspected in all patients presenting with unexplained AKI, and detailed history about dietary intake of oxalate or vitamin C should be inquired.

Overnight 1-mg DST Serum Cortisol in Various Stages of Chronic Kidney Disease-Normative Data and Underlying Mechanisms.

Context: Data on the overnight 1 mg-dexamethasone suppression test (ONDST) in renal dysfunction are limited. Objective: We aim to determine the normative range of ONDST cortisol across chronic kidney disease (CKD) stages and reasons for its alteration. Methods: Prospectively, 180 CKD (30 each in G2-G5/5D) patients and 30 healthy controls underwent ONDST 8 Am serum cortisol (chemiluminescent immunoassay [CLIA]). In an exploratory cohort, 45 (15 each: G3b/G4, G5/G5D, and healthy controls) individuals' blood biochemistry for basal (8 Am) cortisol and adrenocorticotropin (ACTH), post-ONDST 8 Am dexamethasone, ACTH, cortisol (CLIA and liquid chromatography-tandem mass spectrometry), and 4 Pm cortisol was collected. Results: Post-ONDST cortisol (µg/dL) correlated inversely (r = 0.47; P < .005) with estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2), with 95th percentile being 1.2 in controls, 3.0 in G2, 3.2 in G3a, 4.3 in G3b, 4.7 in G4, 5.7 in G5, and 7.1 in G5D. In the exploratory cohort, basal 8 Am cortisol and ACTH, and post-ONDST dexamethasone were similar among controls and CKD subgroups. ONDST ACTH (for evaluating the hypothalamo-pituitary-adrenal axis) was slightly higher in G5/5D vs controls (8.9 vs 6.1 pg/mL), while it was similar in G3b/G4 vs controls. Median 8 Am ONDST cortisol was similar on CLIA and LC-MS/MS in controls and higher on CLIA in G3b/4 (1.7 vs 1.1 µg/dL; P = .012) and G5/5D (2.4 vs 1.7 µg/dL; P = .002) than LC-MS/MS. Post-ONDST serum cortisol drop from 8 Am to 4 Pm was significant in controls (0.5-<0.2 µg/dL) and G3b/4 (1.7-1.2 µg/dL), but not in G5/5D (2.4-2.2 µg/dL). Conclusion: The normative data of ONDST serum cortisol with eGFR-based cutoffs are useful in evaluating Cushing syndrome in CKD. Prolonged cortisol half-life and immunoassay-related assay cross-reaction are likely contributors to higher ONDST cortisol.

Earlier-start versus usual-start dialysis in patients with community-acquired acute kidney injury: a randomized controlled trial.

BACKGROUND: Optimum timing of the initiation of dialysis therapy in acute kidney injury is not clear. STUDY DESIGN: Prospective, open label, 2-arm, randomized, controlled trial. SETTING & PARTICIPANTS: 208 adults with acute kidney injury with progressively worsening azotemia at the artificial kidney dialysis unit of a tertiary-care referral center in western India. INTERVENTION: Earlier-start dialysis was initiated when serum urea nitrogen and/or creatinine levels increased to 70 and 7 mg/dL, respectively, whereas the usual-start dialysis patients (control group) received dialysis when clinically indicated as judged by treating nephrologists. OUTCOMES: Primary outcome was in-hospital mortality and dialysis dependence at 3 months. Secondary outcome in patients receiving dialysis was time to recovery of kidney function, computed from time of enrollment to the last dialysis session. RESULTS: Of 585 screened patients, 102 were assigned to earlier-start dialysis, and 106 to usual-start dialysis. Baseline characteristics were similar between randomized groups. 93 (91.1%) and 88 (83.1%) participants received dialysis in the intervention and control groups, respectively. Mean serum urea nitrogen and serum creatinine levels at dialysis therapy initiation were 71.7 ± 21.7 (SD) and 7.4 ± 5.3 mg/dL, respectively, in the intervention group versus 100.9 ± 32.6 and 10.41 ± 3.3 mg/dL in the control group. Data on primary outcome were available for all patients. In-hospital mortality was 20.5% and 12.2% in the intervention and control groups, respectively (relative risk, 1.67; 95% CI, 0.88-3.17; P = 0.2). 4.9% and 4.7% of patients in the intervention and control groups, respectively, were dialysis dependent at 3 months (relative risk, 1.04; 95% CI, 0.29-3.7; P = 0.9). LIMITATIONS: Study was not double blind, event rate (ie, mortality) was less than predicted, wide CIs preclude definitive findings. CONCLUSIONS: Our data do not support the earlier initiation of dialysis therapy in community-acquired acute kidney injury.

What Is Wrong with the Blood Pressure Target Recommendation of KDIGO 2021 for Hypertension in Chronic Kidney Disease?

CONTEXT: Eighty-five percent of patients with chronic kidney disease (CKD) have hypertension, and blood pressure (BP) control is the cornerstone in the management of CKD. Although it is widely accepted that BP should be optimized, BP targets in CKD are not known. Subject of Review: Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline for the management of BP in CKD (Kidney Int. 2021 Mar 1;99(3S):S1-87) recommends targeting BP to less than 120 mm Hg systolic for patients with CKD. Second Opinion: KDIGO BP target differs from all other hypertension guidelines. This is also a major change from the previous recommendation which was <140 systolic to all patients with CKD and <130 systolic for those with proteinuria. Targeting systolic BP to less than 120 mm Hg is hard to substantiate based on available data and is based primarily on subgroup analysis of a randomized control trial. Intensive BP lowering as suggested by the guidelines may lead to polypharmacy, added cost burden, and risk of serious harms.

Fluoroscopy and CT Guided Translumbar Tunneled Dialysis Catheter for Hemodialysis Access Failure in a Case of Autosomal Dominant Polycystic Kidney Disease.

Vascular access in hemodialysis is essential to end-stage renal disease (ESRD) patients' survival. Unfortunately, even after years of recent advances, a significant number of patients may develop multi-access failure for many reasons. In this situation, arterial-venous fistula (AVF) or catheters placement in traditional vascular sites (jugular, femoral, or subclavian) are not feasible. In this scenario, translumbar tunneled dialysis catheters (TLDCs) may be a salvage option. The use of central venous catheters (CVC) is associated with an increased incidence of venous stenosis that can progressively limit future vascular access routes. The common femoral vein can be used for temporary access in patients in whom traditional approaches for permanent central venous access may not be feasible because of either chronically occluded or not accessible vasculature; however, this location is not preferred for long-term venous access because of the high rate of catheter related blood stream infections (CRBSI). In these patients, a direct translumbar approach to the inferior vena cava is a lifesaving alternative. This approach has been described by several authors as a bail-out option. Fluoroscopy-guided access via a translumbar approach into the inferior vena cava bares the risk of hollow-organ perforation or severe bleeding from the inferior vena cava or even the aorta. To minimize the risk of complications caused by a translumbar central venous access, we hereby present a hybrid approach with CT-guided translumbar access of the inferior vena cava followed by a conventional implantation of the permanent central venous catheter. CT scan-guided access of IVC that further helps in our case as patient has large bulky kidneys secondary to autosomal dominant polycystic kidney disease.

Mercury-associated neural epidermal growth factor-like 1 protein (NELL-1) positive membranous nephropathy after use of skin lightening creams.

INTRODUCTION: Membranous nephropathy, one of the common causes of glomerulonephritis worldwide, is reported in association with mercury exposure. Neural epidermal growth factor-like 1 protein is a recently described target antigen in membranous nephropathy. CASE SERIES: Three woman (ages 17, 39, and 19 years old) presented sequentially for our evaluation with complaints consistent with nephrotic syndrome. All three had nephrotic range proteinuria, hypoalbuminemia, hypercholesterolemia, hypothyroidism, and inactive urinary sediments. Kidney biopsies were performed in the first two patients, which demonstrated findings consistent with membranous nephropathy and positive staining for neural epidermal growth factor-like 1 protein. On discovery that they were all using the same skin-lightening cream, samples of the cream were tested and found to contain between 2,180 parts per million and 7,698 parts per million of mercury. Elevated urine and blood mercury concentrations were also found in the first two patients. All three patients improved following cessation of use and treatment with levothyroxine (all three patients) and corticosteroids and cyclophosphamide in patients one and two. DISCUSSION: We hypothesize the role of autoimmunity triggered by mercury exposure in the pathogenesis of neural epidermal growth factor-like 1 protein membranous nephropathy. CONCLUSION: Mercury exposure should be carefully assessed as a part of the evaluation of patients with neural epidermal growth factor-like 1 protein positive membranous nephropathy.