S28 Introduction S30 Summary of recommendation statements and practice points S88 Chapter 1: General principles for the management of glomerular disease S115 Chapter 2: Immunoglobulin A nephropathy (IgAN)/immunoglobulin A vasculitis (IgAV) S128 Chapter 3: Membranous nephropathy S140 Chapter 4: Nephrotic syndrome in children S153 Chapter 5: Minimal change disease (MCD) in adults S161 Chapter 6: Focal segmental glomerulosclerosis (FSGS) in adults S172 Chapter 7: Infection-related glomerulonephritis S187 Chapter 8: Immunoglobulin-and complement-mediated glomerular diseases with a membranoproliferative glomerulonephritis (MPGN) pattern of injury S193 Chapter 9: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis S207 Chapter 10: Lupus nephritis S231 Chapter 11: Anti-glomerular basement membrane (Anti-GBM) antibody glomerulonephritis S235 Methods for guideline development S243 Biographic and disclosure information S254 Acknowledgments S256 ReferencesThis guideline is published as a supplement supported by KDIGO. The development and publication of this guideline are strictly funded by KDIGO, and neither KDIGO nor its guideline Work Group members sought or received monies or fees from corporate or commercial entities in connection with this work. The opinions or views expressed in this professional education supplement are those of the authors and do not necessarily reflect the opinions or recommendations of the International Society of Nephrology or Elsevier. Dosages, indications, and methods of use for products that are referred to in the supplement by the authors may reflect their clinical experience or may be derived from the professional literature or other clinical sources. Because of the differences between in vitro and in vivo systems and between laboratory animal models and clinical data in humans, in vitro and animal data may not necessarily correlate with clinical results.

Globally, IgA nephropathy (IgAN) is the most common primary glomerulonephritis that can progress to renal failure. The exact pathogenesis of IgAN is not well defined, but current biochemical and genetic data implicate overproduction of aberrantly glycosylated IgA1. These aberrant immunoglobulins are characterized by galactose deficiency of some hinge-region O-linked glycans. However, aberrant glycosylation alone is insufficient to induce renal injury: the participation of glycan-specific IgA and IgG autoantibodies that recognize the undergalactosylated IgA1 molecule is required. Glomerular deposits of immune complexes containing undergalactosylated IgA1 activate mesangial cells, leading to the local overproduction of cytokines, chemokines and complement. Emerging data indicate that mesangial-derived mediators that are released following mesangial deposition of IgA1 lead to podocyte and tubulointerstitial injury via humoral crosstalk. Patients can present with a range of signs and symptoms, from asymptomatic microscopic haematuria to macroscopic haematuria. The clinical progression varies, with 30-40% of patients reaching end-stage renal disease 20-30 years after the first clinical presentation. Currently, no IgAN-specific therapies are available and patients are managed with the aim of controlling blood pressure and maintaining renal function. However, new therapeutic approaches are being developed, building upon our ever-improving understanding of disease pathogenesis.

Inflammation contributes to the tubulointerstitial lesions of diabetic nephropathy. Toll-like receptors (TLRs) modulate immune responses and inflammatory diseases, but their role in diabetic nephropathy is not well understood. In this study, we found increased expression of TLR4 but not of TLR2 in the renal tubules of human kidneys with diabetic nephropathy compared with expression of TLR4 and TLR2 in normal kidney and in kidney disease from other causes. The intensity of tubular TLR4 expression correlated directly with interstitial macrophage infiltration and hemoglobin A1c level and inversely with estimated glomerular filtration rate. The tubules also upregulated the endogenous TLR4 ligand high-mobility group box 1 in diabetic nephropathy. In vitro, high glucose induced TLR4 expression via protein kinase C activation in a time-and dose-dependent manner, resulting in upregulation of IL-6 and chemokine (C-C motif) ligand 2 (CCL-2) expression via IkB/NF-kB activation in human proximal tubular epithelial cells. Silencing of TLR4 with small interfering RNA attenuated high glucose-induced IkB/NF-kB activation, inhibited the downstream synthesis of IL-6 and CCL-2, and impaired the ability of conditioned media from high glucosetreated proximal tubule cells to induce transmigration of mononuclear cells. We observed similar effects using a TLR4-neutralizing antibody. Finally, streptozotocin-induced diabetic and uninephrectomized TLR4-deficient mice had significantly less albuminuria, renal dysfunction, renal cortical NF-kB activation, tubular CCL-2 expression, and interstitial macrophage infiltration than wild-type animals. Taken together, these data suggest that a TLR4-mediated pathway may promote tubulointerstitial inflammation in diabetic nephropathy.

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The incidence and prevalence of heart failure (HF) and chronic kidney disease (CKD) are increasing, and as such a better understanding of the interface between both conditions is imperative for developing optimal strategies for their detection, prevention, diagnosis, and management. To this end, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies Conference titled Heart Failure in CKD. Breakout group discussions included (i) HF with preserved ejection fraction (HFpEF) and nondialysis CKD, (ii) HF with reduced ejection fraction (HFrEF) and nondialysis CKD, (iii) HFpEF and dialysis-dependent CKD, (iv) HFrEF and dialysis-dependent CKD, and (v) HF in kidney transplant patients. The questions that formed the basis of discussions are available on the KDIGO website http:// kdigo.org/conferences/heart-failure-in-ckd/, and the deliberations from the conference are summarized here.

Renal tubulointerstitial injury is characterized by inflammatory cell infiltrate; however, the stimuli for leukocyte recruitment are not fully understood. IL-8 is a potent chemokine produced by proximal tubular epithelial cells (PTECs). Whether nephrotic proteins stimulate tubular IL-8 expression remains unknown. Acute exposure of human PTECs to albumin induced IL-8 gene and protein expression time-and dose-dependently. Apical albumin predominantly stimulated basolateral IL-8 secretion. Electrophoretic mobility shift assay demonstrated nuclear translocation of NF-κB, and the p65/p50 subunits were activated. NF-κB activation and IL-8 secretion were attenuated by the NF-κB inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H 2 O 2 stimulated NF-κB translocation and IL-8 secretion. Albumin-induced ROS generation, NF-κB activation, and IL-8 secretion were endocytosis-and PKC-dependent as these downstream events were abrogated by the PI3K inhibitors LY294002 and wortmannin, and the PKC inhibitors GF109203X and staurosporin, respectively. In vivo, IL-8 mRNA expression was localized by in situ hybridization to the proximal tubules in nephrotic kidney tissues. The intensity of IL-8 immunostaining was higher in nephrotic than non-nephrotic subjects. In conclusion, albumin is a strong stimulus for tubular IL-8 expression, which occurs via NF-κB-dependent pathways through PKC activation and ROS generation.

Research recommendations within each topic area are listed in order of priority, stratified by modality type.JE Flythe et al.: BP and volume control in dialysis: a KDIGO conference report

A growing body of evidence indicates that the renal proximal tubular epithelial cell (PTEC) plays an important role in the pathogenesis of diabetic nephropathy (DN). Microalbuminuria that intensifies over time to overt proteinuria, a hallmark of DN, is already known to activate the PTEC to induce tubulointerstitial inflammation. In addition to proteins, a number of diabetic substrates including high glucose per se, advanced glycation end-products and their carbonyl intermediates, angiotensin II, and ultrafiltered growth factors activate a number of signaling pathways including nuclear factor kappa B, protein kinase C, extracellular signal-regulated kinase 1/2, p38, signal transducer and activator of transcription-1 and the generation of reactive oxygen species, to culminate in tubular cell hypertrophy and the accumulation in the interstitium of a repertoire of chemokines, cytokines, growth factors and adhesion molecules capable of orchestrating further inflammation and fibrosis. More recently, the kallikrein-kinin system (KKS) and toll-like receptors (TLRs) in PTECs have been implicated in this process. While in vitro data suggest that the KKS contributes to the progression of DN, there are conflicting in vivo results on its precise role, which may in part be strain-dependent. On the other hand, there are both in vitro and in vivo data to suggest a role for both TLR2 and TLR4 in DN. In this review, we offer a critical appraisal of the events linking the participation of the PTEC to the pathogenesis of DN, which we believe may be collectively termed diabetic tubulopathy.