Colin C. Geddes

The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.

How to measure renal function in clinical practice.

The reliable measurement of renal excretory function is of great importance in clinical practice and in research. The introduction of routine reporting of estimated glomerular filtration rate and a new definition of chronic kidney disease has renewed interest in methods of measuring renal function. Coupled with this is the fact that several countries are moving towards population screening for renal impairment to try to reduce the associated increased cardiovascular risk. Accurate measurement is methodologically difficult so surrogate measures such as serum creatinine levels and prediction formulas (based on factors such as the patients age, sex, and serum creatinine level) are more commonly used in routine practice. We describe routine and more specialised methods of assessing renal function and discuss estimated glomerular filtration rate. The kidney has several interlinked functions (box). These depend on glomerular filtration rate, the unit measure of kidney function. Glomerular filtration rate can be defined as the volume of plasma cleared of an ideal substance per unit of time (usually expressed as ml/min). The ideal substance is one that is freely filtered at the glomerulus and neither secreted nor reabsorbed by the renal tubules. Creatinine is the closest to an ideal endogenous substance for measuring glomerular filtration rate.w1 Plasma creatinine is almost exclusively a product of the metabolism of creatine and phosphocreatine in skeletal muscle, although ingestion of meat may also contribute slightly.w2 w3 In patients with stable renal function, serum creatinine levels are usually constant, with variability daily of about only 8%.w4 w5 Creatinine is freely filtered at the glomerulus and is not reabsorbed, but up to 15% is actively secreted by the tubules.w6 In advanced renal failure, excretion of creatinine through the gastrointestinal tract increases.w7 Measuring the creatinine clearance using serum creatinine level and a timed urine collection gives an …

Granulomatous Interstitial Nephritis

Granulomatous interstitial nephritis (GIN) is a rare histologic diagnosis. This series reports the presenting features, associated conditions, treatment, and outcome of patients with a diagnosis of GIN in Glasgow during a 15-yr period and compares this with the available literature. Eighteen cases were identified: Five cases were associated with sarcoidosis, two were associated with tubulointerstitial nephritis and uveitis, two were associated with medication, and nine were idiopathic. Patients presented with advanced renal failure (median estimated creatinine clearance 21 ml/min) and minimal proteinuria (urine albumin-to-creatinine ratio 9.9 mg/mmol). Sixteen patients were treated with prednisolone for a mean of 25 mo. Six patients relapsed with reduction in prednisolone dosage, and four patients required steroid-sparing agents. During the mean follow-up of 45 mo, renal function improved or stabilized in 17 patients; the rate of improvement in renal function was most marked in the first year after diagnosis with a gain in function of +1.9 ml/min per mo. The median estimated creatinine clearance at final visit was 56 ml/min. One patient required renal replacement therapy at diagnosis but recovered renal function with treatment. No patient required long-term renal replacement therapy. There was no correlation between the degree of fibrosis or inflammation on biopsy and renal outcome, and the features on biopsy did not help to determine the cause of GIN. GIN is a treatable cause of renal failure that highlights the value of renal biopsy in patients who present with renal failure even when there is minimal proteinuria. The rarity of GIN demonstrates the need for systematic data collection.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.

The Long-Term Quality of Life of Living Kidney Donors: A Multicenter Cohort Study

Previous studies that described the long‐term quality of life of living kidney donors were conducted in single centers, and lacked data on a healthy nondonor comparison group. We conducted a retrospective cohort study to compare the quality of life of 203 kidney donors with 104 healthy nondonor controls using validated scales (including the SF36, 15D and feeling thermometer) and author‐developed questions. Participants were recruited from nine transplant centers in Canada, Scotland and Australia. Outcomes were assessed a median of 5.5 years after the time of transplantation (lower and upper quartiles of 3.8 and 8.4 years, respectively). 15D scores (scale of 0 to 1) were high and similar between donors and nondonors (mean 0.93 (standard deviation (SD) 0.09) and 0.94 (SD 0.06), p = 0.55), and were not different when results were adjusted for several prognostic characteristics (p = 0.55). On other scales and author‐developed questions, groups performed similarly. Donors to recipients who had an adverse outcome (death, graft failure) had similar quality of life scores as those donors where the recipient did well. Our findings are reassuring for the practice of living transplantation. Those who donate a kidney in centers that use routine pretransplant donor evaluation have good long‐term quality of life.

Hypertension, antihypertensive agents and outcomes following renal transplantation.

Abstract:  Hypertension is common following renal transplantation and adversely affects graft and patient survival. However, strategies for antihypertensive drug therapy and target blood pressure have not been clearly defined.

Acute kidney injury: outcomes and quality of care

BACKGROUND Deficiencies in management have been highlighted as contributory factors in the death of many patients with acute kidney injury (AKI). However, there is little evidence addressing the quality of care provided to patients with milder AKI. AIM The aim of this study is to evaluate the quality of care provided to a non-select cohort of patients with AKI and evaluate discrepancies in causation, recognition and management. DESIGN Retrospective inception cohort study. METHODS Demographic data were collected for all 1577 patients admitted to a University Teaching Hospital during a 1-month period. Baseline, admission and peak creatinine were correlated with mortality and length of hospital admission. AKI was classified according to Kidney Disease Improving Global Outcomes criteria. A retrospective case note review of all patients with AKI was carried out to evaluate quality of documentation and clinical management of AKI. Multivariate analysis was undertaken to determine risk factors for AKI. RESULTS Incidence of AKI on admission was 4.6%. A further 10.3% developed AKI while in hospital. All cause mortality was 4-fold higher among patients with AKI compared with those without (19 vs. 3.8%; P < 0.001). Mortality was significantly higher in those patients who developed AKI while an in-patient compared with those with AKI on admission (27.3 vs. 11.8%; P < 0.001). Diabetes, clinician perception of frailty, age and treatment with angiotensin-converting enzyme inhibitor prior to admission were found to be independent risk factors for AKI. AKI was unrecognized in 23.5% of patients, two-thirds of whom were discharged without resolution of renal function. Significant weaknesses in management were poorly kept fluid balance charts (48.2%), failure to withhold nephrotoxic drugs (38.8%) and failure to act upon abnormal biochemistry (41%) in a timely fashion. CONCLUSION AKI is common in hospitalized patients and associated with a significant increase in hospital stay and mortality. AKI is often found in conjunction with other organ failure and in many cases is not preventable. Nevertheless clinicians need to be more vigilant of small creatinine rises to permit early intervention particularly among elderly and frail patients.

Genotypic analysis of two hypervariable human cytomegalovirus genes

Most human cytomegalovirus (HCMV) genes are highly conserved in sequence among strains, but some exhibit a substantial degree of variation. Two of these genes are UL146, which encodes a CXC chemokine, and UL139, which is predicted to encode a membrane glycoprotein. The sequences of these genes were determined from a collection of 184 HCMV samples obtained from Africa, Australia, Asia, Europe, and North America. UL146 is hypervariable throughout, whereas variation in UL139 is concentrated in a sequence encoding a potentially highly glycosylated region. The UL146 sequences fell into 14 genotypes, as did all previously reported sequences. The UL139 sequences grouped into 8 genotypes, and all previously reported sequences fell into a subset of these. There were minor differences among continents in genotypic frequencies for UL146 and UL139, but no clear geographical separation, and identical nucleotide sequences were represented among communities distant from each other. The frequent detection of multiple genotypes indicated that mixed infections are common. For both genes, the degree of divergence was sufficient to preclude reliable sequence alignments between genotypes in the most variable regions, and the mode of evolution involved in generating the genotypes could not be discerned. Within genotypes, constraint appears to have been the predominant mode, and positive selection was detected marginally at best. No evidence was found for linkage disequilibrium. The emerging scenario is that the HCMV genotypes developed in early human populations (or even earlier), becoming established via founder or bottleneck effects, and have spread, recombined and mixed worldwide in more recent times. J. Med. Virol. 80:1615–1623, 2008.

Early Measurement of Pulsatility and Resistive Indexes: Correlation with Long-term Renal Transplant Function

PURPOSE To correlate pulsatility index (PI) and resistive index (RI) measured at early specific intervals after transplantation with 1-year estimated glomerular filtration rate (eGFR) and death-censored transplant survival to assess the long-term prognostic value of these Doppler indexes. MATERIALS AND METHODS The local ethics committee was consulted, and no formal approval was required. This retrospective review included 178 consecutive patients (111 male, 67 female; mean age, 43.9 years ± 13.4 [standard deviation]; age range, 16-72 years) undergoing first deceased-donor renal transplantation between 1997 and 2000. All patients were identified from a prospectively maintained database. Spectral Doppler analysis was performed within 1 week after transplantation in all patients and between 1 week and 3 months after transplantation in 124 patients. Average PI and RI were determined from measurements obtained in the upper, lower, and interpolar regions. For statistical analysis, the χ(2) test, analysis of variance, the Student t test, Kaplan-Meier survival plots, and Cox proportional hazards models were used. RESULTS Within 1 week after transplantation, there was a significant association between PI and 1-year eGFR when analyzed as tertiles (P = .02). Between 1 week and 3 months after transplantation, there was a significant relationship between 1-year eGFR and both PI and RI when comparing the lowest and highest tertiles (47.5 mL/min/1.73 m(2) for PI <1.26 vs 32.7 mL/min/1.73 m(2) for PI >1.49 [P = .01], 42.8 mL/min/1.73 m(2) for RI <0.69 vs 32.3 mL/min/1.73 m(2) for RI >0.74 [P = .03]). Both PI and RI were independent predictors of death-censored transplant survival (hazard ratio, 1.68 per unit [P < .001] and 260.4 per unit, respectively [P = .02]). CONCLUSION PI and RI in the early posttransplantation period correlate with long-term transplant function and can potentially be used as prognostic markers to aid risk stratification for future transplant dysfunction.