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American Journal of Kidney Diseases

Diabetic Kidney Disease: The Tiger May Have New Stripes

      Related Article, p. 653
      Diabetic kidney disease is a common complication of diabetes mellitus (DM) and is the leading cause of end-stage kidney disease (ESKD) in the United States. A natural history study done in the 1970s in patients with type 1 DM by Kussman et al
      • Kussman M.J.
      • Goldstein H.
      • Gleason R.E.
      The clinical course of diabetic nephropathy.
      provided the data that underpin the classic understanding regarding the development and progression of diabetic nephropathy (DN). Patients with type 2 DM have been shown historically to have a similar natural history,
      • Adler A.I.
      • Stevens R.J.
      • Manley S.E.
      • et al.
      Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64).
      • Nelson R.G.
      • Knowler W.C.
      • Pettitt D.J.
      • Saad M.F.
      • Bennett P.H.
      Diabetic kidney disease in Pima Indians.
      although it is more difficult to precisely document because in patients with type 2 DM, the time of onset of DM is often unknown and the time course is censored by cardiovascular death. We understand DN to follow a timeline that starts with microalbuminuria and proceeds sequentially through stages of increasing proteinuria, kidney function decline, and eventually ESKD.
      • Umanath K.
      • Lewis J.B.
      Update on diabetic nephropathy: core curriculum 2018.
      Studies have continued to illustrate the critical prognostic role of proteinuria in DN progression, thereby reinforcing the classic DN progression timeline.
      • Packham D.K.
      • Alves T.P.
      • Dwyer J.P.
      • et al.
      Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database.
      However, in recent years, several studies have revealed the existence of a sizable population of individuals with DM, reduced kidney function, and no albuminuria (also known as normoalbuminuria).
      • Dwyer J.P.
      • Parving H.H.
      • Hunsicker L.G.
      • Ravid M.
      • Remuzzi G.
      • Lewis J.B.
      Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: results from the DEMAND Study.
      • Garg A.X.
      • Kiberd B.A.
      • Clark W.F.
      • Haynes R.B.
      • Clase C.M.
      Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III.
      • Kramer H.J.
      • Nguyen Q.D.
      • Curhan G.
      • Hsu C.Y.
      Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.
      • Parving H.H.
      • Lewis J.B.
      • Ravid M.
      • Remuzzi G.
      • Hunsicker L.G.
      • DEMAND Investigators
      Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective.
      The largest of these studies was the Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes (DEMAND)
      • Parving H.H.
      • Lewis J.B.
      • Ravid M.
      • Remuzzi G.
      • Hunsicker L.G.
      • DEMAND Investigators
      Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective.
      Study. Of 32,308 participants in the cohort, 11,315 were noted to have reduced kidney function, which was defined as Cockcroft-Gault estimated creatinine clearance < 60 mL/min. It was noted that 20.5% of these 11,315 patients had normoalbuminuria and 30.7% had microalbuminuria.
      • Dwyer J.P.
      • Parving H.H.
      • Hunsicker L.G.
      • Ravid M.
      • Remuzzi G.
      • Lewis J.B.
      Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: results from the DEMAND Study.
      This and the other cited studies have demonstrated the existence of a population of patients who “haven’t read the textbook.” Very little is known about the nature of this population’s kidney disease because there has not been a large prospective biopsy study including similar participants. Although it is clear that patients with greater amounts of proteinuria have faster progression to ESKD, the time course of patients without proteinuria has not been well documented. In this issue of AJKD, Koye et al
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes: the CRIC (Chronic Renal Insufficiency Cohort) Study.
      present an analysis of the Chronic Renal Insufficiency Cohort (CRIC) Study aimed at elucidating kidney disease progression risk in this very population, namely individuals with DM, reduced kidney function, and normoalbuminuria.
      The authors analyzed the subset of the CRIC cohort with DM (n = 1,908) and assessed their risk for developing ESKD (initiation of maintenance dialysis therapy or kidney transplantation) or chronic kidney disease (CKD) progression (incident ESKD or ≥ 50% reduction in estimated glomerular filtration rate [eGFR] from baseline). Outcome ascertainment was done by participant self-report at biannual assessments by CRIC Study personnel and annual laboratory data during a median follow-up of 6.3 years. The authors demonstrated a strong and positive association with increasing albuminuria/proteinuria and ESKD/CKD progression, which continued to exist even with adjustment for multiple covariates, including age, sex, race, systolic blood pressure, angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor blocker (ARB) use, and glycated hemoglobin level, to name a few. Only 5% of the 515 participants with normal/mildly increased (<30 mg/24 h) urinary albumin excretion at baseline progressed to ESKD and only 5% of all ESKD events occurred in this subgroup.
      There are several interesting and important findings noted within this analysis. First, this study reinforces the critical role of albuminuria/proteinuria in predicting risk for DN progression. In this analysis of the CRIC database, ∼80% of participants were using an ACE inhibitor/ARB at baseline and progression risk increased substantially as albuminuria/proteinuria increased, reaching a hazard ratio of 9.19 (95% confidence interval [CI], 6.55-12.90) for participants with excretion ≥ 1,000 mg/24 h.
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes: the CRIC (Chronic Renal Insufficiency Cohort) Study.
      Similar trends were noted in the analysis of the Diabetes Mellitus Treatment for Renal Insufficiency Consortium (DIAMETRIC) database, which is the combination of the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in Non-Insulin-dependent Diabetes with the Angiotensin II Antagonist Losartan (RENAAL) trial. Relative risk for an ESKD event reached 7.40 (95% CI, 3.32-16.47) for participants with eGFRs at baseline >45 mL/min and albumin-creatinine ratios > 2 g/g.
      • Packham D.K.
      • Alves T.P.
      • Dwyer J.P.
      • et al.
      Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database.
      This subset of the DIAMETRIC cohort is similar to the subset of the CRIC cohort analyzed by Koye et al because baseline eGFR was 41.2 ± 14.8 mL/min in their analysis.
      Patients with decreased GFR, proteinuria, and DM are at high risk for cardiovascular disease, and cardiovascular death is often considered a competing risk for ESKD in individuals with reduced kidney function, albuminuria, and DM. In this analysis of the CRIC cohort, there were fewer overall death events (323 [17.8%]) as compared with ESKD events (583 [32.2%]). Additionally, sensitivity analysis was done analyzing death as a competing risk for ESKD and results did not appreciably change.
      This is important to note because it illustrates a couple of key points. First, as the authors state, albuminuria/proteinuria remains the single best predictor of ESKD events, and this is not influenced by death before developing ESKD. Second, in the modern era of aggressive cardiovascular risk reduction and ACE-inhibitor/ARB therapy for diabetic kidney disease, even patients with normo- or microalbuminuria and reduced GFRs are more likely to reach ESKD than to die before having an ESKD event. This echoes the findings of the DIAMETRIC analysis (incidence rate ratio of 4.92 for ESKD vs 2.61 for all-cause mortality)
      • Packham D.K.
      • Alves T.P.
      • Dwyer J.P.
      • et al.
      Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database.
      and is important to consider because it alters the traditional understanding of event risk in patients with diabetic kidney disease.
      Although these findings are important, the focus of the analysis was to add to our understanding and phenotyping of the population of individuals with DM, reduced kidney function, and normoalbuminuria. How could one account for these participants progressing to substantially decreased GFR or ESKD without having proteinuria? One possibility is that this clinical presentation is accounted for by the use of ACE-inhibitor/ARB treatment and blood pressure controls, because both these interventions have been shown to reduce albuminuria/proteinuria and CKD progression.
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • et al.
      Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
      • Lewis E.J.
      • Hunsicker L.G.
      • Bain R.P.
      • Rohde R.D.
      The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
      • Parving H.H.
      • Lehnert H.
      • Brochner-Mortensen J.
      • et al.
      The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
      That said, the residual risk for an ESKD/CKD progression event while on ACE-inhibitor/ARB therapy and optimal blood pressure control remains substantial.
      • Lambers Heerspink H.J.
      • Fowler M.J.
      • Volgi J.
      • et al.
      Rationale for and study design of the sulodexide trials in type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.
      In the analysis presented by Koye et al, risk for progression in this population is low and mirrors that of the general population with DM, yet 5% of these persons reach ESKD. The nature of the data set limits our ability to distinguish between 2 distinct populations that may have arrived at normoalbuminuria differently. A subset of the normoalbuminuria cohort are likely patients in whom albuminuria/proteinuria existed before the introduction of ACE-inhibitor/ARB treatment, and the therapy suppressed it into the normoalbuminuria range. These patients may be more likely to have traditional DN. Another subset of these participants may never have had proteinuria/albuminuria. It is possible that these individuals are more likely to have CKD from some other cause with co-existing DM, and the disease mechanism accounting for their CKD may not be traditional DN. One small biopsy study in this population (n = 8) gives some insight.
      • Ekinci E.I.
      • Jerums G.
      • Skene A.
      • et al.
      Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function.
      Of the 8 participants with normoalbuminuira, DM, and reduced kidney function who underwent kidney biopsy, only 3 had evidence of DN. Interestingly, 7 of 8 participants had evidence of varying degrees of renal arteriosclerosis, suggesting that hypertension and aging may be playing a role in the decreased kidney function seen in these individuals. A limitation of the Koye et al
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes: the CRIC (Chronic Renal Insufficiency Cohort) Study.
      study is that it does not provide data to elucidate the relative contribution of these subpopulations to the normoalbuminuria cohort.
      A growing concern in the development and progression of CKD is acute kidney injury (AKI) events. Multiple studies have shown AKI with and without the return of serum creatinine levels to baseline to be a risk factor for subsequent CKD and CKD progression/ESKD events.
      • Bucaloiu I.D.
      • Kirchner H.L.
      • Norfolk E.R.
      • Hartle 2nd, J.E.
      • Perkins R.M.
      Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury.
      • Jones J.
      • Holmen J.
      • De Graauw J.
      • Jovanovich A.
      • Thornton S.
      • Chonchol M.
      Association of complete recovery from acute kidney injury with incident CKD stage 3 and all-cause mortality.
      • Pannu N.
      • James M.
      • Hemmelgarn B.
      • Klarenbach S.
      Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge.
      The reduced kidney function seen in these normoalbuminuric individuals could also be the result of an AKI event in which serum creatinine level did not return to baseline. The annual rate of progression noted in this analysis of the CRIC cohort was minimal (−0.17 mL/min/1.73 m2) in the normoalbuminuria cohort,
      • Koye D.N.
      • Magliano D.J.
      • Reid C.M.
      • et al.
      Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes: the CRIC (Chronic Renal Insufficiency Cohort) Study.
      which is reassuring. However, the risk for interceding AKI events along the course of these individuals contributing to progression events is real.
      A recent assessment of biopsy findings in individuals with DM who were undergoing kidney biopsy found acute tubular necrosis to be an emerging cause of non–DM-related findings.
      • Sharma S.G.
      • Bomback A.S.
      • Radhakrishnan J.
      • et al.
      The modern spectrum of renal biopsy findings in patients with diabetes.
      This study included participants with varying levels of proteinuria, so it is not directly relevant to understanding the disease phenotype of this normoalbuminuric population of individuals, but it generates a hypothesis for future kidney disease progression studies. The analysis of the CRIC cohort used annual laboratory assessment and semiannual event ascertainment and statistical modeling assuming a linear decline in kidney function. More creatinine data points are critical to fitting these models, and analysis of individual patient-level data is needed to ensure that the assumption of linear decline is warranted because the presence of AKI events may cause one to “stair-step” during the decline in kidney function.
      In conclusion, the analysis of the CRIC cohort with DM presented in this issue of AJKD sheds very important light on CKD progression and ESKD event risk for a sizable, but not well understood, population of individuals with DM, reduced kidney function, and minimal proteinuria. It is a population seen often in our clinics; thus, understanding their prognosis is critical. This study adds substantially to that understanding. It is reassuring that this population has low risk for kidney disease progression events. We also suggest that future CKD progression studies will benefit from more frequent serum creatinine sampling, better capturing of AKI events, and advanced statistical analytic methods to account for the increasing role of AKI events influencing the progression of CKD.

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