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Current guidelines recommend under 2g/day sodium intake in chronic kidney disease, but there are a few studies relating sodium intake to long-term outcomes. Here we evaluated the association of mean baseline 24-h urinary sodium excretion with kidney failure and a composite outcome of kidney failure or all-cause mortality using Cox regression in 840 participants enrolled in the Modification of Diet in Renal Disease Study. Mean 24-h urinary sodium excretion was 3.46g/day. Kidney failure developed in 617 participants, and the composite outcome was reached in 723. In the primary analyses, there was no association between 24-h urine sodium and kidney failure (HR 0.99 (95% CI 0.91–1.08)) nor on the composite outcome (HR 1.01 (95% CI 0.93–1.09)), each per 1g/day higher urine sodium. In exploratory analyses, there was a significant interaction of baseline proteinuria and sodium excretion with kidney failure. Using a two-slope model, when urine sodium was under 3g/day, higher urine sodium was associated with increased risk of kidney failure in those with baseline proteinuria under 1g/day and with lower risk of kidney failure in those with baseline proteinuria of ⩾1g/day. There was no association between urine sodium and kidney failure when urine sodium was⩾3g/day. Results were consistent using first baseline and time-dependent urinary sodium excretion. Thus, we noted no association of urine sodium with kidney failure. Results of the exploratory analyses need to be verified in additional studies and the mechanism explored.

Initiation of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) occurs when kidney tubule cells are rendered null for either PKD1 or PKD2 by somatic ‘second hit’ mutations. Subsequent cyst progression remodels the organ through changes in tubule cell shape, proliferation and secretion. The kidney develops inflammation and fibrosis. We constructed a mouse model in which adult inactivation of either Pkd gene can be followed by reactivation of the gene at a later time. Using this model, we show that re-expression of Pkd genes in cystic kidneys results in rapid reversal of ADPKD. Cyst cell proliferation is reduced, autophagy is activated and cystic tubules with expanded lumina lined by squamoid cells revert to normal lumina lined by cuboidal cells. Increases in inflammation, extracellular matrix deposition and myofibroblast activation are reversed, and the kidneys become smaller. We conclude that phenotypic features of ADPKD are reversible and that the kidney has an unexpected capacity for plasticity controlled at least in part by ADPKD gene function. Re-expression of Pkd genes in cystic kidneys results in rapid reversal of autosomal dominant polycystic kidney disease phenotypes in mice, revealing an unexpected capacity for renal plasticity under the control of Pkd gene function.

Cystic kidneys are common causes of end-stage renal disease, both in children and in adults. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are cilia-related disorders and the two main forms of monogenic cystic kidney diseases. ADPKD is a common disease that mostly presents in adults, whereas ARPKD is a rarer and often more severe form of polycystic kidney disease (PKD) that usually presents perinatally or in early childhood. Cell biological and clinical research approaches have expanded our knowledge of the pathogenesis of ADPKD and ARPKD and revealed some mechanistic overlap between them. A reduced ‘dosage’ of PKD proteins is thought to disturb cell homeostasis and converging signalling pathways, such as Ca 2+ , cAMP, mechanistic target of rapamycin, WNT, vascular endothelial growth factor and Hippo signalling, and could explain the more severe clinical course in some patients with PKD. Genetic diagnosis might benefit families and improve the clinical management of patients, which might be enhanced even further with emerging therapeutic options. However, many important questions about the pathogenesis of PKD remain. In this Primer, we provide an overview of the current knowledge of PKD and its treatment. Autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD are progressive cilia-related disorders that often lead to chronic kidney disease and end-stage renal disease. This Primer provides an overview of the current knowledge of PKD pathogenesis and its treatment.

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux — mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies.In this Review, the authors summarize the basics of autophagy and the signalling pathways involved in its regulation, and examine the multiple roles of autophagy in kidney cells, from its involvement in kidney maintenance and responses to injury, to its potential contribution to glomerular and tubulointerstitial disease.

Polycystic kidney disease is marked by progressive growth of renal tubular epithelia and thus the formation of pathological cysts in the organ over time. Alessandra Boletta and her colleagues now show that this cystic growth has the hallmarks of the Warburg effect (that is, the primary reliance of cells on glycolysis for their energy demands) and that blocking this effect in vivo is sufficient to improve disease progression in two mouse models. Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation 1 . Recent identification of signaling cascades deregulated in ADPKD has led to the initiation of several clinical trials, but an approved therapy is still lacking 2 , 3 . Using a metabolomic approach, we identify a pathogenic pathway in this disease that can be safely targeted for therapy. We show that mutation of PKD1 results in enhanced glycolysis in cells in a mouse model of PKD and in kidneys from humans with ADPKD. Glucose deprivation resulted in lower proliferation and higher apoptotic rates in PKD1 -mutant cells than in nondeprived cells. Notably, two distinct PKD mouse models treated with 2-deoxyglucose (2DG), to inhibit glycolysis, had lower kidney weight, volume, cystic index and proliferation rates as compared to nontreated mice. These metabolic alterations depend on the extracellular signal-related kinase (ERK) pathway acting in a dual manner by inhibiting the liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) axis on the one hand while activating the mTOR complex 1 (mTORC1)-glycolytic cascade on the other. Enhanced metabolic rates further inhibit AMPK. Forced activation of AMPK acts in a negative feedback loop, restoring normal ERK activity. Taken together, these data indicate that defective glucose metabolism is intimately involved in the pathobiology of ADPKD. Our findings provide a strong rationale for a new therapeutic strategy using existing drugs, either individually or in combination.

Tissue mimics are of great interest in understanding diseases. Here, organoids were developed that resemble polycystic kidney disease cysts and it was demonstrated how material environment and adhesion can affect cystogenesis and disease progression. Polycystic kidney disease (PKD) is a life-threatening disorder, commonly caused by defects in polycystin-1 (PC1) or polycystin-2 (PC2), in which tubular epithelia form fluid-filled cysts 1 , 2 . A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis 3 , 4 . Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids 5 , 6 . Here we show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls. These biomaterials establish a highly efficient model of PKD cystogenesis that directly implicates the microenvironment at the earliest stages of the disease.

Mouse models of autosomal dominant polycystic kidney disease (ADPKD) show that intact primary cilia are required for cyst growth following the inactivation of polycystin-1. The signaling pathways underlying this process, termed cilia-dependent cyst activation (CDCA), remain unknown. Using translating ribosome affinity purification RNASeq on mouse kidneys with polycystin-1 and cilia inactivation before cyst formation, we identify the differential ‘CDCA pattern’ translatome specifically dysregulated in kidney tubule cells destined to form cysts. From this, Glis2 emerges as a candidate functional effector of polycystin signaling and CDCA. In vitro changes in Glis2 expression mirror the polycystin- and cilia-dependent changes observed in kidney tissue, validating Glis2 as a cell culture-based indicator of polycystin function related to cyst formation. Inactivation of Glis2 suppresses polycystic kidney disease in mouse models of ADPKD, and pharmacological targeting of Glis2 with antisense oligonucleotides slows disease progression. Glis2 transcript and protein is a functional target of CDCA and a potential therapeutic target for treating ADPKD. Cyst growth in autosomal dominant polycystic kidney disease (ADPKD) is driven by unknown molecular signals that require the presence of intact primary cilia in the absence of the PKD gene products. Here, the authors show that the transcription factor Glis2 is a key effector of this cilia dependent cyst growth pathway and a potential target for therapy in ADPKD

Polycystic kidney disease (PKD) is a common genetic disorder characterized by the growth of fluid-filled cysts in the kidneys. Several studies reported that the serine-threonine kinase Lkb1 is dysregulated in PKD. Here we show that genetic ablation of Lkb1 in the embryonic ureteric bud has no effects on tubule formation, maintenance, or growth. However, co-ablation of Lkb1 and Tsc1, an mTOR repressor, results in an early developing, aggressive form of PKD. We find that both loss of Lkb1 and loss of Pkd1 render cells dependent on glutamine for growth. Metabolomics analysis suggests that Lkb1 mutant kidneys require glutamine for non-essential amino acid and glutathione metabolism. Inhibition of glutamine metabolism in both Lkb1/Tsc1 and Pkd1 mutant mice significantly reduces cyst progression. Thus, we identify a role for Lkb1 in glutamine metabolism within the kidney epithelia and suggest that drugs targeting glutamine metabolism may help reduce cyst number and/or size in PKD. Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) affects an estimated 1 in 1,000 people and slowly progresses to end-stage renal disease (ESRD) in about half of these individuals. Tolvaptan, a vasopressin 2 receptor blocker, has been approved by regulatory authorities in many countries as a therapy to slow cyst growth, but additional treatments that target dysregulated signalling pathways in cystic kidney and liver are needed. Metabolic reprogramming is a prominent feature of cystic cells and a potentially important contributor to the pathophysiology of ADPKD. A number of pathways previously implicated in the pathogenesis of the disease, such as dysregulated mTOR and primary ciliary signalling, have roles in metabolic regulation and may exert their effects through this mechanism. Some of these pathways are amenable to manipulation through dietary modifications or drug therapies. Studies suggest that polycystin-1 and polycystin-2, which are encoded by PKD1 and PKD2, respectively (the genes that are mutated in >99% of patients with ADPKD), may in part affect cellular metabolism through direct effects on mitochondrial function. Mitochondrial dysfunction could alter the redox state and cellular levels of acetyl-CoA, resulting in altered histone acetylation, gene expression, cytoskeletal architecture and response to cellular stress, and in an immunological response that further promotes cyst growth and fibrosis.